Background

IMpower010 (NCT02486718) showed a statistically significant benefit in primary-endpoint disease-free survival (DFS) with adjuvant atezo vs BSC in resected stage II-IIIA PD-L1 tumour cell (TC) ≥1% (SP263) NSCLC after platinum-based chemotherapy. This finding led to the approval of atezo in this setting in the US, China, Japan and other countries and to its approval for stage II-IIIA PD-L1 TC ≥50% NSCLC in the EU and other countries. At the first pre-specified interim analysis (IA) of OS (cutoff 18 Apr 2022), the secondary endpoint of OS in the ITT population was not mature, but OS is of clinical interest in this curative setting; in pts with stage II-IIIA and stage II-IIIA PD-L1 ≥1% NSCLC, the respective OS HRs were 0.95 (95% CI: 0.74, 1.24) and 0.71 (95% CI: 0.49, 1.03) (Wakelee JTO 2022; 17:S2). We present OS data in pts with stage II-IIIA PD-L1 TC ≥50% NSCLC.

Methods

The IMpower010 study design and primary endpoint analysis have been reported (Felip Lancet 2021). We report exploratory OS in pts with stage II-IIIA (UICC/AJCC v7) PD-L1 TC ≥50% (VENTANA SP263 assay) NSCLC and updated safety at this OS IA.

Results

In 229 pts with stage II-IIIA PD-L1 TC ≥50% NSCLC, the OS HR was 0.43 (95% CI: 0.24, 0.78); after excluding 20 pts with known EGFR/ALK+ status, the OS HR was 0.42 (95% CI: 0.23, 0.78). The OS subgroup analysis is presented in the table. No new safety signals emerged since the previous cutoff.

Conclusions

Pts with stage II-IIIA PD-L1 TC ≥50% NSCLC derived OS benefit with atezo vs BSC. OS benefit was consistent across most pt subgroups, albeit with limited numbers in this exploratory analysis. The atezo safety profile remained unchanged. These data support the previously reported positive benefit-risk profile of adjuvant atezo in stage II-IIIA PD-L1+ resected NSCLC and contribute further evidence to support this new standard of care for patients with early-stage resectable NSCLC. Table: 123P

OS in stage II-IIIA PD-L1 TC ≥50% pt subgroups

Clinical trial identification

NCT02486718.

Editorial acknowledgement

Medical writing support for this abstract was provided by Samantha Santangelo, PhD, of Health Interactions, Inc and funded by F. Hoffmann-La Roche, Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

A. Rittmeyer: Financial Interests, Personal, Advisory Board: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche; Financial Interests, Personal, Invited Speaker: BMS, Eli Lilly, MSD, Novartis, Roche. E. Felip: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Mirati, Merck, MSD, Novartis, Pfizer, Sanofi, Roche; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Roche, Glaxo Smith Kline, Medical Trends, Peptomyc, Puma Biotechnology, Regeneron, Sanofi, Takeda; Other, Institutional, Research Grant, Research Funding: Oncology Innovation, Merck Healthcare KGAa, Fundacion Merck Salud; Other, Personal, Member, Independent Member of the Board: GRIFOLS. N.K. Altorki: Financial Interests, Personal, Research Grant, Principal Investigator: AstraZeneca, Janssen; Non-Financial Interests, Personal, Other, Steering Committee Member: Roche. E. Vallieres: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Oncocyte; Financial Interests, Personal, Advisory Board: BMS. C. Zhou: Financial Interests, Personal, Invited Speaker: Roche China; Financial Interests, Personal, Other, Speaker: Lily China, BI, Sanofi, C-Stone, Qilu, Hengrui, Innovent Biologics, LUYE Pharma, TopAlliance Bioscience Inc, Amoy Diagnostics. A. Martinez-Marti: Financial Interests, Personal, Advisory Board, Speaker's Bureau: Bristol Myers Squibb, F. Hoffmann La Roche AG, Merck Sharp & Dohme, MSD Oncology, AstraZeneca/MedImmune; Financial Interests, Personal, Other, Speaker's Bureau: Pfizer; Financial Interests, Personal, Invited Speaker, And Local PI: AstraZeneca/MedImmune; Financial Interests, Personal, Invited Speaker: F. Hoffmann La Roche AG, Bristol Myers Squibb, Merck Sharp & Dohme, MSD Oncology; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca/MedImmune, F. Hoffmann La Roche AG, Bristol Myers Squibb, Merck Sharp & Dohme, MSD Oncology. M. Reck: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Novartis, Merck, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Mirati, Pfizer, Sanofi, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Roche. M.E. Teixeira: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Janssen, MSD, Takeda; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, MSD, Boehringer Ingelheim; Financial Interests, Institutional, Research Grant, Research: Roche, Janssen, MSD, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Principal Investigator: Roche, Janssen, MSD, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Other, Consultation: AstraZeneca, Roche, Janssen, Takeda. Y. Deng: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. M. Huang: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. V.A. McNally: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Personal, Stocks/Shares: Roche. E. Bennett: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. B.J. Gitlitz: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. M. Srivastava: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. H. Wakelee: Financial Interests, Institutional, Research Grant, Research Funding: ACEA Biosciences, Arrys Therapeutics, AstraZeneca/MedImmune, BMS, Celgene, Clovis Oncology, Genentech/Roche, Helsinn, Merck, Novartis, Pharmacyclics, Seagen, Xcovery,; Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Daiichi Sankyo, Blueprint, Mirati; Non-Financial Interests, Personal, Advisory Board: Merck, Genentech/Roche; Other, Personal, Leadership Role, President: IASLC; Other, Personal, Leadership Role, Executive Committee: ECOG-ACRIN. All other authors have declared no conflicts of interest.

Background

Neoadjuvant chemo-immunotherapy (CheckMate 816 regimen) has become a standard of care in treatment of resectable non-small cell lung cancer (NSCLC) patients in some countries. Addition of radiation therapy (RT) may further improve local control in locally advanced NSCLC patients. Here, we report the primary endpoint, major pathologic response (MPR), of the SQUAT trial (WJOG 12119L, JapicCTI- 195069)-a multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B N2 NSCLC.

Methods

Patients with resectable stage IIIA-B N2 NSCLC received concurrent chemoradiotherapy [weekly paclitaxel (40 mg/m²)/carboplatin (AUC 2) for 5 weeks plus involved-field RT 50 Gy] and immunotherapy [durvalumab (1500 mg) Q4W for 2 cycles] followed by surgical resection and adjuvant immunotherapy (durvalumab for up to 1 year). The primary endpoint was MPR rate according to an independent central review (ICR). We assumed the threshold of the MPR rate to be 40% and the expected rate to be 65% with a significance level α=0.05 (one-sided) and power 0.8. The sample size was 31 patients, including the 10% ineligible patients.

Results

Between Jan 2020 and Feb 2022, 31 patients were enrolled from 10 institutions in Japan. Thirty-one patients were evaluated for safety, and 30 patients for efficacy. Of 30 patients (median age, 64 years), 70% and 63% had clinical stage IIIA and non-squamous histology, respectively. The MPR and pathological complete response (pCR) rates by ICR were 63% (90% CI, 47-78, 95% CI, 44-80) and 20% (95% CI, 8-39), respectively. Complete resection was not performed due to adverse events (2 pts) and disease progression (3 pts). Among 25 patients who received complete resection, the MPR and pCR rates were 76% (95% CI, 55-91) and 24% (95% CI, 9-45), respectively. No 30-day postoperative mortality was reported.

Conclusions

The primary endpoint of MPR rate was met in SQUAT trial. This result suggests that this treatment strategy is promising for resectable stage IIIA-B N2 NSCLC.

Clinical trial identification

JapicCTI-195069.

Legal entity responsible for the study

WJOG (West Japan Oncology Group).

Funding

AstraZeneca.

Disclosure

T. Miyoshi: Financial Interests, Institutional, Research Grant: AstraZeneca. A. Hamada: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Ono Pharmaceuticals; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca. J. Soh: Financial Interests, Personal, Invited Speaker: Ethicon, Covidien, Intutive; Financial Interests, Institutional, Research Grant: AstraZeneca. A. Hata: Financial Interests, Institutional, Research Grant: MSD, Eli Lilly, Boehringer Ingelheim, AstraZeneca; Financial Interests, Personal, Invited Speaker: Eli Lilly, Chugai, Pfizer, AstraZeneca, Boehringer Ingelheim. Y. Yatabe: Financial Interests, Personal, Invited Speaker: MSD, Chugai-pharma, AstraZeneca, Pfizer, Thermo Fisher Science, ArcherDx, Novartis, Elli-Lily, Daiichi Sankyo, Jansen-Pharma, Amgen; Financial Interests, Institutional, Research Grant: Thermo Fisher Science, ArcherDx, AstraZeneca. J. Suzuki: Financial Interests, Institutional, Research Grant: AstraZeneca. M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan; Financial Interests, Personal, Advisory Board, Lectures, Advisory boards: AstraZeneca KK, Chugai Pharmaceutical Co.,Ltd, MSD; Financial Interests, Personal, Invited Speaker, Lectures: Eli Lilly Japan, Bristol Myers Squibb KK, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical Co.,Ltd; Financial Interests, Personal, Advisory Board, Advisory boards: Novartis; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo company limited, MSD, AstraZeneca, Novartis; Financial Interests, Institutional, Research Grant: Beohringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical Co.,Ltd, Bristol Myers Squibb KK, Novartis; Financial Interests, Institutional, Invited Speaker: Eli Lilly Japan. H. Horinouchi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Novartis, Pfizer, Boehringer Ingelheim, Kyowa-Kirin, Nihon Kayaku, AbbVie, Roche/Chugai; Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Amgen, Nihon Kayaku; Financial Interests, Institutional, Research Grant: Roche/Chugai, Merck Sharp & Dohme, Daiichi Sankyo, ONO pharmaceutical, AstraZeneca; Financial Interests, Institutional, Invited Speaker: AbbVie. I. Yoshino: Financial Interests, Institutional, Research Grant: AstraZeneca. T. Masayuki: Financial Interests, Institutional, Research Grant: AstraZeneca. S. Toyooka: Financial Interests, Personal, Invited Speaker: Chugai, Taiho, Ono Pharmaceuticals, Kyorin, Daiichi Sankyo, Medtronic, Johnson and Johnson; Financial Interests, Personal, Advisory Role: Kyorin; Financial Interests, Institutional, Research Grant: Illumina, Eurofins, Taiho, Chugai, Eli Lilly, AstraZeneca. M. Okada: Financial Interests, Institutional, Research Grant: AstraZeneca. T. Go: Financial Interests, Institutional, Research Grant: AstraZeneca. M. Yamashita: Financial Interests, Institutional, Research Grant: AstraZeneca. N. Yamamoto: Financial Interests, Personal, Invited Speaker: MSD K.K, AstraZeneca, Ono Pharmaceutical Co., Ltd., Thermo Fisher Scientific, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Pfizer Inc., Bristol Myers Squibb, Nippon Kayaku, GlaxoSmithKline K.K., Sanofi K.K., Hisamitsu Pharmaceutical Co.,Inc., Merk biopharma; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Bristol Myers Squibb, Nippon Kayaku, Life Technologies Japan Ltd., Amgen Inc., Guardant Health Japan, Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Research Grant: MSD K.K; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., Amgen Inc., Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Toppan printing, Terumo. K. Nakagawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Nippon Kayaku Co., Ltd., AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd., MSD K.K., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., Taiho Pharmaceutical Co.,Ltd., Bayer Yakuhin, Ltd., CMIC ShiftZero K.K., Life Technologies Japan Ltd., Neo Communication, Merck Biopharma Co., Ltd., Kyowa Kirin Co., Ltd., Takeda Pharmaceutical Co., Ltd., 3H Clinical Trial Inc., Care Net, Inc., Medical Review Co., Ltd., Medical Mobile Communications co., Ltd, Yodosha Co., Ltd., Nikkei Business Publications, Inc., Japan Clinical Research Operations, CMIC Co., Ltd., Novartis Pharma K.K., Taiyo Pharma Co., Ltd.; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co.,Ltd., Eli Lilly Japan K.K.; Financial Interests, Institutional, Other, patents sales fee: Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Research Grant: Parexel International Corp., Pra Healthsciences, Eps Corporation., Kissei Pharmaceutical Co., Ltd., EPS International Co.,Ltd,., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co.,Ltd., MSD K.K., Ono Pharmaceutical Co.,Ltd., PPD-SNBL K.K, SymBio Pharmaceuticals Limited., IQVIA Services Japan K.K., Syneos Health Clinical K.K., Nippon Kayaku Co.,Ltd., EP-CRSU Co., Ltd., Mebix, Inc., Bristol Myers Squibb K.K., Janssen Pharmaceutical K.K., Eisai Co., Ltd., AstraZeneca K.K., Mochida Pharmaceutical Co., Ltd., Covance Japan Inc., Japan Clinical Research Operations, Takeda Pharmaceutical Co.,Ltd., GlaxoSmithKline K.K., Sanofi K.K., Chugai Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Sysmex Corporation, Medical Reserch Support, Eli Lilly Japan K.K., Amgen Inc., Novartis Pharma K.K., Novartis Pharma K.K., Srl, Inc. T. Mitsudomi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfizer, Eli Lilly, Merck Biopharma; Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Chugai, Novartis, MSD, Bristol Myers Squibb, Ono, Pfizer, Amgen, Janssen, Takeda, Eli-Lilly; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, AstraZeneca, Chugai, MSD, Taiho, Daiichi Sankyo, Ono; Non-Financial Interests, Personal, Leadership Role: Interanational Association for Study of Lung Cancer. All other authors have declared no conflicts of interest.

Background

PT-112 is an immunogenic small molecule with reported clinical activity. In preclinical models, it induces ICD and synergizes with immune checkpoint inhibitors. Monotherapy and avelumab combination dose escalation studies have shown PT-112 to be well-tolerated. The recommended phase 2 dose was established at 360 mg/m² (days 1, 8 and 15) when combined with 800 mg of avelumab (days 1 and 15) over a 28-day cycle. Here, we present safety and efficacy findings from the phase 2a PAVE cohort in metastatic NSCLC.

Methods

NSCLC pts were eligible following no more than 4 prior lines of therapy (requiring prior anti-PD-(L)1 and platinum treatment). Correlative sampling included baseline tumor biopsy profiling and blood T cell receptor sequencing.

Results

Eighteen pts were enrolled. Common treatment-related adverse events (TRAEs) were anemia (50%), fatigue (50%), thrombocytopenia (44%), nausea (44%) and anorexia (44%). 72% of pts had ≥1 grade 3-4 TRAEs. Treatment-related peripheral neuropathy was noted in 4 pts (22%). There were 5 cases (28%) of infusion-related reactions, which led to the discontinuation of avelumab in two. Of the 15 pts evaluable for efficacy, 6 pts (40%) had stable disease by iRECIST. Two cases of radiographic and clinical improvement were noted: one pt with primary resistance to prior therapy (nivolumab, ipilimumab, carboplatin and gemcitabine) had a complete response in target and non-target lesions and relief of pulmonary symptoms before experiencing single nodal progression; another pt experienced a multi-site FDG-PET response and remained stable with a PFS of 7.3 months. Both pts had PD-L1 TPS of 5% and 10%, respectively; MSS; and TMB <10. Furthermore, the study population experienced a significant increase in the fraction of T cells within total nucleated blood cells while on treatment.

Conclusions

PT-112 in combination with avelumab was safe and AEs were manageable. Evidence of drug activity was observed, including meaningful clinical benefit in pretreated patients without known predictive markers for immunotherapy response. These results support further study of PT-112 combinations in NSCLC, and assessment of PT-112’s immunological effects in pts.

Clinical trial identification

NCT03409458.

Legal entity responsible for the study

Promontory Therapeutics Inc.

Funding

Promontory Therapeutics Inc.

Disclosure

M. Imbimbo: Financial Interests, Institutional, Invited Speaker: Infomedica; Non-Financial Interests, Personal, Principal Investigator: BMS, MedImmune; Non-Financial Interests, Personal, Other, Independet Safety Data Monitoring board member: Immatics. N. Mederos Alfonso: Non-Financial Interests, Institutional, Advisory Board: Merck. D. Karp: Non-Financial Interests, Institutional, Advisory Board, Scientific Advisory Board: Promontory Therapeutics Inc.; Non-Financial Interests, Institutional, Principal Investigator: Promontory Therapeutics Inc. . D.R. Camidge: Financial Interests, Institutional, Advisory Board: AbbVie, Anheart, EMD Serono, Elevation, Hummingbird, Janssen, Medtronic , Mirati, Nalo Therapeutics, Onkure, Regeneron, Roche, Sanofi, Takeda, Theseus, Xcovery, Amgen, Blueprint, Mersana, Ribon, Roche/Genentech, Seattle Genetics, Turning Point, AstraZeneca, BMS, Eisai, Eli Lilly, GSK, Helssin, Pfizer, Qilu; Financial Interests, Institutional, Other, Safety Review Committee: Appolomics, Elevation; Financial Interests, Institutional, Other, Interstitial Lung Disease adjudication committee: AstraZeneca/Daiichi , Mersana , Daiichi Sankyo; Financial Interests, Institutional, Other, Data Safety Monitoring Board: Beigene Dizal , Hengrui, Bio-Thera, Helsinn; Financial Interests, Institutional, Other, Safety Review Committee/Steering Committee: AstraZeneca; Financial Interests, Institutional, Other, Data Safety Monitoring Committee: Beigene , Hengrui; Financial Interests, Institutional, Other, Data Safety Monitoring Board and NCCN: Eli Lilly; Financial Interests, Institutional, Advisory Board, Scientific Advisory Board: Kestrel, Nuvalent, Anchiarno; Financial Interests, Institutional, Stocks/Shares: Kestrel; Financial Interests, Institutional, Other, NCCN: Puma; Financial Interests, Institutional, Funding, Research funding: Inivata; Financial Interests, Institutional, Principal Investigator: AbbVie, AstraZeneca, Blueprint, Dizal, Inhibrx, Karyopharm, Nuvalent, Pfizer, Phosplatin (now Promontory), Psioxus, Rain, Roche/Genentech, Seattle Genetics, Takeda, Turning Point, Verastem. A.S. Mansfield: Financial Interests, Institutional, Other, Expert Think Tank: TRIPTYCH Health Partners; Financial Interests, Institutional, Other, Steering Committee: Janssen, Johnson & Johnson Global Services; Financial Interests, Institutional, Invited Speaker: BeiGene, Chugai Pharmaceutical (Roche); Financial Interests, Personal, Invited Speaker, CME Presentation: Antoni van Leeuwenhoek Kanker Instituut, University of Miami International Mesothelioma Symposium; Financial Interests, Institutional, Invited Speaker, CME Presentation: AXIS Medical Education, Intellisphere Llc, Answers in CME; Financial Interests, Institutional, Other, Travel Support: Roche; Financial Interests, Institutional, Advisory Board: AbbVie, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Takeda; Financial Interests, Institutional, Other, Study funding, article processing charges: Bristol Myers Squibb; Financial Interests, Institutional, Other, Grant Reviewer: Rising Tide; Financial Interests, Institutional, Other, Moderator: Ideology Health; Financial Interests, Institutional, Research Grant: Novartis, Verily; Non-Financial Interests, Personal, Invited Speaker, Non-remunerated Director: Mesothelioma Applied Research Foundation. C.Y. Yim: Financial Interests, Institutional, Stocks/Shares: Promontory Therapeutics Inc. T.D. Ames: Financial Interests, Institutional, Stocks/Shares: Promontory Therapeutics Inc. M. Price: Financial Interests, Institutional, Stocks/Shares: Promontory Therapeutics Inc. J. Baeck: Financial Interests, Institutional, Stocks/Shares: Promontory Therapeutics Inc. J.F. O'Donnell: Financial Interests, Institutional, Stocks/Shares: Promontory Therapeutics Inc. S. Peters: Financial Interests, Institutional, Advisory Board: Vaccibody, Takeda, Seattle Genetics, Sanofi, Roche/Genentech, Regeneron, Phosplatin Therapeutics, PharmaMar, Pfizer, Novartis, Mirati, Merck Serono, MSD, Janssen, Incyte, Illumina, IQVIA, GlaxoSmithKline, Gilhead, Genzyme, Foundation Medicine, F-Star, Eli Lilly, Debiopharm, Daiichi Sankyo, Boehringer Ingelheim, Blueprint Medicines, Biocartis, Bio Invent, BeiGene, Bayer, BMS, AstraZeneca, Arcus, Amgen, AbbVie, iTheos, Novocure; Financial Interests, Institutional, Invited Speaker: Takeda, Sanofi, Roche/Genentech, RTP, Pfizer, PRIME, PER, Novartis, Medscape, MSD, Imedex, Illumina, Fishawack, Eli Lilly, Ecancer, Boehringer Ingelheim, AstraZeneca, BMS, OncologyEducation, RMEI, Mirati; Financial Interests, Personal, Other, Associate Editor Annals of Oncology: Elsevier; Financial Interests, Institutional, Invited Speaker, MERMAID-1: AstraZeneca; Financial Interests, Institutional, Invited Speaker, MERMAID-2, POSEIDON, MYSTIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering committee CheckMate 743, CheckMate 73L, CheckMate 331 and 451: BMS; Financial Interests, Institutional, Invited Speaker, RELATIVITY 095: BMS; Financial Interests, Institutional, Invited Speaker, BGB-A317-A1217-301/AdvanTIG-301: Beigene; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair ZEAL-1: GSK; Financial Interests, Institutional, Invited Speaker, Clinical Trial steering Committee PEARLS, MK-7684A: MSD; Financial Interests, Institutional, Invited Speaker, Clinical Trial Steering Committee SAPPHIRE: Mirati; Financial Interests, Institutional, Invited Speaker, LAGOON: Pharma Mar; Financial Interests, Institutional, Invited Speaker, phase 1/2 trials: Phosplatin Therapeutics; Financial Interests, Institutional, Invited Speaker, Clinical Trial Chair Skyscraper-01; chair ALEX; steering committee BFAST; steering committee BEAT-Meso; steering committee ImPower-030, IMforte: Roche/Genentech; Financial Interests, Institutional, Invited Speaker, Phase 2 Inupadenant with chemo: iTeos; Non-Financial Interests, Personal, Officer, ESMO President 2020-2022: ESMO; Non-Financial Interests, Personal, Officer, Council Member & Scientific Committee Chair: ETOP/IBCSG Partners; Non-Financial Interests, Personal, Officer, Vice-President Lung Group: SAKK; Non-Financial Interests, Personal, Other, Involved in Swiss politics: Swiss Political Activities; Non-Financial Interests, Personal, Officer, President and Council Member: Ballet Béjart Lausanne Foundation; Non-Financial Interests, Personal, Principal Investigator, Involved in academic trials: ETOP / EORTC / SAKK; Non-Financial Interests, Personal, Member: Association of Swiss Physicians FMH (CH), IASLC, ASCO, AACR; Non-Financial Interests, Personal, Leadership Role, ESMO President: ESMO; Non-Financial Interests, Personal, Member, Vice-President Lung Group: SAKK; Non-Financial Interests, Personal, Leadership Role, Vice -President: SAMO; Non-Financial Interests, Personal, Member, Association of Swiss interns and residents: ASMAC/VSAO. All other authors have declared no conflicts of interest.

Background

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor with an anti-programmed cell death protein 1 (PD-1) antibody is a promising combination showing antitumor activity in solid tumors. Phase 1/1b open-label study AdvanTIG-105 assessed safety and preliminary antitumor activity of anti-TIGIT monoclonal antibody (mAb) OCI + anti-PD-1 mAb TIS in pts with advanced solid tumors (NCT04047862). During dose-escalation, OCI + TIS was well tolerated showing antitumor activity, establishing the recommended phase 2 dose (RP2D) of OCI 900mg IV Q3W plus TIS 200mg IV Q3W. We report Cohort 5 dose-expansion results.

Methods

Eligible adults had histologically/cytologically confirmed locally advanced/metastatic CPI-experienced NSCLC for which they received ≤2 prior therapies, including anti-PD-(L)1 in the most recent line, and progressed after complete or partial response (CR or PR) or stable disease. Pts received RP2D OCI + TIS until disease progression, intolerable toxicity or withdrawal of consent. Primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DOR) and safety.

Results

As of June 20, 2022, 26 pts were enrolled; 25 were efficacy evaluable. Median study follow-up was 46.1 weeks (range 25.4-59.0). The confirmed ORR was 8.0% (95% confidence interval [CI]: 1.0, 26.0), with two pts experiencing PR, and the confirmed DCR was 56.0% (95% CI: 34.9, 75.6); median DOR was not reached. Overall, 23 pts (88.5%) experienced ≥1 treatment-emergent adverse event (TEAE); 11 pts (42.3%) experienced Grade ≥3 TEAEs and nine pts (34.6%) experienced serious TEAEs. The most common TEAEs were fatigue (30.8%) and cough (26.9%). TEAEs leading to treatment discontinuation occurred in four pts (15.4%), and were related to treatment in two patients, with no TEAEs leading to death.

Conclusions

OCI 900mg + TIS 200mg was generally well tolerated and showed preliminary antitumor activity in pts with locally advanced/metastatic CPI-experienced NSCLC.

Clinical trial identification

NCT04047862.

Editorial acknowledgement

This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Sophie Cook, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

S.C. Kao: Financial Interests, Personal and Institutional, Advisory Board: AZ, Pfizer, Boeringher, Takeda, MSD, BMS, Roche, Specialised Therapeutics; Financial Interests, Personal and Institutional, Other, Honoraria: AZ, Pfizer, Boeringher, Takeda, MSD, BMS, Roche, Specialised Therapeutics; Financial Interests, Personal, Funding: AstraZeneca. J. Coward: Non-Financial Interests, Institutional, Advisory Board: GOG. T.D. Clay: Financial Interests, Personal, Other, Honoraria: Specialised Therapeutics Australia; Financial Interests, Personal, Advisory Board: AstraZeneca, Foundation Medicine; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Writing Engagements: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: MSD; Financial Interests, Personal and Institutional, Principal Investigator: MSD; Financial Interests, Personal and Institutional, Sponsor/Funding: MSD; Financial Interests, Institutional, Principal Investigator: Pfizer, BMS, Amgen, Daiichi Sankyo, AbbVie, Beigene, Immutep, Clovis, Janssen; Financial Interests, Institutional, Other, Honoraria: Amgen; Financial Interests, Personal, Other, Travel / Accommodation Expenses: Astellas. W. Xu: Financial Interests, Personal and Institutional, Advisory Board: Merck ; Financial Interests, Personal and Institutional, Invited Speaker: Merck ; Financial Interests, Personal and Institutional, Research Grant: Merck ; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: MSD. R. Gao: Financial Interests, Personal and Institutional, Full or part-time Employment: BeiGene, Ltd. R. Wang: Financial Interests, Personal, Full or part-time Employment: BeiGene, Ltd. H. Zheng: Financial Interests, Institutional, Full or part-time Employment: BeiGene USA; Financial Interests, Institutional, Stocks/Shares: BeiGene USA. W. Tan: Financial Interests, Personal and Institutional, Full or part-time Employment: BeiGene, Ltd. All other authors have declared no conflicts of interest.

Background

Concurrent blockade of LAG-3 may enhance efficacy of anti–programmed cell death-1 (anti–PD-1) therapies. We present safety and clinical activity data from a phase 1 study in patients (pts) with NSCLC treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab).

Methods

Pts with unresectable stage IIIB–C or IV NSCLC who were anti–PD-1/PD-L1-naive (expansion cohort [EC] 1) or anti–PD-1/L1-experienced within 3 months (mo) of screening (EC2) were eligible. Pts received fianlimab 1600 mg + cemi 350 mg intravenously every 3 weeks (wks) for 12 mo.

Results

As of the 1 July 2022 data cutoff, 15 EC1 and 15 EC2 pts were treated. For EC1 and EC2 respectively, median age was 70.0 and 67.0 years, 73.3% and 73.3% were male, and 33.3% and 73.3% were White. 40.0% of pts in EC1 were systemic treatment-naive. In EC2, 53.3% of pts had at least two lines of therapy including anti–PD1/L1 therapy. Median treatment duration was 12.1 wks and median follow-up was 8.5 mo and 5.4 mo for EC1 and EC2 respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) and serious TEAEs occurred in 33.3% & 20.0% and 40.0% & 13.3% of EC1 and EC2 pts, respectively. One pt in EC1 and no pts in EC2 discontinued due to a TEAE. No treatment-related deaths were reported. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 26.7% (four partial responses [PRs]) in EC1 and 6.7% (one PR) in EC2. In EC1, the ORR for treatment-naive pts (n=6) was 50%; the ORR for pts with PD-L1 expression ≥50% (n=3) was 100%. Kaplan–Meier estimation of median progression-free survival was 2.6 mo (95% confidence interval [CI], 1.2–8.3) in EC1 and 4.1 mo (95% CI, 1.3–6.2) in EC2 pts. Median duration of response was not reached in EC1 and was 4.8 mo (95% CI, not evaluable [NE]–NE) in EC2. Fianlimab concentrations in serum in pts were similar in both EC1 and EC2 cohorts. LAG-3 and PD-L1 correlative biomarker analysis will be included in the presentation.

Conclusions

Fianlimab + cemiplimab demonstrated promising signs of clinical activity with durable responses among pts with anti–PD-1/L1-naive NSCLC and in pts with PD-L1 expression ≥50%, with a similar safety profile and with no new safety signals compared to cemiplimab monotherapy.

Clinical trial identification

NCT03005782.

Editorial acknowledgement

Medical writing and editorial support provided by John G Facciponte, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc.

Funding

Regeneron Pharmaceuticals, Inc.

Disclosure

B.C. Cho: Financial Interests, Personal, Research Grant: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan Corporation, Ono Pharmaceutical, Dizal Pharma, Merck Sharp & Dohme, AbbVie, Medpacto, GI Innovation, Eli Lilly, Blueprint Medicines, and Interpark Bio Convergence; Financial Interests, Personal, Royalties: Champions Oncology; Financial Interests, Personal, Advisory Role: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Ono Pharmaceutical, Yuhan Corporation, Pfizer, Eli Lilly, Janssen, Takeda, Merck Sharp & Dohme, Medpacto, and Blueprint Medicines; Financial Interests, Personal, Advisory Board: Kanaph Therapeutics, BridgeBio Therapeutics, Cyrus Therapeutics, Guardant Health, and Joseah Biopharma; Financial Interests, Personal, Member of the Board of Directors: Interpark Bio Convergence Corporation and Gencurix Inc.; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc., Gencurix Inc., BridgeBio Therapeutics, Kanaph Therapeutics, Cyrus Therapeutics, and Interpark Bio Convergence Corporation; Financial Interests, Personal, Other, Founder: DAAN Biotherapeutics. T.M. Kim: Financial Interests, Personal, Advisory Role: AstraZeneca/MedImmune, BeiGene, Boryung, F. Hoffmann-La Roche Ltd/Genentech, Inc, Janssen, Novartis, Sanofi, Takeda, Yuhan; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Uncompensated relationship: Bayer, Boryung, Novartis, Regeneron Pharmaceuticals, Inc., Roche/Genentech, and Sanofi. D. Sarker: Financial Interests, Personal, Other, Nonfinancial support: Medivir and MiNA Therapeutics; Financial Interests, Personal, Other, Personal fees and nonfinancial support: Eisai and Ipsen; Financial Interests, Personal, Other, Personal fees: AAA, AstraZeneca, Bayer, MSD, Sirtex, and Surface Oncology; Financial Interests, Personal, Research Grant: UCB. O. Hamid: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Novartis, Pfizer, Sanofi and Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Advisory Role: Aduro Biotech, Akeso Biopharma, Amgen, Arcus Biosciences, Bioatla, Bristol Myers Squibb, CytomX Therapeutics, Exelixis, Genentech, GlaxoSmithKline, Idera, Immunocore, Incyte, Iovance Biotherapeutics, Merck, Merck Serono, Moderna Therapeutics, NextCure, No. S. Williamson: Financial Interests, Personal, Research Grant: Novartis. H. Hatim: Financial Interests, Personal, Research Grant: Bristol Myers Squibb, Eli Lilly, Pfizer, and Roche Sequencing Solutions; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Blueprint Medicine, and Janssen; Financial Interests, Personal, Advisory Role: AstraZeneca, Blueprint Medicine, Foundation Medicine, Merck, Mirati Therapeutics, Neogenomics, Takeda and Turning Point Therapeutics. S. Chen: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. J. Mani: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. V. Jankovic: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. A.J. Paccaly: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. S. Masinde: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. I. Lowy: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. L. Brennan: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. G. Gullo: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Background

Stage III non-small cell lung cancer (NSCLC) is highly heterogeneous with great variations in clinical practice. Though neoadjuvant immunotherapy plus chemotherapy significantly improved pCR and EFS in resectable NSCLC patients compared with chemotherapy alone in previous study, the evidence in stage III NSCLC are limited. This is the first study to evaluate durvalumab neoadjuvant/adjuvant in stage III NSCLC patients.

Methods

A prospective phase II, single-arm study enrolled the patients (according to the MDT) with histologically confirmed stage IIIa-IIIc NSCLC without known EGFR/ALK mutations. Patients received neoadjuvant durvalumab (1500mg) plus platinum-based chemotherapy q3w for 2-4 cycles followed by surgery, then adjuvant durvalumab mono q4w for 12 cycles. The primary endpoint was MPR (≤10% viable tumor cells). Secondary endpoints included pCR (0% viable tumor cells), ORR, DFS, OS, and safety. Predictive biomarkers was exploratory endpoint.

Results

From February 7, 2021 to May 30, 2022, a total of 14 patients were enrolled with median follow-up of 9.5 months. The median age was 64.5 and 71.4% were squamous carcinoma histology. The number of patients with stage IIIa, IIIb, IIIc were 2 (14.3%), 10 (71.4%) and 2 (14.3%), respectively. All patients completed neoadjuvant therapy, 6 patients received 3 cycles and 8 patients received 4 cycles. Currently, the ORR was 64.3% (9/14), 10 patients underwent surgery, 4 patients were ineligible for surgery due to 2 with unresectable stage IIIc disease, 1 with tumor wrapping around the right bronchus and 1 with poor lung function. Among 10 resected patients, 50.0% achieved MPR and 20.0% achieved pCR. The TCR clone counts after 1 cycle neoadjuvant therapy was positively corelated with imaging regressions (p=0.044). The median DFS was not reached. Grade 3 or 4 treatment-related adverse events rate was 14.3%.

Conclusions

The results suggest that stage IIIa-IIIb NSCLC can benefit from neoadjuvant Durvalumab plus chemotherapy. Two stage IIIc patients failed to convert from neoadjuvant therapy. TCR diversity is positively correlated with imaging regression, analysis of its correlation with survival outcomes is ongoing.

Clinical trial identification

NCT04897386.

Legal entity responsible for the study

X. Dong.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

IMpower150 subgroup analysis showed patients with EGFR mutated advanced NSCLC could achieve efficacy from ICI-combination therapy after resistance to EGFR TKIs, but the safety should be improved. A retrospective study from our center showed that ICI plus single-agent chemotherapy (chemo-reform¹) might be a better choice. This study was designed to further explore the efficacy and safety of tislelizumab (Tis) plus bevacizumab (Beva) and nab-paclitaxel for advanced NSCLC failed to EGFR TKIs. Herein, the preliminary analysis for early safety and efficacy is reported.

Methods

This is a single-arm, phase II study (NCT04310943). Pts with EGFR mutations who had failed to prior EGFR-TKIs accepted Tis (200mg, d1) plus Beva (15mg/kg, d1) and nab-paclitaxel (100mg/m², d1,8,15) Q3W for up to 4 cycles, followed by Tis plus Beva (7.5mg/kg) maintenance therapy. Primary endpoints are safety and 1-year PFS rate, and secondary endpoints include ORR and 1-year OS rate. We planned to enroll 24 pts.

Results

As of 26 August 2022, 14 pts were enrolled and treated. The median age was 57 (range: 30-70). Seven pts (50.0%) harbored EGFR exon 19del and 7 pts (50.0%) had exon 21 L858R at the initial diagnosis. Ten pts (71.4%) had progression on both 1st/2nd and 3rd EGFR-TKIs. Two pts (14.3%) had prior chemotherapy. The median follow-up time was 11.2 months. Among 14 pts, the safety was manageable: the incidence of ≥grade 3 TEAE and ≥grade 3 irAE were 35.7% and 14.3% respectively. Among 9 efficacy evaluable pts, the ORR was 66.7% (95%CI: 29.9-92.5), mDOR was 5.3 months (95% CI: 4.9-5.7), and DCR was 100.0%. Table: 129P

Conclusions

Tislelizumab combined with bevacizumab plus nab-paclitaxel has shown a promising anti-tumor efficacy with a manageable safety profile for patients who failed to EGFR TKIs. The results will be monitored continuously.

Clinical trial identification

NCT04310943.

Editorial acknowledgement

BeiGene.

Legal entity responsible for the study

The authors.

Funding

BeiGene.

Disclosure

All authors have declared no conflicts of interest.

Background

Novel agents are urgently needed for the treatment [tx] of patients [pts] with metastatic NSCLC including post immune checkpoint inhibitors (ICI). COM701 [anti-PVRIG] is a novel 1st in class ICI. We hypothesized that COM701 ± nivolumab will demonstrate antitumor activity with a favorable safety and tolerability profile in pts with heavily pretreated NSCLC. Here, we present preliminary results on antitumor activity.

Methods

We enrolled 7 pts with NSCLC: 5 COM701 monotherapy [mtx] [4 - COM701 20 mg/kg IV Q4W mtx expansion, 1 pt COM701 0.01 mg/kg IV Q3W], 2 pts COM701 + nivolumab [COM701/nivolumab 3mg/kg/360 mg both IV Q3W, COM701/nivolumab 10 mg/kg/480 mg both IV Q4W]. Key study objectives were safety/tolerability and preliminary antitumor activity; OS was an exploratory endpoint. Key inclusion criteria: Age ≥ 18 yrs, histologically confirmed metastatic solid malignancy and has exhausted all standard tx. Key exclusion criteria: history of immune toxicities on prior ICI tx leading to discontinuation. Safety per CTCAE v4.03, investigator-assessed response per RECIST v1.1.

Results

Age >65 4/7 [57%], female 6/7 [86%], prior lines median [Min, Max] 4 [3, 6], all pts received prior ICI, 4/7 [57%] received ≥2 prior lines with ICI. Disease control rate [CR+PR+SD) 5/7 [71%], no CR or PR. Median [m] PFS [all pts] 84 days 95% CI [22, 231], mOS in all pts 9.5 months [mos] [95% CI, 2.7-11.6] – [COM701 mtx 9.5 mos [2.7, NE]; combination 10.1 mos [95% CI, 8.6, NE]. The most frequent AE was G1 nausea in 2 pts. Post ICI NSCLC data - 1 prior line of ICI in metastatic setting, mOS 14.5 mos for ramucirumab + pembrolizumab¹.

Conclusions

COM701 ± nivolumab has preliminary encouraging signal of antitumor activity in a heavily pretreated popn of pts with NSCLC with prior ICI txp comparable to historical data. A P1 study in post IO NSCLC evaluating COM902+COM701+PD-1 inhibitor, COM902+COM701+chemotherapy is planned. Datacut 07/17/2022. 1. Reckamp KL, et al Phase 2 Randomized Study of Ramucirumab and Pembrolizumab vs SOC in Advanced NSCLC Previously Treated With Immunotherapy-Lung-MAP S1800A. J Clin Oncol. 2022 Jul 20;40(21):2295-2306.

Clinical trial identification

NCT03667716.

Legal entity responsible for the study

Compugen Ltd.

Funding

Compugen Ltd in collaboration with Bristol Myers Squibb.

Disclosure

E. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen, Arcus, iTeos, Janssen, Loxo, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Orinove, Leap Therapeutics, Zenith Epigenetics, Harpoon, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, Myraid Genetic Labs, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Vincerx Pharma. B. Izar: Other, Personal, Other, Consulting: Janssen, Volastra Therapeutics; Other, Personal, Other, Paid speaking engagement: AstraZeneca. J. Gainor: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Genentech/Roche, Takeda, Lilly, Moderna, AstraZeneca, Pfizer, Novartis, iTeos, Karyopharm, Silverback Therapeutics, GlydeBio, BeiGene; Financial Interests, Personal, Stocks/Shares, Immediate family member is an employee. Note: Ironwood Pharmaceuticals is not involved in any oncology drug development. It is focused on gastroenterology; Financial Interests, Personal and Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: Genentech, Bristol Myers Squibb, Merck, AstraZeneca, Moderna, Jounce, Alexo. H.H. Adewoye: Financial Interests, Personal, Full or part-time Employment: Compugen Ltd. P.J. Ferre: Financial Interests, Personal, Full or part-time Employment: Compugen Ltd. E. Ophir: Financial Interests, Personal, Full or part-time Employment: Compugen Ltd. M. Patel: Financial Interests, Institutional, Funding, paid to institution: See https://coi.asco.org/share/BLY-NDGV/Manish%20Patel. A. Patnaik: Financial Interests, Institutional, Other, Institutional research funding: Compugen. All other authors have declared no conflicts of interest.

Background

Resistance to ICIs remains a challenge. HDAC inhibitors may synergize with PD-1 antibodies by inducing and activating NK cell and cytotoxic T cell (CTL) -mediated cellular immunity. Tislelizumab is an anti-PD-1 mAb approved for the treatment of NSCLC. Chidamide, a subtype-selective HDACi. This phase 2 study assessed antitumor activity and tolerability of chidamide and tislelizumab combined with chemotherapy in advanced NSCLC.

Methods

This was an open-label, prospective study. Patients with histologically or cytologically confirmed NSCLC (stage IIIB-IV) without prior systemic treatment was enrolled. EGFR/ALK mutation or fusion and symptomatic brain metastases were ineligible. Patients received chidamide 20 mg twice weekly orally, tislelizumab 200 mg Q3W intravenously, chemotherapy Q3W(≤4∼6 cycles) until unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was ORR. Secondary endpoints include DCR、PFS and safety. Tumor response was assessed using RECIST V1.1.

Results

20 patients were enrolled in the study. At the data cut-off September 15, 2022, the median age was 63.5 years (range: 49-75) and all patients were male 90% of who with smoking history. Most patients were stage IV(95%) .40% of the patients whose PD-L1 expression was positive (PD-L1 TPS≥1%). The confirmed ORR was 73.7%(95%CI:63.6-83.8) and 1 patient was evaluated as CR. The DCR was 100%. The median follow-up was 10.7 months, median PFS was 13.8 months (95%CI:5.4m-22.2m) and 1-year PFS rate was 76.6% (95%CI:64.3%-88.9%). 11 patients (55.0%) had Grade ≥ 3 TRAEs. The most common Grade≥ 3 TRAEs were leukopenia (25.0%), neutropenia (20.0%) and thrombocytopenia (15%). Table: 131P

Incidence of TRAEs

Conclusions

Adding HDACi(Chidamide) plus Tislelizumab combined with chemotherapy showed encouraging antitumor activity and a favorable safety profile as first-line therapy for advanced NSCLC. Efficacy and safety of the combination will be continuously monitored.

Clinical trial identification

ChiCTR2000041542; Date of Registration: 2020.12.28.

Legal entity responsible for the study

The authors.

Funding

BeiGene (Beijing) Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

Interim analysis of the open-label phase 3 RATIONALE-307 study (NCT03594747) demonstrated clinical benefit, including significantly improved progression-free survival (PFS) with a manageable safety profile, of tislelizumab (TIS) plus chemotherapy (chemo) as first-line (1L) therapy in patients (pts) with advanced sq-NSCLC vs chemo alone. Here, we report updated results.

Methods

Adults with previously untreated stage IIIB (not amenable to curative surgery/radiotherapy)/IV sq-NSCLC were randomized (1:1:1) to intravenous TIS (200mg, 21-day cycles) + paclitaxel + carboplatin (Arm A); TIS + nab-paclitaxel + carboplatin (Arm B); or paclitaxel + carboplatin (Arm C). The primary endpoint was PFS in Arms A and B vs Arm C, per independent review committee (IRC). Secondary endpoints included overall survival, objective response rate (ORR), duration of response (DoR), and safety.

Results

As of 30 September 2020 (median follow-up 16.7 months), of 360 randomized pts, 355 received treatment. The updated median (95% confidence interval [CI]) PFS benefit was maintained for Arms A (7.7 [95%CI: 6.7, 10.4] months [mo], stratified hazard ratio [HR] 0.45 [95%CI: 0.33, 0.62]) and B (9.6 mo [95%CI: 7.4, 10.8], HR 0.43 [95%CI: 0.31, 0.60]) vs C (5.5 mo [95%CI: 4.2, 5.6]). Consistent improvements in ORR in Arms A (74.2% [95%CI: 65.4, 81.7]) and B (73.9% [95%CI: 65.1, 81.6]) vs C (47.9% [95%CI: 38.8, 57.2]) were observed. Median DoR in Arms A and B was 8.4 (95%CI: 5.0, 15.8) mo and 8.6 (95%CI: 7.1, 12.5) mo, respectively vs 4.3 (95%CI: 2.9, 5.4) mo in Arm C. The incidences of any grade (Arm A 100%; Arm B 99.2%; Arm C 100%) or ≥grade 3 (Arm A 89.2%; Arm B 87.3%; Arm C 84.6%) treatment-emergent adverse events (TEAE) were similar between arms. The rate of treatment discontinuation due to TEAE was similar between Arms A (17.5%) and C (15.4%), and lower than in Arm B (32.2%). No new safety signal was identified.

Conclusions

In RATIONALE-307, the addition of TIS to chemo continued to demonstrate clinical benefit as 1L treatment of advanced sq-NSCLC vs chemo alone after a longer follow-up, with a manageable safety profile.

Clinical trial identification

NCT03594747.

Editorial acknowledgement

Medical writing support, under the direction of the authors, was provided by Arezou Hossein, MPharm, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

S. Lu: Financial Interests, Personal, Other, Research support: AstraZeneca, Hutchison, BMS, Heng Rui Beigene and Roche, Hansoh ; Financial Interests, Personal, Other, Speaker fees: AstraZeneca, Roche, Hansoh; Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Hutchison MediPharma, ZaiLab, GenomiCare, Novarti, Yuhan Corporation, Menarini., Mirati Therapeutics Inc, and Roche. C. Hu: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca. X. Lin, L. Liang, S. Leaw, W. Zheng: Financial Interests, Personal, Full or part-time Employment: BeiGene, Ltd. All other authors have declared no conflicts of interest.

Background

Bone metastasis is frequently seen in NSCLC (non small-cell cancer )and have got poor prognosis. Bone is a hematopoietic organ and actively regulates our immune system. Nivolumab is a fully human IgG4 PD-1 ICI (immune checkpoint inhibitor) antibody, which disrupts PD-1 mediated signaling and restores antitumor immunity. We have studied the clinical outcome of Nivolumab monotherapy in NSCLC patients with bone metastasis.

Methods

All patients with NSCLC with bone metastasis treated in our institute between Jan2018 to Aug2021 were included in our study. Patients who have received immunotherapies in past were excluded. Out of total 23 patients (16 men and 7 women), with median age of 58 years, 18 had adenocarcinoma and 5 had squamous cell carcinoma. Median followup was 13months. All patients were previously treated with chemotherapies (platinum based/epidermal growth factor receptor-tyrosine kinase inhibitor), Bone modifying agents, Denosumab, Zolendronic acid. Now they are given IV infusion of Nivolumab every 2 weeks. Tumor response were defined as complete/partial response and stable/progressive disease according to RECIST1.1. Responders were classified as either CR or PR and non responders as either PD or SD. Radiological responses were assessed using the MDA (MD Anderson response classification) criteria and it divided response into 4 categories and can assess both the egression of extaskeletal lesions and osteosclerotic change (OC) on computed tomography due to the repairative process.

Results

A median of 5 doses of Nivolumab was given to patients (2-18 doses) with median treatment duration of 2.1 months (1-16months). It resulted in overall survival(OS) of 58% at 1 year and overall response rate(ORR) of 21%, and time to response(TTR) was 2.5 months, which is consistent with previous studies. Bone response was achieved in 10 lytic lesions in 8 patients. No change was seen in mixed and blastic lesions. Univariate analysis showed that the no. of bone metastasis was the only risk factor for non responders.

Conclusions

Bone metastasis impairs immunotherapy efficacy. Nivolumab monotherapy is effective for NSCLC patients with bone metastasis. Early bone response to this immunotherapy can be useful for early prediction and prognosis of such patients.

Clinical trial identification

CMCH/32/2021.

Legal entity responsible for the study

CMCH.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Vascular endothelial growth factor (VEGF) inhibition may reverse suppressive microenvironment and recover sensitivity to subsequent immune checkpoint inhibitors (ICIs).

Methods

This is a phase Ib/IIa, single-arm study, comprising dose finding (Part A) and expansion cohort (Part B). Immune checkpoint-inhibitor refractory NSCLC were enrolled. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort (nivolumab 360mg, every 3 weeks, plus anlotinib, RP2D, 14 days on and 7 days off). The primary objective is recommended phase 2 dose (RP2D, part A) safety (part B) and ORR (part B), respectively.

Results

Between November 2020 and March 2022, 35 patients were screened and 21 eligible patients were enrolled (6 patients in Part A). The PR2D is anlotinib 12 mg/day orally (14 days on and 7 days off) and nivolumab (360mg every 3 weeks). Adverse events of any cause and treatment-related were reported in all patients. Two patients (9.5%) experience grade 3 TRAE. No grade 4 or higher adverse events were observed. Serious adverse were reported in 4 patients. There were 6 and 4 patients experience anlotinib and nivolumab disruption due to TRAE. Dese reduction to 10mg at any time was required in 5 patients and no patients decreased to 8mg. ORR and DCR was 19.0% and DCR is 76.2%, respectively. Median PFS and OS were PFS was 7.43 months (95% CI, 4.54-10.21m) and 19.1months (95% CI, 10.37-NE).

Conclusions

Our study suggested that full dose anlotinib combined with nivolumab showed positive safety and efficacy signal. Further study is warranted.

Clinical trial identification

NCT04507906.

Legal entity responsible for the study

Baohui Han.

Funding

This work was supported by Shanghai Committee of Science and Technology (Project No. 21Y11913800), National Natural Science Foundation of China (Project No.82072573). Study drugs were provided by Bristol Myers Squibb and Jiangsu Chia Tai Tianqing Pharmaceutical Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

The phase 3 CameL and CameL-sq studies have proven the superiority of first-line camrelizumab plus chemotherapy (camre-chemo) vs chemo for progression-free survival (PFS) in patients (pts) with advanced non-squamous and squamous NSCLC, respectively. Here, we report pooled outcomes of pts from the two trials with long-term follow-up.

Methods

Pts with stage IIIB–IV NSCLC, no EGFR/ALK alterations, ECOG PS of 0 or 1, and no prior systemic therapy for metastatic disease were randomized to 4–6 cycles of carboplatin-pemetrexed ± camre followed by maintenance pemetrexed ± camre (non-squamous) or carboplatin-paclitaxel + placebo/camre followed by placebo/camre (squamous). Crossover from chemo to camre was permitted at radiographic progression, and RPSFT model was used to adjust for crossover. Total camre exposure was up to 2 yrs.

Results

801 pts were included (camre-chemo, N=398; chemo, N=403). Baseline characteristics were well balanced between the two groups (male, 82% with camre-chemo vs 82% with chemo; median age, 61 vs 61 yrs; ECOG PS of 1, 78% vs 80%; smoking history of ≥20 packs/yr, 73% vs 71%; PD-L1 TPS of ≥1%, 59% vs 52%). As of Jan 31, 2022, median follow-up was 21.6 mo (range 0.2–51.3) in camre-chemo group and 15.2 mo (range 0.5–48.6) in chemo group. Median PFS (mPFS) per investigator was 11.0 mo (95% CI 9.3–12.6) with camre-chemo vs 5.5 mo (95% CI 5.5–5.6) with chemo (HR 0.44 [95% CI 0.38–0.52]; 1-sided p <0.0001). Median overall survival (mOS) was 26.1 mo (95% CI 22.9–29.2) with camre-chemo vs 16.8 mo (95% CI 14.9–19.9) with chemo (HR 0.66 [95% CI 0.55–0.79]; 1-sided p <0.0001); the OS rate was 52.3% (95% CI 47.1–57.3) vs 37.7% (95% CI 32.8–42.6) at 24 mo, 31.9% (95% CI 25.6–38.4) vs 21.0% (95% CI 16.0–26.4) at 36 mo, and 26.8% (95% CI 19.5–34.7) vs 12.4% (95% CI 7.4–18.7) at 48 mo. Crossover-adjusted mOS was 14.5 mo (95% CI 12.9–16.5) with chemo (HR 0.52 [95% CI 0.43–0.63]; 1-sided p <0.0001). No new safety signals were observed.

Conclusions

With extended follow-up, camre plus chemo continued to provide clinically meaningful survival benefits over chemo with manageable safety in pts with previously untreated, advanced non-squamous and squamous NSCLC.

Clinical trial identification

NCT03134872 (First Posted: May 1, 2017) and NCT03668496 (First Posted: September 12, 2018).

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Funding

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Disclosure

C. Zhou: Financial Interests, Personal, Invited Speaker: Roche, Lily China, Boehringer Ingelheim, Merck, Hengrui, Qilu, Sanofi, Merck Sharp & Dohme, Innovent Biologics, C-Stone, Luye Pharma, TopAlliance Biosciences, and Amoy Diagnostics; Financial Interests, Personal, Advisory Role: Innovent Biologics, Hengrui, Qilu, and TopAlliance Biosciences. Y. Tai, X. Ma, X. Lu: Financial Interests, Personal, Full or part-time Employment: Hengrui. All other authors have declared no conflicts of interest.

Background

Treatment option is limited for EGFR-mutated NSCLC after failure to EGFR TKIs. This multicenter, open-label, phase II study aims to evaluate the efficacy and safety of TIS plus chemo (cohort 1) or TIS plus chemo and bevacizumab (cohort 2) in EGFR-mutated nsq-NSCLC pts failed to EGFR TKI therapies. Herein, the primary analysis of cohort 1 is reported.

Methods

In cohort 1, pts with EGFR sensitizing mutations who had failed prior EGFR-TKIs received TIS plus carboplatin and nab-paclitaxel (induction), followed by TIS plus pemetrexed (maintenance). Primary endpoint was 1-year PFS rate; the planned sample size was 66 with a historical control of 7% (chemo), an expected value of 20%, one-sided α of 0.05, and power of 85%.

Results

From Jul 2020 to Dec 2021, 69 pts were enrolled; 39 pts (56.5%) harbored EGFR exon 19del; 28 pts (40.6%) had exon 21 L858R. 34 pts (49.3%) had progression on both 1^st /2^nd and 3^rd EGFR-TKIs. As of 30 Jun 2022 (median follow-up, 8.2 months), 23.2% (n=16) of pts remained on treatment. Among 62 pts in EAS (Table), the confirmed ORR and DCR were 50.0% (95% CI 37.0-63.0%) and 87.1 % (95% CI 76.1-94.3%), respectively. Median PFS was 7.6 (95% CI, 6.4-9.8) months, with a 1-year PFS rate of 23.8% (90% CI, 13.1-36.2%). Pts with L858R mutation or having prior 1^st/2^nd EGFR-TKIs tended to have a longer PFS compared with pts with EGFR exon 19del mutation or progressed on 1^st /2^nd and 3^rd EGFR-TKIs. Median OS was not reached (95% CI, 14.0-NE), and 1-year OS rate was 74.5% (95% CI, 56.5-86.0%). Safety profile was consistent with previous reports of TIS plus chemo in pts with EGFR-wt NSCLC. Grade 3-4 TEAEs occurred in 40.6% (28/69) of pts. 27.5% (19/69) of pts experienced irAEs; grade 3-4 irAEs occurred in 5 (7.2%) pts. Table: 136P

Conclusions

The study met the primary endpoint for cohort 1. TIS plus chemo is effective with acceptable safety profile for EGFR-mutated non-squamous NSCLC after EGFR TKI failure.

Clinical trial identification

NCT04405674.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

B. Han: Financial Interests, Institutional, Research Grant: AstraZeneca, BeiGene, Roche, Innovent Biologics, Chia Tai Tianqing Pharmaceutical. All other authors have declared no conflicts of interest.

Background

Recently, multiple clinical trials demonstrated neoadjuvant chemoimmunotherapy is a promising treatment option for resectable non-small-cell lung cancer (NSCLC). However, there is still limited evidence for using chemoimmunotherapy as neoadjuvant treatment in potentially resectable stage III squamous NSCLC. TACT (NCT05024266) is a phase II, open label, single arm trial evaluating the efficacy and safety of tislelizumab(Tis) plus chemotherapy(CT) as neoadjuvant treatment for potentially resectable stage IIIA-IIIB(N2) squamous NSCLC.

Methods

Treatment-naive adults confirmed clinical stage IIIA-IIIB (AJCC 8th), potentially resectable squamous NSCLC and ECOG PS 0-1 were eligible. Patients(pts) intravenously received Tis (200mg d1) + Albumin-bound paclitaxel (260mg/m2 d1) + Carboplatin (AUC 5 d1), Q3W for 2-4 cycles before surgery and 0-2 cycles post surgery (totally 4 cycles). The primary endpoint was major pathological response (MPR) rate and safety. Secondary endpoints included pathologic complete response (pCR) rate, R0 resection rate, overall response rate (ORR), median disease-free survival (DFS) and median overall survival (OS). Exploratory endpoints included biomarkers analysis.

Results

Between September 13, 2021 and May 17, 2022, 35 pts (median age: 65, IQR: 48-78; male: 100%; stage IIIB disease:17%; TPS PD-L1≥1% (22C3): 67.9% ,19/28) were enrolled. After 2-4 cycles of neoadjuvant treatment, 32 pts underwent surgical resection and all of them achieved R0 resection. 23 pts (71.9%) achieved MPR (95% CI, 53.3-86.3) and 11 pts (34.4%) achieved pCR (95% CI, 18.6-53.2). 31 pts(96.9%) had pathological downstaging (95% CI, 83.8-99.9) and no major surgical complications were observed. ORR was 88.6% (95% CI,73.3-96.8). DFS and OS data was immature. One patient (2.9%) experienced grade 3 immune-related hepatitis. No grade 4-5 adverse events were reported.

Conclusions

Neoadjuvant Tis with CT was feasible and safe for pts with potentially resectable stage IIIA-IIIB(N2) squamous NSCLC. Ongoing analysis of predictive biomarker on efficacy and safety will be available in the future meeting.

Clinical trial identification

NCT05024266. First Posted: August 27, 2021.

Legal entity responsible for the study

Jianzhen Shan.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Interim analysis of the open-label phase 3 RATIONALE-304 study (NCT03663205) demonstrated clinical benefit of tislelizumab (TIS) plus chemotherapy (chemo) as first-line (1L) therapy in patients with advanced nsq-NSCLC vs chemo alone, with significantly improved progression-free survival (PFS) and a manageable safety profile. Here, we report the updated results.

Methods

Adults with treatment-naive, stage IIIB (not amenable to curative surgery/radiotherapy)/IV nsq-NSCLC were randomized (2:1) to receive platinum (carboplatin or cisplatin) and pemetrexed (PEM) every 3 weeks either with TIS (Arm A) or without (Arm B), followed by maintenance TIS + PEM (Arm A) or PEM (Arm B). The primary endpoint was PFS in Arm A vs Arm B, per independent review committee (IRC). Secondary endpoints included overall survival, objective response rate (ORR), duration of response (DoR), and safety.

Results

As of 15 July 2022, the median PFS per IRC was 9.8 (95% confidence interval [CI]: 8.9, 11.7) vs 7.6 (95% CI: 5.4, 8.0) months (mo) in Arm A vs Arm B, respectively (stratified hazard ratio 0.61 [95% CI: 0.46, 0.82]). ORR was greater in Arm A (51.6% [95% CI: 44.8, 58.3]) vs Arm B (27.9% [95% CI: 19.8, 37.2]) and median DoR was longer (14.5 [95% CI: 10.1, 24.4] vs 8.4 [95% CI: 6.0, 15.5] mo, respectively). TIS plus chemo was tolerable with no new safety signals identified after longer follow-up. The incidences of ≥grade 3 treatment-emergent adverse events (TEAEs) and of TEAEs leading to death (including disease progression-related AEs) in Arm A and Arm B were 69.4% and 56.4%, and 4.1% and 1.8%, respectively.

Conclusions

In RATIONALE-304, the addition of TIS to platinum plus PEM continued to demonstrate favorable efficacy and was generally well tolerated as 1L treatment of advanced nsq-NSCLC vs chemo alone, with no new safety signals identified.

Clinical trial identification

NCT03663205.

Editorial acknowledgement

This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Arezou Hossein, MPharm, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

S. Lu: Financial Interests, Personal, Other, Research support: AstraZeneca, Hutchison, BMS, Heng Rui Beigene and Roche, Hansoh ; Financial Interests, Personal, Other, Speaker fees: AstraZeneca, Roche, Hansoh; Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Hutchison MediPharma, ZaiLab, GenomiCare, Novarti, Yuhan Corporation, Menarini, Mirati Therapeutics Inc, and Roche. W. He, Y. Bao: Financial Interests, Personal, Full or part-time Employment: BeiGene, Ltd. All other authors have declared no conflicts of interest.

Background

Immune related adverse events (irAEs) due to immune checkpoint inhibitors (ICI) can lead to significant morbidity. Most clinical trials only report irAE frequency, but there is a significant need to better understand complicated irAE clinical courses. We sought to comprehensively evaluate irAE data, including timing, dynamics, and occurrence of multiple events.

Methods

The data from 2457 patients who participated in the Impower 130, 132, and 150 clinical trials investigating the PD-L1 inhibitor atezolizumab for metastatic non-small cell lung cancer were pooled for this analysis. Longitudinal irAE data with landmark analysis, changes in grading severity, and concurrent events were summarized.

Results

1557 patients were treated with atezolizumab (A) and 900 patients were in control (C) groups. Median follow up time was 32.3 months and 23.5 months for the A and C groups, respectively. In the A group, 753 patients (48.4%) experienced an irAE compared to 289 patients (32.1%) in the C group who experienced a non-immune adverse event attributed to irAE. The most common events in the A group were rash (28%), hepatitis (15%), hypothyroidism (12%), and pneumonitis (6%). 13% of these patients experienced two irAEs, most commonly rash and hepatitis (4%) followed by rash and hypothyroidism (3%), and 4% experienced three irAEs. Within five months, the cumulative incidence for all irAEs was 39.2%, but this varied between different irAEs with a lower incidence in the first five months for rash (23%), hepatitis (11%), hypothyroidism (7%), and pneumonitis (4%). IrAE grading increased in severity for some patients with grade 1 events increasing for 39% of patients, grade 2 events increasing for 21%, and grade 3 increasing for 16%. We utilized shift tables and upset plots to visually represent these complex patterns.

Conclusions

We identified differences in irAE patterns, including expected time to onset, frequency at which severity increases, and incidence of developing more than one irAE. These results can improve clinical management, represent a new standard for adverse event reporting, and inform better prospective data collection methodology to enable more comprehensive longitudinal analyses.

Clinical trial identification

NCT02367781, NCT02657434, NCT02366143.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

W. Yu: Financial Interests, Institutional, Other, Employee: Roche/Genentech. I. Bara: Financial Interests, Institutional, Full or part-time Employment: Genentech/Roche; Financial Interests, Institutional, Stocks/Shares: Genentech/Roche. G. Thanarajasingam: Non-Financial Interests, Institutional, Advisory Board: Seattle Genetics. M. Kaul: Financial Interests, Institutional, Full or part-time Employment: Genentech/Roche; Financial Interests, Institutional, Stocks/Shares: Genentech/Roche. K.A. Williams: Financial Interests, Personal, Other, Employee: Roche/Genentech. A.S. Mansfield: Financial Interests, Institutional, Research Grant: Novartis, verily; Financial Interests, Institutional, Other, grant reviewer: Rising Tide; Financial Interests, Institutional, Other, expert think tank: Triptych Health Partners; Financial Interests, Institutional, Other, steering committee: Janssen; Financial Interests, Institutional, Invited Speaker: BeiGene, Chugai Pharmaceutical (Roche); Financial Interests, Personal, Other, CME Presntation: Antoni van Leeuwenhoek Kanker Instituut; Financial Interests, Institutional, Other, CME Presentation: AXIS Medical Education, Intellisphere Llc, Answers in CME; Financial Interests, Institutional, Other, steering vommittee: Johnson & Johnson Global Services; Financial Interests, Personal, Other, CME Presentation: University of Miami Int’l Mesothelioma Symposium; Other, Personal and Institutional, Other, travel support: Roche; Financial Interests, Institutional, Advisory Board: AbbVie, AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Takeda Oncology; Non-Financial Interests, Personal and Institutional, Other, non-remunerated Director: Mesothelioma Applied Research Foundation; Financial Interests, Institutional, Funding: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Background

In ORIENT-12 trial, sintilimab plus gemcitabine and platinum provided a significant and clinically meaningful PFS improvement comparing to placebo plus gemcitabine and platinum in Chinese patients with advanced/metastatic squamous NSCLC. This abstract summarizes PRO results.

Methods

357 participants were randomized (179 in sintilimab and 178 in placebo arm). PRO was assessed using LCSS and QLQ-C30 before the first dose, at each imaging evaluation and end-of-treatment visit. Clinically meaningful differences were defined as ≥10 points on a 0-100 scale, except for LCSS three-item global index (3-IGI; ≥30 points). Deterioration was defined as the onset of ≥10-point increase from baseline. P-value <0.05 was considered statistically significant.

Results

PRO compliance rates maintained high until week 30. Baseline scores for each item were similar between arms. During the overall treatment period, QLQ-C30 scores were maintained regardless of the addition of sintilimab [Least square mean changes from baseline (95%CI): sintilimab: -1.04 (-3.42, 1.33); placebo: -0.74 (-3.33, 1.85); Between-group difference (95%CI): -0.30 (-3.81, 3.22)]; LCSS total score, 3-IGI, and average symptom burden index were maintained for both groups. LCSS composite endpoint and respiratory symptoms endpoint showed statistically significant improvement at week 6 and 12 for both arms, but changes did not reach a clinically meaningful difference. Sintilimab arm showed a numerical trend towards delayed deterioration across most LCSS and QLQ-C30 items. Notably, sintilimab arm showed significantly delayed in pain and major symptoms in QLQ-C30, as well as blood in sputum (Median: 56.9 vs 44.9 weeks, HR: 0.56; 95% CI: 0.37, 0.84, p=0.006) and painful sensations (Median: 49.1 vs 44.0 weeks, HR: 0.65; 95% CI: 0.44, 0.95, p=0.027) in LCSS.

Conclusions

The addition of sintilimab to chemotherapy treatment maintained the quality-of-life and delayed the main symptoms deterioration compared to placebo. The data support sintilimab plus platinum and gemcitabine as first-line treatment for advanced/metastatic squamous NSCLC.

Clinical trial identification

NCT03629925.

Legal entity responsible for the study

Lilly Suzhou Pharmaceutical Co. Ltd., Shanghai, People's Republic of China.

Funding

Lilly Suzhou Pharmaceutical Co. Ltd., Shanghai, People's Republic of China.

Disclosure

C. Zhou: Financial Interests, Personal, Invited Speaker: Roche China, Lilly China, Sanofi, C-Stone, Qilu, Hengrui, Innovent Biologics, TopAlliance Bioscience Inc, Amoy Diagnoistics, BI. All other authors have declared no conflicts of interest.

Background

Immunotherapy combined with targeted therapy have become recommended regimens for advanced HCC. Considering that patients are strictly screened in clinical trials, while the efficacy and safety in the real-world are affected by various factors, real-world data of anti-PD-1 antibody combined with targeted therapy is urgently needed.

Methods

In this non-interventional study, patients with histologically or clinically confirmed unresectable HCC with BCLC Stage B/C who were planning to receive or have already received tislelizumab combination therapy were enrolled. Treatment included tislelizumab (200 mg IV Q3W) plus a tyrosine kinase inhibitor (TKI) or VEGFR2 inhibitor selected from lenvatinib (12mg/8mg PO QD), sorafenib (400 mg PO BID) and apatinib (750 mg QD). During the treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was ORR assessed by RECIST 1.1. Secondary endpoints included DCR, PFS, OS and safety.

Results

From March 2020 to March 2021, 44 patients were enrolled with a median age of 55 (range: 31-71) years old. Among them, 37 (84.1%) patients were male, 13 (29.5%) patients had extrahepatic metastase. Child-Pugh class A (n=42,95.5%) or B (n=2, 4.5%); ECOG PS 0 (n=24, 54.5%) or 1 (n=20, 45.5%). Patients received tislelizumb plus lenvatinib (n=33; 3 of which also received TACE), or plus sorafenib (n=7), or plus apatinib (n=3). The ORR and DCR were 47.7% (21/44) and 84.1% (37/44), respectively. 15 (34.1%) patients were evaluated as operable after the combination treatment; 3 of them achieved pathological complete response (pCR). No severe postoperative complications were observed. Grade 3 or higher AEs were mainly hypertension (11.4%), rash (9.1%), proteinuria (6.8%), thrombocytopenia (6.8%), hand-foot syndrome (6.8%) and febrile neutropenia (6.8%).

Conclusions

In the real-world setting, tislelizumab plus targeted therapy shows favorable efficacy with reasonable tolerability as 1L treatment options for patients with unresectable HCC. The combination may also provide an opportunity for curative resection.

Clinical trial identification

NCT04996459. Enrollment of this study began in March 2020.

Legal entity responsible for the study

Lu Wang.

Funding

Beijing Medical Award Foundation.

Disclosure

All authors have declared no conflicts of interest.

Background

There is a lack of real-world data on the effectiveness of durvalumab in the UK clinical practice setting. The ongoing observational CODAK (NCT04667312) study addresses this data gap.

Methods

CODAK is a non-interventional cohort study with retrospective data collection and a prospective observational period of patients (pts) with locally advanced, unresectable Stage III NSCLC initiated on durvalumab following concurrent or sequential CRT in the UK from September 2017 through December 2019. Data on demographic and clinical characteristics, treatment with durvalumab and outcomes were extracted from medical records of eligible pts identified at 10 participating centres by direct care teams (planned enrolment, 120 pts). The primary outcome is real-world overall survival (rwOS) rate at 12- and 24-months post durvalumab initiation. Interim results are reported.

Results

Data cut-off for this analysis was 24 March 2022 (median follow-up from durvalumab initiation: 16.5 months). In 47 pts for whom outcomes data on durvalumab were available, 36 (77%) were aged ≥60 years and 30 (64%) were male. The 12- and 24-month rwOS rate was 75.2% (95% CI: 63.5–89.1) and 50.9% (95% CI: 37.3–69.4), and the 12- and 24-month real-world progression-free survival (rwPFS) rate was 53.6% (95% CI: 40.9–70.4) and 43.3% (95% CI: 30.7–61.1), respectively. Median rwOS and rwPFS was not reached and 15.2 months (95% CI: 7.1–not reached), respectively. The median time to subsequent therapy was 16.0 months (95% CI: 11.0–not reached). Mean duration of durvalumab treatment for the 47 pts was 195 days (range: 8–456). Mean radiotherapy dose and number of fractions per pt was 60.8 Gy and 28.4, respectively. Durvalumab treatment was discontinued due to toxicity/adverse event (AE) in 11 (23%) pts. Pneumonitis/interstitial lung disease was the most common AE leading to discontinuation (reported in 8 [17%] pts).

Conclusions

Interim results from CODAK, based on both limited sample size and follow-up, demonstrate the effectiveness of consolidation durvalumab after CRT in a real-world cohort of UK pts with unresectable Stage III NSCLC. Safety data were comparable to results from PACIFIC (NCT02125461).

Clinical trial identification

NCT04667312.

Editorial acknowledgement

Medical writing and editorial assistance, was provided by Patrick Foley, PhD, of NexGen Healthcare (London, UK) and funded by AstraZeneca UK.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

K. Franks: Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal and Institutional, Writing Engagements: AstraZeneca; Financial Interests, Personal and Institutional, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca; Financial Interests, Personal and Institutional, Other, Support for conferences: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol Meyers Squibb, Boehringer Ingelheim, Amgen, Lilly, Roche, Takeda; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Roche, Takeda; Financial Interests, Personal, Speaker’s Bureau: Boehringer Ingelheim; Financial Interests, Personal, Other, Support for conferences: Boehringer Ingelheim, Roche, Takeda. M. Ahmed: Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, MSD; Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb. D. Smith: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Principal Investigator: AstraZeneca. P.H. Shaw: Financial Interests, Personal, Advisory Board: Takeda, Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca. G. Banna: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Astellas. T. Talbot: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Principal Investigator: AstraZeneca. P. Taylor: Financial Interests, Institutional, Invited Speaker: AstraZeneca. B. Blak: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. L. Lindqvist: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. S.K. Paul: Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Speaker’s Bureau: AstraZeneca; Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Full or part-time Employment: AstraZeneca; Financial Interests, Institutional, Ownership Interest: AstraZeneca; Financial Interests, Institutional, Stocks/Shares: AstraZeneca; Financial Interests, Institutional, Project Lead: AstraZeneca; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Leadership Role: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: NovoNordisk, Genentech, Amylin Pharmaceuticals, Sanofi Avensis, South Asian Health Foundation, Chinese Diabetes Society, American Diabetes Associatio, European Association for Studies in Diabetes; Financial Interests, Personal and Institutional, Research Grant: NovoNordisk, Genentech, Amylin Pharmaceuticals, Sanofi Avensis, South Asian Health Foundation, Chinese Diabetes Society, American Diabetes Associatio, European Association for Studies in Diabetes; Financial Interests, Personal and Institutional, Funding: NovoNordisk, Genentech, Amylin Pharmaceuticals, Sanofi Avensis; Financial Interests, Personal and Institutional, Project Lead: NovoNordisk, Genentech, Amylin Pharmaceuticals, Sanofi Avensis; Financial Interests, Personal and Institutional, Principal Investigator: NovoNordisk, Genentech, Amylin Pharmaceuticals, Sanofi Avensis. D. Vincent: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Immunotherapy and BACE are important therapy for NSCLC. This trial is designed to determine the efficacy and safety of immunotherapy with tislelizumab in addition to BACE in stage III-IV NSCLC patients (pts) who failed, refused or ineligible to receive standard treatments.

Methods

This trial enrolled stage III-IV pts without EGFR, ALK or ROS1 aberrations who have failed, refused, or assessed ineligible to receive conventional treatments (surgery, chemoradiotherapy, chemotherapy). Pts were treated with BACE and tislelizumab as induction therapy during which BACE was performed on the first day and tislelizumab was given 3-5 days later, then tislelizumab was administered at 200mg Q3W as maintenance therapy. Primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety, etc. Herein, the treatment response at 6 weeks is reported.

Results

30 pts were enrolled with 24 (80%) males pts and a median age of 65.1y; 21 (70%) squamous, 9 (30%) adenocarcinomas; 4 (13%) stage IIIA, 11 (37%) stage IIIB, 15 (50%) stage IV; 8 (27%) with ECOG score 0, 17 (57%) with score 1, and 5(17%) with score 2. Among the 30 pts, 5 (17%) pts had bronchial stenosis, 2 (7%) had superior vena cava syndrome, 8 (27%) had pneumonia, 4 (13%) had pulmonary heart disease, and 4 (13%) had hemoptysis. The ORR and DCR were 66.7% and 83.3% respectively per RECIST1.1, 2 pts (6.7%) achieved complete response (CR), 18 pts (60.0%) and 5 pts (16.7%) got partial response (PR) and stable disease (SD). The main TEAEs related to BACE mainly include nausea (20.0%, 6/30), fever (16.7%, 5/30), hemoglobin decrease (6.7%, 2/30), leukopenia (10.0%, 3/30) and thrombocytopenia (6.7%, 2/30). TEAEs related to tislelizumab mainly included fatigue (6.7%, 2/30)，rash (10.0%, 3/30) and cough (10.0%, 3/30). Grade≥3 AEs were not observed.

Conclusions

Tislelizumab combined with BACE for advanced NSCLC pts appears to be safe and feasible, and the comorbidities of patients can be alleviated after treatment. Compared with previous studies on BACE, the addition of immunotherapy may improve the ORR and DCR.

Clinical trial identification

NCT05286957.

Legal entity responsible for the study

Hennan Medical Information Society.

Funding

BeiGene.

Disclosure

All authors have declared no conflicts of interest.

Background

Neoadjuvant chemoimmunotherapy have a promising efficacy in resectable non-small cell lung cancer (NSCLC). We aimed to investigate the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy for stage IIB-IIIB NSCLC.

Methods

Pts with stage IIB-IIIB, wildtype EGFR/ALK NSCLC, ECOG PS 0-1 were eligible. All pts received 2-4 cycles of toripalimab (240mg, q3w) plus double platinum-based chemotherapy. All pts were assessed by imaging/surgical indication after 2 cycles of treatment. Pts who cannot undergo surgery will be reassessed after another 1-2 cycles of neoadjuvant therapy. Primary endpoints were major pathological response (MPR), complete pathological response (pCR). Secondary endpoints were objective response rate (ORR), R0 resection rate and safety.

Results

A total of 81 pts (median age: 62, IQR: 45-76; female: 7, 8.6%, squamous cell carcinoma: 63, 77.8%) were enrolled since Dec 2020. Disease distribution in stage IIB, IIIA and IIIB consisted of 27, 41 and 13 pts, respectively. 16 pts were in the preoperative stage or unsuitable for surgery. 65 pts underwent R0 resection. 42 pts (42/65, 64.6%) achieved MPR, including 31 pts (31/65, 47.7%) with pCR. 62 pts received 2 or 3 cycles of treatment, and no significant difference in MPR or pCR rate was observed between 2 and 3 cycles of treatment (32/48, 66.7% vs 8/14, 57.1%, p=0.512; 25/48, 52.1% vs 5/14, 35.7%, p=0.281). After 2 cycles of treatment, the primary tumor shranked significantly with a -40% (IQR: -100%, +25%) median regression rate, and tended to flatten with a -4.63% (IQR: -21.54%, +21.15%) median regression rate after another 1-2 cycles. Among 31 pts who underwent imaging evaluation again after 2-cycle treatment assessment, 19 pts (19/31, 61.3%) still had tumor regression. 10 pts of these (10/19, 52.6%) received 3-4 cycles of treatment, and 9 pts (9/19, 47.4%) did not receive further treatment and continued regression was also observed. 69 pts (69/81, 85.2%) experienced TRAEs.

Conclusions

Neoadjuvant toripalimab and chemotherapy is a promising treatment for pts with stage IIB-IIIB NSCLC. Continued tumor regression after chemoimmunotherapy is not uncommon, and it is not entirely dependent on further cycles of neoadjuvant therapy.

Clinical trial identification

NCT04606303.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Fruquintinib(F) is an orally available VEGFR inhibitor that is highly selective for VEGFR-1,2 and 3. In the phase Ⅱ and Ⅲ trials, F has been shown an improved progression-free survival(PFS) compared to placebo and a manageable safety profile with advanced NSCLC. This study aimed to investigate the efficacy and safety of F plus PD-1 inhibitor sintilimab(S) and platinum-based chemotherapy(chemo) as the first-line treatment for advanced naive EGFR- and ALK-negative nsq-NSCLC.

Methods

This single-arm, open-label, phase Ⅱ study (NCT04956146) consists of a safety lead-in phase(Part 1) and dose expansion phase(Part 2). In Part 1 the F taken orally at 5 mg (2 weeks on/ 1 weeks off, Q3W) plus S (200mg, iv, d1,Q3W) and chemo(Q3W). After 4∼6 cycles followed by maintenance therapy with F(RP2D) plus S and pemetrexed or not. DLT was observed for 1 cycle. The primary objective of Part 1 is to assess the safety and confirm the RP2D of F. The primary objective of Part 2 is to estimate the PFS and the secondary endpoints including ORR, DCR, OS, and safety.

Results

From February 2022 to September 2022, 15 pts were enrolled. Median age was 66, male 93.3%, ECOG PS 0 66.7%, adenocarcinoma 80%. No DLTs were reported in Part 1. The dose of F (5mg, 2 weeks on/ 1 weeks off, Q3W) was established as the RP2D. Of 9 evaluable pts, ORR and DCR were 66.7% and 100%(6 partial response and 3 stable disease). Median PFS was not reached yet. The most common treatment-emergent adverse events (TEAEs) (Total; Grade ≥3) were Alanine aminotransferase increased (100%; 7.7%), hypoalbuminaemia (100%; 0), Aspartate aminotransferase increased (92.3%; 0), White blood cell count decreased (84.6%; 38.5%) and Gamma-glutamyltransferase increased (84.6%, 23.1%).

Conclusions

This finding showed promising efficacy for fruquintinib combined with sintilimab and chemo in pts with advanced NSCLC as first-line treatment with a manageable safety profile. These findings support fruquintinib plus sintilimab and chemo as a potential new first-line treatment option for unresectable or metastatic advanced naive EGFR- and ALK-negative nsq-NSCLC.

Clinical trial identification

NCT04956146 Release date: February 2, 2022.

Legal entity responsible for the study

The First Affiliated Hospital with Nanjing Medical University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

This is a prospective, open-label, phase 1b study to evaluate the safety and feasibility of stereotactic body radiotherapy (SBRT) and anlotinib ± toripalimab in untreated oligometastatic brain metastases (BMs) NSCLC patients (pts).

Methods

Ten pts were randomized into 2 groups. Induction therapy: SBRT (35 Gy/5 F) plus anlotinib (12 mg, d1∼14, q3w) with (group A) or without (group B) toripalimab (240 mg, d1, q3w). Then will continue toripalimab and anlotinib on d22 for 1 year until disease progression or intolerable toxicity. Key inclusion criteria: ≥ 18 years old, ECOG ≤ 1, driver mutation-negative, untreated NSCLC BMs (1∼5 lesions). Primary endpoints: intracranial response rate (iORR) and treatment-related adverse events (TRAEs). Secondary endpoints: intracranial progression-free survival, intracranial disease control rate (iDCR), and overall survival.

Results

As of Sep 15, 2022, 8 males (group A: 5, group B: 3) were included. The median age of A was 67 (range 59-71) years. The median age of B was 63 (range 61-68) years, with 1 squamous cell carcinoma in each group. The median follow-up time was 147 days. Intracranial efficacy: after the induction therapy cycle, all pts in group A had SD, 2 in group B had SD and 1 had PR. During 3∼4 months of treatment, the iORR and iDCR were 60% and 80% in group A (3 PR, 1 SD, and 1 PD: investigator error, missing brain radiotherapy, later stage salvage SBRT). Group B had 1 PR and 2 SD. In terms of systemic efficacy, group A: ORR was 40% and DCR was 80%; group B: ORR was 33.3% and DCR was 100%. 80% of group A pts developed any grade (G) TRAEs, mainly hypertension (3/5), including 1 G 3 hypertension; 1 concurrent had hypothyroidism, hypertension, elevated myocardial enzymes, and hand-foot syndrome, causing suspension of one cycle of toripalimab therapy, anlotinib was reduced to 8 mg. 66.7% (2/3) in group B experienced any grade TRAEs, 1 had G 3 hand-foot syndrome led to anlotinib dose reduction.

Conclusions

SBRT plus anlotinib ± toripalimab showed good short-term efficacy in untreated BMs NSCLC. The induction part combined immunotherapy increases manageable TRAEs incidence. Further efficacy and safety data require follow-up confirmation after enrollment.

Clinical trial identification

NCT05021328.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Tarlatamab (AMG 757) binds DLL3 on SCLC cells and CD3 on T cells leading to T cell-mediated tumor lysis. Updated phase 1 tarlatamab data in relapsed/refractory SCLC showed an ORR of 23%, median DOR of 13 months, and an acceptable safety profile with cytokine release syndrome (CRS) as the most common treatment-related (TRAE).¹ Here, we describe clinical CRS seen with tarlatamab and explore associations between cytokine levels and CRS in cycle 1 (C1)-where CRS mostly occurs.

Methods

Tarlatamab (0.003–100.0 mg) was given intravenously every 2 weeks ± step dosing in patients (pts) with SCLC progressing after ≥1 platinum-based regimen. Safety/efficacy were evaluated as previously described.¹ Serum was drawn at time points up to 24 hours (hrs) after first dose from pts receiving ≥1 mg initial dose and up to 100 mg in subsequent doses in C1. Peak level and elevation speed were evaluated for a panel of soluble factors in pts with CRS vs no CRS in C1.

Results

By 15 June 2022, 106 pts had received ≥1 dose tarlatamab with median follow-up time of 8.5 months (range, 0.2–30.7). Median treatment duration was 11.6 weeks (range, 0.1–80.0). TRAEs occurred in 97 pts (92%) and grade (gr) ≥ 3 in 33 pts (31%). CRS occurred in 56 pts (53%) with maximum gr1 in 41 pts and gr3 in 1 (1.0%), and 8 pts received tocilizumab for CRS. Most CRS events were in C1 (55 pts in C1, 5 pts in C2+). CRS had median onset of 17.5 hrs (in pts with both date and hr of onset data), was transient (median duration, 3 days), and resolved in all cases. While initial tarlatamab infusion is characterized by immune activation and inflammatory cytokine induction, among biomarker-evaluable pts (N=86), those with any grade CRS in C1 (n=45 or 46) showed trends in increased peak levels of IL-6, IL-8, IL-10, and TNF-α by 24 hrs after first dose vs those without (n=40).

Conclusions

Prior results from this study show manageable safety and promising efficacy of tarlatamab in pts with heavily pretreated SCLC. CRS is not unexpected based on tarlatamab’s mechanism of action, is associated with rises in some cytokines yet remains generally low-grade, reversible, and confined to C1. Further characterization of tarlatamab’s safety is ongoing. References 1. Borghaei H, et al. OA12.05. WCLC 2022. Aug 8, 2022.

Clinical trial identification

NCT03319940.

Editorial acknowledgement

Medical writing support was provided by Eugene Gillespie, PhD of Amgen Inc.

Legal entity responsible for the study

Amgen Inc.

Funding

Amgen Inc.

Disclosure

S. Champiat: Financial Interests, Personal, Invited Speaker: Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Eisai, Genmab, Janssen, Merck, Novartis and Roche; Financial Interests, Personal, Other, Principal Investigator of Clinical Trials: AbbVie, Amgen, Cytovation, Eisai, Imcheck Therapeutics, Molecular Partners Ag, Merck, Ose Pharma, Pierre Fabre, Sanofi Aventis, Sotio A.S, Transgene; Financial Interests, Personal, Advisory Board: Alderaan Biotechnology, Amgen, AstraZeneca, Avacta, Celanese, Ellipses Pharma, Immunicom, Inc., Nanobiotix, Oncovita, Pierre Fabre, Seagen, Tatum Bioscience, Tollys SAS, UltraHuman8; Financial Interests, Personal, Other, Travel and congress: Amgen, AstraZeneca, Bristol Myers Squibb, Merck, Ose Pharma, Roche, Sotio; Financial Interests, Institutional, Other, As part of the Drug Development Department (DITEP) =Principal/sub-Investigator of Clinical Trials: AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, BicycleTx Ltd, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Casi Pharmaceuticals, Inc, Celgene Corporation, Cellcentric, Chugai Pharmaceutical Co, Cullinan-Apollo, Curevarc, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Faron Pharmaceuticals Ltd, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Iteos Belgium SA, Janssen Cilag, Janssen Research Foundation, Janssen R&D Llc, Kura Oncology, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, MedImmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Genomics, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre Medicament, Relay Therapeutics, Inc, Roche, Sanofi Aventis, Seattle Genetics, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Transgene S.A, Turning Point Therapeutics, Xencor; Financial Interests, Institutional, Research Grant, As part of the Drug Development Department (DITEP) =Research Grants: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Pfizer, Roche, Sanofi; Non-Financial Interests, Institutional, Product Samples, As part of the Drug Development Department (DITEP) =Non-financial support (drug supplied): AstraZeneca, BMS, Boringher Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. M. Boyer: Financial Interests, Personal, Invited Speaker: AstraZeneca, Merck Sharpe & Dohme; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Merck Sharpe & Dohme, Amgen, Janssen, Eli Lilly, EARLI, Immugene, Dizal; Non-Financial Interests, Personal, Leadership Role: Thoracic Oncology Group Australasia. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, Beigene, Daichii, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme corp, BMS, Janssen-cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Member: AACR, ASCO, ESMO; Financial Interests, Personal, Other, Foundation Board Member: AECC; Financial Interests, Personal, Other, President. ASEICA( Spanish Association of Cancer Research ): ASEICA; Financial Interests, Personal, Other, Foundation president: ONCOSUR; Financial Interests, Personal, Other, member: Small Lung Cancer Group. A. Schoenfeld: Financial Interests, Personal, Other, Consulting: Johnson and Johnson, KSQ Therapeutics, Perceptive Advisors; Non-Financial Interests, Personal, Principal Investigator: GSK, Achilles Therapeutics, Iovance Therapeutics, BMS, Merck, PACT pharma. H. Izumi: Financial Interests, Institutional, Research Grant: Amgen Inc, Eisai; Financial Interests, Personal and Institutional, Research Grant, Invited Speaker: Ono Pharmaceutical Company, AstraZeneca; Financial Interests, Personal, Other, Invited Speaker: Chugai Pharmaceutical Co., Merck Biopharma Co., Takeda Pharmaceutical Co. R. Govindan: Financial Interests, Institutional, Invited Speaker: Amgen, AbbVie, Boehringer Ingelheim, Calithera, GSK, Novartis, Adaptimmune. J. Carlisle: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Amgen, Hutchmed. H. Borghaei: Financial Interests, Personal, Advisory Board: BMS, Genentech, Eli-Lilly, Merck, EMD-serono, AstraZeneca, Novartis, Genmab, Regeneron, Amgen, Takeda, PharmaMar, Jazz Pharma, Mirati, Daiichi, Guardant, Natera, Oncocyte, Beigene, iTeo, Boehringer Ingelheim; Financial Interests, Personal, Other, Training discussion: Pfizer; Financial Interests, Personal, Other, DSMB: Novartis; Financial Interests, Institutional, Other, Clinical trial support: BMS, Amgen; Financial Interests, Personal, Stocks/Shares, Options for scientific advisory role: Sonnetbio; Financial Interests, Personal, Stocks/Shares, Options for scientific advisory board: Nucleai, Inspira (Rgenix); Financial Interests, Institutional, Invited Speaker, Investigator initiated trial support: BMS, Amgen, Lilly; Financial Interests, Personal and Institutional, Invited Speaker, Chair steering committee: Miratti; Financial Interests, Personal and Institutional, Invited Speaker: Amgen, AstraZeneca; Other, Personal, Other, DSMB: Novartis, Takeda, Incyte. M.L. Johnson: Financial Interests, Institutional, Research Grant: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array Biopharma, Artios Pharma, AstraZeneca, Atreca, Beigene, Bergenbio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon , Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, Ideaya Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals , Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, Oncomed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Pharmaceuticals, Shattuck Labs, Silicon Therapeutics, StemCentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, Tmunity Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, Y-mAbs Therapeutics; Financial Interests, Institutional, Advisory Role: AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics; Financial Interests, Institutional, Other: Genentech/Roche. N. Steeghs: Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, Cogent Biosciences, Ellipses Pharma, Luszana; Financial Interests, Institutional, Invited Speaker: AbbVie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Crescendo Biologics, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda; Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer, GlaxoSmithKline, Novartis, Merck, Deciphera, Pfizer. E.E. Vokes: Financial Interests, Personal, Stocks/Shares: McKesson, Coordination Pharmaceuticals; Non-Financial Interests, Personal, Leadership Role, ASCO President last fiscal year: ASCO. A. Dowlati: Financial Interests, Personal, Advisory Role: Takeda, AbbVie, Seattle Genetics, AstraZeneca, BMS; Financial Interests, Personal, Speaker’s Bureau: Loxo, Bayer, Incuron, Takeda, Regeneron, Tesaro, Seattle Genetics, Symphogen, AbbVie, Ipsen. Y. Zhang: Financial Interests, Personal, Stocks/Shares: Amgen; Financial Interests, Personal, Full or part-time Employment: Amgen. A. Pati: Financial Interests, Personal, Full or part-time Employment, I am an employee of Amgen: Amgen; Financial Interests, Personal, Stocks/Shares: Amgen, Roche; Financial Interests, Institutional, Royalties, Inventions on Metagenome Binning Application developed at LBL: Lawrence Berkeley National Labs. C. Ju: Financial Interests, Personal, Stocks/Shares: Amgen; Financial Interests, Personal, Full or part-time Employment: Amgen. S. Mukherjee: Financial Interests, Personal, Stocks/Shares: Amgen; Financial Interests, Personal, Full or part-time Employment: Amgen. X. Chen: Financial Interests, Personal, Full or part-time Employment: Amgen. N. Hashemi Sadraei: Financial Interests, Personal, Full or part-time Employment: Amgen; Financial Interests, Personal, Stocks/Shares: Amgen. H. Hummel: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Invited Speaker: Amgen, Bristol Myers Squibb, Amgen; Financial Interests, Institutional, Invited Speaker: Amgen, Amgen, Revolution Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Merck, Novartis, AstraZeneca, Drachen, Daiichi Sankyo, AvenCell Europe GmbH, Celgene; Non-Financial Interests, Personal, Principal Investigator: AIO-Studien-gGmbH, Lung Cancer Group Cologne.

Background

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor with an anti-programmed cell death protein 1 (PD-1) antibody is a promising combination showing antitumor activity in solid tumors. Phase 1/1b open-label study AdvanTIG-105 assessed safety and preliminary antitumor activity of anti-TIGIT monoclonal antibody (mAb) OCI + anti-PD-1 mAb TIS in pts with advanced unresectable solid tumors (NCT04047862). In dose-escalation, OCI + TIS was well tolerated showing preliminary antitumor activity, establishing the recommended phase 2 dose (RP2D) of OCI 900mg IV every 3 weeks (Q3W) plus TIS 200mg IV Q3W. We report dose-expansion results in pts with ES-SCLC.

Methods

Eligible adults had histologically/cytologically confirmed ES-SCLC and had received no prior systemic therapies. Pts received RP2D of OCI + TIS with cisplatin or carboplatin + etoposide Q3W for 4 cycles, followed by RP2D OCI + TIS Q3W until disease progression, intolerable toxicity, or withdrawal of consent. Primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), and safety.

Results

As of June 20, 2022, 42 pts were enrolled, of which 40 were efficacy evaluable; median study follow-up time was 24.9 weeks (range 3.0-67.9). Confirmed ORR was 65.0% (95% confidence interval [CI]: 48.3, 79.4) and median DoR was 4.3 months (95% CI: 3.2, 5.6). Median PFS was 4.9 months (95% CI: 4.2, 5.7) with a 6-month PFS rate of 27.3%. All 42 pts experienced at least 1 treatment-emergent adverse event (TEAE); 25 (59.5%) had Grade ≥ 3 TEAEs and 17 (40.5%) had serious TEAEs. Most common TEAEs were neutrophil count decreased and anemia (54.8% each). Immune-mediated TEAEs were reported in 12 pts (28.6%) and TEAEs led to treatment discontinuation in two pts. Pneumonia (unrelated to treatment) and disease progression led to death in two pts.

Conclusions

OCI 900mg + TIS 200mg with cisplatin/carboplatin plus etoposide was generally well tolerated and showed antitumor activity in pts with ES-SCLC.

Clinical trial identification

NCT04047862.

Editorial acknowledgement

This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Sophie Cook, PhD, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. The authors would like to thank Rang Gao and Ruihua Wang for their contributions.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

J. Zhang: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Biodesix, BMS, Cardinal Health, Daiichi Sankyo, Hengrui, Eli Lilly, Mirati, Nexus Health, Novocure, Sanofi, Takeda Oncology; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, MJH Life Sciences, Novartis, Regeneron, Sanofi; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Genentech, Mirati, Nilogen; Financial Interests, Institutional, Funding: AbbVie, BeiGene, Hengrui, InnoCare Pharma, Merck, Mirati, Novartis; Financial Interests, Institutional, Principal Investigator: AbbVie, BeiGene, Hengrui, InnoCare Pharma, Merck, Mirati, Novartis; Financial Interests, Institutional, Sponsor/Funding: AbbVie, BeiGene, Hengrui, InnoCare Pharma, Merck, Mirati, Novartis. M. Hussein: Financial Interests, Personal, Advisory Board: Integra Connect, Coherus Biosciences, Karyopham Therapeutics, BMS, AstraZeneca, Mirati Therapeutics, Exelixis, Biopharma, AbbVie, Oncotype, Aptitude Helth; Financial Interests, Personal, Advisory Role: Karyopham Therapeutics, BMS, AstraZeneca, Mirati Therapeutics, Exelixis, Biopharma, AbbVie, Oncotype, Aptitude Helth. S.C. Kao: Financial Interests, Personal and Institutional, Advisory Board: AZ, Pfizer, Boeringher, Takeda, MSD, BMS, Roche, Specialised Therapeutics; Financial Interests, Personal and Institutional, Other, Honoraria: AZ, Pfizer, Boeringher, Takeda, MSD, BMS, Roche, Specialised Therapeutics; Financial Interests, Personal, Funding: AstraZeneca. T.D. Clay: Financial Interests, Personal, Other, Honoraria: Specialised Therapeutics Australia; Financial Interests, Personal, Advisory Board: AstraZeneca, Foundation Medicine; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Writing Engagements: AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Principal Investigator: Pfizer, BMS, Amgen, Daiichi Sankyo, AbbVie, Beigene, Immutep, Clovis, Janssen; Financial Interests, Institutional, Other, Honoraria: Amgen; Financial Interests, Personal, Other, Travel / Accommodation Expenses: Astellas. G. Chang: Financial Interests, Personal, Other, Honoraria: F. Hoffmann–La Roche, Ltd, Eli Lilly and Company Oncology, AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim, Bristol Myers Squibb, and Merck Sharp & Dohme. H. Zheng: Financial Interests, Institutional, Full or part-time Employment: BeiGene USA; Financial Interests, Institutional, Stocks/Shares: BeiGene USA. W. Tan: Financial Interests, Institutional, Full or part-time Employment: BeiGene, Ltd. All other authors have declared no conflicts of interest.

Background

Surufatinib (S, a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus toripalimab (T, an anti-PD-1 antibody) has exhibited encouraging efficacy in an SCLC cohort in a trial evaluating S + T in pts with selected solid tumors. This study is assessing the safety, tolerability, and preliminary efficacy of S+ T+ chemotherapy (EP) as first-line regimen for SCLC pts. Here, we report the preliminary efficacy results.

Methods

This study is a phase Ⅰb/Ⅱ, single-arm study(NCT04996771). Eligible pts were≥18 years old with histologically confirmed SCLC, ECOG PS 0-1, with at least one measurable lesion. Pts with treated, stable, and asymptomatic brain metastases(BMs) are allowed. A 3+3 dose-escalation was done to determine the recommended RP2D of S+T+EP. S was dosed at 150mg, 200mg, and 250mg qd, po, Q3W in the dose level(DL)1, 2, and 3, respectively, in combination with a fixed dose of T(200mg, iv, d1, Q3W) and EP(Q3W). After 4 cycles followed by maintenance therapy with S plus T every 3 weeks. This study started escalation in the DL2. DLT was observed for 1 cycle. The primary objective of phase Ⅰb is to assess the safety and confirm the RP2D of S. The primary objective of phase Ⅱ is to estimate the PFS and the secondary endpoints including ORR, DCR, OS, and safety.

Results

At cutoff date (Sep 20, 2022), 24 pts (phase Ⅰb DL2, n=6; phase Ⅱ, n=18) were enrolled and received treatment(median age 59 years, male 70.8% , ECOG PS 1 62.5%, BMs 8.3%). Two DLTs occurred in the DL2, The RP2D was identified as S(200mg, po, qd, Q3W). Among pts with at least one post-baseline tumor assessment (evaluable pts, n=17), the confirmed ORR was 88.2%, and DCR(15 PRs, 2 SDs) was 100%. Median PFS was not reached yet. The most common treatment-emergent adverse events (TEAEs) (Total; Grade ≥3) were alopecia(66.7%; 0), white blood cell count decreased (57.1%; 28.6%), anemia(57.1%; 0), decreased appetite(52.4%; 0) and constipation(47.6%; 0).

Conclusions

Surufatinib plus toripalimab and etoposide combined with cisplatin showed promising anti-tumor activity and acceptable toxicity for the 1L treatment of SCLC. The combination of the 4 agents might be a novel 1L therapeutic option for SCLC.

Clinical trial identification

NCT04996771 Release date: November 9, 2021.

Legal entity responsible for the study

Sun Yat-sen University Cancer Center.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Concurrent blockade of LAG-3 may enhance efficacy of anti-programmed cell death-1 (PD-1) therapies. We previously presented safety and efficacy data from the phase 1 study in patients (pts) with advanced mel treated with anti-LAG-3 (fianlimab) in combination with anti-PD-1 (cemiplimab). We demonstrated high clinical activity among pts with anti–PD-1/PD-ligand (L)1-naive (expansion cohort [EC] 6 and 15) advanced mel. Among pts in EC6+EC15 (N=80), the objective response rate (ORR) was 63.8%, the disease control rate (DCR) was 80.0%, and the median duration of response (mDOR) was not reached (NR). Factors associated with a poorer prognosis and reduced response to immunotherapy in pts with advanced mel include advanced stage of disease, elevated lactate dehydrogenase (LDH) levels, and metastasis sites, including liver or other visceral organs (M1c).

Methods

Pts with advanced mel were treated with fianlimab 1600 mg and cemiplimab 350 mg intravenously every 3 weeks for 12 months. In this subgroup analysis we evaluated fianlimab and cemiplimab in pts with advanced mel with poor prognostic features. ORR, DCR and mDOR are reported here for pts with liver mets at baseline (BL), LDH>upper limit of normal (ULN) at BL, and LDH>ULN at BL and M1c stage in pts in EC6+EC15.

Results

As of 1 July 2022, data cutoff date, 80 pts in EC6+EC15 (40 pts each) were treated with fianlimab and cemiplimab. For EC6+EC15 combined, at BL,19 pts (23.8%) had liver mets, 28 pts (35.0%) had LDH>ULN; and 13 pts (16.3%) had LDH>ULN at BL and any M1c. In pts with liver mets at BL, the ORR for EC6+15 combined was 47.4%, the DCR was 63.2%, and the mDOR was 9.0 months (95% confidence interval [CI], 2.8–not evaluable [NE]). In pts with LDH>ULN at BL, the ORR for EC6+15 was 57.1%, the DCR was 71.4, and the mDOR was NR (95% CI, 7.3–NE). In pts with LDH>ULN at BL and any M1c, the ORR for EC6+15 was 53.8%, the DCR was 69.2%, and the mDOR was NR (95% CI, 5.7–NE).

Conclusions

Despite small numbers in subgroups, the efficacy analysis from EC6 and EC15 combined demonstrates high activity of fianlimab in combination with cemiplimab in pts with advanced mel and poor prognosis features at BL.

Clinical trial identification

NCT03005782.

Editorial acknowledgement

Medical writing and editorial support provided by John G Facciponte, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc.

Funding

Regeneron Pharmaceuticals, Inc.

Disclosure

O. Hamid: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Novartis, Pfizer, Sanofi and Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Advisory Role: Aduro Biotech, Akeso Biopharma, Amgen, Arcus Biosciences, Bioatla, Bristol Myers Squibb, CytomX Therapeutics, Exelixis, Genentech, GlaxoSmithKline, Idera, Immunocore, Incyte, Iovance Biotherapeutics, Merck, Merck Serono, Moderna Therapeutics, NextCure, No. K. Lewis: Financial Interests, Personal, Other, Honoraria: Array BioPharma, Iovance Biotherapeutics; Financial Interests, Personal, Advisory Role: Array BioPharma, Iovance Biotherapeutics, Merck, Roche, Regeneron Pharmaceuticals, Inc., Sanofi; Financial Interests, Personal, Research Grant: Alkermes, Amgen, Array BioPharma, Bristol Myers Squibb, Incyte, Iovance Biotherapeutics, Kartos Therapeutics, Merck, Nektar, Neon Therapeutics, OncoSec, Regeneron Pharmaceuticals, Inc., Replimune, Roche/Genentech, Senhwa Biosciences, Ultimovacs; Financial Interests, Personal, Other, Travel, accommodation, or expenses: Alkermes, Merck, Neon Therapeutics, Regeneron Pharmaceuticals, Inc., Roche/Genentech; Financial Interests, Personal, Other, Uncompensated relationships: Roche/Genentech, Regeneron Pharmaceuticals, Inc. M. McKean: Financial Interests, Institutional, Research Grant: Alpine Immune Sciences, Arcus Biosciences, Arvinas, Ascentage Pharma Group, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, Dragonfly Therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, Genentech, Gilead Sciences, ; Financial Interests, Institutional, Advisory Role: Astellas Pharma, AstraZeneca, BicycleTX Limited, Castle Biosciences, Eisai, Ideaya Biosciences, iTeos, Moderna, Pfizer, Regeneron Pharmaceuticals, Inc. K. Papadopoulos: Financial Interests, Personal, Advisory Role: Basilea and Turning Point Therapeutics; Financial Interests, Personal, Research Grant: 3D Medicines, AbbVie, ADC Therapeutics, Amgen, Anheart Therapeutics, Bayer, Calithera Biosciences, Daiichi Sankyo, EMD Serono, F-star, Incyte, Jounce Therapeutics, Lilly, Linnaeus Therapeutics, MabSpace Biosciences, MedImmune, Merck, Mersana, Mirati Thera. S. Thomas: Financial Interests, Personal, Speaker’s Bureau: Amgen, BMS, Genentech, Ipsen, Merck, Novartis, Pfizer. J. Kaczmar: Financial Interests, Personal, Advisory Role: Bicara Therapeutics, Rakuten Medical, and Regeneron Pharmaceuticals, Inc. N. Lakhani: Financial Interests, Personal, Advisory Role: Innovent Biologics, Ikena, and S.K. Life Sciences; Financial Interests, Personal, Research Grant: Innovent Biologics, Alexo Therapeutics, Ascentage Pharma, Asana Biosciences, BeiGene, Constellation Pharmaceuticals, Alexion Pharmaceuticals, Cerulean Pharma, Forty Seven, Loxo, Macrogenics, Merck, Pfizer, Regeneron Pharmaceuticals, Inc., Apexian Pharmace. T.M. Kim: Financial Interests, Personal, Advisory Role: AstraZeneca/MedImmune, BeiGene, Boryung, F. Hoffmann-La Roche Ltd/Genentech, Inc, Janssen, Novartis, Sanofi, Takeda, Yuhan; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Uncompensated relationship: Bayer, Boryung, Novartis, Regeneron Pharmaceuticals, Inc., Roche/Genentech, and Sanofi. K. Kim: Financial Interests, Personal, Advisory Board: Bristol-Myers Squib, Genentech Inc., Novartis, Regeneron and Sanofi; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Novartis, Merck, Regeneron and Sanofi. G. Rabinowits: Financial Interests, Personal, Advisory Role: Castle, EMD Serono, Pfizer, Merck, Regeneron Pharmaceuticals, Inc., Sanofi; Financial Interests, Personal, Stocks/Shares: Syros Pharmaceuticals and Regeneron Pharmaceuticals, Inc. A.S. Spira: Financial Interests, Personal, Stocks/Shares: Lilly; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, Bayer; Financial Interests, Personal, Advisory Role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck, Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, LAM Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb,. J. Mani: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. S. Chen: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. G. Gullo: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Background

Immune related adverse events (irAEs) can possess a major challenge in patient symptom burden and risk of fatalities. In addition, it is a barrier for the development of multi-agent immunotherapy regimen. Management of these irAEs using corticosteroids as first-line therapy may have detrimental impact on cancer outcomes and worsen survival. We have previously demonstrated that interleukin-6 (IL-6) plays a role in the pathogenesis of irAEs in tumor resistance. Based on this data, we conducted this trial to assess the safety and efficacy of IL-6 blockade, using Tocilizumab, in combination with ipilimumab and nivolumab in melanoma patients.

Methods

Phase II clinical study to evaluate the safety and efficacy of the triplet therapy in melanoma (n=35). Pts received subcutaneous tocilizumab 162 mg bi-monthly for up to 12 weeks plus ipi 3mg/kg + nivo 1mg/kg every 3 weeks. The primary endpoints: 1) assess the frequency ofgrade 3/4 irAEs; 2) objective response rate (ORR); and 3) assess biomarker analysis from tumor, blood and inflamed tissue.

Results

A total of 25 melanoma patients were enrolled; duration of treatment ranged from 6 to 41 weeks. Eleven patients (44%) had grade 3/4 irAEs; median time to onset was 8.3 weeks (2.7-17.3). This included colitis (20%), hepatitis (16%), pancreatitis (8%), and fibromyalgia rheumatica-like and type I diabetes (4% each) and led to study disconsolation in 4% but no treatment-related deaths. The ORR was 60% (44% in patients with elevated LDH). Our longitudinal immune analysis from tumor tissue demonstrates increase infiltration of immune cells Th1, Th17, and CD8 cells. Furthermore, gene expression data exhibits enrichment of IL-1, IL-6, and IL-17 pathways in patients with high grade toxicity post treatment.

Conclusions

Our preliminary data showed a trend to mitigate irAEs with the triplet therapy with no negative impact on tumor immunity. Furthermore, exploratory biomarker analysis suggests that we are not sufficiently blocking the IL-6/Th17 pathway with the current dosing of Tocilizumab. The protocol will enroll a new cohort of patients with increased Tocilizumab administration.

Legal entity responsible for the study

A. Diab.

Funding

MD Anderson.

Disclosure

A. Diab: Financial Interests, Institutional, Sponsor/Funding: Bristol Myers. All other authors have declared no conflicts of interest.

Background

HBM4003 is a fully human heavy chain only monoclonal antibody targeting CTLA-4. In addition to blocking the CTLA-4 pathway, HBM4003 is also engineered to deplete Treg cells by enhanced antibody-dependent cellular cytotoxicity (ADCC) activity that was clinically validated. Here we reported updated results of a phase I study that evaluated HBM4003 plus toripalimab (anti-PD-1 antibody) in advanced melanoma.

Methods

This study includes two parts. In the dose-escalation part, patients with solid tumors received HBM4003 at 3 dose levels (0.03 mg/kg [n=1], 0.1 mg/kg [n=3], and 0.3 mg/kg [n=10]) plus toripalimab 240 mg every three weeks (Q3W). In the dose-expansion part, patients with advanced melanoma (n=26) received the recommended phase 2 dose (RP2D) of HBM4003 0.3 mg/kg plus toripalimab 240 mg Q3W.

Results

As of 27 Jun 2022, a total of 40 patients had been dosed. Median follow-up time was 106.5 days. Treatment-related adverse events (TRAEs) were reported in 85.0% (34/40) patients, and ≥Grade 3 TRAEs were reported in 20.0% (8/40) patients. The most commonly reported TRAE was rash (30.0%). Patients with advanced melanoma treated with RP2D (including 8 patients in Part 1 and 26 patients in Part 2) were categorized as anti-PD-(L)1 naïve group (Cohort A, 17 patients) and anti-PD-(L)1 pretreated group (Cohort B, 17 patients). For cohort A, the ORR and DCR were 53.3% (95%CI: 26.6-78.7) and 73.3% (95%CI: 44.9-92.2) respectively in the 15 patients with post-treatment tumor assessment. The ORR of cutaneous, acral, mucosal and unknown subtype were 66.7% (2/3), 50% (2/4), 60.0% (3/5) and 33.3% (1/3), respectively. For Cohort B, the ORR and DCR were 11.8% (95%CI: 1.5-36.4) and 35.3% (95%CI: 14.2-61.7) respectively, including one patient achieving PR after pseudo-progression. Both of the PR cases were mucosal subtype.

Conclusions

HBM4003 0.3 mg/kg plus toripalimab 240mg Q3W showed promising anti-tumor activity in anti-PD-(L)1 naive patients with advanced melanoma including acral and mucosal subtypes, as well as an acceptable safety profile.

Clinical trial identification

NCT04727164.

Legal entity responsible for the study

Peking University Cancer Hospital.

Funding

Harbour BioMed.

Disclosure

All authors have declared no conflicts of interest.

Background

The effect of comprehensive treatment for locally advanced nasopharyngeal carcinoma (LANPC) is still unsatisfied, especially for stage IVa NPC. 2 or 3 cycles of neoadjuvant therapy may not be enough. Immunotherapy has been reported to benefit patients with LANPC. Therefore, this study investigated the efficacy and safety of four cycles tislelizumab combined with neoadjuvant chemotherapy in treating stage IVa NPC.

Methods

Patients with stage IVa NPC were enrolled and treated with neoadjuvant chemotherapy (gemcitabine, 1000 mg/m2, days 1 and 8, cisplatin, 80 mg/m2, day 1) and tislelizumab (200mg, day 1) every 3 weeks for 4 cycles followed by standard concurrent chemoradiotherapy. The primary endpoint was complete response (CR) rate after neoadjuvant treatment. Secondary endpoints included overall response rate (ORR) after neoadjuvant treatment, disease-free survival, safety and so on.

Results

From February 2022 to June 2022, 25 patients were enrolled at Jiangmen Central Hospital. As of Sep 15^th 2022, the median follow-up time was 124.5 days. Overall, 24 patients were assessed by investigator according to RECIST v1.1 and 1 patient was withdrawn from the trial due to treatment of acute viral parotitis. All the 24 evaluable patients completed protocol-specified 4 cycles of therapy without delaying radiotherapy. 12 patients (50%) achieved CR after neoadjuvant therapy. The ORR of all evaluable patients was 91.7%. 13 (52%) of 25 patients had grade 3-4 treatment-related adverse events. Grade 1-2 immune-related adverse events(irAE) was recorded in 18 patients (72%). There were no grade 3-4 irAEs. Any grade of irAEs included hyperthyroidism, hypothyroidism, rash, and pruritus. A numerically higher CR rate of PD-L1 positive（TC≥1%）patients than PD-L1 negative(TC=0) patients (61% vs 0).

Conclusions

Four cycles tislelizumab in combination with neoadjuvant chemotherapy demonstrated a manageable safety profile and improved clinical response in high-risk LANPC patients. Patients with PD-L1 positive may be associated with favorable response. Long-term survival benefit will be followed continuously in this ongoing trial.

Clinical trial identification

ChiCTR2200056941.

Legal entity responsible for the study

Jiangmen Central Hospital.

Funding

BeiGene (Beijing) Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

Prognosis of NPC with T4 or N3 remains unsatisfactory due to high-risk of distant metastasis. More effective treatment strategies are needed for these patients. GP plus immune checkpoint blockade regimen has been shown to improve the survival in recurrent or metastatic NPC We investigated the efficacy and safety of neoadjuvant with GP plus tislelizumab followed by concurrent chemoradiotherapy, and adjuvant treatment with tislelizumab, an anti-PD-1 monoclonal antibody, in previously untreated T4 or N3 NPC.

Methods

In this phase II, single-arm study, eligible patients aged 18-70 yrs who were diagnosed with stage IVa (AJCC 8^th) non-keratinizing nasopharyngeal received neoadjuvant therapy with gemcitabine (1000mg/m² on day 1,8), cisplatin (25 mg/m² on day 1-3) and tislelizumab (200mg) Q3W for 2 cycles followed by concurrent IMRT and cisplatin (100 mg/m²) Q3W during radiotherapy, then followed by adjuvant therapy with tislelizumab (200 mg) Q3W for 13 cycles. The primary endpoint was 2-years progression-free survival (PFS). The secondary endpoint included objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and safety. This study planned to enroll 50 patients in 2 years.

Results

A total of 27 patients were enrolled from Sep. 2021 to Sep. 2022. 23 patients were evaluable for response assessment to neoadjuvant therapy with a median age of 49 (24-66) yrs and 82.6% (n=19) of male. According to RECIST1.1, 20 (87.0%) patients had objective response to neoadjuvant treatment, including 2 (8.7%) patient with CR, 18 (78.3%) patients with PR. The other 3 patients had SDa with a definition of tumor shrinkage occured and below a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The incidence of adverse events of grade 3 or 4 was in 52.2% (12/23) patients, including nausea (7 [30.4%]) leukopenia (3 [13.0%]) neutropenia (2 [8.7%]) and hepatotoxicity (2 [8.7%]). Long-term efficacy is awaited.

Conclusions

Neoadjuvant with tislelizumab plus GP and adjuvant tislelizumab treatment achieved an impressive ORR with manageable toxicities. Further follow-up is needed to confirm the long-term efficacy.

Clinical trial identification

NCT05448885.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

BNT113 is an IV administered liposomal ribonucleic acid (RNA-LPX) cancer vaccine encoding the human papillomavirus (HPV)16 oncoproteins E6 and E7. Preclinically, PD-L1 inhibition augments the anti-tumor effect of RNA-LPX-based vaccines, supporting combining BNT113 + pembrolizumab.

Methods

AHEAD-MERIT is an open-label, randomized, phase II trial of pembrolizumab (q3w) vs pembrolizumab + BNT113 (8xq1w, then q3w) as first-line treatment in patients (pts) with unresectable recurrent/metastatic HPV16 and PD-L1 positive HNSCC. Following a safety run-in of BNT113 + pembrolizumab, pts are randomized 1:1 to BNT113 + pembrolizumab or pembrolizumab. Primary endpoints: safety, OS, and ORR.

Results

As of 05 July 2022, of 15 treated pts, 12 had completed the safety run-in (pembrolizumab + 4 BNT113 doses). In the treated pts, the median age was 66 yrs (range: 41–74) and all were male. All pts in the safety run-in had ≥1 AE, the most frequent were pyrexia (8 pts) and chills (6 pts). There were 3 pts (25%) that had Grade ≥3 AEs with all classed as SAEs (pyrexia, hypercalcemia, pleural effusion, shaking/rigors). In 2/3 pts, the AEs (pyrexia, shaking/rigors) were considered related. No deaths were reported.

Conclusions

Safety was acceptable and in line with the safety profile of BNT113 and pembrolizumab as single agents; no new safety signals were observed for the combination. The randomized part of the trial is ongoing.

Clinical trial identification

BNT113-01: NCT04534205; EudraCT: 2020-001400-41.

Editorial acknowledgement

The authors would like to acknowledge Frank Smeets for clinical trial support and Camilla West (BioNTech SE) for medical writing support.

Legal entity responsible for the study

BioNTech SE.

Funding

BioNTech SE.

Disclosure

K. Klinghammer: Financial Interests, Personal and Institutional, Advisory Role: MSD, Merck, Roche, Novartis, BMS; Financial Interests, Personal and Institutional, Other, Travel, accommodation, expenses: Merck, BMS. N.F. Saba: Financial Interests, Personal and Institutional, Advisory Role: Pfizer, Merck, GlaxoSmithKlein; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Funding: Exilexis. E. Castelluci: Other, Institutional, Principal Investigator: IO Biotech, Adlai Nortye USA, ECOG-ACRIN, ETCTN, BioNTech SE. A.D. Colevas: Other, Institutional, Other, Support for clinical trial: BioNTech SE. T. Rutkowski: Other, Personal, Principal Investigator: BioNTech SE. R. Greil: Financial Interests, Personal, Advisory Role: Celgene, Novartis, Roche, BMS, Takeda, AbbVie, AstraZeneca, Jannssen, MSD, Merck, Gilead, Daiichi Sankyo, Sanofi; Financial Interests, Institutional, Funding: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo. D. Thurner: Financial Interests, Personal, Advisory Board: MSD, Merck. U. Müller-Richter: Non-Financial Interests, Personal, Advisory Board: BMS, MSD, Sanofi, Merck; Non-Financial Interests, Personal, Invited Speaker: BMS, MSD; Non-Financial Interests, Personal, Writing Engagements: BMS, MSD; Non-Financial Interests, Personal, Principal Investigator: BMS, BioNTech SE, Sanofi, AstraZeneca; Non-Financial Interests, Personal, Stocks/Shares: BioNTech SE. A.M. Di Giacomo: Non-Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Bristol Myers Squibb, IncytePierre Fabre, Sanofi, GlaxoSmithKline , Novartis, SunPharma, Immunocore. J. Grewal: Financial Interests, Personal, Speaker’s Bureau: BMS, Ipsen, Eli Lilly; Non-Financial Interests, Personal, Advisory Board: Eisai. C.H.H. Ottensmeier: Non-Financial Interests, Institutional, Funding: BioNTech SE, MSD, Touchlight Genetics, Verastem; Non-Financial Interests, Personal, Invited Speaker: BMS; Non-Financial Interests, Personal, Advisory Role: Sebastian Bio, Neuvogen; Non-Financial Interests, Institutional, Principal Investigator: PsiOxus, Transgene. A. Atasoy: Financial Interests, Personal, Full or part-time Employment: BioNTech US Inc. S. Shpyro: Financial Interests, Personal, Full or part-time Employment: BioNTech SE. P. Brück: Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Stocks/Shares: BioNTech SE. J. Dias: Financial Interests, Personal, Full or part-time Employment: BioNTech SE. C. Ganser: Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Stocks/Shares: BioNTech SE. î Türeci: Financial Interests, Personal, Full or part-time Employment: BioNTech SE; Financial Interests, Personal, Stocks/Shares, Co-founder: BioNTech SE; Financial Interests, Personal and Institutional, Member of the Board of Directors: BioNTech SE; Financial Interests, Personal and Institutional, Ownership Interest, Co-founder: BioNTech SE, TRON; Financial Interests, Personal, Royalties, Holds patents: BioNTech SE, TRON; Financial Interests, Personal, Other: BioNTech SE; Financial Interests, Personal, Funding: TRON; Financial Interests, Personal, Leadership Role, CIMT President: TRON. U. Sahin: Financial Interests, Personal and Institutional, Member of the Board of Directors, CEO: BioNTech SE, TRON; Financial Interests, Personal and Institutional, Ownership Interest, Co-founder: BioNTech SE, TRON; Financial Interests, Personal, Stocks/Shares, Co-founder: BioNTech SE, TRON; Financial Interests, Personal, Royalties: BioNTech SE; Financial Interests, Personal, Other: BioNTech SE, TRON; Financial Interests, Personal, Funding: TRON; Financial Interests, Personal, Royalties, Holds patents: TRON.

Background

EBV is associated with NPC, with the virus in a latent state. Nstat is a Class-I selective oral HDAC inhibitor that induces expression of the lytic BGLF4 EBV protein kinase in EBV⁺ tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-mediated inhibition of viral and cellular DNA synthesis and apoptosis. Nstat plus VGCV (oral prodrug of GCV) showed a favorable safety profile with anti-tumor activity in a phase 1b/2 study in R/R EBV⁺ lymphoma (recommended phase 2 dose [RP2D]: Nstat 20 mg daily [QD], 4 d/wk + VGCV 900 mg QD). Here, phase 1b uses a 3+3 dose escalation for Nstat + VGCV RP2D selection in RM-NPC, followed by an expansion at the RP2D in other EBV⁺ solid tumors. In phase 2, up to 60 RM-NPC pts will be randomized 1:1 to receive Nstat + VGCV at the RP2D +/- PEM. Herein we report preliminary safety results from phase 1b in RM-NPC (NCT05166577).

Methods

Pts aged ≥18 with EBV⁺ RM-NPC (1-3 prior therapies) with measurable disease (RECIST v1.1) and no curative options receive daily Nstat 20-40 mg 4d per wk with VGCV 900-1800 mg daily in phase 1b. Primary endpoints are incidence of dose limiting toxicities (DLTs) (phase 1b) and overall response rate (phase 2); secondary endpoints include duration of response, disease control rate, progression free survival and overall survival. Responses are assessed per RECIST v1.1 from week 8.

Results

As of 15-Sept-22, 7 male pts (median age 51y [19-61y]) were enrolled; 3 in dose level (DL) 1 and 4 in DL2 received Nstat 20 and 30 mg QD, respectively, 4 d/wk, plus VGCV 900 mg QD. Median no. prior systemic therapies was 2; all pts were refractory to last therapy with bone (6/7), liver (5/7), and lung (3/7) metastases. Related AEs were all G1-2, most commonly fatigue, nausea, and increased creatinine (n=3 each); no G3+ AEs/DLTs and 1 SAE (cancer pain) were reported. Of 6 pts evaluable for response, 2 had SD (with decreasing/stable plasma EBV DNA, pEBVd); 4 had PD (with rising pEBVd).

Conclusions

The combination of Nstat and VGCV represents a novel approach for the treatment of EBV⁺ NPC and is tolerated at doses exceeding the RP2D for lymphoma. Dose escalation continues.

Clinical trial identification

NCT05166577.

Legal entity responsible for the study

Viracta Therapeutics.

Funding

Viracta Therapeutics.

Disclosure

L.L. Siu: Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, Roche, Oncorus, Seattle Genetics, Voronoi, Arvinas, Tessa, Navire, Relay Therapeutics, Janpix, Amgen, Marengo, InterRNA, Medicenna, Hoopika, Coherus; Financial Interests, Personal, Other, Spouse is co-founder: Treadwell Therapeutics; Financial Interests, Personal, Stocks/Shares, Spouse has stock ownership: Agios; Financial Interests, Institutional, Invited Speaker: Novartis, Bristol Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Astellas, Bayer, Amgen, Symphogen, Intensity Therapeutics, Shattucks, EMD Serono; Non-Financial Interests, Personal, Advisory Role: ICR. D.W. Lim: Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, MSD, Pfizer, Novartis; Financial Interests, Institutional, Invited Speaker: Roche, Novartis; Financial Interests, Institutional, Invited Speaker, Grant funding for investigator-sponsored study: Bristol Myers Squibb. S.A. Khan: Financial Interests, Personal, Advisory Board, I conduct molecular tumor boards for FMI: Foundation Medicine; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: Eisai; Financial Interests, Personal, Other, give educational lectures to oncologists about molecular testing: Roche Pakistan. P.J. Voon: Financial Interests, Personal, Invited Speaker: AstraZeneca, Merck Sharp & Dohme, Pfizer; Financial Interests, Personal, Advisory Board: Novartis, Ipsen; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Novartis, Boehringer Ingelheim, Janssen-Cilag, Johnson & Johnson, Viracta Therapeutics Inc, Roche, Merck KGaA, Merck Sharp & Dohme. M. Ahn: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Takeda, MSD, Yuhan, Amgen, Alpha Pharmaceutical, Janssen, BMS, Roche, Daichi Sankyo. A. Elguindy, A. Katkov, L. Rojkjaer, Y. Katz: Financial Interests, Personal, Full or part-time Employment: Viracta Therapeutics. B.B.Y. Ma: Financial Interests, Personal, Invited Speaker, Advisory Board/Consultancy: Novartis, BMS, MSD; Financial Interests, Personal, Advisory Board, Consultancy: Y-biologics, Boehringer Ingelheim, Merck Serono; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board and consultancy: Viracta Therapeutics; Financial Interests, Institutional, Research Grant, Preclinical Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Merck Serono; Financial Interests, Institutional, Research Grant, Research Grant Preclinical: Novartis. All other authors have declared no conflicts of interest.

Background

ImmTAC® bispecific proteins redirect polyclonal T cells to target intra/extracellular proteins using a T cell receptor as targeting domain. IMC-C103C (MAGE-A4 × CD3) is an ImmTAC against MAGE-A4, which is expressed in several tumors including ovarian carcinoma (OC). ≥ 90 μg IMC-C103C was demonstrated as the clinically active range (Davar 2021). Pre-selection for MAGE-A4 expression was not required as a majority of OC express MAGE-A4 (H score ≥ 1) and tebentafusp demonstrated OS benefit and ctDNA reductions regardless of H score, although RECIST responses were enriched at higher H scores (Leach 2021).

Methods

HLA-A*02:01+ OC pts were enrolled as all-comers in escalation and expansion cohorts with MAGE-A4 expression tested by IHC retrospectively. Ph1 primary objective is to identify expansion dose. Other objectives: adverse events (AE), ORR (RECIST v1.1), OS and biomarkers including ctDNA (Guardant 360).

Results

As of 24Jun2022, 31 heavily pretreated OC pts (87% platinum resistant) received 90 - 240 μg IMC-C103C. Of 28 OC pts with evaluable MAGE-A4 IHC expression, 16 (57%) were positive (pos) with median H score 28 (maximum 300). 12/28 (43%) pts had H score = 0 (neg). Only 1 pt had H score > 130. The AE profile is consistent with previously reported (Davar 2021). Most common related AEs were pyrexia (68%), chills (52%), and CRS (45%), the vast majority were Grade 1/2. No related AEs resulted in treatment discontinuation or death. 27 of 31 were response evaluable. 15 pts were MAGE-A4 pos; 1 had confirmed PR (duration 12+ months) and 5 had SD. 6/15 pts had any tumor shrinkage. Of 12 MAGE-A4 neg/unknown (unk) pts, 1 had SD and 1 had any tumor shrinkage. Of 21 ctDNA evaluable pts, 4/11 MAGE-A4 pos and 1/10 MAGE-A4 neg/unk had ≥ 50% ctDNA reduction. After first dose, serum IFNγ and TNFα were not induced in MAGE-A4 neg pts or minimally induced in MAGE-A4 pos pts, consistent with mostly low H scores.

Conclusions

When enrolled as all-comers, the vast majority of heavily pre-treated OC pts had either zero or very low MAGE-A4 expression. IMC-C103C is clinically active but the low MAGE expression may have resulted in few RECIST responses. Dose optimization and signal detection continue in MAGE-A4 pos pts with additional tumor types.

Clinical trial identification

NCT03973333.

Legal entity responsible for the study

Immunocore Ltd.

Funding

Immunocore Ltd and Genentech.

Disclosure

R. Sweis: Financial Interests, Personal, Advisory Board: Aduro, Astellas, AstraZeneca, BMS, EMD serono, Editas, Exelixis, Eisai, Janssen, Mirati, Pfizer, Silverback, Seattle Genetics; Financial Interests, Personal, Invited Speaker: Aveo; Financial Interests, Institutional, Invited Speaker: AbbVie, Aduro, Ascendis, Bayer, BMS, CytomX, Eisai, Genentech/Roche, Immunocore, Novartis, Merck, Mirati, Moderna, QED, Astellas; Financial Interests, Institutional, Research Grant: Epivax. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol Mayers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. O. Saavedra Santa Gadea: Financial Interests, Personal, Other, Travel/Accomodation/Expense: Affimed. K.N. Moore: Financial Interests, Personal, Advisory Board: AstraZeneca, Aravive, Alkemeres, Blueprint Pharma, Eisai, EMD Serono, GSK/Tesaro, Genentech/Roche, Hengrui, Immunogen, IMab, Mereo, Myriad, Caris, Mersana, Novartis, Novocure, OncXerna, OncoNova, Tarveda, VBL Therapeutics; Financial Interests, Personal, Full or part-time Employment: GOG Partners Associate Director; Financial Interests, Institutional, Full or part-time Employment: NRG Ovarian Cancer Chair; Financial Interests, Personal, Royalties: UP to Date; Financial Interests, Institutional, Invited Speaker, international CO-PI, local site PI: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Immunogen, GSK/Tesaro, Lilly, PTC Therapeutics, Daiichi Sankyo, Regeneron, Artios, Bolt, verastem; Non-Financial Interests, Personal, Invited Speaker: GOG. D. Davar: Financial Interests, Institutional, Research Grant: Arcus, BMS, Checkmate Pharmaceuticals, CellSight Technologies, Merck, Tesaro/GSK; Financial Interests, Personal, Advisory Role: Checkmate Pharmaceuticals, Shionogi, Vedanta CE; Financial Interests, Personal, Other, US Patent 63/124,231, Dec 11, 2020; Patent 63/208,719, June 9, 2021: Intellectual Property. O. Hamid: Financial Interests, Personal, Invited Speaker: BMS, Novartis, Pfizer, Sanofi / Regeneron; Financial Interests, Personal, Advisory Board: Aduro, Akeso, Amgen, Beigene, BMS, Roche Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, SEAGEN, Tempus, Zelluna, Bioatla, Alkermes, Instil Bio, Iovance; Financial Interests, Institutional, Invited Speaker: Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck Serono, Nextcure, Novartis, Pfizer, Sanofi / Regeneron, Seagen, Torque, Zelluna, Rubius. N.H. Segal: Financial Interests, Personal, Advisory Board: Immunocore, PsiOxus, Roche/Genentech, Boehringer Ingelheim, Revitope, ABL Bio, Novartis; Financial Interests, Institutional, Research Grant: Regeneron, Immunocore, Incyte, AstraZeneca, BMS, Merck, Pfizer, Roche/Genentech. T.R.J. Evans: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bicycle Therapeutics, Bristol Myers Squibb, Clovis, Eisai, Medivir, MSD, Nucana, Roche/ Genentech; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Medivir, MSD, Nucana, Roche/ Genentech; Financial Interests, Personal, Other, Support to attend international conferences: Bayer, Bristol Myers Squibb, Celgene, MSD, Nucana, Pierre Fabre, Roche/ Genentech; Financial Interests, Institutional, Principal Investigator, Coordinating PI, reimbursement of study costs for commercial studies: Adaptimmune, Bristol Myers Squibb, Eisai, iOnctura, MSD, Nucana, Sanofi; Financial Interests, Institutional, Principal Investigator, Local PI, reimbursement of study costs for commercial studies: Astellas, Basilea, Bayer, Beigene, Bicycle Therapeutics, Boehringer Ingelheim, Celgene, Codiak, CytomX, GSK, Immunocore, Johnson & Johnson, Lilly, Medivir, MiNa Therapeutics, Novartis, Pfizer, Roche, Sapience Therapeutics, Seagen, Sierra, Starpharma, UCB; Financial Interests, Institutional, Principal Investigator, Educational grant for investigator-led study and reimbursement of study costs for commercial studies: AstraZeneca; Financial Interests, Institutional, Principal Investigator, Support for non-commercial investigator-led study: Verastem; Non-Financial Interests, Personal, Other, Member of Clinical Experts Review Panel / Clinical Research Committee: Cancer Research UK; Non-Financial Interests, Personal, Other, Annual Meeting abstracts committee: International Liver Cancer Association; Non-Financial Interests, Personal, Other, Member of Scientific Advisory Panel: Pancreatic Cancer Research Fund; Non-Financial Interests, Personal, Member: America Association for Cancer Research, American Society of Clinical Oncology, Association of Cancer Physicians (UK), British Association for Cancer Research, European Association for Cancer Research, International Liver Cancer Association; Other, Personal, Other, Clinical Subjects Editor: British Journal of Cancer; Other, Personal, Other, Chair of Independent Data Monitoring Committee- honorarium payable to the employing institution: Genmab. M. Dar, Y. Yuan: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. L. Collins, P.B. Kirk: Financial Interests, Personal, Stocks/Shares: Immunocore; Financial Interests, Personal, Full or part-time Employment: Immunocore. O. Karakuzu: Financial Interests, Personal, Full or part-time Employment: Immunocore; Financial Interests, Personal, Stocks/Shares: Immunocore. J.S. Lopez: Financial Interests, Institutional, Research Grant: Roche-Genentech, Basilea, Genmab; Financial Interests, Personal, Advisory Board: Basilea, Ellipses. I. Melero: Financial Interests, Personal, Advisory Board: Gossamer Bio, Highlight Therapeutics, MSD, Alligator Bioscience, Genmab, Numab, NOXXON Pharma AG, BMS, CRISPR Therapeutics, Genentech, AstraZeneca, Boehringer Ingelheim, EMD Serono, Roche, CatalYm GmbH, BioLineRx, Boston Pharma, Janssen, Hookipa Pharma, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Monopteros Therapeutics; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator.

Background

Treatment [tx] options for platinum-resistant ovarian cancer [PROC] are limited [ltd]. Immune checkpoint inhibitors (ICI) have ltd activity in PROC. Clinical studies evaluating novel therapies are urgently needed. COM701, a novel, 1^st in-class ICI binds to PVRIG, leading to activation of T-cells. BMS-986207 is an ICI blocker of TIGIT. We reported a partial response [PR] with COM701 monotherapy in a pt with primary peritoneal CA¹. We hypothesized that in pts with PROC, blocking the DNAM axis with the triplet: COM701 + BMS-986207 + nivolumab, would demonstrate antitumor activity with a favorable safety and tolerability profile. We present preliminary results.

Methods

All 20 pts enrolled received COM701 20 mg/kg + BMS-986207 480 mg + nivolumab 480 mg IV Q4W. Primary objectives [obj] were safety/tolerability; secondary obj of antitumor activity. Key inclusion criteria: Age ≥ 18 yrs, histologically confirmed advanced malignancies and exhausted all available standard tx. Key exclusion criteria: prior receipt of any inhibitor of PVRIG, TIGIT, or PD-1/PD-L1. Investigator assessed responses per RECIST v1.1, safety per CTCAE v5.0.

Results

Median [med] age 61yr, med follow-up 51 days [range 1-202], med number of prior lines of therapy - 4 [range 1-10]. Objective response rate 4/20 [20%] pts [all ongoing study tx, 3 confirmed PR], 3 PRs - serous adenoCA, 1 PR - clear cell histology. No complete responses (CR); 4pts with stable disease (SD), disease control rate [CR+PR+SD] 8/20 [40%]. Most frequent [freq] histology - serous adenoCA 10/20 [50%], clear cell 3/20 [15%]. Most freq AE G1/2 fatigue in 11 pts. A sustained immune activation induced by the tx, with a maximum 7.6-fold average increase of peripheral IFNɣ in 16pts evaluated [p<0.005].

Conclusions

The combination of COM701 + BMS-986207 + nivolumab has encouraging signal of antitumor activity with immune activation in pts with heavily pre-treated PROC and is well tolerated. Additional data will be presented at the conference. Data extract 08/29/2022. 1. Vaena D et al, COM701±nivolumab: Results of an ongoing P1 study of safety, tolerability & preliminary antitumor activity in pts with advanced solid malig. J Clin Onco 39, 2021 (suppl 15; abst 2504).

Clinical trial identification

NCT04570839.

Legal entity responsible for the study

Compugen Ltd.

Funding

Compugen Ltd in collaboration with Bristol Myers Squibb.

Disclosure

J. Moroney: Financial Interests, Institutional, Principal Investigator: Compugen Ltd. O. Yeku: Financial Interests, Institutional, Principal Investigator: Compugen Ltd. G. Fleming: Financial Interests, Personal, Advisory Board: tersera; Financial Interests, Institutional, Invited Speaker, salary support: compugen, celldex, corcept, plexxicon, AstraZeneca, Molecular Templates, Molecular Templates, CytomX, Astellas, K Group beta, iovance; Non-Financial Interests, Personal, Other, co-coordinating PI for clinical trial, uncompensated: AbbVie; Non-Financial Interests, Institutional, Other, supply of product for mouse testing by a collaborator: corcept; Non-Financial Interests, Personal, Member: ASCO; Other, Personal, Other, support for CME activity: DSI, Merck, Caris, Eisai, AstraZeneca. L.A. Emens: Financial Interests, Personal, Other, member of Steering Committee for IMpassion130, KATE3, incompensatedtransfers of value for writing support for conference abstracts, slide presentations, and publications: Genentech; Financial Interests, Personal, Other, member of Steering Committee for IMpassion130, KATE3, uncompensated transfers of value for writing support for conference abstracts, slide presentations, and publications: F Hoffman La Roche; Financial Interests, Personal, Other, Steering Committee Member for clinical trial CTMX-2009-002, uncompensated: CytomX; Financial Interests, Personal, Advisory Board, Advisory Board, compensated: Gilead, Immune Onc, Shionogi, AstraZeneca; Financial Interests, Personal, Advisory Board, Standing Advisor, compensated: Mersana; Financial Interests, Personal, Other, Consultant, compensated: GPCR; Financial Interests, Personal, Other, Advisor, uncompensated: Immutep; Financial Interests, Personal, Advisory Board, Advisory Meeting, compensated: Chugai; Financial Interests, Personal, Full or part-time Employment, Faculty Member: University of Pittsburgh; Financial Interests, Personal, Full or part-time Employment, Physician: University of Pittsburgh Medical Center Physicians Group; Financial Interests, Personal, Stocks/Shares, potential for future stock options: Molecuvax; Financial Interests, Institutional, Invited Speaker, clinical trial: AbbVie, Bolt Therapeutics, Bristol Myers Squibb, Compugen, CytomX, EMD Serono, Genentech/F Hoffman La Roche, Genentech/F Hoffman La Roche, Immune Onc, Merck, Next Cure, Silverback, Takeda, Tempest; Financial Interests, Institutional, Other, Investigator-Initiated trial at Johns Hopkins transferred to another PI: AstraZeneca; Non-Financial Interests, Personal, Leadership Role, Vice President: Society for Immunotherapy of Cancer. D. Vaena, E.E. Dumbrava, D. Rasco, M.R. Sharma: Financial Interests, Institutional, Principal Investigator: Compugen Ltd. A. Patnaik: Financial Interests, Institutional, Other, Institutional research funding: Compugen. R.J. Sullivan: Financial Interests, Personal, Advisory Board: Merck, Novartis, Bristol Myers Squibb, Eisai, Iovance, Oncosec, Pfizer, Replimmune; Financial Interests, Personal, Royalties: Up-to-date; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Invited Speaker: GlaxoSmithKline, Pfizer, Sanofi, Moderna, Roche-Genentech, BiomedValley DIscoveries, Astex, Compugen, Beigene, Novartis, Rubius, Alkermes, Simcha Therapeutics, OnKure. H.H. Adewoye, E. Ophir, G. Cojocaru, P.J. Ferre: Financial Interests, Personal, Full or part-time Employment: Compugen Ltd. B. Izar: Other, Personal, Other, Consulting: Janssen, Volastra Therapeutics; Other, Personal, Other, Paid speaking engagement: AstraZeneca. S. Gaillard: Financial Interests, Personal, Invited Speaker: Curio Science, NCCN, GOG Partners; Financial Interests, Personal, Advisory Board: Arcus, Elevar Therapeutics, GSK Diagnostics, Immunogen, Lumanity, Novartis; Financial Interests, Institutional, Invited Speaker: Sermonix Pharmaceuticals, AstraZeneca, Compugen, GOG Partners, Genentech, Iovance, NRG Oncology, Tempest; Financial Interests, Personal, Royalties: UpToDate. All other authors have declared no conflicts of interest.

Background

There is a high unmet medical need for the treatment of patients [pts] with platinum-resistant epithelial ovarian cancer [PROC]. Immune checkpoint inhibitors (ICI) have limited activity in this pt population. COM701 is a novel, 1^st-in-class ICI that binds to PVRIG, a DNAM-1 axis member, leading to activation of T-and NK-cells. We hypothesized that in pts with PROC, dual blockade of PVRIG and PD1 would demonstrate antitumor activity with a favorable safety and tolerability profile. We present encouraging preliminary results.

Methods

We enrolled 20 patients [pts] with PROC. All pts received COM701 20 mg/kg + nivolumab 480 mg both IV Q4W. Primary objectives were safety/tolerability, with secondary objective of preliminary antitumor activity. Key inclusion criteria: Age ≥ 18 yrs, histologically confirmed locally advanced or metastatic solid malignancy and has exhausted all available standard therapy. Key exclusion criteria: prior receipt of anti-PVRIG, anti-TIGIT, no limitation on the number of prior lines of therapy or prior PD-1/PD-L1 inhibitor. Investigator assessed responses were per RECIST v1.1, safety per CTCAE v4.03.

Results

Median age 61.5yrs, median of 6 prior lines of therapy [Min, Max: 2,9]. Objective response rate (ORR) of 2/20 [10%] pts: 1 pt with fallopian tube CA, 6 prior lines of therapy, clear cell histology; 1 pt with OVCA, serous adenoCA, 7 prior lines of therapy [including prior nivolumab with best response of progressive disease]; both subjects with PR have an ongoing response to therapy, no complete responses (CR); 5 pts with stable disease (SD). Disease control rate [CR + PR + SD] 7/20 [35%]. Most frequent AEs were G1/2 nausea 11 pts, fatigue 11 pts [all G1/2]. Increase of serum IFNg was observed, confirming the expected immune activation induced by COM701 given in combination with nivolumab.

Conclusions

COM701 + nivolumab demonstrates encouraging preliminary signal of antitumor activity and immune activation in pts with heavily pre-treated PROC with a favorable safety/tolerability profile. Additional data analyses and pt followup are ongoing and will be presented at the conference. Data extract 09/18/2022.

Clinical trial identification

NCT03667716.

Legal entity responsible for the study

Compugen Ltd.

Funding

Compugen Ltd in collaboration with Bristol Myers Squibb.

Disclosure

M. Patel: Financial Interests, Institutional, Funding, paid to institution: See https://coi.asco.org/share/BLY-NDGV/Manish%20Patel. G. Fleming: Financial Interests, Personal, Advisory Board: tersera; Financial Interests, Institutional, Invited Speaker, salary support: compugen, celldex, corcept, plexxicon, AstraZeneca, Molecular Templates, Molecular Templates, CytomX, Astellas, K Group beta, iovance; Non-Financial Interests, Personal, Other, co-coordinating PI for clinical trial, uncompensated: AbbVie; Non-Financial Interests, Institutional, Other, supply of product for mouse testing by a collaborator: corcept; Non-Financial Interests, Personal, Member: ASCO; Other, Personal, Other, support for CME activity: DSI, Merck, Caris, Eisai, AstraZeneca. E. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, Daiichi Sankyo, AstraZeneca, Arvinas, Deciphera Pharmaceuticals, Eisai, Seagen, Arcus, iTeos, Janssen, Loxo, Relay Therapeutics; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Silverback Therapeutics, Millenium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, Merck, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses, Incyte, Jacobio, Mabspace Biosciences, Myraid Genetic Labs, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Vincerx Pharma. R.J. Sullivan: Financial Interests, Personal, Advisory Board: Merck, Novartis, Bristol Myers Squibb, Eisai, Iovance, Oncosec, Pfizer, Replimmune; Financial Interests, Personal, Royalties: Up-to-date; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Invited Speaker: GlaxoSmithKline, Pfizer, Sanofi, Moderna, Roche-Genentech, BiomedValley DIscoveries, Astex, Compugen, Beigene, Novartis, Rubius, Alkermes, Simcha Therapeutics, OnKure. B. Izar: Other, Personal, Other, Consulting: Janssen, Volastra Therapeutics; Other, Personal, Other, Paid speaking engagement: AstraZeneca. G. Cojocaru, E. Ophir, P.J. Ferre: Financial Interests, Personal, Full or part-time Employment: Compugen Ltd. All other authors have declared no conflicts of interest.

Background

Despite advances in the treatment of mCRC combining chemotherapy regimens with biologics, most patients (pts) still progress within 11 months of receiving 1L chemotherapy. Addition of novel therapies to the standard of care (SoC) to improve antitumor activity is urgently needed. The randomized part 2 of COLUMBIA-1 (NCT04068610) evaluated the safety and efficacy of combining SoC (bevacizumab [BEV] + FOLFOX) with the PD-L1 inhibitor durvalumab (D) and the anti-CD73 monoclonal antibody oleclumab (O).

Methods

Pts with previously untreated, MSS-mCRC and ECOG PS ≤1 received either SoC alone or SoC + D (1500 mg, Q4W) + O (3000 mg Q2W x4 then Q4W) in the experimental arm (EXP). The primary endpoint was objective response rate (ORR) per investigator assessed RECIST v1.1.

Results

As of 10 Dec 2021, 52 pts were enrolled, of whom 51 were response evaluable. The confirmed ORR with SoC was 44.0% (95% confidence interval [CI], 24.4–65.1%) compared to 61.5% (95% CI, 40.6–79.8%) in the EXP arm. Median OS was not reached (SoC) vs 19.1 mos (EXP); median PFS was 11.1 mos (SoC) vs 10.9 mos (EXP; Table). Grade ≥3 treatment emergent adverse events (TEAEs) occurred in 76.9% of pts in SoC and 65.4% EXP. Fatal TEAEs (all unrelated) were observed in 3 pts in the EXP arm: 1 with sepsis and 2 with intestinal perforation. One pt with intestinal perforation deemed related to BEV experienced fatal peritonitis. In the SoC arm, there was a single fatal COVID-19 TEAE. The most frequent treatment-related AEs in the EXP arm were diarrhea (38.5%), peripheral sensory neuropathy (38.5%) and fatigue (26.9%). There was no identified association between CD73 expression and clinical benefit.

Conclusions

Addition of D + O to FOLFOX + BEV SoC showed a moderate response increase without PFS benefit vs SoC alone. Safety was consistent with known safety profiles. Table: 160P

Clinical trial identification

NCT04068610.

Editorial acknowledgement

Editing support for this abstract, under the direction of the authors, was provided by Catherine Crookes of Ashfield MedComms (Macclesfield, UK), an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

N.H. Segal: Financial Interests, Personal, Advisory Board: Immunocore, PsiOxus, Roche/Genentech, BI, Revitope, ABL Bio, Novartis, GSK, AstraZeneca, Numab; Financial Interests, Personal, Research Grant: Regeneron, Immunocore, PureTech, AstraZeneca, BMS, Merck, Pfizer, Roche/Genentech. J. Tie: Financial Interests, Personal, Invited Speaker, Honorarium: Novartis, Amgen, Merck Serono, Merck Sharp and Dohme, Pierre Fabre; Financial Interests, Personal, Advisory Board: Haystack Oncology, Amgen, Novartis, AstraZeneca, Merck Serono, Merck Sharp and Dohme, Pierre Fabre, BMS; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, Pfizer, Daiichi Sankyo, Novartis. S. Kopetz: Financial Interests, Personal, Ownership Interest: MolecularMatch, Lutris, Iylon; Financial Interests, Personal, Research Grant: Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, AstraZeneca, Novartis, Amgen, Lilly, Daiichi Sankyo; Financial Interests, Personal, Other: Genetech, EMD Serono, Merck, Holy Stone, Novartis, Lilly, BI, Boston Biomedical, AstraZeneca, Bayer Health, Pierre Fabre, Redx Pharma, Ipsen, Daiichi Sankyo, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GSK, Jazz Pharmaceuticals, Iylon, Xilis, AbbVie, Amal Therapeutics, Gilead, Mirati, Flame Biosciences, Servier, Carina Biotechnology, Bicara Therapeutics, Endeavor BioMedicines, Numab Pharma, Johnson and Johnson/Janssen. M.P. Ducreux: Financial Interests, Personal, Invited Speaker: Roche, Beigene, MSD, Servier, Pierre Fabre, Amgen; Financial Interests, Personal, Advisory Board: Terumo, Roche, Merck Serono, Bayer, Daiichi Sankyo, Sotio; Financial Interests, Institutional, Research Grant: Keocyt, Roche, Bayer. E. Chen: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Principal Investigator: AstraZeneca. R. Dienstmann: Financial Interests, Personal, Speaker’s Bureau: Roche, BI, Ipsen, Amgen, Servier, Sanofi, Libbs, Merck Sharp and Dohme, Lilly, AstraZeneca; Financial Interests, Personal, Advisory Board: Roche, BI; Financial Interests, Personal, Research Grant: Merck, Pierre Fabre. A. Hollebecque: Financial Interests, Personal, Invited Speaker: Servier, Incyte, EISAI; Financial Interests, Personal, Advisory Board: Basilea, Tahio, Relay Theraeutics, QED Therapeutics, Debiopharm; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, M19-345: AbbVie; Non-Financial Interests, Personal, Principal Investigator, CO42216: Roche; Non-Financial Interests, Personal, Principal Investigator, MCLA-158: Merus; Non-Financial Interests, Personal, Principal Investigator, SGNB6A: Seattle Genetics; Non-Financial Interests, Personal, Principal Investigator, TAS-120-202: Tahio; Non-Financial Interests, Personal, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Personal, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Personal, Principal Investigator, ACT16902: Sanofi; Non-Financial Interests, Personal, Principal Investigator, C4201002: Pfizer; Non-Financial Interests, Personal, Principal Investigator, RLY-4008: Relay Therapeutics; Non-Financial Interests, Personal, Principal Investigator, CC-90011: Celgene/BMS; Non-Financial Interests, Personal, Principal Investigator, Loxo-IDH: Loxo/Lilly; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca. M. Reilley: Financial Interests, Personal, Advisory Board: BMS, Helsinn, ZielBio. M.E. Elez Fernandez: Financial Interests, Personal, Invited Speaker: Novartis, Organon; Financial Interests, Personal, Advisory Board: Amgen, Bayer, F. Hoffman La Roche, Merck Serono, MSD, Pierre Fabre, Sanofi, Servier; Financial Interests, Institutional, Funding: Amgen, Array Biopharma, AstraZeneca, BeiGene, BI, BMS, Celgene, Debiopharm International SA, F. Hoffman La Roche, Genentech, HalioDX SAS, Hutchinson MediPharma International, Janssen-Cilag SA, Menarini, Merck Health KgaA, MSD, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, PharmaMar, Sanofi Aventis Recherche & Developpement, Servier, Taiho Pharma; Financial Interests, Personal, Other, ASCO Scientific Program Committee: Developmental Therapeutics – Immunotherapy: ASCO; Financial Interests, Personal, Other, Speaker of the ESMO Academy: ESMO; Financial Interests, Personal, Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: SEOM; Financial Interests, Personal, Other, Travel, accommodations, expenses: Amgen, Array BioPharma, BMS, Merck Serono, Roche, Sanofi, Servier. J. Cosaert: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Member: AstraZeneca. J. Cain: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. M. Hernandez: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. N. Hewson: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. Z.A. Cooper: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. M. Dressman: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J. Tabernero: Financial Interests, Personal, Advisory Role: Array BioPharma, AstraZeneca, Bayer, BI, Chugai, Daiichi Sankyo, F. Hoffman-La Roche Ltd, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandio Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc; Financial Interests, Personal, Stocks/Shares: Oniria Therapeutics; Financial Interests, Personal, Other, educational collaboration: Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, Physicians Education Resource (PER).

Background

IK-007 is a selective oral inhibitor of prostaglandin (PG) E₂ receptor 4 (EP4). EP4 plays a key role in mediating PGE₂-dependent immunosuppression and IK-007 may overcome mechanisms driving CPI resistance. MSS CRC is primary refractory to checkpoint inhibitors and high levels of PGE₂ metabolite (PGEM) are associated with poor prognosis of CRC and may be predictive of response.

Methods

This is a phase 1b study of IK-007 in combination with pembro in patients with advanced or metastatic MSS CRC who have received at least 2 lines of prior therapy. Cohort 1 had a 7-day run-in with single agent IK-007 followed by IK-007 in combination with pembro (200 mg IV every 3 weeks), Cohort 2 received combination only. Endpoints included safety (mTPI design), antitumor activity (RECIST 1.1), pharmacokinetics, pharmacodynamics, and RP2D.

Results

Study enrolled 54 patients: 26 in Cohort 1 and 28 in Cohort 2 at 4 dose levels (300, 450, 600, and 900mg BID PO) with 12 patients prospectively enrolled with high urinary PGEM (enrichment). Median age was 70 years (28-82). Events of clinical interest included decreased renal function, liver toxicity, and upper GI ulcers. Treatment-related adverse events ≥ Grade 2 were reported in 26 patients (48%). Of these, increased AST was seen in 5 patients (9.3%). Serious adverse events (SAEs) were reported in 23 patients (43%) including intestinal obstruction, pneumothorax, and acute kidney injury. Two unrelated Grade 5 SAEs (cardiac arrest and aspiration pneumonia) were reported. A 5.3% ORR (2/39) was observed in the response population: 1 cCR (300mg BID) with DoR of 18+ months and 1 cPR (900mg Q12h) with DoR 4+ months (ongoing). Disease control rate was 28% (11/39) with the median duration of response of 8.3 months in the 5 patients with prolonged clinical benefit.

Conclusions

IK-007 in combination with pembro had an acceptable safety profile and showed limited antitumor activity in heavily pretreated MSS CRC patients. Correlation of response with PGEM status was inconclusive. Of note, 28% achieved disease control, many showing prolonged clinical benefit. Investigation in additional indication is warranted, including the ongoing IIT in inflammatory breast cancer.

Clinical trial identification

NCT03658772.

Legal entity responsible for the study

Ikena Oncology.

Funding

Ikena Oncology.

Disclosure

A.W. Tolcher: Financial Interests, Institutional, Advisory Board, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, Llc d/b/a NEXT Oncology of which he is the CEO and Founder: Adagene, Inc., ARO Biotherapeutics, Bioinvent, Boehringer Ingelheim International GmbH, Deka Biosciences, Eleven Bio, Elucida, EMD Serono/ Merk KGaA, Immunome, NBE Therapeutics, Pelican, Pieris Pharma, Pyxis Oncology, Vincerx, Zymeworks Inc., MIRATI; Financial Interests, Institutional, Other, Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, Llc d/b/a NEXT Oncology of which he is the CEO and Founder: Asana BioSciences, Llc., Axlmmune, Bayer, Gilde Healthcare Partners, HBM Partners, Immunomet Therapeutics, Inc., Karma Oncology, Menarini Ricerche, Mersana, Nanobiotix, Partner Therapeutics, Pfizer Inc., Pierre Fabre, RYVU Therapeutics, Seattle Genetics, SOTIO Biotechnology Co., Spirea Limited Inc., Transcenta Therapeutics Inc., Trillium Therapeutics Inc., AbbVie, Inc, Agenus, Inc., Ascentage, Mekanistic Therapeutics; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, Llc d/b/a NEXT Oncology of which he is the President and Founder: Aclaris Therapeutics; Financial Interests, Institutional, Other, Fees for consulting for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, Llc d/b/a NEXT Oncology of which he is President and Founder: Daiichi Sankyo, Inc.; Financial Interests, Institutional, Other, Note: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, Llc d/b/a NEXT Oncology of which he is President and Founder: Immuneering, Impact Therapeutics US, Inc., Ocellaris Pharma, Inc. & Eli Lilly, SK Life Science, Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd; Financial Interests, Institutional, Advisory Board, NOTE: Fees for consulting and advisory board memberships for Dr. Anthony Tolcher are paid to New Experimental Therapeutics, Llc d/b/a NEXT Oncology of which he is President and Founder: ZielBio, Inc., Ikena Oncology, Hiber Cell, Inc.; Financial Interests, Institutional, Invited Speaker, Dr. Tolcher is the Director of Research, CEO and Founder of NEXT Oncology: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: Pyxis Oncology; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, Llc d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: Adagene Inc, Apros Therapeutics, Inc., AbbVie, Inc, Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, Llc., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, BioNTech RNA Pharmaceuticals GmbH, BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Codiak BioSciences, Inc., Boehringer Ingelheim Pharmaceutical, Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, Llc, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., GlaxoSmithKline Research & Development Limited, IDEAYA Biosciences, Haihe Biopharma Co., Ltd., Heat Biologics, IDEAYA Biosciences, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc., Kiromic Biopharma, Inc, Mabspace Biosciences (Suzhou) Co., Limited, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Mersana Therapeutics, Inc., Mirati Therapeutics, Inc., NatureWise Biotech & Medicals Corporation, Navire Pharma Inc., NBE-Therapeutics AG, NextCure, Inc, Nitto BioPharma, Inc., Odonate Therapeutics, Inc., Pelican Therapeutics, Inc., Petra Pharma, Pfizer, Inc., Pieris Pharmaceuticals, Inc., PMV Pharmaceuticals, Inc., Qilu Puget Sound Biotherapeutics Corporation, Samumed, Llc, Seattle Genetics, Inc., Spring Bank Pharmaceuticals, Inc., Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd., Symphogen A/S, Syndax Pharmaceuticals Inc., Synthorx, Inc., Takeda, Tizona Therapeutics, Zymeworks Inc.; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics SA, Agenus Inc.; Financial Interests, Institutional, Invited Speaker, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, Llc d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: ORIC Pharmaceuticals; Non-Financial Interests, Personal, Principal Investigator: AbbVie, Inc; Non-Financial Interests, Personal, Principal Investigator, Fees for studies are paid for all study related costs, to New Experimental Therapeutics, Llc d/b/a NEXT Oncology of which Dr. Anthony Tolcher is CEO and Founder: ABL Bio Inc., Adagene Inc, ADC Therapeutics SA, Agenus Inc., Aminex Therapeutics, Inc., Amphivena Therapeutics, Inc., Apros Therapeutics, Inc., Arcellx, Inc., ARMO Biosciences, Arrys Therapeutics, Inc., Artios Pharma Limited, Asana BioSciences, Llc., Ascentage Pharma Group Inc., Astex Pharmaceuticals, Basilea Pharmaceutica International Ltd, BioInvent International AB, Boehringer Ingelheim Pharmaceutical, Inc., BioNTech RNA Pharmaceuticals GmbH, Birdie Biopharmaceuticals, HK Ltd., BJ Bioscience Inc., Boston Biomedical, Inc., Calgent Biotechnology Co., Ltd., Codiak BioSciences, Inc., CStone Pharmaceuticals (Suzhou) Co., Ltd., Cybrexa Therapeutics, Inc., Daiichi Sankyo Inc., Deciphera Pharmaceuticals, Llc, eFFECTOR Therapeutics, Inc, Eli Lilly and Company, EMD Serono, Gilead Sciences, Inc., Ideaya Biosciences, GlaxoSmithKline Research & Development Limited, Haihe Biopharma Co., Ltd., Heat Biologics, ImmuneOncia Therapeutics, Inc., IMPACT Therapeutics, Inc., Inhibrx, Inc., Innate Pharma SA, Janssen Research & Development, K-Group Beta, Inc., KeChow Pharma, Inc. D.R. Spigel: Financial Interests, Institutional, Other, Consulting: Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Curio Science, EMD Serono, Evidera, Exelixis, Genentech/Roche, GlaxoSmithKline, Intellisphere, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Mirati Therapeutics, Molecular Templates, Monte Rosa Therapeutics, Novartis, Pfizer, Puma Biotechnology, Regeneron, Sanofi-Aventis; Financial Interests, Institutional, Research Grant, Serve as PI: Amgen, Aeglea Biotherapeutics, Agios, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, BeiGene, Bind Therapeutics, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celldex Therapeutics, Clovis, Daiichi Sankyo, Eisai, Lilly, EMD Serono, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, GRAIL, Hutchinson MediPharma, ImClone Systems, Ipsen, Janssen, Loxo, MacroGenics, MedImmune, Merck, Nektar, Neon Therapeutics, Novartis, Novocure, PTC Therapeutics, Rgenix, SeaGen, Taiho Oncology, Tarveda, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Arcus Biosciences, Oncologie, Molecular Template, Cyteir Therapeutics, BioNTech, Apollomics, Pure Tech Health, Elevation Oncology, Repare Therapeutics, Kronos Bio, Razor Genomics, Denovo Biopharma, Erasca, Zai Laboratory, Faeth Therapeutics, Ascendis Pharma, Lyell Immunopharma, Synthekine, Shenzhen Chipscreen Biosciences. T. Lingaraj: Financial Interests, Institutional, Full or part-time Employment: Ikena. E. Talcove-Berko: Financial Interests, Institutional, Full or part-time Employment: Ikena. N. Ortiz-Otero: Financial Interests, Institutional, Full or part-time Employment: Ikena. W. Bartolini: Financial Interests, Personal, Full or part-time Employment: Ikena. K. Kacena: Financial Interests, Institutional, Full or part-time Employment: Ikena. S.L. Santillana: Financial Interests, Personal, Other, Individual expert consulting work in drug development supporting Biotechnology and Drug Development companies since 2019 under SLSS Consulting Llc work: SLSS Consulting Llc; Financial Interests, Institutional, Full or part-time Employment, Chief Medical Officer since July 2020: Ikena Oncology Inc; Financial Interests, Personal, Officer, Founder and President of SLSS Consulting Llc since 2019: SLSS Consulting Llc; Financial Interests, Institutional, Stocks/Shares, Stock options granted personally as Ikena employee: IkenaOncology Inc; Financial Interests, Personal, Ownership Interest, Owner and founder of individual consulting practice in SLSS Consulting Llc: SLSS Consulting Llc; Non-Financial Interests, Personal, Other, Mentor for Biotech Start Ups companies under MC organization program: Massachussets Challenge organization(MC); Other, Personal, Other, Nonprofit support /work as mentor of Biotechnology Start Up companies under MC program: Massachussets Challenge (MC). All other authors have declared no conflicts of interest.

Background

Gemcitabine-based chemotherapy and durvalumab plus GC are currently the standard regimens for advanced biliary tract cancers (BTC). Further, chemotherapy combined with PD-1 inhibitor and Bevacizumab improved the survival benefits in lung cancer. The effectiveness and safety of GEMOX plus Sintilimab and Bevacizumab in treating initially unresectable BTC are being evaluated in this study.

Methods

Treatment-naïve patients (pts) with histologically or cytologically confirmed unresectable BTC (T_anyN₁M₀) were enrolled. GEMOX (Gemcitabine 1000mg/m², iv, d1,8; Oxaliplatin 100mg/m², iv, d1) plus Sintilimab (200mg, iv, d1) and Bevacizumab (7.5mg/kg, iv, d1) were given every 3 weeks for 5 cycles. pts with partial response (PR) or complete response (CR) and eligible for R0 resection were referred for surgery. After treatment for 5 cycles, subsequent therapy was recommended by the investigator. Tumor response and resectability were assessed every 3 weeks according to RECIST v1.1. The primary endpoint was objective response rate (ORR), and secondary endpoints included surgical conversion, disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety.

Results

Between 08/2020 and 6/2022, 37 pts were enrolled with a median age of 63 years (range 36-78), 49% were male, and 76% had an ECOG PS of 1. Of them, 23 pts (62%) were ICC, 4 pts (11%) were ECC and 10 pts (27%) were GBC. All of the pts were diagnosed with stage III. At a median follow-up duration of 12.7 months (range 3.1-22.0), ORR was 49% in 37 evaluable patients and DCR was 86%. 1 pts achieved CR, and 17 pts achieved PR. 9 pts met the pre-designated criteria for surgery and 3 pts received surgery. Median PFS was 9.82 months (95% CI 5.19-NA), and median OS was 12.6 months (95% CI 9.5-13.9). Most treatment-related AEs (TRAEs) were Grade 1-2, and the incidence of grade 3-4 TRAEs was 35%. The most common TRAEs were asthenia (75%), peripheral neuropathy (46%), and nausea (35%).

Conclusions

Given the encouraging ORR and tolerable safety, the combination of GEMOX plus Sintilimab and Bevacizumab as a conversion therapy may be a new option for initially unresectable BTC.

Legal entity responsible for the study

Longrong Wang.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

This study aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy (nCRT) combined with sequential tislelizumab followed by surgery for resectable thoracic esophageal squamous cell carcinoma (TESCC).

Methods

Patients with pathologically confirmed TESCC and clinical T1-2N1-3M0 or T3-4aN0-3M0 were allocated to receive neoadjuvant radiotherapy (41.4 Gy in 23 fractions) with concurrent chemotherapy (albumin-bound paclitaxel, 50-100 mg/m², once weekly for five weeks; carboplatin, area under the curve of 2 mg/mL/min, once weekly for five weeks) plus sequential tislelizumab (200 mg every three weeks for three cycles, beginning within the first to 14th day after completion of radiotherapy) followed by subtotal esophagectomy with two-field lymphadenectomy. The primary endpoints were safety and pCR rate after surgery. The second endpoints included radical (R0) resection and major pathological response (MPR) rate.

Results

From January 2021 to June 2022, 26 eligible patients were enrolled. Eighteen patients completed neoadjuvant Tislelizumab and 15 underwent planed surgery. R0 resection rate was 100%. pCR rate for primary tumor and resected lymph nodes was 46.7% (7/15). MPR rate for primary tumor was 86.7% (13/15). During neoadjuvant Tislelizumab, no ≥ grade 3 adverse events (AEs) occurred and grade 1–2 AEs developed in 88.9% (16/18) of the patients, including weakness (66.7%, 12/18), chest pain (61.1%, 11/18), pulmonary infection (PI) (33.3%, 6/18) and radiation-induced lung injury (33.3%, 6/18). Grade 3 postoperative complications occurred in 20.0% (3/15) of the patients, including anastomotic fistula (20.0%, 3/15), injury of recurrent laryngeal nerve (6.7%, 1/15) and pleural effusion (PE) (6.7%, 1/15). And grade 1-2 postoperative complications occurred in 80.0% (12/15) of the patients, including anemia (46.7%, 7/15), PI (26.7%, 4/15), PE (26.7%, 4/15) and liver malfunction (13.3%, 2/15).

Conclusions

nCRT combined with sequential tislelizumab followed by surgery may be safe and effective for resectable TESCC and be worthy of further study.

Clinical trial identification

NCT04776590.

Legal entity responsible for the study

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.

Funding

BeiGene, Ltd

Disclosure

All authors have declared no conflicts of interest.

Background

Immunotherapy combined with chemotherapy as first-line treatment in advanced ESCC has been the standard of care. Previously results demonstrated anlotinib, whether combined with chemotherapy as first-line regimen or monotherapy as second-line treatment, had encouraging efficacy and manageable toxicity in advanced ESCC. TQB2450 is a humanized anti-PD-L1 monoclonal antibody, which could recovery T-cells activity and enhance immune responses by preventing the binding of PD-L1 to PD-1 and B7.1 receptors on the surface of T cells. Here, we conducted a phase II trial to evaluate the efficacy and safety of anlotinib combined with TQB2450, cisplatin and paclitaxel as first-line therapy in advanced ESCC.

Methods

Eligible patients (pts) with advanced ESCC who had not previous systemic therapy received TQB2450 (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1∼14, q3w) combined with paclitaxel (135mg/m², iv, d1, q3w) and cisplatin (60∼75mg/m², iv, d1∼3, q3w) for 4 to 6 cycles as initial therapy. Patients, who did not have progressive disease (PD), continued received anlotinib (10mg, po, d1∼14, q3w) and TQB2450 (1200mg, iv, d1, q3w) as maintenance treatment until PD or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints were iPFS (iRECIST), ORR (RECIST 1.1), DCR, DOR and safety.

Results

As of 31 May, 2022, 38 pts were enrolled with a median age of 64 years (range 41-74), male (78.9%) and ECOG PS 1 (78.9%). Of 25 evaluable pts, 1 pts had complete response, 20 pts reached partial response and 4 pts had stable disease. The ORR was 84.0% (95%Cl 63.9%-95.5%) and the DCR was 100.0% (95%Cl: 86.3%-100.0%). Median PFS was not reached. ≥ Grade 3 treatment-related adverse events (TRAEs) was 57.9% (22/38), which mainly included neutropenia (42.1%), leukopenia (18.4%) and hypertension (18.4%). 11 pts (28.9%) suffered from serious AEs. AEs led to discontinuation of TQB2450 in 7.9% and anlotinib in 7.9% of enrolled patients.

Conclusions

TQB2450 plus anlotinib combined with paclitaxel and cisplatin showed significant efficacy and manageable toxicities as first-line treatment in advanced ESCC, which might provide a new treatment strategy for those.

Clinical trial identification

NCT05013697.

Legal entity responsible for the study

The authors.

Funding

Chia Tai-Tianqing Pharmaceutical Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

The potential advantage of combining anti-PD-1 antibodies with tyrosine kinase inhibitors has been revealed by several trials in advanced HCC. TIS, an anti-PD-1 monoclonal antibody, has shown anti-tumor activity in HCC. LEN is a multikinase inhibitor approved for the first-line treatment of uHCC. This study aims to evaluate the efficacy and safety of TIS plus LEN in pts with uHCC.

Methods

Systemic treatment-naïve pts with uHCC received TIS (200 mg, IV, Q3W) and LEN (body weight ≥60 kg: 12 mg; <60 kg: 8 mg, PO, QD). Tolerability evaluated by assessing dose-limiting toxicities (DLTs) in the first 6 pts (Part 1) was the premise of the remaining enrollment (Part 2). Primary endpoint was objective response rate (ORR) assessed by Independent Review Committee (IRC) per RECIST v1.1. Based on the Simon’s two-stage design, >6 responders were needed in stage 1 (n=30) to continue, and ≥18 responders were needed by the end of stage 2 (n=60) to claim statistical superiority to a historical control of 18.8% (from LEN arm of phase III REFLECT study) (α and β errors of 0.05).

Results

A total of 64 pts were enrolled and received TIS plus LEN (Part 1, n=6; Part 2, n=58) with 73.4% in BCLC stage C. As of 7 July 2022 (median follow-up, 12.5 months), 21.9% pts were on treatment. No DLTs were observed in the first 6 pts. The study met the statistical superiority criteria. There were 24 responders assessed by IRC per RECIST v1.1 in the efficacy evaluable analysis set (n=62). Confirmed ORR and DCR were 38.7% (95% CI, 26.6-51.9) and 90.3% (95% CI, 80.1-96.4), respectively (Table). Median PFS was 9.6 months (95% CI, 6.8-NE), and 12-month PFS rate was 42.0% (95% CI, 25.7-57.4). Any grade of TRAEs occurred in 61 (95.3%) pts; 18 (28.1%) pts experienced Grade ≥3 TRAEs. Treatment related SAEs were reported in 6 (9.4 %) pts. Table: 165P

Confirmed tumor response per RECIST v1.1 (efficacy evaluable analysis set*, n=62)

Conclusions

TIS plus LEN showed promising antitumor activity with acceptable safety profile as first-line treatment for uHCC.

Clinical trial identification

NCT04401800.

Legal entity responsible for the study

BeiGene.

Funding

BeiGene.

Disclosure

M. Li, X. Zhang: Financial Interests, Personal, Full or part-time Employment: BeiGene Ltd. All other authors have declared no conflicts of interest.

Background

Fibrolamellar liver cancer (FLC) is a rare malignancy involving multidisciplinary approaches including surgery, liver-directed, and systemic treatment. Combination therapy with 5-fluorouracil (FU) and interferon (IFN)-a2 has long been used for FLC. We hypothesized that addition of anti-PD1 to 5-FU+IFN-a2 may further improve clinical outcome and lead to a favorable modulation of tumor microenvironment.

Methods

We treated 3 patients with unresectable FLC with 5-FU+IFN-a2+nivolumab (N): 5-FU 200 mg/m² 7-day-on/7-day-off, IFN-a2 (4 million U/m² 3 times/week with 5-FU) for 8 weeks, followed by on-treatment biopsy and addition of N 480 mg every 4 weeks to 5-FU+IFN-a2. Tumor tissues were collected under an IRB-approved protocol.

Results

Two patients (26, 29 years) initially had unresectable FLC with a 6.1 cm tumor in seg IV liver invading the common hepatic duct, and a 19.5 cm tumor, peritoneal nodules, and abdominal lymph nodes. After 9 and 5 months of therapy, unresectable tumors were converted to resectable ones: the former had L hepatectomy and bile duct resection; the latter, L hepatectomy, resection of the omentum, spleen, L diaphragm, and lymph node dissection. Both patients completed adjuvant therapy with the same regimen, having no recurrence. The third patient (20 years) had multifocal liver tumors with peritoneal carcinomatosis and lymph nodes. He received treatment for 5 months and achieved stable disease, followed by hepatic tumor bleeding leading to treatment discontinuation. All 3 patients had an increase of CD8+T cells in on-treatment (5-FU+IFN-a2, week 8), compared to pre-treatment biopsies. The available surgical tumor tissues (s/p 5-FU+IFN-a2+N) were also evaluated in patients who underwent surgery with conversation of unresectable to resectable disease, showing a further increase of CD8+T cells.

Conclusions

This clinical outcome of converting an unresectable disease to a resectable one with tumors significantly decreasing in size suggests synergy of 5-FU+IFN-a2 combined with anti-PD1. The robust increased infiltration of CD8+T cells on 5-FU+IFN-a2+N may explain this clinical efficacy. Detailed immune analyses with gene expression profiling will be presented at ESMO Immuno-Oncology Meeting.

Legal entity responsible for the study

The authors.

Funding

Fibrolamellar Cancer Foundation.

Disclosure

All authors have declared no conflicts of interest.

Background

Previously, we have demonstrated that consolidative chemoradiotherapy following induced chemotherapy is an optimal regimen for LAPC. This study aimed to evaluate the clinical benefit of tislelizumab (anti-PD-1) plus AG chemotherapy sequenced by consolidative radiotherapy for therapy-naïve LAPC.

Methods

Patients were given tislelizumab 200mg Q3W, nab-paclitaxel 125 mg/m² and gemcitabine 1,000 mg/m² on days 1 and 8 every three weeks for 4-6 cycles. Those who did not progress continued to sequence radiotherapy and tislelizumab 200 mg Q3W. Then, maintenance chemotherapy with anti-PD-1 was ongoing until progression. The primary endpoint was 12-month progression-free survival rate, and secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The Data cutoff date for this interim analysis was August 30, 2022.

Results

From April 2021 to August 2022, 15 patients were enrolled. Twelve patients completed at least one efficacy assessment. 4 of 12 patients had an optimal partial response (PR), 7 patients had stable disease (SD), and 1 had progressive disease (PD). ORR was 33.3%, and DCR was 91.7%, respectively. Most patients (10/12) showed serum CA19-9 decline with different degrees, but only PR patients (3 cases) fell within normal ranges and declines exceeding 93.7%.The median follow-up time was 283 days, and the median PFS was 266 days (95%CI,176-not reached). The median OS was not reached. 6-month and 12-month PFS rates were 70.7% and 44.2%, separately. Notably, the12-month OS rate was 100%. The most common treatment-emergent adverse events (TEAEs) were myelosuppression, rash, and fatigue. Grade 3/4 TEAEs were neutropenia in 4 patients, anemia in 1 patient, and rash in 1 patient. Immune-related AEs included 1 Grade-1 myocarditis and 1 Grade-1 pneumonia, and no deaths occurred.

Conclusions

Our data suggest that tislelizumab combined with AG chemotherapy sequenced by radiotherapy for LAPC provided encouraging efficacy with reasonable tolerability. Significant CA19-9 decline is predictive of therapeutic response.

Clinical trial identification

ChiCTR2000040872.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Emerging data suggest that liver mets are immune privileged and can induce systemic loss of tumour specific CD8+ T cells, leading to reduced anti-tumour immunity. Liver mets were shown to negatively predict the success of immunotherapy (as opposed to chemotherapy [chemo] or targeted therapy) in several cancer types. However, limited prospective data exist on the effect of immunotherapy in patients (pts) with liver mets.

Methods

This post-hoc analysis included pts with baseline liver mets from three phase 3 trials of cemiplimab (cemi; anti-PD-1) in non-small cell lung cancer (NSCLC) and cervical cancer: EMPOWER-Lung 1, EMPOWER-Lung 3 Part 2, and EMPOWER-Cervical 1. Overall survival (OS), progression free survival (PFS), and objective response rate (ORR) were analysed.

Results

Patients with baseline liver metastases represented 17% of pts in EMPOWER-Lung 1, 15% in EMPOWER-Lung 3 Part 2, and 24% in EMPOWER-Cervical 1. As expected, OS, PFS, and ORR were generally poorer in pts with liver mets regardless of treatment arms. Nonetheless, in EMPOWER-Lung 1 (1L treatment for advanced NSCLC with PD-L1 ≥50%), among pts with liver mets, cemiplimab monotherapy demonstrated notably longer OS (not reached vs 7.4 months; hazard ratio [HR] 0.38) and PFS (6.2 vs 4.2 months; HR 0.51), as well as higher ORR (29% vs 15%) vs chemo (Table). Similar improvement was observed for EMPOWER-Lung 3 Part 2 (1L cemiplimab+chemo vs placebo+chemo for advanced NSCLC with all PD-L1 levels). In EMPOWER-Cervical 1 (2L treatment of recurrent cervical cancer with all PD-L1 levels), cemiplimab showed comparable OS, PFS, and ORR vs chemo in the liver mets subgroup. Table: 168P

OS, PFS, and ORR in patients with baseline liver mets

Conclusions

Despite a lower efficacy of Cemiplimab in patients with liver mets from primary lung/cervix cancer than those without, the relative benefit over prior standard-of-care regimens was preserved, and for some patients, even enhanced.

Clinical trial identification

NCT03088540 (EMPOWER-Lung 1), NCT03409614 (EMPOWER-Lung 3), NCT03257267 (EMPOWER-Cervical 1).

Editorial acknowledgement

Medical writing support was provided by Qing Zhou, PhD, ELS from Regeneron Pharmaceuticals, Inc. with editing supporting from Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc. and Sanofi.

Funding

Regeneron Pharmaceuticals, Inc. and Sanofi.

Disclosure

C. Gessner: Financial Interests, Personal, Advisory Board: GlaxoSmithKline, Pfizer, AstraZeneca, Roche, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Berlin-Chemie, Chiesi, Boehringer Ingelheim and Sanofi. A. Sezer: Financial Interests, Institutional, Research Grant: Roche, Merck Sharp & Dohme, Merck Serono, AstraZeneca, Lilly, Novartis, Johnson & Johnson, Regeneron Pharmaceuticals, Inc., and Sanofi. M. Gumus: Financial Interests, Personal, Other, Honoraria: Roche, Merck Sharp & Dohme, Gen İlaç and Novartis. K.S. Tewari: Financial Interests, Personal, Other, Honoraria: Tesaro and Clovis Oncology; Financial Interests, Personal, Advisory Role: Genentech, Tesaro, Clovis and AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Genentech, AstraZeneca, Merck, Tesaro and Clovis; Financial Interests, Personal, Research Grant: AbbVie, Genentech, Morphotek, Merck and Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Other, travel, accommodations, expenses: Genentech. B.J. Monk: Financial Interests, Personal, Advisory Role: Aravive, Asymmetric Therapeutics, Boston Biomedical, ChemoCare, ChemoID, Circulogene, Conjupro Biotherapeutics, Eisai, Geistlich, Genmab/Seattle Genetics, Gynecologic Oncology Group Foundation, ImmunoGen, Immunomedics, Incyte, Laekna Health Care, Mateon/O; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Clovis, Janssen/Johnson & Johnson, Roche/Genentech, and Tesaro/GlaxoSmithKline. A.C. de Melo: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme Corp, Bristol Myers Squibb and Libbs Farmaceutica; Financial Interests, Personal, Other, travel support: AstraZeneca, Merck Sharp & Dohme Corp, Bristol Myers Squibb and Roche; Financial Interests, Institutional, Research Grant: Clovis Oncology, Bristol Myers Squibb, Roche, Novartis, Amgen, Merck Sharp & Dohme Corp, Lilly, Pierre Fabre, Sanofi and Pfizer. A. Oaknin: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab, Mersana Therapeutics, GlaxoSmithKline and Deciphera Pharmaceuticals; Financial Interests, Personal, Other, travel support: Roche, AstraZeneca and PharmaMar. S. Li: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. B. Gao: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.D. Mathias: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. G. Gullo: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M.E. Salvati: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. F. Seebach: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. I. Lowy: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M. Fury: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. P. Rietschel: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Background

ENPP1 is a type II transmembrane protein with nucleotide pyrophosphatase, and phosphodiesterase enzymatic activities and its expression is associated with poor prognosis in cancer. ENPP1 inhibition protects cGAMP and ATP from hydrolysis and reduces adenosine levels in the TME, activates APCs and increases T-cell infiltration promoting anticancer immunity. RBS2418 is a potent oral ENPP1 inhibitor. Here, we report pharmacokinetic (PK) and immunomodulatory properties of RBS2418 in combination with pembrolizumab (pembro) in a checkpoint-refractory high grade adrenal cancer with an immune-desert tumor phenotype at baseline.

Methods

Pembro was given at 200mg IV every 3 weeks with escalating doses of RBS2418 weekly, at 100 mg p.o. BID, followed by 200 and 400 mg p.o BID. Blood samples were collected at each dose level to determine plasma RBS2418 concentration and serum ENPP1 inhibition. Peripheral blood immune cell subpopulations were analyzed by flow cytometry and TCR/RNA sequencing.

Results

All dose levels of RBS2418 with pembro were safe, well tolerated with no DLTs. Plasma concentrations (Ctrough) of RBS2418 corresponded to > 15-fold and > 30-fold above the 90% inhibition level of ENPP1 (EC90) for the 100 and 200 mg dose, respectively. cGAMP was fully stable in serum. Peripheral blood analyses showed a 2.1-fold increase from baseline in conventional dendritic cells (cDCs) and 2.5-fold expansion of proliferating CD4/Ki67 T cells. Furthermore, CD8/Ki67 proliferating T cells increased 19.5-fold from baseline. TCR/RNA sequencing showed a > 50-fold expansion in TCR CD3β clonotypes, an increase in hyperexpanded TCR clonotypes and upregulation of granzyme B, perforin and granulysin gene expression.

Conclusions

RBS2418 with pembro was safe, well tolerated with no DLTs. RBS2418 PK data showed excellent oral bioavailability with plasma levels leading to complete ENPP1 inhibition. RBS2418 induced increases in peripheral cDCs, proliferation of CD4 and CD8 T cells and expansion of TCR clonotypes as well as upregulation of T cell cytotoxic granule protein gene expression supporting clinical development of this novel first-in-class immunotherapy agent in an ongoing clinical trial (NCT05270213).

Legal entity responsible for the study

The authors.

Funding

Riboscience, Llc.

Disclosure

J. Glenn: Financial Interests, Personal, Member of the Board of Directors: Riboscience; Financial Interests, Personal, Stocks/Shares: Eiger Pharmaceuticals. I. Csiki: Financial Interests, Personal, Full or part-time Employment: Riboscience; Financial Interests, Personal, Stocks/Shares: Riboscience. K. Klumpp: Financial Interests, Personal, Member of the Board of Directors: Riboscience. All other authors have declared no conflicts of interest.

Background

EO2401 was designed to activate memory T cells cross-reacting with tumor associated antigens and includes synthetically produced HLA-A2 peptides with molecular mimicry to antigens (IL13Rα2, BIRC5 and FOXM1) upregulated in glioblastoma, and the CD4 helper peptide UCP2.

Methods

Patients with glioblastoma at first progression after radiotherapy/temozolomide received EO2401 (300 μg/peptide, q2w x4 then q4w) with nivolumab (3 mg/kg q2w; EN), or EN with bevacizumab (10 mg/kg q2w; ENB). In study part 2, low-dose bevacizumab (5 mg/kg q2w) could be used as symptom directed time-limited treatment of edema. In study part 3, 6 evaluable patients are to be treated with neoadjuvant EN, and 15 further patients with ENB (enrollment ongoing).

Results

Part 1 included 40 patients (EN = 29, ENB = 11). Part 2 enrolled 36 patients treated with EN. EN and ENB (n=76) were well tolerated with EO2401 associated tox limited to local administration site reactions (45% of patients; events 70% Grade 1, 26% Grade 2, and 4% Grade 3). The frequency and severity of nivolumab-/bevacizumab-tox was consistent with historical single-agent data. Immune monitoring demonstrated T cell responses against the 3 microbiome-derived peptides for 97% of patients investigated ex vivo or after in vitro stimulation (IVS). Cross-reactivity against the pool of 3 human target peptides was demonstrated in 96% of patients by IFN-γ ELISpot. The strength of the immune response correlated with clinical outcome (progression-free survival [PFS] and objective responses [OR]). For part 1, median PFS, and median survival for EN (n=29, median follow-up 20.1 months) were 1.8 and 10.6 months. Patients on ENB (n=11, median follow-up 13.1 months) had median PFS of 5.5 months and 55% of patients were alive beyond 12 months. OR rate / Disease Control Rate (DCR) (OR rate + stable disease) for EN and ENB were 14%/34% and 55%/82%.

Conclusions

EO2401 was well tolerated and generated rapid and durable immune responses correlating with clinical outcome. Addition of standard bevacizumab to EN improved efficacy. Updated data from all parts of the trial will be presented. NCT04116658.

Clinical trial identification

NCT04116658.

Legal entity responsible for the study

Enterome.

Funding

Enterome.

Disclosure

W. Wick: Financial Interests, Institutional, Funding, Drug/Palbociclib, Torisel for N2M2 trial: Pfizer; Financial Interests, Institutional, Funding, Drug/Asunercept for N2M2: Apogenix; Financial Interests, Institutional, Funding, Drug/Idasanutlin, Atezolizumab, Vismadegib, Alectinib for N2M2: Roche; Financial Interests, Institutional, Invited Speaker: Enterome, Vaximm; Non-Financial Interests, Personal, Leadership Role, Terminated in 2021: NOA; Non-Financial Interests, Personal, Leadership Role: EANO, Deutscher Wissenschaftsrat; Non-Financial Interests, Personal, Leadership Role, terminated in 2021: EORTC; Non-Financial Interests, Personal, Member: Leopoldina/Deutsche Gesellschaft der Wissenschaften. A. IdBaih: Financial Interests, Personal, Advisory Board, Advisory board: Novocure, Leo Pharma, Boehringer Ingelheim, Novartis; Financial Interests, Institutional, Invited Speaker, Clinical research: Enterome, Bristol Myers Squibb, Carthera; Financial Interests, Institutional, Invited Speaker, Basic/Translational research: Carthera; Financial Interests, Institutional, Invited Speaker, Basic and Translational research: Sanofi, Nutrithéragène, Servier, Transgene; Other, Personal, Other, Travel funding: Carthera, Leo Pharma, Novocure, Enterome. M. Vieito Villar: Financial Interests, Personal, Advisory Role: Roche. G. Tabatabai: Financial Interests, Personal, Advisory Role: AbbVie, Bayer, Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria: AbbVie, Bayer. A. Stradella: Financial Interests, Personal, Advisory Role: Novartis, Seagen; Financial Interests, Personal, Speaker’s Bureau: Novartis, Pierre Fabre. F. Ghiringhelli: Financial Interests, Personal, Other, Honoraria: Roche, Amgen, Astra-Zeneca; Financial Interests, Personal, Advisory Role: Enterome; Financial Interests, Personal, Other, Research Funding: Astra-Zeneca, Roche; Financial Interests, Personal, Other, Travel, accomodation, expenses: Roche; Financial Interests, Personal, Other, Travel, Accomodation expenses: Amgen, Servier. M. Burger: Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers, Gilead. U. Herrlinger: Financial Interests, Personal, Advisory Role: Bayer Pharma; Financial Interests, Personal, Invited Speaker: Medac. M. Touat: Financial Interests, Personal, Advisory Role: Agios, Servier, Integragen, Taiho Pharmaceuticals; Financial Interests, Institutional, Other, Research Funding: Sanofi. P. Wen: Financial Interests, Personal, Research Grant: AstraZeneca/ MedImmune, Beigene, Celgene, Chimerix, Genentech/Rochee, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Puma, Servier, Vascular Biogenics, VBI Vaccines, Eli Lilly; Financial Interests, Personal, Advisory Board: Astra-Zeneca, Bayer, Black Diamond, Boston Pharmaceuticals, Boehringer Ingelheim, Celularity, Chimerix, Day One Bio, Genenta, GSK, Karyopharm, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, VBI Vaccines. C. Gouttefangeas: Financial Interests, Personal, Other, Research funding: Enterome; Financial Interests, Personal, Royalties, Patent and Intellectual property: Tübinge University. A. Maia: Financial Interests, Personal, Other, Research Funding: Enterome. C. Bonny: Financial Interests, Personal, Full or part-time Employment: Enterome; Financial Interests, Personal, Stocks/Shares: Enterome. J. Paillarse: Financial Interests, Personal, Full or part-time Employment: Enterome; Financial Interests, Personal, Stocks/Shares: Enterome. J. Fagerberg: Financial Interests, Personal, Full or part-time Employment: Enterome; Financial Interests, Personal, Stocks/Shares: Enterome. D.A. Reardon: Financial Interests, Personal, Research Grant: Celldex, Incyte, Agenus, EMD Serono, Acerta Pharma, Omniox, Enterome; Financial Interests, Personal, Speaker’s Bureau: Merck, Novocure, Regeneron, BMS, Oncorus, Agenus, EMD Serono, Merck KGaA, Taiho Pharmaceuticals, Advantagene, Bayer, Imvax, Medicennnac, Sumitom Dainippon Pharma, Vivacitas Oncology, Anheart Therapeutics, Deciphera, Ellipses Pharma, Genenta Science, Inir Pharma, Kintara Therapeutics, Kyatec, Neuvogen, Y-mAbs; Financial Interests, Personal, Advisory Board: Merck, Novocure, Regeneron, BMS, Oncorus, Agenus, EMD Serono, Merck KGaA, Taiho Pharmaceuticals, Advantagene, Bayer , Imvax, Medicenna, Vivacitas Oncology, Anheart Therapeutics, Ellipses Pharma, Genenta Science, Kintara Therapeutics; Financial Interests, Personal, Invited Speaker: Kiyatec, Agios. All other authors have declared no conflicts of interest.

Background

CM 8KX is a phase 1/2 study of an SC NIVO formulation with a permeation enhancer, recombinant human hyaluronidase PH20 enzyme (rHuPH20), developed to allow rapid delivery and reduced treatment burden compared with intravenous (IV) NIVO administration. We report PD biomarker changes in the tumor microenvironment and peripheral blood from CM 8KX and key PD biomarker comparisons between SC and IV NIVO.

Methods

Patients were checkpoint inhibitor–naive, ≥ 18 years of age, ECOG performance status 0–1, with metastatic/unresectable solid tumors and measurable disease. Patients received SC NIVO 720 mg ± rHuPH20, SC NIVO 960 mg ± rHuPH20, or SC NIVO 1200 mg + rHuPH20. Paired baseline and on-treatment tumor biopsies were assessed for CD8+ tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 expression on tumor cells (TC PD-L1) by immunohistochemistry. Soluble PD-1 (sPD-1), interferon gamma (IFNγ), CXCL9, and CXCL10 were assessed in serum from cycle (C) 1 day (D) 1 to C2D1. sPD-1 changes were compared with unpublished data from IV NIVO 3 mg/kg Q2W administration in CM 038; other biomarkers were compared with published data.

Results

As previously reported, SC NIVO ± rHuPH20 resulted in numerical mean increases from baseline to C1D15 in CD8+ TILs (5.0% [95% CI, −17.5 to 27.5]) and TC PD-L1 (2.8% [95% CI, −12.8 to 18.4]), which are surrogates for tumoral IFNγ activity. These observations were consistent with those published for IV NIVO in several indications. sPD-1 increased significantly following SC NIVO across dose cohorts, similar to increases observed in CM 038. Early increases in IFNγ and CXCL9 were observed following SC NIVO ± rHuPH20, with significant cycle-day effects but no apparent dose dependence. Numerical increases in CXCL10 were also observed. These increases are consistent with published IV NIVO data from CM 038.

Conclusions

Increases in tumor biomarkers and changes in key peripheral PD markers demonstrate immune activation post-SC NIVO. Despite the limitations of cross-trial comparisons, PD effects are consistent with historical IV NIVO data from CM 038. The results support further evaluation of SC NIVO + rHuPH20 in phase 3 studies.

Clinical trial identification

NCT03656718 and NCT01621490.

Editorial acknowledgement

Editorial support was provided by Sandra Page, PhD, of Spark Medica Inc.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

C.G.C.A. Jackson: Non-Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Institutional, Funding: Athenex. D. Perumal: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. I. Lugowska: Financial Interests, Personal, Funding: Roche, MSD, AstraZeneca, Boehringer Ingelheim, Janssen, Pfizer, Amgen, Incyte, Macrogenics, RyVu, Rhizen, Agenus. A. O’Donnell: Other, Institutional, Full or part-time Employment: Capital and Coast Health, Bowen Icon Cancer Centre. R.T. North: Non-Financial Interests, Institutional, Principal Investigator: BOP Clinical Trials Unit. P.A. Calvo Ferrandiz: Non-Financial Interests, Personal, Full or part-time Employment: Hospital Universitario Gregorio Marañón. L.M. Latten-Jansen: Non-Financial Interests, Personal and Institutional, Principal Investigator: Maastricht University Medical Center+. A. Santoro: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, Merck Sharp & Dohme, Incyte; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Speaker’s Bureau: Takeda, Bristol Myers Squibb, Roche, AbbVie , Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Lilly, Sandoz, Eisai, Novartis, Bayer, Merck Sharp & Dohme. L. Li: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. K. Sidik: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. T. Tang: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J.S. Deutsch: Financial Interests, Personal, Other, Application No: 63/313,548: Patent pending. J. Taube: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharpe & Dohme, AstraZeneca, Replimune; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Stocks/Shares: Akoya Biosciences; Financial Interests, Personal and Institutional, Advisory Board: Akoya Biosciences; Financial Interests, Personal and Institutional, Research Grant: Akoya Biosciences; Non-Financial Interests, Institutional, Other, Equipment loan: Akoya Biosciences; Non-Financial Interests, Institutional, Other, Reagent provision: Akoya Biosciences. C. Horak: Financial Interests, Personal, Full or part-time Employment: Palleon Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. S. Ravimohan: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Mirati; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GlaxoSmithKline, Roche; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Background

JTX-8064, a highly selective and potent IgG4 inhibitor of myeloid-specific Leukocyte Immunoglobulin Like Receptor B2 (LILRB2), leads to macrophage reprogramming from an immunosuppressive to an immune activated state, resulting in T cell activation. INNATE (NCT04669899) is a phase (P) 1/2 dose escalation/expansion study of two investigational agents, JTX-8064 monotherapy (mono) and combination (combo) with pimi. P1 data defining Recommended P2 Dose (RP2D) are presented.

Methods

Pts with advanced solid tumors who progressed after all available therapy were treated at 7 dose levels of JTX-8064 mono IV q3w (50, 150, 300, 450, 600, 900, 1200 mg) and 2 dose levels of JTX-8064 (700, 1200 mg) + pimi 500 mg IV q3w using Bayesian design. 1^o objectives: safety, tolerability, RP2D. 2 ^o objectives: receptor occupancy (RO), PK, immunogenicity. Objective response rate (RECIST 1.1) was exploratory.

Results

31 pts were treated in dose escalation, 22 JTX-8064 mono, 9 JTX-8064 + pimi. No dose limiting toxicities; maximum tolerated dose not reached. Safety: Mono: Median age 67. Eleven pts (50%) had treatment-related adverse events (TRAE). Most common were fatigue (n= 5), upper abdominal pain, arthralgia, flushing, nausea, and pyrexia (n= 2 each). The only Grade 3 (G3) TRAE and only serious related AE (SRAE) was tumor flare at 1200 mg. Combo: Median age 63. Six pts (66.7%) had TRAE, most common fatigue (n=4) and pyrexia (n=2). No ≥ G3 TRAEs, no SRAEs. PK was linear. Full RO thru 21 days was achieved at ≥ 300 mg. RP2D of 700 mg q3w was selected for JTX-8064 +/- pimi to optimize RO in tumor, with Cmin at steady state 63.4 (26.0-139.7) ug/mL. Treatment induced antibodies to JTX-8064 occurred in 1 mono and no combo pts. P1 Efficacy: Mono: 0 PR, 7 SD with 2 durable SD (appendiceal cancer 8.3, ovarian cancer 12.2 mo). Combo: 1 PR (6.2 mo) at 700 mg in PD-1i resistant cholangiocarcinoma with resolution of both bone pain and cachexia, 3 SD with 1 durable SD (post-PD-1i NSCLC 6 mo).

Conclusions

JTX-8064 was well-tolerated as mono and with pimi, with 700 mg q3w selected as the preliminary RP2D. Enrollment is ongoing in P2, including cohorts in renal and ovarian cancer that have met Simon’s 2-stage response criteria to expand.

Clinical trial identification

NCT04669899.

Legal entity responsible for the study

Jounce Therapeutics, Inc.

Funding

Jounce Therapeutics, Inc.

Disclosure

K. Papadopoulos: Financial Interests, Personal, Advisory Board: Turning Point Therapeutics, Bicycle, Basilia; Financial Interests, Institutional, Full or part-time Employment: START; Financial Interests, Personal, Ownership Interest: START; Financial Interests, Institutional, Invited Speaker, For conduct of clinical trial: 3D Medicines, AbbVie, ADC Therapeutics, Amgen, Anheart Therapeutics, Bayer, Daiichi Sankyo, EMD Serono, F-Star, Incyte, Jounce Therapeutics, Lilly, Linnaeus Therapeutics, Merck, Mersana, Mirati Therapeutics, Pfizer, Regeneron Pharmaceuticals, Revalution Medicines, Syros Pharmaceuticals, Tempest Therapeutics, Treadwell Therapeutics. T. Li: Financial Interests, Institutional, Research Grant: Merck, OncC4, LabyRx Immuno-Oncology, Genentech, Novartis, AbbVie Inc., Astelas, Atlas Medx, AstraZeneca, EMD Serono, RasCal, Jounce, Coherus, Jiangsu Hengrui, Tempus, Lung Cancer Mutation Consortium. N. Lakhani: Financial Interests, Personal, Advisory Board: Innovent Biologics; Financial Interests, Personal, Advisory Board, Participation in Ad Board: Ikena, SK Life Sciences; Financial Interests, Institutional, Invited Speaker: ALX Therapeutics, Ascentage, Constellation Pharma, Alpine Biosciences, Forty Seven, Merck, Pfizer, Regeneron, Symphogen, InhibRx, Seagen, Sapience Therapeutics, Jounce, Northern Biologics, Odonate, Loxo/Lilly, Ikena, Mersana Therapeutics, Astellas, Celgene, Helsinn, Shattuck Labs, Samumed, Glaxo Smith Kline, Alkermes, Servier, Samumed, Tizona Therapeutics, Gilead, Repare Therapeutics, Alkermes, InhibRx. J. Powderly: Financial Interests, Personal, Other, Consulting: Boxer Capital; Financial Interests, Personal, Invited Speaker, Consulting: Aavocyte; Financial Interests, Personal, Invited Speaker, Founder and Owner: Carolina BioOncology Institute, Pllc, BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner of phase 1 cancer research clinic: Carolina BioOncology Institute, PLLC; Financial Interests, Personal, Other, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Invited Speaker: Bristol Myers Squibb, Cullinan, Genentech/Roche, AstraZeneca/MedImmune, EMD Serono, Macrogenics, InCyte, Top Alliance BioSciience, Seattle Genetics, AbbVie, FLX Bio, Alkermes, Arcus BioSciences, Tempest Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom, Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics, Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics; Financial Interests, Institutional, Funding: Precision for Medicine, MT Group, Stemcell Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal and Institutional, Funding: Pioma; Financial Interests, Personal and Institutional, Invited Speaker, Also funding for contract laboratory services: Nuvation; Other, Personal, Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy: BioCytics Inc. T. George: Financial Interests, Personal, Advisory Board: Pfizer Oncology, Tempus Labs; Financial Interests, Institutional, Invited Speaker: BMS, AZ, Lilly, Bayer, Incyte, Ipsen, Seagen, Genentech, Astellas, GSK, BioMed Valley Discoveries, Amgen, OncoC4, Jounce. D.G.K. Teoh: Financial Interests, Institutional, Invited Speaker: Jounce, Glaxo Smith Kline, Moderna. D. Kilari: Financial Interests, Personal, Invited Speaker: Astellas, Janssen, Pfizer, Aveo Oncology; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Institutional, Invited Speaker: Exelixis, Genentech, Jounce. G. Giaccone: Financial Interests, Personal, Advisory Board: Sanofi, Eisai, Spectrum; Financial Interests, Personal, Full or part-time Employment: Amgen. R.E. Sanborn: Financial Interests, Personal, Advisory Board: AstraZeneca, EMD Serono, Daiichi Sankyo, Lilly, Janssen Oncology, Macrogenics, Sanofi Aventis, Regeneron, Mirati Therapeutics, GlaxoSmithKline; Financial Interests, Personal, Invited Speaker: Amgen, GlaxoSmithKline, Janssen Oncology; Financial Interests, Institutional, Funding, Funding for investigator-sponsored trial: Merck, AstraZeneca; Financial Interests, Institutional, Other, Institutional research support: BMS; Financial Interests, Institutional, Funding, Clinical trial funding: Jounce. S. Ghamande: Financial Interests, Personal, Invited Speaker: Esai; Financial Interests, Personal, Advisory Board, also invited speaker: GSK; Financial Interests, Institutional, Invited Speaker, Clinical trial payments: GSK, Jounce; Financial Interests, Institutional, Invited Speaker, Clinical trial payment: Merck, Esai; Financial Interests, Institutional, Invited Speaker, clinical trial payments: Mersana, AstraZeneca; Non-Financial Interests, Personal, Advisory Role: GOG foundation. P. LoRusso: Financial Interests, Personal, Advisory Board: AbbVie, Genmab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, Glaxo-Smith Kline, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin, Kineta, Zentalis, Molecular Templates, ABL Bio, STCube, Bayer, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana, BAKX Therapeutics, Scenic Biotech, Qualigen, Roivant Sciences, NeuroTrials; Financial Interests, Personal, Other, Data Safety Monitoring Board: Agios, Five Prime, Halozyme; Financial Interests, Personal, Other, imCORE Alliance: Roche-Genentech; Financial Interests, Personal, Other, Consultant: Sotio, SK Life; Financial Interests, Personal, Other, Data Safety Monitoring Committee: Tyme; Financial Interests, Personal, Advisory Board, Advisory Board & Consultant: I-Mab; Financial Interests, Personal, Stocks/Shares: BAXK; Financial Interests, Institutional, Invited Speaker: AbbVie, ADC Therapeutics, ALX Oncology, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, Bayer, Black Diamond, Boehringer Ingelheim, Calico Life Sciences, Corvus Pharmaceuticals, CytomX Therapeutics, Eisai Pharmaceuticals, Eli Lilly, EMD Sernono, Five Prime, FLX Bio, F-Star Delta Limited, Genentech, Genmab, Incyte, Linnaeus Therapeutics, MedImmune, Merck Sharp & Dohme, Moderna Therapeutics, NextCure, Pfizer, Ribon Therapeutics, Sotio, Stemline Therapeutics, Takeda, Tesaro, Jounce; Non-Financial Interests, Personal, Other, AACI Clinical Research Innovation Steering Committee - Member: Association of American Cancer Institutes; Non-Financial Interests, Personal, Other, AACR Methods in Clinical Cancer Research Workshop - Co-Director: American Association for Cancer Research; Non-Financial Interests, Personal, Other, AACR Annual Report Committee - Member: American Association for Cancer Research; Non-Financial Interests, Personal, Other, Continuing Medical Education Committee - Member: American Association for Cancer Research; Non-Financial Interests, Personal, Other, Molecular Cancer Therapeutics Editorial Board - Member: American Association for Cancer Research; Non-Financial Interests, Personal, Other, ASCO Conquer Cancer Young Investigator Award Grand Selection Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Personal, Other, New Drugs in Oncology Seminar Planning Committee - Member: American Society of Clinical Oncology; Non-Financial Interests, Personal, Other, New Agents Committee: Translational Research Panel - Chair: Cancer Research Unite Kingdom; Non-Financial Interests, Personal, Other, Scientific Advisory Board - Member: Targeted Anti-Cancer Therapies; Non-Financial Interests, Personal, Other, Chair - Phase 0 Task Force: American Association of Cancer Research; Non-Financial Interests, Personal, Member: American Association for Cancer Research, ASCO; Other, Personal, Other, Investigational Drug Steering Committee - Committee Member: National Cancer Institute; Other, Personal, Other, Phase I Special Emphasis Panel - Grant Reviewer/Discussion Leader: National Cancer Institute; Other, Personal, Other, NeXT Special Emphasis Panel - Grant Reviewer: National Cancer Institute/National Institute of Health; Other, Personal, Other, Board of Scientific Counselors, Clinical Sciences & Epidemiology: National Cancer Institute; Other, Personal, Other, Young Investigator Meeting, Cancer Therapy Evaluation Program - Professor: National Cancer Institute; Other, Personal, Other, Academic Advisory Board SPORE GI Malignancies - Case Western Reserve University: Case Western Reserve University; Other, Personal, Other, External Advisory Board - Member: University of Arizona; Other, Personal, Other, External Scientific Advisory Board - Member: University of New Mexico; Other, Personal, Other, Scientific External Advisory Board - Member: University of California at San Diego. G. Gibney: Financial Interests, Personal, Advisory Board, Limited Consultant Role: Bristol Myers-Squibb, Merck, Lyell, Eisai, Regeneron, Genentech, Sapience Therapeutics; Financial Interests, Personal, Other, Consultant: Novartis; Financial Interests, Personal, Advisory Board, Consultant for data monitoring committee: Huyabio; Financial Interests, Personal, Advisory Board, Limited role on data monitor committee: Exicure; Financial Interests, Institutional, Invited Speaker, Support for investigator initiated trial: Exelixis, Lucerno Dynamics; Financial Interests, Institutional, Invited Speaker, Support for clinical trial: Jounce. V.T. Ma: Financial Interests, Institutional, Invited Speaker: Jounce Therapeutics; Non-Financial Interests, Personal, Principal Investigator: Jounce Therapeutics. K. Yalamanchili: Financial Interests, Institutional, Invited Speaker, Clinical trial funding: Jounce Therapeutics. J. Brown: Financial Interests, Personal, Invited Speaker, Speaker's Bureau for Avelumab: EMD Serono; Financial Interests, Personal, Invited Speaker, Speaker for MSL Training: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Jounce Pharmaceuticals, Seattle Genetics, Novita, Bicycle Therapeutics. N. Mota: Financial Interests, Personal, Stocks/Shares: Jounce Therapeutics. C. Tasillo Kadra: Financial Interests, Personal, Stocks/Shares: Jounce Therapeutics. B. Umiker: Financial Interests, Personal, Full or part-time Employment, I am an employee of Jounce Therapeutics: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares, I have shares of Jounce Therapeutics: Jounce Therapeutics. X. Xiao: Financial Interests, Personal, Invited Speaker, Employee: Jounce Therapeutics; Financial Interests, Personal, Full or part-time Employment, Full time employee with stock options: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares, have stock options: Jounce Therapeutics. E. Trehu: Financial Interests, Personal, Chief Medical Officer: Jounce Therapeutics, Inc.; Financial Interests, Personal, Invited Speaker, Member of the Board of Directors until Constellation was acquired in 2021: Constellation Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Jounce Therapeutics, Inc.

Background

FS222 is a novel tetravalent bispecific antibody targeting PD-L1 and CD137 that aims to overcome the limitations of current PD-(L)1 and CD137 (4-1BB) monotherapies via a unique mechanism of action that elicits PD-L1-dependent CD137 activation. This has the potential to deliver strong antitumor clinical activity, even in PD-L1 low conditions as seen in preclinical models, with good tolerability.

Methods

FS222 is being evaluated in an open-label, multi-center study in patients with advanced treatment-refractory solid tumors. Part A consists of single patient cohorts in an accelerated dose titration followed by a 3+3 design and pharmacokinetic/pharmacodynamic (PK/PD) expansion cohorts. Patients received FS222 intravenously every 4 weeks until disease progression or unacceptable toxicity. Adverse events and dose-limiting toxicities (DLTs) were primary endpoints. Efficacy (RECIST 1.1), PK, immunogenicity and PD biomarkers were secondary endpoints. Efficacy (iRECIST) and further PD biomarkers were assessed as exploratory endpoints.

Results

As of 20^th July, 2022, 33 patients (median age: 58 years) were treated with FS222 at doses of 300 μg (n=1), 1 mg (n=1), 3 mg (n=1), 10 mg (n=1), 30 mg (n=5), 0.75 mg/kg (n=15) and 1 mg/kg (n=9). 24 patients (73%) were checkpoint inhibitor-naïve. Median time on study was 58 days (range 19-359) with 11 ongoing. One patient experienced a DLT of grade-3 febrile neutropenia and one patient experienced grade-3 transaminase elevation without total bilirubin increase, both at 1 mg/kg. Maximum tolerated dose was not reached and dose escalation is ongoing. Pharmacological activity was demonstrated by increased peripheral soluble target receptors and proliferating CD4⁺ and CD8⁺ T cells. At 8 weeks, one patient experienced a complete response (CR), 6 had disease stabilization, 14 had progressive disease (RECIST 1.1), 3 discontinued before week 8, and 9 were awaiting their week 8 evaluation. The CR occurred in a non-squamous NSCLC patient who was naïve to PD-(L)1 therapy, dosed at 1 mg/kg. The CR remained persistent 10 months later.

Conclusions

Thus far, FS222 has demonstrated manageable tolerability and early signs of antitumor activity.

Clinical trial identification

NCT04740424.

Legal entity responsible for the study

F-star Therapeutics Inc.

Funding

F-star Therapeutics Inc.

Disclosure

G.A. De Velasco Oria: Financial Interests, Personal, Advisory Board: Pfizer, Astellas, BMS, MSD, Ipsen, Bayer, Eusa P., Merck; Financial Interests, Personal, Invited Speaker: Pfizer, Astellas, BMS, MSD, Roche, Ipsen, Merck; Financial Interests, Institutional, Research Grant: Roche. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann-La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol Mayers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer; Financial Interests, Personal, Full or part-time Employment: START; Non-Financial Interests, Personal, Principal Investigator, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. I. Melero: Financial Interests, Personal, Advisory Board: Gossamer Bio, Highlight Therapeutics, MSD, Alligator Bioscience, Genmab, Numab, NOXXON Pharma AG, BMS, CRISPR Therapeutics, Genentech, AstraZeneca, Boehringer Ingelheim, EMD Serono, Roche, CatalYm GmbH, BioLineRx, Boston Pharma, Janssen, Hookipa Pharma, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Monopteros Therapeutics; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator. A. Cervantes: Financial Interests, Institutional, Advisory Board: MerckSerono, Amgen, Roche, Transgene, AnHeart Therapeutics; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, Beigene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda; Non-Financial Interests, Personal, Other, General and Scientific Director: INCLIVA Biomedical Research Institute. D. Jones: Financial Interests, Personal, Stocks/Shares: F-star Therapeutics Inc. M.A. Lakins: Financial Interests, Personal, Stocks/Shares: F-star Therapeutics Inc. L. Kayitalire: Financial Interests, Personal, Stocks/Shares: F-star Therapeutics Incs. All other authors have declared no conflicts of interest.

Background

NGM707 is a humanized monoclonal antibody that binds the immune inhibitory receptors ILT2 and ILT4 and blocks interactions with their HLA ligands.

Methods

NGM707-IO-101 is a phase 1/2, dose escalation/expansion study evaluating NGM707 as a monotherapy and in combination with pembrolizumab. The monotherapy dose escalation enrolled eligible pts with advanced or metastatic solid tumors into escalating dose cohorts of NGM707 (6-1800 mg, Q3W iv). Primary objectives are to assess safety and tolerability of NGM707 and to identify phase 2 doses. Secondary/exploratory objectives include assessment of PK/biomarker correlation, immunogenicity and preliminary antitumor activity per RECIST v1.1.

Results

As of 21 Sep 2022, 33 pts have been enrolled in the monotherapy dose escalation at dose levels up to 1800 mg. Pts had received a median of 4 prior therapies (range 1-11) and all had metastatic disease. Treatment (Tx)-related adverse events (any grade/grade ≥3) occurred in 44%/9% of pts. One dose-limiting toxicity of pneumonitis (G5) in a pt with pulmonary metastasis was observed at 600 mg. A maximum tolerated dose was not reached and the maximum administered dose was 1800 mg. Linear PK was observed at doses ≥200 mg and analysis of peripheral immune cells demonstrated dose-dependent receptor occupancy (RO), with doses ≥200 mg maintaining ILT2 and ILT4 RO for the entire dosing interval. Preliminary evidence of myeloid reprogramming was observed in tumor biopsies, with reduction of the M2 macrophage marker CD163 observed post-treatment. Of 20 response-evaluable pts, best overall responses to date are stable disease in 6 pts and non-complete response/non-progressive disease in 1 pt. Five pts had reduced target lesion size with a maximum decrease in 1 pt of 28%. Seven pts remain on study with a maximum ongoing tx duration of 5 mo.

Conclusions

NGM707 monotherapy appears to be well tolerated at all dose levels. In this advanced, metastatic solid tumor cohort, early signals of efficacy were observed. Preliminary evidence of myeloid reprogramming was seen in tumor biopsies. Monotherapy tx is ongoing and enrollment of pembrolizumab combination cohorts has been initiated.

Clinical trial identification

NCT04913337.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Naing: Financial Interests, Personal, Funding: NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, Immune-Onc Therapeutics, Surface Oncology, Monopteros Therapeutics, BioNTech SE, Seven & Eight Biopharma, SOTIO Biotech AG; Financial Interests, Personal, Advisory Board: Deka Biosciences, NGM Bio, PsiOxus Therapeutics, Immune-Onc Therapeutics, STCube Pharmaceuticals, OncoSec KEYNOTE-695, Pharming, Genome & Company, Horizon Therapeutics, CytomX Therapeutics, Kymab; Financial Interests, Personal, Other, Consulting: Nouscom, Merck Sharp & Dohme Corp, OncoNano, Servier, Lynx Health; Financial Interests, Personal, Invited Speaker: AKH Inc, The Lynx Group, Society for Immunotherapy of Cancer (SITC), Korean Society of Medical Oncology (KSMO), Scripps Cancer Care Symposium, ASCO Direct Oncology Highlights, European Society for Medical Oncology (ESMO), European Society for Immunodeficiencies (ESID), CME Outfitters. J.S. Wang: Financial Interests, Personal, Invited Speaker, Member of Speaker's Bureau for Tagrisso and Imfinzi: AstraZeneca; Financial Interests, Personal, Invited Speaker, Member of Speaker's Bureau for Lenvima: Eisai; Financial Interests, Personal, Advisory Board, Single Event - Advisory Board Participation: BioNTech, Janssen R&D, Stemline/Menarini; Financial Interests, Institutional, Invited Speaker: 7,8 Pharma, Black Diamond Therapeutics, Klus Pharma, Relay Therapeutics, H3 Biomedicine, Genentech/Roche, ORIC, Celgene/BMS, Olema Therapeutics, Novartis, Portola, MabSpace, Prelude Therapeutics, Treadwell Therapeutics, IGM Biosciences, Forty Seven, StingThera, PureTech Health, Aevi Genomics, Erasca, Artios Pharma, Nurix, Teneobio, BioTheryX, Boehringer Ingelheim, Biosplice, Zymeworks, Bayer Healthcare, ImmunoOnc, Cullinan, Immuno-Gen, Accutar, Blueprint, Hutchinson MediPharma, BioNTech, Macrogenics, TopAlliance, AstraZeneca, Revolution Medicines, Kymab, Clovis Pharma, Qilu Pugent Sound, Ribon Therapeutics, Xencor, LSK BioPartners, Syndax, Sanofi, Daiichi Sankyo, Phoenix Molecular Designs, Cyteir, Bicycle Therapeutics. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono , Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. All other authors have declared no conflicts of interest.

Background

GEN1042 (DuoBody-CD40x4-1BB) is an investigational, novel, agonistic bispecific antibody that combines targeting and conditional activation of CD40 and 4-1BB on immune cells. GEN1042 demonstrated biologic and early clinical activity with a manageable safety profile in patients (pts) with advanced solid tumors in the dose escalation part of the ongoing phase 1/2 trial (NCT04083599). Previously presented preclinical data suggest that the immune response generated by GEN1042 treatment (Tx) can be amplified by co-administration of a PD-1 inhibitor. Combination with chemotherapy (CTx) is hypothesized to further enhance antitumor responses by increasing antigen release and PD-L1 expression. We present data from the safety run-in (SRI) and expansion cohorts investigating GEN1042 + pembrolizumab (PEM) ± standard of care (SoC) CTx.

Methods

Tx-naive pts with advanced, metastatic/unresectable/recurrent non-CNS tumors received GEN1042 + PEM ± CTx (nab-paclitaxel + gemcitabine or cis/carboplatin + 5-FU) until disease progression or unacceptable toxicity. Primary endpoint was dose-limiting toxicity (DLT) for SRI and objective response rate (ORR) for the expansion cohorts. Secondary endpoints included AEs, PK, antitumor activity (RECIST v1.1), and pharmacodynamic biomarkers.

Results

As of July 27, 2022, 20 pts (median age, 70.5 y; 12 pts with NSCLC, 3 pts with melanoma, 5 pts with HNSCC) had received GEN1042 + PEM; 17 pts (median age, 64.0 y; 5 pts with HNSCC, 12 pts with PDAC) had received GEN1042 + PEM + CTx. Tx-related AEs in ≥15% of pts (all grades; grade ≥3) were pruritus (20%; 0%), rash (15%; 5%), and pyrexia (15%; 0%) in the GEN1042 + PEM cohorts, and transaminase elevation (23.5%; 5.9%), rash (17.6%; 5.9%), diarrhea (17.6%; 0%), fatigue (23.5%; 0%), and nausea (17.6%; 0%) in the GEN1042 + PEM + CTx cohorts. No DLTs were observed in either group, and irAEs were as expected and manageable. Encouraging preliminary activity was observed in all patients with HNSCC treated with GEN1042 + PEM + CTx; updated results will be presented.

Conclusions

GEN1042 + PEM ± SoC CTx was overall well tolerated and showed initial antitumor activity in pts with advanced/metastatic disease.

Clinical trial identification

NCT04083599; Study Start Date: September 17, 2019.

Editorial acknowledgement

Medical writing and editorial assistance were provided by Peloton Advantage, Llc, an OPEN Health company, Parsippany, NJ, USA, and funded by Genmab.

Legal entity responsible for the study

Genmab A/S.

Funding

Genmab A/S and BioNTech.

Disclosure

I. Melero: Financial Interests, Personal, Advisory Board: Gossamer Bio, Highlight Therapeutics, MSD, Alligator Bioscience, Genmab, Numab, Noxxon Pharma AG, BMS, CRISPR Therapeutics, Genentech, AstraZeneca, Boehringer Ingelheim, EMD Serono, Roche, CatalYm GmbH, BioLineRx, Boston Pharma, Janssen, Hookipa Pharma, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Monopteros Therapeutics; Financial Interests, Personal, Other, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator. E. Grande Pulido: Financial Interests, Personal, Invited Speaker: Adacap, AstraZeneca, Bristol Myers Squibb, Eisai, Eusa Pharma, Ipsen, Janssen, Lilly, Merck KGa, Pfizer, Roche; Financial Interests, Personal, Advisory Board: Astellas, Bayer, MSD, Novartis, Sanofi-Genzyme; Financial Interests, Institutional, Advisory Board: Caris Life Sciences, OncoDNA (Biosequence); Financial Interests, Institutional, Research Grant, Independent research grant: Astellas, AstraZeneca, Lexicon, MTEM/Threshold, Nanostring Technologies, Pfizer, Roche, Merck; Financial Interests, Institutional, Invited Speaker, Independent research grant: Ipsen; Non-Financial Interests, Personal, Other, AD Board Member: ENETS. M.J. De Miguel Luken: Financial Interests, Personal, Other, Consulting Fees: Roche, MSD, Janssen. M.L. Johnson: Financial Interests, Institutional, Funding: AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals / Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, Y-mAbs Therapeutics; Financial Interests, Institutional, Other, Consulting/Advisory fees: AbbVie, Achilles Therapeutics, Amgen, AstraZeneca, Axelia Oncology, Atreca, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech / Roche, Genmab, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Ideaya Biosciences, iTeos, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Oncorus, Pfizer, Regeneron Pharmaceuticals, Ribon Therapeutics. J.R. Bauman: Financial Interests, Personal, Advisory Board: Kura, Janssen, Pfizer, Blueprint Medicine, Lilly, Merck, Mirati, Turning Point Therapeutics, Beigene. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer; Financial Interests, Personal, Full or part-time Employment: START; Non-Financial Interests, Personal, Principal Investigator, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. A.O. Walter: Financial Interests, Personal, Full or part-time Employment: BioNTech. H. Adams III: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab. î Türeci: Financial Interests, Personal, Full or part-time Employment: BioNTech; Financial Interests, Personal, Member of the Board of Directors: BioNTech. G. Russo: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab. U. Sahin: Financial Interests, Personal, Full or part-time Employment: BioNTech; Financial Interests, Personal, Member of the Board of Directors: BioNTech. J. Steinberg: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab. T. Ahmadi: Financial Interests, Personal, Full or part-time Employment: Genmab; Financial Interests, Personal, Stocks/Shares: Genmab. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Merck Sharp & Dohme, Pfizer, Sanofi, Takeda, Merck Serono, Peptomyc, F. Hoffmann-La Roche, Novartis, Daichii Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dome, Peervoice, Pfizer, Amgen, F. Hoffmann-La Roche, Janssen, Medical Trends, Merck Serono, Sanofi, Takeda, TouchONCOLOGY; Financial Interests, Institutional, Other, Grant for oncology innovation: Merck Healthcare KGAa; Financial Interests, Institutional, Other: Fundaciön Merck Salud; Financial Interests, Personal, Invited Speaker, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme Corp, AstraZeneca AB, Daiichi Sankyo Inc, Exelixis Inc, Merck KGAA, Janssen Cilag International NV, GlaxoSmithKline Research & Development Limited, AbbVie Deutschland GmbH & Co KG, Novartis Farmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim International GmbH, Pfizer S.L.U., Amgen Inc, Bristol Myers Squibb International Corporation (BMS), Mirati Therapeutics Inc; Non-Financial Interests, Personal, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Personal, Member, Member of ESMO Nominating Committee and Compliance Committee: ESMO; Non-Financial Interests, Personal, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform).

Background

A2A/A2B receptors drive adenosine-mediated immunosuppression in the tumor microenvironment; blockade has shown clinical activity in advanced solid tumors. This ongoing, 2-part (dose-escalation/expansion) phase 1 study is investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of INCB106385, an oral, potent, selective dual A2A/A2B receptor antagonist, alone or combined with an anti-PD-1 antibody retifanlimab for advanced solid tumors (NCT04580485). Part 1 (dose-escalation) monotherapy results are reported herein.

Methods

Eligible adults had confirmed advanced solid tumors by histology/cytology, disease progression after available therapy (including PD-[L]1 therapy, if applicable), measurable disease (RECIST v1.1), and ECOG PS 0-1. INCB106385 dosing started at 40 mg QD and was escalated using a BOIN design. PK parameters were calculated from INCB106385 plasma concentrations using non-compartmental, model-independent methods. PD was evaluated by measuring the reversal of adenosine-dependent inhibition of T cell and monocyte inflammatory cytokine production.

Results

As of July 16, 2022, 18 pts (male, n=16; age ≥65 years, n=17) had received INCB106385 monotherapy (40 mg QD, n=4; 40 mg BID, n=4; 80 mg BID, n=6; 160 mg BID, n=4); 16 discontinued therapy (progressive disease, n=14). The median (range) duration of treatment was 9.5 (0.9–40) weeks. Treatment-emergent AEs (TEAEs) occurred in 17 pts, most commonly asthenia, constipation, and diarrhea (each n=4). One pt had a grade ≥3 TEAE (grade 3 neutropenia; 40 mg BID); 2 had serious TEAEs (tumor pain; encephalopathy; both 40 mg BID); none were treatment-related. There were no dose-limiting toxicities or discontinuations due to TEAEs. INCB106385 plasma concentration remained above EC₉₀ (∼300 nM) for all BID doses during the inter-dose 0-12 h. In PD analysis, doses ≥80 mg BID approached EC₉₀ at steady state in most pts.

Conclusions

INCB106385 was generally well tolerated in pts with advanced solid tumors, with asthenia and gastrointestinal events being the most common TEAEs. Doses ≥80 mg BID were sufficient for target inhibition in most pts. Further dose escalation is ongoing in parallel with dose expansion.

Clinical trial identification

NCT04580485.

Editorial acknowledgement

Medical writing assistance was provided by Simon J. Slater, PhD, CMPP, of Envision Pharma Group (Philadelphia, PA, USA), and funded by Incyte Corporation.

Legal entity responsible for the study

Incyte Corporation.

Funding

Incyte Corporation.

Disclosure

A. Italiano: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, IPSEN, Merck CgA, MSD, Novartis, Parthenon, Roche, Springworks; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Bayer, Daiichy Sankyo, Ipsen, Merck CgA, Merck CgA, MSD, Novartis, Parthenon, Roche. O. Saavedra Santa Gadea: Financial Interests, Personal, Other, Travel, accommodations: Affimed. K. Papadopoulos: Financial Interests, Personal, Advisory Role: Basilia, Turning Point Therapeutics, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant: AbbVie, MedImmune, Daiichi Sankyo, Regeneron, Amgen, Calithera Biosciences, Incyte, Merck, Peloton Therapeutics, ADC Therapeutics, 3D Medicines, EMD Serono, Syros Pharmaceuticals, Mersana, MabSpace Biosciences, Jounce Therapeutics, Bayer, Anheart, F-star, Linnaeus, Mirati, Tempest Therapeutics, Treadwell Therapeutics, Lilly, Pfizer, Biontech, Bicycle Therapeutics, Kezar Life Sciences. A. Naing: Financial Interests, Institutional, Research Grant: Amplimmune, Arcus Biosciences, Armo BioSciences, Atterocor/Millendo, Bristol Myers Squibb, Calithera Biosciences, CytomX Therapeutics, Eli Lilly, EMD Serona, Healios Oncology Nutrition, ImmuneOncia, Incyte, Karyopharm, Kymab, MedImmune, Merck, NCI, NeoimmuneTech, Neon Therapeutics, Novartis, Pfizer, PsiOxus, Regeneron, Surface Oncology, TopAlliance Biosciences; Financial Interests, Personal, Advisory Board: CytomX Therapeutics, Genome & Company, Kymab, Novartis, OncoSec KEYNOTE-695, STCube Pharmaceuticals; Financial Interests, Personal, Other, Travel and accomodation expense: Armo BioSciences. C.A. Gomez-Roca: Financial Interests, Personal, Other, Honoraria/Speaker fee: AstraZeneca, Bristol Myers Squibb, Foundation Medicine Eisai, Pierre Fabre, Roche/Genentech; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Foundation Medicine, Genentech, Macomics, PharmaMar; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Roche/Genentech; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bristol Myers Squibb, Pierre Fabre, Roche. M. Mita: Financial Interests, Institutional, Research Grant: Seattle Genetics. M. Stein: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb/Medarex, Exelixis, Janssen Oncology, Merck Sharp & Dohme, Vaccitech, Xencor, Oxford Oncology; Financial Interests, Institutional, Research Grant: Advaxis, Bellicum Pharmaceuticals, Bristol Myers Squibb, Exelixis, Genocea Biosciences, Harpoon, Janssen Oncology, Lilly, Medivation/Astellas, Merck Sharp & Dohme, Nektar, Oncoceutics, Seattle Genetics, Suzhou Kintor Pharmaceuticals, Xencor, (Inst); Tmunity Therapeutics, Inc. . I. Rybicka: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. M. van der Velden: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. P. Zhang: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. M. Smith: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. O. Ivanova: Financial Interests, Personal, Full or part-time Employment: Incyte Corporation; Financial Interests, Personal, Stocks/Shares: Incyte Corporation. Y. Loriot: Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, Clovis Oncology, CureVac, Exelixis, Incyte Corporation, Janssen, Medivation, MSD, Nektar, OncoGeneX, Pfizer, Sanofi; Financial Interests, Personal, Advisory Role: Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Immunomedics, Janssen, MSD, Roche, Seattle Genetics, Taiho Pharmaceutical; Financial Interests, Personal, Other, Honoraria: Pfizer, Sanofi; Financial Interests, Personal, Officer, Travel/Accommodation expenses: Astellas Pharma; Financial Interests, Personal, Other, Travel/Accommodation expenses: AstraZeneca, Janssen, MSD, Roche, Seattle Genetics.

Background

Immune checkpoint blockade (ICB) has resulted in impressive clinical response rates in the treatment of melanoma and squamous cell carcinoma. Unfortunately, systemic administration of ICB therapy is associated with inconsistent patient responses alongside severe immune-related adverse events (iRAEs), resulting in discontinuation of treatment, especially when anti-PD-1 and anti-CTLA-4 mAb therapies are used in combination. Preclinical studies indicate that locoregional administration of ICB to internal solid tumours enhances immune responses with minimal toxicities, but this approach has not been fully explored in cutaneous tumours.

Methods

A triple combination (TC) of mAbs targeting (4-1bb/PD-1/VISTA) were injected peritumourally (10ug/mAb) or systemically (100ug/mAB) to C57BL/6J mice bearing TC-1 ears tumours, 3x over 9 days and compared to isotype control mAb treated mice. Tumour volumes, resistance to secondary tumour rechallenge, IFN-g ELISPOT and serum ALT assays and flow cytometry analysis of tumour bearing ears of therapy and isotype mAb treated mice was undertaken to characterize the mechanism, efficacy and safety following therapy administration.

Results

TC administered locally to ear tumours, induced potent anti-tumour responses and had superior efficacy to monotherapy. An abscopal effect was observed after one of two tumour bearing ears were administered TC therapy, resulting in 66% of treated mice regressing tumours in both ears. Surviving treated mice were resistant to subcutaneous TC-1 tumour rechallenge, implying the later induction of systemic immune memory. Mechanistically, the central role of CD8 T cells in driving therapy mediated anti-tumour responses was confirmed using systemic CD8 depletion. Increased proportions of Granzyme B+ CD8+ T cells and lower CD4+ T_regs were concurrently observed in TC treated animals compared to isotype control. While i.v. therapy resulted in elevated serum ALT and liver immune cell infiltrates, locally administered TC mAbs were well tolerated.

Conclusions

Our results demonstrate a novel, safe, dose-sparing strategy to administer combinations of checkpoint therapies for immune targeting of advanced, local cutaneous tumours.

Legal entity responsible for the study

The authors.

Funding

The University of Queensland Research Training Scholarship; Tour de Cure.

Disclosure

All authors have declared no conflicts of interest.

Background

Recombinant immunotherapeutic fusion proteins (rIFPs) were designed to target triple-negative breast cancer (TNBC). This is a heterogeneous and aggressive subset of breast cancer accounting for 15-20% of all diagnosed breast cancer cases, with women of premenopausal age and African descent inordinately predisposed. Based on previous studies, we hypothesised that the ability to bind to two identical antigens through a bivalent antibody increases the total strength of the reaction and that increasing the affinity and valency of tumour-targeting antibodies results in improved tumour uptake. Furthermore, the rate of internalisation and intracellular routing of rIFPs may be significant for their therapeutic efficacy. Understanding these factors could impact the use of such biopharmaceuticals for targeted treatment with relevant cell surface biomarkers.

Methods

Mono- and bivalent rIFPs targeting a tumour-associated antigen were transiently expressed in mammalian cell culture and purified using ion metal affinity chromatography (IMAC). Following SDS-PAGE and Western Blot protein analysis, the proteins were fluorescently labelled and the differences between the mono- and bivalent rIFP formats were evaluated in vitro using confocal imaging. The efficacy in binding to targeted cell surface receptors, rate of internalisation, and intracellular routing of internalised rIFPs were evaluated to determine such differences. Differences in rIFP-mediated cytotoxicity were evaluated in vitro using XTT-based cell viability assays.

Results

The rIFPs were successfully expressed, purified, and characterised. Imaging results indicate that the bivalent rIFPs display increased binding affinity and faster internalisation rate compared to the monovalent counterpart when applied to a confirmed antigen-positive TNBC cell line. This is correlated with an enhanced cytotoxic effect of the bivalent rIFP.

Conclusions

The results of this study may have implications for the future designs of rIFPs, however, in vivo pharmacokinetic studies are needed to further elucidate the effect of valency on the efficacy of recombinant immunotherapeutic fusion proteins.

Legal entity responsible for the study

Medical Biotechnology & Immunotherapy Research Unit.

Funding

National Research Foundation (South Africa).

Disclosure

All authors have declared no conflicts of interest.

Background

cNeT therapy addresses limitations of TIL therapies including the requirement for high dose lymphodepletion and IL-2 which restricts application to fitter patients, and limited understanding of the active component that limits product optimisation and potency assay development. We have initiated trials evaluating cNeT in advanced, heavily pre-treated patients with NSCLC (CHIRON, NCT04032847) or melanoma (THETIS, NCT03997474) utilising lower dose lymphodepletion and IL-2 (1M IU/m2 sc x10d).

Methods

14 patients (8 CHIRON, 6 THETIS) received a single dose of cNeT characterised using cytokine-based antigen-specific assays, flow cytometry and single cell RNA/TCRseq, that were also used to track cNeT post-infusion. These form the safety data set. Median cNeT dose was 18M cells (0.1-287M), with a median clonal reactivity of 16% (0.2-77%).

Results

There were 28 G≥3 treatment-related AEs with lymphopenia and neutropenia the most common. One cNeT related SAE (ICANS) and 3 episodes of cytokine release syndrome (G≤2) were reported with no high-grade toxicities associated with IL-2. 6 patients have died on study, all due to disease progression. With 15-115 wk follow up 7 NSCLC patients have ≥2 restaging scans (1 pending). Best response was PR in 1 (33+wk), SD in 5 (ongoing in 2 at 15+, 26+ wk), and PD in 1, with an overall durable clinical benefit ≥18 wk in 3/7 (43%). The PR showed 57% total tumour reduction at week 24 (investigator reported). Flow cytometry revealed early expansion of CD8+KI67+ T cells previously associated with response to checkpoint inhibitors. Peak expansion of cNeT was seen at d21 coincident with a peak in IL-6. In depth characterisation of the cNeT product using single cell RNA and TCRseq suggests the active component is polyfunctional in nature with reactive T cell clusters bearing signatures of T cell proliferation, IL-2 sensitivity, cytokine secretion and tissue migration.

Conclusions

We demonstrate an encouraging early safety and tolerability profile consistent with further application to a broader patient population along with the potential for deep and durable clinical responses in NSCLC despite low doses of cNeT and reduced dose lymphodepletion and IL-2.

Clinical trial identification

NCT04032847, NCT03997474.

Legal entity responsible for the study

Achilles Therapeutics.

Funding

Achilles Therapeutics.

Disclosure

M.D. Forster: Financial Interests, Personal, Advisory Board: Bayer, Merck, MSD, Novartis, Roche, Takeda, Ultrahuman, Transgene, Ixogen, Immunotep; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, MSD, Merck; Financial Interests, Institutional, Invited Speaker: StarPharma, Roche. J. Cave: Financial Interests, Personal, Other: Novartis, Eli Lilly, Boehringer Ingelheim. A. Greystoke: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Roche, Novartis; Financial Interests, Personal, Invited Speaker: Merck, MSD, Pfizer, Janssen; Financial Interests, Institutional, Invited Speaker: MSD, Pfizer, AstraZeneca, Novartis, Achilles; Non-Financial Interests, Personal, Advisory Role: National Institue for Health and Clinical Excellence; Other, Personal, Other, Clinical Lead for Cancer (paid position): North East Englad and Yorkshire Genomic Laboratory Hub. R. Plummer: Financial Interests, Personal, Advisory Board: Pierre Faber, Bayer, Novartis, BMS, Cybrexa, Ellipses, CV6 Therapeutics, Astex Therapetics, Sanofi Aventis, Immunocore, Genmab, Medivir, Onexo; Financial Interests, Institutional, Royalties, Royalties relating to rucaparib licencing: Clovis Oncology; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO, Alligator Biosciences; Financial Interests, Personal, Other, Honoraria as member of IDMC: GSK. J. Spicer: Financial Interests, Institutional, Advisory Board: Lilly, AstraZeneca, Boehringer Ingelheim, BMS, Genmab, GSK, RS Oncology, Seattle Genetics, Merck; Financial Interests, Personal, Stocks/Shares, Co-founder: Epsilogen; Financial Interests, Institutional, Invited Speaker: Achilles, Genmab, Roche, Seattle Genetics, Starpharma, Trizell, BergenBio, BMS, IO Biotech, MSD; Non-Financial Interests, Personal, Invited Speaker, National strategy board: Experimental Cancer Medicine Centres; Non-Financial Interests, Personal, Invited Speaker, Steering Committee: British Thoracic Oncology Group. F. Thistlethwaite: Financial Interests, Personal, Advisory Board, honoraria: Bayer; Financial Interests, Personal, Advisory Board, Ad board: BMS, Zelluna; Financial Interests, Personal, Advisory Board, Ad boards: GSK; Financial Interests, Personal, Advisory Board, Adboard/consultancy: Tknife; Financial Interests, Personal, Advisory Board: Adicet, Janssen, EnaraBio, Immatics, Ixaka, Scenic Biotech; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Other, iMATCH is a 12 partner consortium funded by not for profit Innovate UK (UK government body) partners include commercial, clinical and academic institutes. I am director and my salary (0.2WTE) is supported through this work as a grant to my institution (The Christie NHS foundation trust - not for profit NHS hospital) from IUK: iMATCH director; Financial Interests, Institutional, Officer, Clinical lead for this 10 partner consortium of clinical academic and commercial partners. My salary is partly supported (approx. 0.05WTE) through this by a grant paid by Innovate UK (a NFP government body) to my institution (The Christie NHS foundation trust a NFP UK hospital): SAMPLE; Financial Interests, Institutional, Invited Speaker: Pfizer, GenMab, synthon, CytomX, Incyte, Janssen, Adaptimmune, Aveo, BMS, GSK, Roche, AbbVie, Immunocore, Achilles ltd, Agalimmune Ltd, Kymab Ltd, Chugai, Millenium Pharmaceuticals/Takeda, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Novartis, GSK; Financial Interests, Personal, Invited Speaker: AstraZeneca; Non-Financial Interests, Personal, Other, Panel member for a funding committee (MRC is a UK government NFP organisation): MRC DPFS panel member. S. Turajlic: Financial Interests, Personal, Invited Speaker: IDEA Pharma, Roche, Ventana, MSD, Merck; Financial Interests, Institutional, Funding, Uncommon theme pump priming funds: NIHR; Financial Interests, Institutional, Funding, Digital theme funding: RMH/ICR/BRC/Imperial AHSC/Faculty of Medicine; Financial Interests, Institutional, Funding, Tracking renal cancer evolution in blood: Rosetrees Trust; Financial Interests, Institutional, Funding, Clinical PhD Fellowship over 3 years: CRUK Welcome Trust; Financial Interests, Institutional, Funding, Investigating the relationship between primary melanomas and their metastases: The Robert McAlpine Foundation; Financial Interests, Institutional, Funding, Innovation Grant Award for biomarker development: The Francis Crick Institute; Financial Interests, Institutional, Funding, Developing a novel method of representative tumour in sampling in clinical setting: Ventana; Financial Interests, Institutional, Funding, Mapping clonal evolution in renal cell carcinoma: CRUK training and career development board - clinician scientist fellowship; Financial Interests, Institutional, Funding: Harry J Lloyd Charitable Trust Career Development Award; Financial Interests, Institutional, Funding, Clinical Research Fellowship in melanoma: Andy Quick Charitable fund; Financial Interests, Institutional, Funding, Mechanisms of BRAF resistance: Complete Genomics; Financial Interests, Institutional, Funding, Molecular profiling of non-cutaneous melanoma: CRUK; Financial Interests, Institutional, Funding, Target discovery in acral melanoma: Rosetrees Trust. A. Craig, K. Newton, M. Saggese, S. Quezada, K. Peggs: Financial Interests, Institutional, Full or part-time Employment: Achilles Therapeutics.

Background

The gut microbiome has the singular property of shaping the immune system through a multitude of antigens that educate the T cell repertoire. Since microbial peptides can share similarities with tumor antigens, cross-reactive memory T cells that recognize both bacterial and tumor-derived peptides can thus emerge from the imprinting of the T cell repertoire by gut commensals. Harnessing the full potential of cross-reactive CD8+ T cells against tumor cells could therefore be achieved through the rational design of a microbiota-derived peptide vaccine.

Methods

Enterome developed a novel peptide-based immunotherapy built on the principle of T cell cross-reactivity and molecular mimicry between bacterial-derived peptides called OncoMimics^TM peptides (OMP) and Tumor-Associated Antigens (TAA). HLA-A2-restricted OMP candidates targeting human TAA were first selected in silico from our proprietary metagenomic bank of human gut microbiota and then confirmed through in vitro binding assays, and in vivo evaluations of their immunogenicity and capacity to induce cross-reactive T cell responses against TAA in HLA-A2/DR1 humanized mice. Finally, the prevalence and functionality of OMP-specific T cells were assessed in human blood from healthy donors using tetramers, in vitro stimulation, and cytotoxicity assays.

Results

Selected OMPs could elicit cross-reactive cytotoxic T cell (CTL) responses against human TAA. This was demonstrated by the propensity of these CTL to secrete IFN-γ upon recognition of OMP or TAA peptides, reject TAA peptide-pulsed splenocytes as well as tumors ectopically expressing the selected TAA targets. We finally demonstrated that OMP-specific memory CD8+ T cells pre-exist in human blood, with high prevalence (>80% in the population), and harbor strong CTL functions against TAA when activated ex vivo with OMPs.

Conclusions

We show that gut microbiota-derived peptides mimicking TAAs can elicit strong immune responses against tumors. The pre-existence of these cross-reactive CD8+ T cells in healthy donors exemplifies the strong promises of this innovative approach to develop efficient therapeutic cancer immunotherapies. To date, two OMP-based immunotherapies are evaluated in 3 clinical trials (Glioblastoma, Adrenal cancers, B lymphomas).

Legal entity responsible for the study

Enterome.

Funding

Enterome SA.

Disclosure

All authors have declared no conflicts of interest.

Background

SELECT is a phase 2 randomized study of P, an investigational PD-1 inhibitor (PD-1i) plus V, an investigational ICOS agonist, vs P in TIS^vopra selected, immunotherapy naïve, 2^nd line non-small cell lung cancer (NSCLC). Tumor inflammation signature (TIS) at and above a designated cut-off, termed TIS^vopra, was previously associated with improved clinical outcomes in patients treated with V +/- nivolumab. SELECT was designed to demonstrate superiority of P + V vs P in TIS^vopra selected pts and evaluate 2 doses of V with different pulsatile target engagement (TE) profiles to reduce T cell exhaustion.

Methods

69 TIS^vopra positive pts with metastatic NSCLC after 1 prior platinum-containing regimen were randomized 2:1:1 to P 1000 mg (MC1, n=36), P+V 0.1 mg/kg (CC1, n=18) or P+V 0.03 mg/kg (CC2, n=15) q6w. Primary (1°) endpoint was mean % change from baseline size of all measurable lesions averaged over 9 & 18 weeks by independent central radiology review (ICR); the study was powered to compare MC1 vs pooled CC1+CC2. Overall response rate (ORR) per RECIST v1.1 by ICR, progression free survival (PFS), and overall survival (OS) were secondary (2°) endpoints. Safety, TE and association between PD-L1 and efficacy were evaluated.

Results

1° endpoint was numerically better in CC1+CC2 vs MC1 but not statistically significant. CC2 trended favorably for 1° endpoint, ORR, and PFS. ORR (95% confidence interval [CI]) was 40% (16, 68) for CC2, 25% (12, 42) for MC1, 17% (4, 41) for CC1. 6 month (mo) PFS rate (95% CI) was 80% (50, 93) for CC2, 33% (16, 50) for MC1, 29% for CC1 (10, 52). Except for CC2 6 mo PFS rate data are not mature. PD-L1 was evenly distributed across TIS^vopra pts but not associated with efficacy. Study treatment was well tolerated with 7.2% of pts reporting Grade ≥3 treatment related adverse events (TRAEs). Most common TRAEs were Grade 1/2 hyperthyroidism, hypothyroidism, rash. The pulsatile pattern of V 0.03 mg showed shorter duration of TE vs 0.1 mg.

Conclusions

P +/- V was well tolerated. The 1° endpoint was not met. P+V 0.03 mg/kg trends toward improved clinical benefit in 1° and 2° endpoints and responses are durable. P is active and continues to be used in combination trials. Shorter TE duration of V 0.03 mg/kg may contribute to clinical activity.

Clinical trial identification

NCT04549025.

Legal entity responsible for the study

Jounce Therapeutics, Inc.

Funding

Jounce Therapeutics, Inc.

Disclosure

M. Gumus: Financial Interests, Institutional, Invited Speaker: Pfizer, Gen Pharmaceuticals, Novartis, Bayer, Amgen, Jounce Therapeutics; Financial Interests, Institutional, Advisory Board: Amgen, Roche, BMS, Astra-Zeneca. A. Sukalinskaya: Financial Interests, Institutional, Invited Speaker: Jounce Therapeutics. Z.G. Andric: Financial Interests, Personal, Invited Speaker: MSD, Roche, AstraZeneca, Novartis, Merck-D. V. Cheshuk: Financial Interests, Personal, Principal Investigator: Jounce Therapeutics. T. Ciuleanu: Financial Interests, Institutional, Other, Principal Investigator: Jounce Therapeutics. S. Sezgin Goksu: Financial Interests, Personal, Advisory Board: Novartis, MSD; Financial Interests, Personal, Invited Speaker: Novartis, Roche, Phizer, BMS, MSD; Financial Interests, Personal and Institutional, Invited Speaker: BMS, MSD, Lilly, Roche, Jounce Therapatics. T. Cil: Financial Interests, Institutional, Invited Speaker: Jounce Therapeutics. I. Cicin: Other, Personal, Other, Principal investigator for Jounce Therapeutic: Jounce Therapeutic. I.V. Bulat: Financial Interests, Personal and Institutional, Invited Speaker: Jounce Therapeutics. Y.V. Ostapenko: Financial Interests, Institutional, Other, Principal Investigator: Jounce Therapeutics. K.D. Penkov: Financial Interests, Personal, Advisory Board: Nektar terapeutics; Financial Interests, Personal and Institutional, Invited Speaker: AbbVie, AstraZeneca, Pfizer, Jounce Terapeutics, Polyphor, GSK, Mabscale, Biocad, Sanofi, Novartis. C. Hart: Financial Interests, Personal, Full or part-time Employment: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares, Shareholder: Jounce Therapeutics. M. Lai: Financial Interests, Personal, Full or part-time Employment: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares: Jounce Therapeutics. B. Chaao: Financial Interests, Personal, Full or part-time Employment: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares, Shareholder: Jounce Therapeutics. J. Jimenez: Financial Interests, Personal, Full or part-time Employment: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares, Shareholder: Jounce Therapeutics. A. Sepahi: Financial Interests, Personal, Full or part-time Employment: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares, Shareholder: Jounce Therapeutics. G. Shi: Financial Interests, Personal, Full or part-time Employment: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares, Shareholder: Jounce Therapeutics. S. Trott: Financial Interests, Personal, Full or part-time Employment: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares, Shareholder: Jounce Therapeutics. E. Hooper: Financial Interests, Personal, Other, Full time employee of Jounce; have spoken at public events regarding Jounce related programs: Jounce Therapeutics; Financial Interests, Personal, Full or part-time Employment, Sr. Medical Director at Jounce: Jounce Therapeutics; Financial Interests, Personal, Stocks/Shares, Owner of Jounce stock as a benefit of full time employment: Jounce Therapeutics.

Background

Vaccines represent attractive components of the tumor immunotherapy armamentarium. Although whole tumor-based vaccines and private neoantigens-based vaccines; each have pros and cons, their relative efficacy has never been comprehensively investigated. Furthermore, neoantigens prioritization to enrich for tumor-rejection antigens remains challenging.

Methods

In this study, we used a murine lung cancer model (LLC1) to investigate the effect of immunization with DCs pulsed with oxidized whole tumor lysate (WTL_DC vax) or neoantigen peptides (Neo_DC vax) on tumor growth. Distinct algorithms were used to predict and prioritize LLC1 candidate neoepitopes. Finally, we retrospectively meta-analyzed neoepitopes selection in a cohort of vaccine-treated ovarian and lung patients to improve correlates of immunogenicity and efficacy.

Results

WTL-DC vax was more effective in suppressing LLC1 tumor growth than Neo_DC vax (when neoepitopes were selected with any of the commonly-used in silico predictors based on peptide-MHC affinity). In contrast, vaccine efficacy significantly improved when immunogens were selected on the basis of the effective in vitro binding of candidate neoepitopes to cognate MHC alleles that was experimentally determined. Vaccine efficacy also significantly improved when immunogens had pre-validated or predicted (using PRIME1.0) immunogenicity. Finally, as opposed to their in silico scores, the effective in vitro binding efficacy of candidate immunogens better correlated with vaccine efficacy (clinical responses) in cohorts of lung cancer patients and with immunogenicity in cohorts of ovarian cancer patients.

Conclusions

Vaccine based on private neoepitopes predicted using common in silico predictors of peptide-MHC affinity are outperformed by WTL-based vaccines. Parameters such as in vitro peptide-MHC binding and peptide immunogenicity significantly improve the prioritization of tumor-rejecting neoepitopes and should be taken into consideration to increase vaccines’ clinical efficacy.

Legal entity responsible for the study

CHUV.

Funding

LICR CHUV UNIL.

Disclosure

All authors have declared no conflicts of interest.

Background

SQZ-eAPC-HPV (eAPC) is an autologous, cell based, HLA-genotype agnostic HPV therapeutic cancer vaccine that leverages clinical and manufacturing experience from the SQZ-PBMC-HPV clinical candidate (NCT04084951). eAPC is engineered from peripheral blood mononuclear cells by using Cell Squeeze® technology to simultaneously deliver 5 mRNAs encoding for full length HPV16 E6 and E7 proteins, CD86, and membrane-bound (mb) IL-2 and mbIL-12 cytokines. By driving co-localized MHC-I antigen presentation (E6/E7), costimulation (CD86), and cytokine signaling (IL-2/IL-12), the eAPCs may enable more potent T cell activation and proliferation while limiting known toxicity of interleukin therapy.

Methods

Part 1A assesses eAPC as a monotherapy with intravenous dosing every 3 weeks (Q3W). In Cohort 1 enrolled patients (pts) receive 0.5 x 10⁶eAPC/kg Q3W for up to 1 year. Following a Bayesian optimal interval design, 3 - 12 pts may be enrolled per cohort. Eligible pts undergo a single leukapheresis. Preconditioning is not required and eAPCs are administered outpatient after the first dose. Adverse events were assessed by CTCAEv5.0. Tumor response was assessed by RECIST1.1. Baseline and on-treatment pharmacokinetic and pharmacodynamic samples were also collected.

Results

4 pts with HPV16+ solid tumors (cervical, 2; oropharyngeal, 1; vaginal, 1) were dosed in Cohort 1. Cell collection to product release was ∼1 week; adequate eAPC doses were manufactured for all pts. All pts completed the 28-day dose limiting toxicity (DLT) period without experiencing a DLT. No related serious adverse events were reported. Only one eAPC related treatment emergent adverse event was reported (Grade 1 fall). Enrollment in Cohort 2 has commenced at a dose of 2.5 x 10⁶ eAPC/kg. The presentation may include safety, preliminary efficacy, and pharmacokinetic/pharmacodynamic data from a cut-off proximal to presentation.

Conclusions

eAPC explores the impact of multiplexed mRNA-based engineering of a cancer vaccine. As of the data cut-off for this abstract (17Aug22), it is thus far well tolerated.

Clinical trial identification

NCT05357898.

Legal entity responsible for the study

SQZ Biotechnologies Company.

Funding

SQZ Biotechnologies Company.

Disclosure

J. Moser: Financial Interests, Institutional, Advisory Role: BMS, Amunix, Thirona Bio, Adagen, Imaging Endpoints, Caris; Financial Interests, Institutional, Funding: NovoCure (Inst), Genentech (Inst), Alpine Immune Sciences (Inst), Amgen (Inst), Trishula Therapeutics (Inst), BioEclipse Therapeutics (Inst), FujiFilm (Inst), ImmuneSensor (Inst), Simcah (Inst), Repertiore Immune Sciences (Inst), Nektar Therapeutics (Inst), Synthorax Inc (Inst), Istari Oncology (Inst), Ideaya Biosciences (Inst), Rubius (Inst), University of Arizona (Inst); Financial Interests, Institutional, Other, Honoraria: Caris Life Sciences, TGen; Financial Interests, Institutional, Member: Caris Molecular Tumor Board; Financial Interests, Institutional, Invited Speaker: Caris Life Sciences, Immunocore. M. Pelster: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Bayer, Novartis, Astellas, CytomX, Gritstone Oncology, Arcus Biosciences, Surface Oncology, Codiak BioSciences, Immune-Onc Therapeutics, HiberCell; Financial Interests, Institutional, Principal Investigator: SQZ Biotechnologies. A. Jimeno: Financial Interests, Institutional, Funding, for 3 trials: NCI; Financial Interests, Institutional, Principal Investigator: Cantargia, DebioPharm, Iovance, Khar Biopharma, Merck, Moderna, Pfizer, Sanofi, SQZ Biotechnologies. J.C. Park: Financial Interests, Institutional, Other, Honoraria: Cancer Expert Now, Alira Health; Financial Interests, Institutional, Advisory Role: GC Calls, Selexcine, ABL Bio, MitoImmune; Financial Interests, Institutional, Advisory Board: BW Biomed; Financial Interests, Institutional, Funding: ALX Oncology (Inst), SQZ Biotech (Inst), Inhibrx (Inst), Merck (Inst), Oncorus (Inst), ISA Therapeutics (Inst), Monopteros Therapeutics (Inst). W.T. Iams: Financial Interests, Institutional, Funding, Young Investigator Award: NCCN; Financial Interests, Institutional, Advisory Role: Genentech, Jazz Pharma, G1 Therapeutics, Mirati, BMS, Takeda, Janssen, EMD Serono, OncLive, Curio Science, Chardan, Cello Health, Outcomes Insights, Clinical Care Options; Financial Interests, Institutional, Principal Investigator: Takeda, Amgen, Nitto Biopharma, Lilly, Merck, SQZ Biotechnologies. T. Wise-Draper: Financial Interests, Institutional, Stocks/Shares, Stocks and Other Ownership Interests: High Enroll; Financial Interests, Institutional, Other, Honoraria: Physician Education Resource; Financial Interests, Institutional, Advisory Role: Shattuck Labs, Rakuten, Exicure, Merck, Caris Life Sciences; Financial Interests, Institutional, Funding: Merck, Caris Life Sciences, AstraZeneca/MedImune, Bristol Myers Squibb, GlaxoSmithKline, GSK, Janssen Oncology; Financial Interests, Institutional, Other, travel, accomodations: Merck, Caris Life Sciences; Financial Interests, Institutional, Other, travel, accomodations, expenses: AstraZeneca/MedImune, Bristol Myers Squibb, Bexion, Lilly, Tesaro. J. Jennings: Financial Interests, Institutional, Full or part-time Employment: SQZ Biotechnologies. N.R. Miselis: Financial Interests, Institutional, Full or part-time Employment: SQZ Biotechnologies. R.R. Ji: Financial Interests, Institutional, Full or part-time Employment: SQZ Biotechnologies. S.M. Loughhead: Financial Interests, Institutional, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Institutional, Other, Named inventor of patents either licensed by or assigned to SQZ Biotechnologies: SQZ Biotechnologies. R. Zwirtes: Financial Interests, Institutional, Full or part-time Employment: SQZ Biotechnologies. M. Warren: Financial Interests, Institutional, Officer: SQZ Biotechnologies. A. Sharei: Financial Interests, Institutional, Officer: SQZ Biotechnologies; Financial Interests, Institutional, Other, Named inventor of patents either licensed by or assigned to SQZ Biotechnologies: SQZ Biotechnologies. H. Bernstein: Financial Interests, Institutional, Officer: SQZ Biotechnologies; Financial Interests, Institutional, Other, Named inventor of patents either licensed by or assigned to SQZ Biotechnologies: SQZ Biotechnologies. M. Gordon: Financial Interests, Institutional, Advisory Role: Imaging Endpoints, Instil Bio, Tracon, Daiichi, Qualigen; Financial Interests, Institutional, Other, Patents planned, issued, or pending: Caremission; Financial Interests, Institutional, Funding: GSK, AbbVie, Merck Serono, MedImmune, Incyte, Pfizer, Amgen, Gilead Sciences, Endocyte, Seattle Genetics, Plexxicon/Daiichi, Celldex, Tracon, Deciphera, Fujifilm, Minnemarita, Nektar, Novita, Biosplice, Corcept, Novartis, Toray, Genzada, Salarius, Agenus, Inhibrx, AADi, Revolution Medicine, Blueprint, Astellas, BioNTech, Helix, IgM Biosciences, ImmuneSensor, Bioeclipse, Bioline, Black Diamond, Codiak, Dracen, Elevation Oncology, Framewave, Forma Therapeutics, IntraImmun SG, Pionyr, Trishula, Tolero, Vedanta Biosciences, Coordination Therapeutics, Ideaya Biosciences, I-Mab, NiKang, Nimbus Therapeutics, OncoResponse, Riboscience, Rubius Therapeutics, Simcha Therapeutics, Siranomics, Synthorx, Theseus Pharmaceuticals, Zai Labs, Genentech/Roche.

Background

FMPV-1 is a novel injectable vaccine to generate anti-cancer T cell responses. The vaccine is an immunogenic frameshift mutated transforming growth factor β receptor 2 (TGFβR2) peptide commonly occurring in microsatellite instability cancers (MSI-H). FMPV-1 is administered in combination with the adjuvant granulocyte macrophage colony stimulating factor (GM-CSF). This is the first clinical study to assess the safety and immunogenicity of FMPV-1/GM-CSF in man.

Methods

This was a single centre, open-label study in 16 healthy male subjects. Primary safety endpoints were adverse events (AEs), laboratory tests, vital signs, electrocardiograms (ECGs) and physical examination. Immunogenicity was assessed by FMPV-1-specific delayed type hypersensitivity (DTH) responses and FMPV-1-specific T-cell proliferation. All subjects received FMPV-1 (0.15 mg/injection) plus GM-CSF (0.03 mg/injection) as two separate injections on days 1, 8, 15, 29, and 43. DTH skin reactivity test was performed with FMPV-1 only on days 1, 29 & 43 with DTH response assessment 2 days later. T cell analyses were performed. Subjects were followed to Day 80 with further immunogenicity to be assessed at 6 and 12 months.

Results

16 subjects were enrolled and completed day 80 per protocol. FMPV-1/GM-CSF was well tolerated with no dose limiting toxicities reported, no major protocol deviations and no serious adverse events. Of the 17 treatment-emergent AEs occurring in 11 subjects, all were Grade 1 except 1 unrelated to IMP Grade 2 rise of creatine kinase. Six related AEs occurred in 6 subjects, being Grade 1 pruritus at injection site. No other clinically significant changes to ECG, vital signs or laboratory measures were seen. All subjects were DTH negative at baseline before dosing; after 3 FMPV-1/GM-CSF vaccinations, 8/16 (50%) subjects were positive at Day 31 with 15/16 (94%) at Day 45 after 4 vaccinations. In vitro T cell proliferation post-vaccination increased compared to pre-vaccination in subjects tested, with analysis ongoing.

Conclusions

The excellent safety profile of FMPV-1/GM-CSF and vaccine-specific immune responses in healthy subjects support further clinical development in a patient population for a phase 2 study in MSI-high colorectal cancer.

Clinical trial identification

NCT05238558.

Legal entity responsible for the study

Hubro Therapeutics AS.

Funding

Hubro Therapeutics AS.

Disclosure

N. Singh: Other, Institutional, Principal Investigator: Quotient Sciences. R.M. Miller: Financial Interests, Institutional, Full or part-time Employment: Hubro Therapeutics AS. S.J. Arbe-Barnes: Financial Interests, Institutional, Full or part-time Employment: Hubro Therapeutics AS. H. Kvalheim Eriksen: Financial Interests, Institutional, Full or part-time Employment, Stock options: Hubro Therapeutics AS. B. Iverson: Financial Interests, Institutional, Full or part-time Employment: Hubro Therapeutics AS; Financial Interests, Personal, Stocks/Shares: Hubro Therapeutics AS. J.A. Eriksen: Financial Interests, Personal and Institutional, Ownership Interest: Hubro Therapeutics AS; Financial Interests, Personal and Institutional, Stocks/Shares: Hubro Therapeutics AS; Financial Interests, Institutional, Full or part-time Employment: Hubro Therapeutics AS. All other authors have declared no conflicts of interest.

Background

EO2401 is a therapeutic vaccine designed to activate memory commensal-specific T cells cross-reacting with tumor-associated antigens (TAAs). EO2401 includes synthetically produced HLA-A2 peptides with molecular mimicry to TAAs (IL13Rα2, BIRC5 and FOXM1) upregulated in glioblastoma, and the CD4 helper peptide UCP2.

Methods

Patients with glioblastoma at first progression after radiotherapy/temozolomide received EO2401 (300μg/peptide, q2w x4 then q4w) with nivolumab (3 mg/kg q2w; EN), or EN with bevacizumab (10 mg/kg q2w; ENB) (NCT04116658). Blood collection was performed at baseline and then every 2-4 weeks. Immune responses were investigated on PBMCs ex vivo or in vitro stimulation (IVS) using tetramer staining, IFN-γ ELISpot and intracellular cytokine staining.

Results

Vaccination with EO2401 induces a strong and durable CD8+ T cell response against bacterial peptides and human TAAs. Immune monitoring using ELISpot demonstrated T cell responses against the 3 microbiome-derived peptides for 97% of patients investigated ex vivo or after IVS. Cross-reactivity against theTAA target peptides was demonstrated in 96% of patients by IFN-γ ELISpot. Frequency of CD8+ T cells against bacterial peptides after IVS is extremely high, with max value above 40% for EO2317 and EO2318. Ex vivo, CD8+ T cell against at least one of the EO2401 peptides or human peptides are detected in almost all evaluable patients with some patients exhibiting up to 5% of circulating specific CD8+ T cells. Polyfunctionality of CD8+ T cell induce upon vaccination was demontrated in most patients (CD107a,IFN-γ and TNF-α production after stimulation). Memory-specific CD8+ T cell response is found as early as 2 weeks after the 1st vaccination and maintenance of a strong immune response could be detected for more than 10 months.

Conclusions

EO2401 vaccine demonstrates ability to generate fast and durable immune responses in patients treated with E02401/nivolumab +/- bevacizumab. Activation of specific T cells cross-reacting with commensal antigens and TAAs is thereby validated as an efficient approach to activate strong immune responses in a difficult to treat tumor. Updated immuno-monitoring data will be presented.

Clinical trial identification

Trial EOGBM1-18 (NCT04116658).

Legal entity responsible for the study

Enterome Sa.

Funding

Enterome Sa.

Disclosure

W. Wick: Financial Interests, Institutional, Funding, Drug/Palbociclib, Torisel for N2M2 trial: Pfizer; Financial Interests, Institutional, Funding, Drug/Asunercept for N2M2: Apogenix; Financial Interests, Institutional, Funding, Drug/Idasanutlin, Atezolizumab, Vismadegib, Alectinib for N2M2: Roche; Financial Interests, Institutional, Invited Speaker: Enterome, Vaximm; Non-Financial Interests, Personal, Leadership Role, Terminated in 2021: NOA; Non-Financial Interests, Personal, Leadership Role: EANO, Deutscher Wissenschaftsrat; Non-Financial Interests, Personal, Leadership Role, terminated in 2021: EORTC; Non-Financial Interests, Personal, Member: Leopoldina/Deutsche Gesellschaft der Wissenschaften. J. Gamelas Magalhaes: Financial Interests, Personal, Stocks/Shares: Enterome. A. IdBaih: Financial Interests, Personal, Advisory Board, Advisory board: Novocure, Leo Pharma, Boehringer Ingelheim, Novartis; Financial Interests, Institutional, Invited Speaker, Clinical research: Enterome, Bristol Myers Squibb, Carthera; Financial Interests, Institutional, Invited Speaker, Basic/Translational research: Carthera; Financial Interests, Institutional, Invited Speaker, Basic and Translational research: Sanofi, Nutrithéragène, Servier, Transgene; Other, Personal, Other, Travel funding: Carthera, Leo Pharma, Novocure, Enterome. All other authors have declared no conflicts of interest.

Background

Pancreatic adenocarcinoma (PDAC) is projected to significantly increase and become the second cause of cancer-related deaths before 2030. Immunotherapy has revolutionized the treatment of cancer, however, it has failed to show benefits in PDAC treatment. Recent efforts to synergize chemotherapy and immunotherapy have shown promising results in clinical trials. With this rationale, we tested the anti-tumor effect of the combination of the chemotherapeutic agent gemcitabine with a chitosan-based nanoparticle vaccine that contains the immunogenic cancer germline antigen Ny-eso1. Nyeso1-nanovaccine formulation alone or combined with gemcitabine was tested in vitro in mouse PDAC organoids.

Methods

Mouse peripheral blood mononuclear cells (PBMCs) were obtained and stimulated in vitro with Nyeso1- nanovaccine for 48 hours. Mouse PDAC organoids from KPC-orthotopic injected tumors were directly stimulated with Nyeso1-peptide nanovaccine, with respective nanovaccine controls, or indirectly with the Nyeso1- or nanovaccine controls-stimulated PBMCs or with unstimulated PBMCs. Two different gemcitabine concentrations, 0.38 μM and 0.84 μM, were added to the stimulated-PBMCs and the PDAC organoid co-culture system. During 10 days of co-culture, PDAC organoids were imaged using an Incucyte system, and the organoid areas were measured over time in response to treatment.

Results

The addition of Nyeso1-nanovaccine-stimulated PBMCs to the co-culture did not result in an alteration of PDAC organoids growth. However, the combination of Nyeso1-nanovaccine-stimulated PBMCs with gemcitabine led to a total reduction in sizes of PDAC organoids in comparison to PDAC organoids co-cultured with unstimulated- or nanovaccine-formulation stimulated PBMCs. Administration of gemcitabine in the medium of PDAC organoids alone only induced a slight decrease in the size of the PDAC organoids.

Conclusions

Gemcitabine treatment together with Nyeso1-nanovaccine stimulated PBMCs resulted in a synergistic anti-tumor effect in mouse PDAC organoids. Further studies will be carried out to potentiate the antitumor effect of the PBMCs and to analyze antigen-specific response upon nanovaccine treatment.

Legal entity responsible for the study

Frauke Alves.

Funding

European Union.

Disclosure

The author has declared no conflicts of interest.

Background

Preclinical studies with oral CCR4 antagonists have demonstrated inhibition of suppressive regulatory T cell (T_reg) migration into the tumor microenvironment and antitumor efficacy. The FLX475-02 trial is a phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and antitumor activity of the oral CCR4 antagonist FLX475 as monotherapy and in combination with pembrolizumab in subjects with several types of advanced cancer.

Methods

A standard 3+3 design was used in phase 1 testing FLX475 given orally once daily as monotherapy or in combination with pembrolizumab (200 mg IV Q3 weeks). In phase 2, expansion cohorts of subjects both naïve to and pretreated with checkpoint inhibitor with tumor types predicted to be enriched for T_eff, T_reg, and CCR4 ligand expression (i.e. “charged tumors”) – including EBV+ tumors and NSCLC– are being enrolled using a Simon 2-stage design.

Results

Phase 1 dose escalation has been completed and a recommended phase 2 dose of 100 mg once daily was selected for FLX475. The safety profile of FLX475 was consistent with that previously described in healthy volunteers, and there has been no evidence of increased severity or frequency of adverse events in combination therapy vs either FLX475 or pembrolizumab given alone. In phase 2 expansion, FLX475 monotherapy has induced complete responses in the first two subjects of five evaluable enrolled with EBV+ NK/T cell lymphoma. In addition, enrollment of the Stage 1 portion has been completed in several phase 2 expansion cohorts for the combination of FLX475 and pembrolizumab. In a cohort enrolling subjects with non-small-cell lung cancer (NSCLC) not previously treated with checkpoint inhibitor, 4/13 subjects (31%) have had confirmed partial responses (PRs), including several ongoing for over 6 months, meeting criteria to proceed to Stage 2 enrollment.

Conclusions

In this ongoing phase 1/2 trial of the oral CCR4 antagonist, FLX475, as monotherapy and in combination with pembrolizumab, antitumor activity including complete responses to FLX475 monotherapy and encouraging combination activity have been observed with an acceptable safety profile.

Clinical trial identification

NCT03674567.

Legal entity responsible for the study

RAPT Therapeutics, Inc.

Funding

RAPT Therapeutics, Inc.

Disclosure

M. Chisamore: Financial Interests, Personal, Full or part-time Employment: Merck. R. Goyal: Financial Interests, Personal, Full or part-time Employment: RAPT Therapeutics. N. Nasrah: Financial Interests, Personal, Full or part-time Employment: RAPT Therapeutics. W. Ho: Financial Interests, Personal, Leadership Role: RAPT Therapeutics. All other authors have declared no conflicts of interest.

Background

IPH5201 is an anti-CD39 monoclonal antibody that may promote antitumour immunity by increasing immunostimulatory ATP and reducing immunosuppressive adenosine levels in the tumour microenvironment. This first-in-human, multicentre, non-randomised, open-label, phase 1 study (NCT04261075) assessed the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of IPH5201 in patients (pts) with advanced solid tumours.

Methods

The study consisted of 2 dose-escalation parts: ascending doses of IPH5201 (100, 300, 1000 and 3000 mg) IV Q3W, and ascending doses of IPH5201 + D 1500 mg IV Q3W. Primary endpoints were safety and tolerability; key secondary endpoints were preliminary efficacy and PK. Biomarkers were assessed as exploratory endpoints.

Results

Overall, 57 pts received treatment (IPH5201, n=38; IPH5201 + D, n=19). Median age was 62 years (range, 41–78); 54.4% were male. Pts had a median of 3 prior therapies (range, 2–11). As of 7 Jul 2022, all pts had discontinued treatment, 89.5% due to disease progression. Treatment-emergent adverse events (AEs) occurred in 96.5% of pts. Treatment-related AEs (TRAEs) occurred in 66.7% of pts (37/57 [64.9%] related to IPH5201; 11/19 [57.9%] related to D); 10.5% had grade 3 TRAEs, with no grade 4 or 5 TRAEs. The most common TRAEs were infusion-related reactions (21.1%), fatigue (17.5%), and nausea, arthralgia, tumour pain and pruritus (each 8.8%). Median duration of exposure to IPH5201 was 9.3 wks (range, 3.0–66.1) and to D was 8.7 wks (range, 3.0–66.1). 22/57 pts (38.6%) had stable disease; there were no partial or complete responses. Median progression-free survival was 1.4 mo (range, 0–15.2); median overall survival was 8.2 mo (range, 1.0–22.1). IPH5201 saturated soluble CD39 at ≥300 mg and CD39 on immune cells at 3000 mg and decreased tumoural enzymatic activity in 5/8 pts. IPH5201 PK were non-linear at ≤300 mg and linear at ≥1000 mg. An indirect response PD model describing the relationship between IPH5201 concentration and free membrane CD39 on monocytes proposed 3000 mg Q3W or Q4W as the recommended phase 2 dose.

Conclusions

IPH5201 was well tolerated when used alone or in combination with D, with no new safety signals identified. PD were consistent with the mechanism of action.

Clinical trial identification

NCT04261075.

Editorial acknowledgement

Medical writing support for this abstract, under the direction of the authors, was provided by Werner Gerber of Ashfield MedComms (Kimberley, South Africa), an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M. Imbimbo: Financial Interests, Personal, Advisory Board: Immatics Therapeutics; Financial Interests, Institutional, Principal Investigator: BMS, T3P Therapeutics, AstraZeneca. A. Hollebecque: Financial Interests, Institutional, Research Grant: Incyte; Non-Financial Interests, Personal, Principal Investigator: Sanofi, Celgene, BMS, Lilly, Mirati, Seattle Genetics, AbbVie, Pfizer, AstraZeneca, Gilead, Merus; Financial Interests, Personal, Advisory Role: Amgen, BMS, Basilea, Incyte, Servier, Relay Therapeutics, Taiho, QED Therapeutics. A. Italiano: Financial Interests, Institutional, Research Grant: AstraZeneca, Bayer, BMS, MSD, Merck, Novartis, Parthenon, PharmaMar. M. McKean: Financial Interests, Institutional, Principal Investigator: Aadi Biosciences, Accutar Biotechnology, Alpine Immune Sciences, Arcus Biosciences, Arvinas, Ascentage Pharma Group, Astellas, Bayer, Bicycle Therapeutics, BioMed Valley Discoveries, BioNTech, Dragonfly therapeutics, EMD Serono, Epizyme, Erasca, Exelixis, Foghorn Therapeutics, G1 Therapeutics, Genentech, Gilead, GSK, IDEAYA Biosciences, Ikena Oncology, ImmVira Pharma, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, AstraZeneca, Mereo BioPharma, Metabomed, Moderna, NBE Therapeutics, Nektar, Novartis, OncoC4, Oncorus, PACT Pharma, Pfizer, Plexxikon, Poseida, Prelude Therapeutics, Pyramid Biosciences, Regeneron, Sapience Therapeutics, Scholar Rock, Seattle Genetics, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Tizona Therapeutics, Tmunity Therapeutics, TopAlliance Biosciences, Xilio; Financial Interests, Institutional, Other, Consulting: Astellas Pharma, AstraZeneca, BicycleTX Limited, Castle Biosciences, Eisai, IDEAYA Biosciences, iTeos, Moderna, Pfizer. T. Macarulla: Financial Interests, Personal, Other, Travel: Servier, AstraZeneca, Sanofi, Incyte; Financial Interests, Personal, Other, Consultancy: Swedish Orpahn Biovitrum AB, Ability Pharmaceuticals SL, AstraZeneca, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Incyte, Ipsen Bioscience, Eli Lilly, Marketing Farmacéutico & Investigación Clínica, S.L, MDS, Novocure, QED Therapeutics, Roche, Sanofi-Aventis, Servier, Zymeworks. E. Castanon Alvarez: Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Advisory Board: Roche, Beigene; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, BMS, Roche, Merck, MSD; Financial Interests, Personal, Training: BMS. B.A. Carneiro: Financial Interests, Institutional, Research Grant: AstraZeneca, AbbVie, Actuate Therapeutics, Astellas, Bayer, Dragonfly Therapeutics, Pfizer, Repare Therapeutics; Financial Interests, Personal, Advisory Board: Foundation Medicine, Seattle Genetics. R. Mager: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. V. Barnhart: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. E. Murtomaki: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. Y. He: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. Z.A. Cooper: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. E. Tu: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Linke: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. C. Fan: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. D. Zhao: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Boyer Chammard: Financial Interests, Personal, Full or part-time Employment: Innate Pharma. C.L. Paturel: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. P.G. Fraenkel: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J. Powderly: Financial Interests, Personal, Other, Consulting: Aavocyte, Boxer Capital; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc; Financial Interests, Personal, Ownership Interest, Founder: Carolina BioOncology; Non-Financial Interests, Personal and Institutional, Principal Investigator: AbbVie, Adagene, Alkermes, Apros, Arcus Biosciences, AstraZeneca, Atreca, BJ BioScience, BMS, Calico Life Sciences, Conjunpro BioTherapeutics, Cullinan, EMD Serono, Fate Therapeutics, FLX Bio, Genentech/Roche, I-MAB Pharma, Immune-Onc, Incyte, Jounce Therapeutics, Macrogenics, Molecular Templates, NexCure, Nuvation, Repertoire Immune Medicine, Seattle Genetics, Sequenom, Tempest Therapeutics, Top Alliance BioScience, Trethera, Xilio, Zenshine Pharma; Non-Financial Interests, Institutional, Research Grant: Merck, MT Group, Precision for Medicine, Replimmune, STEMCELL Technologies, Xilis; Financial Interests, Personal and Institutional, Research Grant: PIOMA.

Background

There is an urgent need to improve the safety and efficacy of immunotherapy, which has focused primarily on the adaptive immune system. Macrophages are the most common infiltrating immune cells in tumors and they can be directed to kill cancer cells by targeting macrophage-specific immune checkpoints, such as the CD47/SIRPa axis. CD47 serves as a “don’t eat me” signal on cancer cells and binds to SIRPa on macrophages to inhibit phagocytosis. Cytokines can influence macrophage polarization states, but how cytokines influence macrophage activation, particularly in the setting of macrophage checkpoint blockade, remains unknown.

Methods

To study how cytokines modulate macrophage anti-tumor function, we conducted an unbiased screen of 113 recombinant human cytokines using a novel co-culture assay that measures long-term interactions between primary human macrophages and human cancer cells. We tested how each cytokine alters macrophage-mediated cytotoxicity at baseline or in the presence of CD47 blockade. In validation studies, we tested more generally if candidate cytokines could enhance the macrophage response to tumor-opsonizing antibodies such as cetuximab (anti-EGFR mAb). We also confirmed the cross-species relevance of these findings in a murine in vitro system.

Results

Surprisingly, we found that despite not having single-agent activity, interleukin 10 (IL-10) synergizes with anti-CD47 therapy to enhance human macrophage anti-tumor function in long-term co-culture with non-small cell lung cancer (NSCLC) cells. These findings were conserved in a murine model of NSCLC in vitro. IL-10 also synergizes with tumor opsonizing antibodies, such as cetuximab, to enhance macrophage killing of cancer cells. IL-10 priming of macrophages enhanced antibody-dependent phagocytosis of multiple cancer cell lines, likely underlying its mechanism of action.

Conclusions

We discovered an unexpected role for IL-10 in enhancing macrophage anti-tumor functions in response to CD47 blockade and tumor-opsonizing antibodies. These findings illuminate a novel strategy to harness macrophages for cancer immunotherapy and provides preclinical rationale for testing this therapeutic combination in patients with cancer.

Legal entity responsible for the study

The authors.

Funding

Whitehead Institute.

Disclosure

A. Maoz: Non-Financial Interests, Personal, Other, Patent application: Whitehead Institute. K. Vaccaro: Financial Interests, Personal, Full or part-time Employment: DEM Biopharma; Financial Interests, Personal, Stocks/Shares: Orchard therapeutics. K. Weiskopf: Financial Interests, Personal, Advisory Board, Scientific co-founder, SAB member, equity ownership, royalties: ALX Oncology; Financial Interests, Personal, Advisory Board, Scientific co-founder, SAB member, equity ownership, royalties, compensation: DEM Biopharma; Financial Interests, Personal, Other, Scientific advisor, compensation: Carisma Therapeutics; Financial Interests, Personal, Stocks/Shares: Adaptimmune, Gingko Bioworks, Guardant Health, Immunity Bio, Myovant Sciences, Arbutus Biopharma, Arvinas Inc, Beyond Air, Biomarin Pharmaceutical Inc, Trillium Therapeutics, Bluebird Bio, Medicenna Therapeutics, Kura Oncology, Sesen Bio; Financial Interests, Personal, Royalties, Patents, royalties, and licensing fees: Stanford University; Financial Interests, Personal, Other, Patent applications, anticipated royalties and licensing fees: Whitehead Institute; Financial Interests, Personal, Invited Speaker, Royalties and licensing fees: Gilead Sciences, Inc; Financial Interests, Personal and Institutional, Research Grant: AACR-AstraZeneca Career Development Award for Physician-Scientists, in Honor of José Baselga. All other authors have declared no conflicts of interest.

Background

CD39 is an extracellular ectonucleotidase highly expressed in the tumor microenvironment (TME) that, sequentially with CD73, contributes to the production of adenosine (Ado), via hydrolysis of adenosine triphosphate (ATP). IPH5201 is a blocking anti-CD39 monoclonal antibody (mAb) that may promote antitumor immunity by accumulating immunostimulatory ATP released by necrotic cells and reducing immunosuppressive Ado levels in the TME. Targeting the Ado pathway has recently been reported to improve Durvalumab (D) efficacy in early-stage NSCLC patients, through the use of Oleclumab, an anti-CD73 mAb. In a first-in-human study (NCT04261075), IPH5201 was well tolerated alone or in combination with D. Here we explored preclinical efficacy of IPH5201 in combination with anti-PD-L1 and chemotherapies (CT).

Methods

CD39 expression was assessed in early and late stage NSCLC biopsies. In vitro, CT were assessed for their ability to induce ATP release by dying tumor cells and IPH5201 was evaluated for its ability to accumulate the released ATP. In vivo, human (hu) CD39 Knock-In (KI) mice were used to engraft syngeneic tumors and evaluate the efficacy of a mouse (mo) version of IPH5201 (moIPH5201) alone or in combination with CT and anti-PD-L1.

Results

CD39 was expressed in both squamous and adenocarcinoma subtypes of NSCLC with no difference according to the stage of the disease. In a mouse tumor model engrafted in huCD39KI mice, moIPH5201 was able to decrease the human CD39 enzymatic activity and to lower the Ado level in situ. In vitro, CT induced ATP release by tumor cells and IPH5201 was able to accumulate the released ATP. Finally, in vivo, in a mouse tumor model engrafted in huCD39KI mice, moIPH5201 improved the anti-tumor efficacy of gemcitabine and anti-PD-L1 combination.

Conclusions

IPH5201 was shown to block CD39 enzymatic activity, to lower Ado and increase ATP levels in the TME and finally to improve anti-tumor efficacy in preclinical models. Altogether, the expression profile of CD39 in early stage NSCLC and preclinical combination data support the clinical evaluation of IPH5201 in combination with D and CT in early stage NSCLC patients.

Legal entity responsible for the study

Innate Pharma, AstraZeneca.

Funding

Innate Pharma, AstraZeneca.

Disclosure

C.L. Paturel: Financial Interests, Personal, Project Lead: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. N. Anceriz: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. J. Eyles: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J. Lapointe: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. C. Denis: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. V. Breso: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. R. Courtois: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. S. Augier: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma. L. Brown: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. N. Luheshi: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Watkins: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. Z.A. Cooper: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. E. Tu: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. E. Vivier: Financial Interests, Personal, Full or part-time Employment: Innate Pharma; Financial Interests, Personal, Stocks/Shares: Innate Pharma; Financial Interests, Personal, Leadership Role: Innate Pharma. P.G. Fraenkel: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Leadership Role: AstraZeneca.

Background

Cancer vaccines strive to produce robust, antigen-targeted, T cell-mediated anti-tumor responses, but have struggled to induce tumor regression in patients. The Cell Squeeze® system achieves efficient antigen presentation by delivering target antigens directly into the cytosol of a patient’s PBMCs. SQZ-PBMC-HPV is an autologous cell vaccine that presents epitopes of HPV16 viral oncoproteins on HLA-A*02 to induce CD8 T cell activation. Monotherapy data showed tumor inflammation markers that may indicate correlation with clinical response motivating expansion of the monotherapy and combination with immune checkpoint inhibitors (ICIs).

Methods

SQZ-PBMC-HPV-101 enrolls patients (pts) with advanced HPV16+ cancers who have progressed after standard therapy, have an ECOG 0-1, adequate organ function, and measurable lesion(s) per RECIST1.1. Manufacturing of the cell product takes <24 hours with a collection-to-release time of about 1 week. The RP2D dose of SQZ-PBMC-HPV is 5x10⁶ live cells/kg double prime, given IV q3w. Pts also receiving atezolizumab or ipilimumab are dosed IV q3w. Blood samples and paired biopsies are collected for pharmacodynamic (PD) analyses.

Results

As of Aug 17, 2022, 14 pts have been treated at the RP2D +/- ICI [head and neck (10), cervical (2), vulvar (1), and anal (1)]. These pts have received a median of 3 prior lines of systemic cancer therapy. Treatment was well-tolerated with no dose limiting toxicities, Grade (G) >2 related SAEs, related G >3 AEs, or cytokine release syndrome. In addition to assessment by RECIST1.1 criteria, 8 pts in the monotherapy cohort provided paired tumor biopsies for assessment of changes in the tumor microenvironment including CD8 influx, Treg presence, antigen expression, and evasion mechanisms (MHCI and PD-L1). This report will be the first to summarize the PD and safety endpoints for pts receiving SQZ-PBMC-HPV + ICI therapy.

Conclusions

Building on encouraging earlier monotherapy response data with SQZ-PBMC-HPV, this monotherapy and ICI combination data will further elucidate the impact of this therapeutic vaccine’s mechanism and evaluate its place in patient treatment.

Clinical trial identification

NCT04084951.

Legal entity responsible for the study

SQZ Biotechnologies Company.

Funding

SQZ Biotechnologies Company.

Disclosure

A. Jimeno: NCI R01CA149456, R01DE024371, and P50CA261605. AJ institution has contracts with Cantargia, DebioPharm, Iovance, Khar Biopharma, Merck, Moderna, Pfizer, Sanofi, and SQZ for trials where he is the local PI N.R. Miselis: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies; Financial Interests, Personal, Stocks/Shares: SQZ Biotechnologies, Merck & Co, BMS, Iovance, Abbott, Quest Diagnostics, Baxter International. J.C. Park: JCP reports honoraria from Cancer Expert Now and Alira Health; consulting or advisory roles with GC Cells, Selexcine, ABL Bio, BW Biomed, and Mitoimmune; and institutional contracts with ALX Oncology, Inhibrx, Merck, Oncorus, ISA Therapeutics, and Monopteros Therapeutics. J. Jennings: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. N. Dhani: Financial Interests, Personal and Institutional, Principal Investigator: SQZ Biotechnologies; Financial Interests, Personal, Full or part-time Employment: Princess Margaret Cancer Centre. U. Holtick: Honoraria & Consultancies BMS/ Celgene, Kite/ Gilead, GlaxoSmithKline, Janssen-Cilag, Miltenyi Biotec, Novartis, Pfizer, Sanofi. W.T. Iams: WTI reports support from an NCCN Young Investigator Award, consulting relationships with Genentech, Jazz Pharma, G1 Therapeutics, Mirati, Bristol Myers Squibb, Takeda, Janssen, EMD Serono, OncLive, Curio Science, Chardan, Cello Health, Outcomes Insights, and Clinical Care Options. WTI - Vanderbilt University Medical Center has contracts with Takeda, Amgen, Nitto Biopharma, Lilly, and Merck for trials where he is the local PI. N. Nair: Non-Financial Interests, Institutional, Advisory Role: SQZ Biotechnologies; Financial Interests, Personal, Full or part-time Employment: Roche. M. Kornacker: Non-Financial Interests, Institutional, Advisory Role: SQZ Biotechnologies; Financial Interests, Personal, Full or part-time Employment: Roche. S.M. Loughhead: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. Named inventor of patents either licensed by or assigned to SQZ Biotechnologies. H. Bernstein: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. Named inventor of patents either licensed by or assigned to SQZ Biotechnologies and SQZ officer. R. Zwirtes: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. R.R. Ji: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. M. Warren: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. SQZ officer. A. Sharei: Financial Interests, Personal, Full or part-time Employment: SQZ Biotechnologies. Named inventor of patents either licensed by or assigned to SQZ Biotechnologies; SQZ officer.

Background

The highly selective inhibitor of PI3Kδ, IOA-244, has a unique safety and pharmacodynamic profile showing immune modulation in patients with solid tumours.

Methods

IOA-244 was investigated in a two-part FIH study: Part A investigated the safety and pharmacokinetics of continuous daily dosing of IOA-244 at 10, 20, 40 and 80 mg. Primary objective: safety of the anticipated biologically effective dose (BED), or of the recommended phase 2 dose (RP2D). Secondary objectives: PK; PD (e.g., inhibition of CD63 expression on basophils, changes in immune cell subsets in peripheral blood); RECIST 1.1.-based responses; PFS and OS. Exploratory studies: changes in circulating immune cells by mass cytometry (Cytometry by Time of Flight; CyTOF); response assessments by radiomics. Analysis of Part B expansion cohorts will be reported at future meetings.

Results

Part A Solid Tumor: Sixteen patients (pts) were treated in 4 cohorts each with 4 pts. Pts characteristics: uveal melanoma (9/16; 56%), cutaneous melanoma (5/16; 31%) and pleural mesothelioma (2/16; 13%). There were no DLTs or treatment-emergent adverse events (TEAE) leading to study drug dose modification. 7/16 pts (44%) were treated for more than 6 months and had SD during this period. At the estimated IC₉₀ (80 mg QD), patients had improvements of their liver enzymes unless tumour progressed in the liver. Four patients at lower dose levels were increased to 80 mg QD with no additional toxicities. 5/16 were treated after RECIST 1.1-defined PD and 2/4 are still on IOA-244 (>2 years on treatment). The median OS has not been reached. In the UM group 2/9 patients are still on IOA-244 (>18 months on treatment; Median OS: 5.4 - not reached) Part A Follicular Lymphoma: Eight patients were treated at 20 mg (4/4 pts) and 80 mg QD (4/4). No DLT. At 80 mg, there was one PR for 4 months and 1 transient clinical response for 6 weeks. All patients had low circulating blood Tregs during the treatment.

Conclusions

IOA-244 at the 80 mg dose shows less than 5% Grade 3/4 toxicities. In contrast to other PI3Kδ inhibitors, long-term administration of IOA-244 (>6 months) was not associated with diarrhoea or hepatic toxicity.

Clinical trial identification

NCT04328844.

Legal entity responsible for the study

iOnctura SA.

Funding

iOnctura SA.

Disclosure

A.M. Di Giacomo: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, MSD, Pierre Fabre, Novartis; Financial Interests, Personal, Invited Speaker: Sanofi. M. Lahn: Financial Interests, Personal, Leadership Role: iOnctura. L. van der Veen: Financial Interests, Personal, Leadership Role: iOnctura. T. Hammett: Financial Interests, Personal, Full or part-time Employment: iOnctura. C.A. Pickering: Financial Interests, Personal, Leadership Role: iOnctura. M. Durini: Financial Interests, Personal, Full or part-time Employment: LabCorp. M. Occhipinti: Financial Interests, Personal, Leadership Role: Radiomics. All other authors have declared no conflicts of interest.

Background

Claudin 1 (CLDN1) is a protein confined within the normal epithelial tight junctions of different tissues. Upon malignant transformation, CLDN1 is overxpressed and epitopes become exposed outside the tight junctions (non-Junctional CLDN1). ALE.C04 is a highly specific humanized monoclonal antibody that recognizes a unique CLDN1 exposed epitope in different solid tumors.

Methods

More than 1200 paraffin embedded tumor biopsies from 12 different indications have been stained by Immunohistochemistry (IHC) for both CLDN1 and CD3 (T cell marker). Different tumor mouse models have been used to assess the anti-tumor activity of ALE.C04 as single agent and/or in combination with either check-point inhibitors (CPIs) /or chemotherapy.

Results

Herein we show that non-Junctional CLDN1 (NJ-CLDN1) is frequently overexpressed in solid tumors. Notably, CLDN1 expression on tumor cells positively correlates with the localization of T-cells into a fibrotic tissue environment. T cell exclusion is one the mechanisms described to hinder the efficacy of Checkpoint inhibitors (CPIs). On this line, the overexpression of Cldn1 in Hepa1-6 mouse liver tumor cells promoted T cell exclusion and resistance to anti-PD1 treatment. Importantly, ALE.C04 restored both T-cell infiltration and anti-PD1 efficacy in Hepa1-6 Cldn1+ tumors. Mechanistically, NJ-CLDN1 interacts with different component involved in extracellular matrix remodeling, thus establishing a physical barrier that exclude immune cells from the tumor nest. ALE.C04 has a direct antifibrotic effect that perturbs the interface between CDLN1+ tumor cells and the stroma, thus restoring im mune cell infiltration. The rationale for developing a CDLN1-based Oncology platform will be also presented.

Conclusions

We have shown that NJ-CLDN1 is overexpressed in different solid tumor, drives T -cell exclusion and resistance to CPIs. Importantly, ALE.C04 restored T cell infiltration and CPI efficacy in a mouse model for liver tumor . Based on our pre-clinical data, rationale and safety profile, we plan a phase 1b study with ALE.C04 in combination with CPIs in solid tumors.

Clinical trial identification

INT: 1011.

Legal entity responsible for the study

Alentis Therapeutics AG.

Funding

Alentis Therapeutics AG.

Disclosure

A. Toso: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutic AG. G. Teixiera: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutics. T. Zimmermann: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutics AG. D. Schmitter: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutics AG. M. Meyer: Financial Interests, Personal, Stocks/Shares: Alentis Therapeutics AG. T. Baumert: Financial Interests, Personal and Institutional, Member of the Board of Directors: Alentis Therapeutic AG. R. Iacone: Financial Interests, Personal, Stocks/Shares, CEO: Alentis Therapeutics AG. All other authors have declared no conflicts of interest.

Background

The induction of immunogenic cell death by thermal ablation (TA) with local immunostimulation is a novel approach to address advanced, immune “cold”, treatment-refractory cancer. Glycated N-acetylglucosamine polymer, IP-001® , is a novel immune stimulant that drives the activation of innate immune cells through multiple pathways (Stimulator of Interferon Genes STING, Inflammasome, and others) and acts as an antigen depot, which may enhance downstream adaptive anti-tumor immunity. When combined with TA, IP-001 stimulated abscopal effects at distant, untreated tumors, and immune memory in animal models. Safety of IP-001 was tested in the phase IB part of the SAKK66/17 phase 1b/2 trial.

Methods

Patients (pts) with advanced solid tumors who have failed standard treatment received up to 6 four-week cycles of TA using a laser device (TRANBERG Thermal Therapy System) on an accessible lesion at a time followed by intratumoral injection of IP-001 (single dose of 4 ml, with possible de-escalation). Primary endpoint: Dose limiting toxicities (DLTs). Key secondary endpoints: Disease control per RECIST/iRECIST and safety.

Results

Four pts (2F/2M) were enrolled; 2 NSCLC; 1 leimyosarcoma; 1 follicular thyroid cancer FTC; median age=66-yrs. All pts were metastatic and had received multiple prior lines of chemo- and / or immunotherapies including nivolumab (n=2), olaratumab (n=1) and lenvatinib (n=2). Treatment related AEs of grade ≥ 2, included fatigue (50%), fever (25%), hypotension (25%), maculopapular rash (25%), increased CRP (25%) and abdomial pain (25%). No DLTs were observed and no SAEs were considered related to IP-001.

Conclusions

TA followed by IP-001 at a dose of 4 mL is well tolerated in pts with advanced solid tumors who have failed standard treatment. The combined use of thermal tumor ablation and IP-001® at a dose of 4 ml can safely be administered in patients with advanced solid malignancies with the potential to stimulate an abscopal effect via immune stimulation.

Clinical trial identification

NCT03993678.

Legal entity responsible for the study

Swiss Group for Clinical Cancer Research (SAKK).

Funding

Immunophotonics Inc.

Disclosure

M. Joerger: Financial Interests, Institutional, Invited Speaker, Clinical study activity: Basilea, Bayer, BMS, Immunophotonics, Innomedica, MSD, Novartis, Roche; Financial Interests, Institutional, Other, Clinical study activity: DaiichySankyo; Non-Financial Interests, Personal, Advisory Role: Novartis, AstraZeneca, Basilea, Bayer, BMS, Debiopharm, MSD, Roche, Sanofi. L. Alleruzzo: Financial Interests, Personal, Member of the Board of Directors: Immunophotonics Inc. S.K. Lam: Financial Interests, Personal, Officer: Immunophotonics Inc. D. Anderson: Financial Interests, Personal, Officer: Immunophotonics Inc. W. Chen: Financial Interests, Personal, Officer: Immunophotonics Inc. E. Baskin-Bey: Financial Interests, Personal, Officer: Immunophotonics Inc. T. Hode: Financial Interests, Personal, Member of the Board of Directors: Immunophotonics Inc. All other authors have declared no conflicts of interest.

Background

ENPP1 is a type II transmembrane protein with nucleotide pyrophosphatase, and phosphodiesterase enzymatic activities and its expression is associated with poor prognosis in cancer. ENPP1 inhibition protects cGAMP and ATP from hydrolysis and reduces adenosine levels in the TME, activates APCs and increases T-cell infiltration promoting anticancer immunity. RBS2418 is a potent oral ENPP1 inhibitor. The current study evaluates RBS2418 as monotherapy and combination with pembrolizumab (pembro), supporting preclinical data and complementary mechanism of action with the aim of generating improved anti-tumor immunity and overcoming checkpoint inhibitor resistance in the combination setting. First clinical experience with RBS2418 was within an EA IND to an advanced adrenal cancer patient where the drug was safe, well tolerated and immunologically active.

Trial Design

This is a phase 1a/b, open-label, non-randomized study in patients (pts) (≥18 years) with advanced, unresectable, recurrent or metastatic solid tumors, who have progressed on, or are ineligible for standard therapies. The study begins with dose-escalation where in a 3+3 fashion pts will receive in one cohort RBS2418 starting at 100mg bid as monotherapy and in a second cohort RBS2418 in combination with pembro (200 mg IV q3w). In the dose-escalation portion, fixed dose as the 10X OBA (OBA as the dose of RBS2418 that inhibits >90% of ENPP1 enzyme activity in human serum) or MTD will be determined, to be used in the expansion cohort which will enroll pts as monotherapy and combination therapy with pembro in tumor types where pembro is approved. The study will enroll up to 64 pts at 10 sites in the US. The primary objectives of the study are safety, tolerability, ENPP1 inhibition and cGAMP protection of RBS2418 as monotherapy and in the combination setting. Immune biomarkers predictive of anti-tumor responses will be explored as well as translational analyses will be done to explore the depth and breadth of immune activation both in tumor tissue and blood. This study is being funded by Riboscience, Llc.

Clinical trial identification

NCT05270213; Released June, 2022.

Legal entity responsible for the study

The authors.

Funding

Riboscience Llc.

Disclosure

J. Glenn: Financial Interests, Personal, Ownership Interest: Riboscience; Financial Interests, Personal, Stocks/Shares: eiger pharmaceuticals. I. Csiki: Financial Interests, Personal, Full or part-time Employment: Riboscience; Financial Interests, Personal, Stocks/Shares: Riboscience. J. Powderly: Financial Interests, Personal, Other, Consulting: Boxer Capital; Financial Interests, Personal, Invited Speaker, Consulting: Aavocyte; Financial Interests, Personal, Invited Speaker, Founder and Owner: Carolina BioOncology Institute, PLLC, BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner of phase 1 cancer research clinic: Carolina BioOncology Institute, PLLC; Financial Interests, Personal, Other, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Invited Speaker: Bristol Myers Squibb, Cullinan, Genentech/Roche, AstraZeneca/MedImmune, EMD Serono, Macrogenics, InCyte, Top Alliance BioSciience, Seattle Genetics, AbbVie, FLX Bio, Alkermes, Arcus BioSciences, Tempest Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom, Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics, Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics; Financial Interests, Institutional, Funding: Precision for Medicine, MT Group, STEMCELL Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal and Institutional, Funding: PIOMA; Financial Interests, Personal and Institutional, Invited Speaker, Also funding for contract laboratory services: Nuvation; Other, Personal, Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy: BioCytics Inc. K. Klumpp: Financial Interests, Personal, Member of the Board of Directors: Riboscience. All other authors have declared no conflicts of interest.

Background

REGN6569 is a fully human immunoglobulin G1 mAb that is highly specific for glucocorticoid-induced tumour necrosis factor receptor–related protein (GITR). GITR is expressed on several immune cell subtypes, notably regulatory T cells (Tregs). REGN6569 has demonstrated in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) with greater cytotoxicity against GITR expressing Tregs than CD8+ T cells. GITR mAbs have shown preclinical antitumour efficacy. Anti-GITR and anti–programmed cell death-1 (PD-1) combination therapy has synergistic biological activity and may optimise immune checkpoint inhibitor (ICI) treatment in patients with advanced solid tumours.

Trial Design

This ongoing first-in-human study (NCT04465487) will assess safety, tolerability, pharmacokinetics, pharmacodynamics and antitumour activity of REGN6569 in combination with cemiplimab (anti-PD-1) in patients with advanced solid tumours, for which ICI therapies have not been approved or are not available. Patients must be at least 18 years old, have Eastern Cooperative Oncology Group performance status (0 or 1), and be naive to ICIs. The study includes dose-escalation (a “4+3” design; in advanced solid tumours) and dose-expansion (in patients with advanced head and neck squamous cell carcinoma) parts. The dose-escalation part will cover 5 dose levels (DL1-DL5) for REGN6569, administered intravenously (IV) every 3 weeks (Q3W). Patients will receive REGN6569 as monotherapy lead-in for the first dose followed by REGN6569 in combination with standard cemiplimab 350 mg IV Q3W. Dose expansion will open after review of safety, efficacy and pharmacodynamic data from the dose-escalation phase. The primary objective of the dose-escalation phase is to evaluate safety and tolerability. The co-primary objectives of the dose-expansion phase are to assess preliminary efficacy of REGN6569 in combination with cemiplimab, as measured by objective response rate, and preliminary pharmacodynamic activity of REGN6569 as lead-in monotherapy, as measured by intratumoural GITR⁺ Treg depletion. The study is currently open to enrolment.

Clinical trial identification

NCT04465487.

Editorial acknowledgement

Medical writing support was provided by Sameen Yousaf, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc. Responsibility for all opinions, conclusions, and data interpretation lies with the authors.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc.

Funding

Regeneron Pharmaceuticals, Inc.

Disclosure

N. Lakhani: Financial Interests, Personal, Advisory Role: Innovent Biologics; Financial Interests, Institutional, Research Grant: Alexion Pharmaceuticals, Alexo Therapeutics, Alpine Immune Sciences, Alpine Immune Sciences, Apexian Pharmaceuticals, Asana Biosciences, Ascentage Pharma, Astellas Pharma, BeiGene, Celgene, Cerulean Pharma, Constellation Pharmaceuticals, Coordination Ther. O. Hamid: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb, Novartis, Pfizer, Sanofi and Regeneron Pharmaceuticals, Inc; Financial Interests, Personal, Advisory Role: Aduro Biotech, Akeso Biopharma, Amgen, Arcus Biosciences, Bioatla, Bristol Myers Squibb, CytomX Therapeutics, Exelixis, Genentech, GlaxoSmithKline, Idera, Immunocore, Incyte, Iovance Biotherapeutics, Merck, Merck Serono, Moderna Therapeutics, NextCure, No. I. Braña: Financial Interests, Personal, Other, Financial interests: Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm, Dragonfly therapeutics, GlaxoSmithKline, Gliknik, Immutep, Incyte, ISA pharmaceuticals, Janssen Oncology, Kura, MacroGenics, Merck Serono, Merck Sharp & Dohme (MSD), Na; Financial Interests, Personal, Advisory Board: Achilles Therapeutics, Rakuten Pharma, PCI Biotech, Merck Sharp & Dohme (MSD), eTheRNA Immunotherapies, Bristol Myers Squibb, AstraZeneca. P.L. Swiecicki: Financial Interests, Institutional, Research Grant: Ascentage Pharma and Pfizer; Financial Interests, Personal, Advisory Board: Prelude Therapeutics, Elevar Therapeutics, and Regeneron Pharmaceuticals. M.J. De Miguel Luken: Financial Interests, Personal, Advisory Board: Syneos; Financial Interests, Personal, Other, Educational fees: Roche, Janssen, MSD . H. Khong: Financial Interests, Personal, Advisory Board: Celcuity; Financial Interests, Institutional, Research Grant: AstraZeneca. V. Moreno Garcia: Financial Interests, Personal, Advisory Role: Bayer, Basilea Pharmaceuticals, Bristol Myers Squibb, Janssen and Pieris. M.J. Lostes Bardaji: Financial Interests, Personal, Advisory Role: Bayer, Basilea Pharmaceuticals, Bristol Myers Squibb, Janssen and Pieris. F. Sun: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. S. Sandigursky: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. M. Zambrano: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. M. Cristea: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. M. Fury: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Background

Mucin-16 is a cell surface glycoprotein that is overexpressed in epithelial OC. Ubamatamab (REGN4018) is a mucin-16 x cluster of differentiation 3 (MUC16xCD3) bispecific antibody that promotes T cell–mediated cytotoxicity by facilitating contact between cancer cells and T cells. Cemiplimab is an anti–programmed cell death-1 monoclonal antibody. The phase 1 study in patients with recurrent OC found ubamatamab monotherapy had an acceptable safety profile, durable clinical activity across a range of doses (as measured by RECIST and cancer antigen 125 [CA-125] response rates), and linear pharmacokinetics up to 800 mg weekly intravenous (IV)¹. These clinical data support further evaluation of a once every 3-week (Q3W) regimen of ubamatamab alone and in combination with cemiplimab.

Trial Design

In phase 2, up to 150 patients with advanced platinum-resistant OC and elevated serum CA-125 will be randomised to three IV arms (1:1:1) to receive ubamatamab 250 mg IV Q3W or 800 mg IV Q3W as monotherapy, or ubamatamab 250 mg IV Q3W in combination with cemiplimab 350 mg Q3W. All arms will include weekly step-up dosing of ubamatamab (1 mg week 1, 20 mg week 2, and full dose weeks 3 and 4) to limit risk of cytokine release syndrome prior to proceeding to Q3W dosing. Expansion cohorts will use a Simon 2-stage study design, with an interim analysis after the first 20 patients. Any arm with ≥3 objective responses will be expanded to 50 patients. In this dose expansion phase the primary endpoint will be the objective response rate for each arm as defined by RECIST 1.1 criteria. Secondary endpoints include evaluation of duration of response and progression-free survival as well as further evaluation of safety and pharmacokinetics. Exploratory endpoints include evaluation of baseline tumour MUC16 immunohistochemistry expression and other biomarkers as predictors of response. The impact of ubamatamab on quality of life and physical functioning will also be assessed. Final data are pending for this TiP. Reference 1: Annals of Oncology (2022) 33 (suppl_7): S235-S282. 10.1016/iotech/iotech1054.

Clinical trial identification

NCT03564340.

Editorial acknowledgement

Medical writing support was provided by Rachel McGrandle, BSc, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc.

Legal entity responsible for the study

Regeneron Pharmaceuticals, Inc.

Funding

Regeneron Pharmaceuticals, Inc.

Disclosure

K.N. Moore: Financial Interests, Personal, Advisory Role: AstraZeneca, Aravive, Alkemeres, Blueprint Pharma, Caris, Elevar, Eisai, Genentech/Roche, GSK/Tesaro, Hengrui, Immunogen, Inxmed, IMab, Iovance, Lilly, Mereo, Myriad, Mersana, Novocure, Novartis, Tarveda, Verastem and VBL Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca, Regeneron, Novocure, Genentech/Roche, AbbVie, GSK/Tesaro, Immunogen, PTC Therapeutics, Merck, Lilly, Mereo, Artios and Daichii. S. Bouberhan: Financial Interests, Personal, Advisory Role: ImmunoGen. E. Hamilton: Financial Interests, Institutional, Research Grant: Regeneron, AbbVie, Acerta Pharma, ADC Therapeutics, Akesobio Australia, Amgen, Aravive, ArQule, Arvinas, AstraZeneca, AtlasMedX, Black Diamond, Boehringer Ingelheim, Clovis, Compugen, Curis, CytomX, Dana Farber Cancer Inst, Daiichi Sankyo, Deciphera, eFFE; Financial Interests, Institutional, Advisory Role: Arcus, Arvinas, AstraZeneca, Black Diamond, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Deciphera Pharmaceuticals, Eisai, H3 Biomedicine, iTeos, Janssen, Lilly, Loxo, Merck, Mersana, Novartis, Pfizer, Puma Biotechnology, Relay Therapeutics, Roc. J. Liu: Financial Interests, Personal, Advisory Role: AstraZeneca, Clovis Oncology, Eisai, EpsilaBio, Genentech/Roche, GlaxoSmithKline and Regeneron Pharmaceuticals, Inc.; Financial Interests, Institutional, Research Grant: 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro, Vigeo Therapeutics and Zentalis. R.E. O'Cearbhaill: Financial Interests, Personal, Other, Personal fees: Tesaro/GSK, Regeneron, Seattle Genetics, Fresenius Kabi, Bayer, Immunogen, Curio and MJH; Financial Interests, Personal, Other, Travel support for meeting: Hitech Health; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Role: PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca); Non-Financial Interests, Personal, Advisory Role: Carina Biotech; Financial Interests, Institutional, Research Grant: Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, AbbVie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma and. D. O'Malley: Financial Interests, Personal, Advisory Role: AstraZeneca, Tesaro/GSK, Immunogen, Janssen/Johnson & Johnson, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, GOG Foundation, Iovance, Eisai, Agenus, SeaGen, Mersana, Clovis and SDP Oncology (BBI), Ambry, Myriad Genetics, Tarveda, Novartis, Rubis, Elevar, Takeda, Toray, INXMED, Arquer Diagnostics, Roche Diagnostics MSA, Sorrento, Corcept Therapeutics and Celsion Corp; Financial Interests, Personal, Research Grant: AstraZeneca, Tesaro/GSK, Immunogen, Janssen/Johnson & Johnson, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, GOG Foundation, Iovance, Eisai, Agenus, SeaGen, Mersana, Clovis and SDP Oncology (BBI), VentiRx, Array Biopharma, EMD Serono, Ergomed, Ajinomoto Inc., Ludwig Cancer Research, Stemcentrx, Inc., Cerulean Pharma, Bristol Myers Squibb Co., Serono Inc., TRACON Pharmaceuticals, New Mexico Cancer Care Alliance, INC Research, Inc., inVentiv Health C. S. Yoo: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. M. Peterman: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. P. Goncalves: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. T. Schmidt: Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc. M. Zhu: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. I. Lowy: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. T. Uldrick: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. E.A. Miller: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.

Background

PACIFIC regimen is the gold standard for patients with unresectable locally advanced Non-Small Cell Lung Cancer (NSCLC). Moving forward on developing the best treatment combination, this study aims to assess the safety and efficacy of a regimen of induction chemo-immunotherapy followed by de-intensified, hypo-fractionated RT given concurrently with Durvalumab followed by Durvalumab maintenance in patients with unresectable, stage III NSCLC.

Trial Design

Dedalus trial is a phase 2, open-label, single-arm, multi-center, Italian study designed to determine safety of chemo-immunotherapy followed by reduced-dose hypo-fractionated radiotherapy and maintenance immunotherapy with a fixed dose of Durvalumab monotherapy. 45 patients will be enrolled from March 2022 to March 2024. Patients will meet the following major criteria could be included: NSCLC stage III, PD-L1 all comers, judged unresectable and ineligible for cCRT by thoracic multidisciplinary board and then candidate to sCRT. After three cycles of Cisplatin/Carboplatin (AUC5) plus Etoposide plus Durvalumab every three weeks, responders will be receiving hypo-fractionated thoracic RT (45 Gy over 3 weeks) plus Durvalumab, followed by Durvalumab maintenance up to 12 months or progression. Primary endpoint is safety, defined by the incidence of grade 3-4 possibly related adverse events within 6 months from the initiation of treatment. Secondary objectives are PFS and OS (median and 12 months) and quality of life (investigated through EORTC QLQ-C30 and LC13 questionnaires). Ancillary studies consist of radiomic and molecular analyses: correlation of radiomic signatures extracted form baseline and post-RT TC-scans with PFS; molecular alterations detected on tumor tissue specimens obtained at diagnosis will be monitored on ctDNA in plasma specimens trough liquid biopsies at 3 different time-points (at baseline, after radiotherapy and at progression). First patient was enrolled in March 2022; at the time of submission, eight patients are included in the trial.

Clinical trial identification

NCT05128630.

Legal entity responsible for the study

Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Funding

AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.

Background

CD73 is an extracellular ectonucleotidase overexpressed in the tumor microenvironment (TME) of multiple cancers. Extracellular adenosine triphosphate (ATP) released by necrotic cells is hydrolyzed into adenosine monophosphate (AMP), which is subsequently degraded by CD73 into immunosuppressive adenosine. CD73 overexpression has been associated with poor prognosis, conferring resistance to chemotherapy and anti-HER2 therapy. IPH5301 is a humanized IgG1 monoclonal antibody (mAb) with a functionally silent Fc domain, specifically inhibiting both soluble and membrane CD73 enzymatic activity, and restoring proliferation of immune T cells more effectively than other anti-CD73 mAbs in clinical development. IPH5301 has the potential to release TME from adenosine-mediated immune suppression, thereby leading to increased anti-tumor immunity.

Trial Design

CHANCES is a first-in-human, open label, European, multi cohort phase I study (NCT05143970). The dose escalation cohort will evaluate 4 dose levels of IPH5301 administered alone IV every 2 weeks until progression or toxicity. The escalation will be guided by an adaptive Bayesian model, enrolling cohorts of 2 to 3 patients with advanced and/or metastatic cancer. A maximum of 15 patients is planned. In the expansion cohort, IPH5301 will be administered at the recommended dose (RP2D) and the next lower dose (RP2D-1) in combination with trastuzumab and paclitaxel in 12 patients with advanced/metastatic HER2-positive breast and gastric/esogastric cancer. The primary objectives are to evaluate the safety profile, to determine the maximum tolerated dose (MTD) of IPH5301 alone in advanced /metastatic tumors (dose-escalation part) and to recommend a dose of IPH5301 to be combined with paclitaxel and trastuzumab in patients with advanced/metastatic HER2-positive breast and gastric/esogastric cancer (expansion part). The secondary objectives are to evaluate pharmacokinetic, immunogenicity and to assess preliminary clinical activity. Finally, exploratory objectives include pharmacodynamics such as CD73 expression, occupancy and enzymatic activity.

Clinical trial identification

NCT05143970 Initial release 11/17/2021.

Legal entity responsible for the study

Paoli Calmettes Institute.

Funding

Innate-Pharma.

Disclosure

A. Gonçalves: Non-Financial Interests, Personal and Institutional, Project Lead: Paoli Calmettes Institute. N. Kotecki: Non-Financial Interests, Personal and Institutional, Advisory Board: Innate-Pharma. D.B. Marie: Financial Interests, Personal, Full or part-time Employment: Innate Pharma. A. Boyer Chammard: Financial Interests, Personal, Full or part-time Employment: Innate Pharma. C.L. Paturel: Financial Interests, Personal, Full or part-time Employment: Innate Pharma. P. André: Financial Interests, Personal, Full or part-time Employment: Innate-Pharma. All other authors have declared no conflicts of interest.