Background

In FLAURA2 (NCT04035486), osi, a 3rd gen CNS-active EGFR-TKI, combined with platinum-pemetrexed (osi-CTx) showed a statistically significant improvement vs osi-monotherapy (osi-mono) in PFS per investigator (HR [95% CI]: 0.62 [0.49–0.79], p<0.001) with a manageable and tolerable safety profile. Addition of CTx did not affect osi exposure. 76% of pts completed 4 CTx cycles; median duration of pemetrexed exposure was 8.3 mos. 40% of FLAURA2 pts had baseline CNS metastases (mets); we report exploratory analyses of CNS efficacy by CNS blinded independent central review (BICR; conducted by neuroradiologist). Updated safety data will be reported.

Methods

Eligible pts (≥18 y [Japan: ≥20] with EGFRm advanced NSCLC, no prior tx for advanced NSCLC; asymptomatic CNS mets not requiring steroids or stable >2 wks after definitive tx/steroids were allowed) were randomised 1:1 to 1L osi-CTx or osi-mono until progression/discontinuation. Brain imaging (MRI preferred) was performed in all pts at baseline + progression, and at scheduled assessments until progression for pts with baseline CNS mets. CNS endpoints (modified RECIST1.1) included CNS PFS, CNS response and CNS DoR by CNS BICR. Safety was assessed by CTCAE v5. Data cutoff: 3 Apr 2023.

Results

Of 557 pts randomised, 118/279 (osi-CTx) and 104/278 (osi-mono) were included in the CNS BICR full analysis set (cFAS; pts with ≥1 measurable and/or non-measurable lesion); 40/118 (osi-CTx) and 38/104 (osi-mono) were included in the CNS evaluable for response set (cEFR; pts with ≥1 measurable lesion). Demographics were balanced across tx arms. CNS efficacy is shown (Table). Safety profile was similar in the cFAS and overall population. The safety and tolerability profile during the course of tx will be described.

Conclusions

In FLAURA2, pts with CNS mets in the osi-CTx arm had a clinically meaningful reduction in the risk of CNS progression, with high CNS ORR (and high CR) and durable responses, with a manageable and tolerable safety profile. Table: LBA68

Clinical trial identification

NCT04035486.

Editorial acknowledgement

The authors would like to acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice (GPP) guidelines.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

D. Planchard: Financial Interests, Institutional, Funding, Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Janssen, AbbVie; Financial Interests, Personal, Advisory Role, Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung, Janssen, AbbVie, Seagen, Gilead, Pierre Fabre; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung, Janssen, AbbVie, Gilead, Seagen, Pierre Fabre. P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Mirati Therapeutics, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly and Company, Ignyta, Takeda Oncology, Novartis, Voronoi, SFJ Pharmaceuticals, Biocartis, Loxo Oncology, PUMA, Sanofi, Transcenta, Daiichi Sa; Financial Interests, Personal, Other, Dr. Jänne is a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer-Ingelheim, Eli Lilly and Company, Takeda Oncology, PUMA, Astellas Pharmaceuticals, Daiichi Sankyo ; Financial Interests, Personal, Royalties, Post marketing royalties from DFCI owned intellectual property on EGFR mutations licensed to Lab Corp: Lab Corp. C.K. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Takeda, Pfizer, Novartis, GSK, Merck KGA, Roche, Janssen, and MSD; Financial Interests, Personal, Research Grant: AstraZeneca, Amgen, Roche, Merck KGA. K. Laktionov: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad; Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad, Pfizer; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche AG, Biocad. T. Kato: Financial Interests, Personal, Full or part-time Employment, Family member: Lilly; Financial Interests, Institutional, Funding: AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Chugai Pharma, Daiichi Sankyo, Haihe Biopharma, Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Takeda, Turning Point Therapeutics; Financial Interests, Personal, Advisory Role: AstraZeneca, BeiGene, Daiichi Sankyo, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer; Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, GSK, Janssen, Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Takeda, Taiho Pharmaceutical. L. Jiang: Non-Financial Interests, Personal, Local PI: Shanghai Chest Hospital, Shanghai Jiao Tong University, PR China. B. Chewaskulyong: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Other, Honoraria: AstraZeneca. S. Lucien Geater: Financial Interests, Personal, Other, Honoraria: AstraZeneca. F.A. Shepherd: Financial Interests, Personal, Invited Speaker, Honoraria: AstraZeneca; Financial Interests, Personal, Advisory Board, Honoraria: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Lilly; Financial Interests, Institutional, Funding: AstraZeneca/MedImmune, Squibb, Lilly, Roche Canada, Pfizer. K. Tanaka: Financial Interests, Speaker’s Bureau: AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, BMS, MSD, Merck; Financial Interests, Advisory Board: Pfizer, AstraZeneca. D. Ghiorghiu: Financial Interests, Full or part-time Employment: AstraZeneca; Financial Interests, Stocks/Shares: AstraZeneca. E. Armenteros Monterroso: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. X. Huang: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J.C. Yang: Financial Interests, Institutional, Advisory Board, My institute received fee for my role as advisory board: AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roache/Genetech, Takeda, Yuhan Pharmaceuticals, Janssen, Puma Technology, Gilead, GSK, Dizal Pharmaceutica; Financial Interests, Coordinating PI: AstraZeneca, MSD, Dizal Pharmaceutical; Financial Interests, Member: ASCO, ESMO, IASLC; Financial Interests, Research Funding: AstraZeneca, Roche; Financial Interests, Steering Committee Member: AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Takeda, Yuhan Pharmaceuticals, Janssen, Dizal Pharmaceutical. All other authors have declared no conflicts of interest.

Background

The standard first-line treatment for locally advanced or metastatic EGFR-mutated NSCLC patients (pts) is the third-generation EGFR-TKI alone, which has limitations. Combining EGFR-TKI with a small molecule anti-angiogenic agent may be a potential solution due to synergistic effects. The ATTENTION study aims to evaluate the efficacy and safety of aumolertinib plus apatinib (AUM + APA) versus aumolertinib (AUM) alone as the first-line therapy for EGFR-mutated NSCLC.

Methods

Eligible pts were aged 18-75 years old, stage IIIB or IV NSCLC, with EGFR 19del or 21L858R mutation or EGFR uncommon mutations, ECOG PS of 0 or 1, measurable lesion according to RECIST v1.1. We randomly assigned eligible pts in a 1:1 ratio to receive oral aumolertinib (110 mg PO QD) or adding apatinib (250 mg PO QD) until assessed progressive disease (PD). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), intracranial ORR (iORR), intracranial DCR (iDCR), overall survival (OS) and safety.

Results

From Jun. 2021 to Nov. 2022, a total of 104 pts were enrolled, 98 included in the efficacy analysis set. Of these, 48 pts received AUM + APA, while 50 pts received AUM. As of Sep. 12, 2023, the overall ORR was 72.9% and 64%, DCR was 100% and 94% in AUM + APA and AUM arms, respectively. In EGFR sensitizing mutation (19 del or L858R) subgroup, ORR was 75% and 68% in AUM + APA and AUM arms, respectively. In brain and liver metastasis subgroup, ORR were 100% and 60%, 60% and 33%, iORR was 82% and 63% in AUM + APA and AUM arms. PFS has beneficial trend in AUM + APA arm. The most common treatment-emergent adverse events (TEAEs) in AUM + APA and AUM arms were diarrhea (31% vs 12%), rash (29% vs 10%), proteinuria (27% vs 6%), platelet count decreased (25% vs 4%), hypertension (25% vs 6%), creatine kinase increase (23% vs 16%), respectively.

Conclusions

The combination of AUM + APA may provide a more effective and well tolerable treatment option for the first line treatment in EGFR mutated NSCLC patients.

Clinical trial identification

ChiCTR2100047453.

Legal entity responsible for the study

The authors.

Funding

Shanghai Hansoh Biomedical Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

Dual inhibition of the EGFR/VEGF pathways has demonstrated superior efficacy with 1st generation EGFR tyrosine kinase inhibitor (TKI) in patients with non small cell lung cancer (NSCLC) harboring EGFR mutations. This study aims to evaluate the efficacy and safety of combining osimertinib (Osi), a 3rd generation TKI considered the standard of care, with ramucirumab (Ram).

Methods

Previously untreated patients with advanced NSCLC and EGFR mutations were randomized to receive Osi daily with or without Ram every 2 weeks. Eligibility included asymptomatic and/or treated brain metastases. Stratification was based on gender and mutation type (exon 19 del, L858R). The primary endpoint was progression free survival (PFS) assessed by central radiologic review.

Results

Between November 2018 and April 2020, 122 patients (Osi+Ram arm: 59, Osi arm: 63) were enrolled. With a median follow up of 36.0 months (m), median PFS was 20.0 m for Osi+Ram arm and 24.0 m for Osi arm, resulting in a hazard ratio of 1.054 (95% CI 0.674-1.648, p = 0.82). The overall response rate was 77.2% and 79.3%, with a median duration of response of 24.7 m and 25.1 m in the Osi+Ram and Osi arms respectively. Notable grade 3 or higher adverse events (≥10%) included CK elevation (13%) in Osi arm, neutropenia (10%) and hypertension (17%) in Osi+Ram arm. Pneumonitis of any grade occurred in 9% and 16% of Osi+Ram and Osi arms. Median treatment durations for Osi and Ram were 18.8 (0.5-49.7) and 4.6 (0.5-40.7) m in the Osi+Ram arm, and 17.4 m in the Osi arm. The treatment period of Ram was shorter compared to previous studies. In a post hoc analysis, PFS favored the Osi+Ram combination among patients with brain metastasis (n=34) with a hazard ratio of 0.655 (95% CI 0.296-1.451).

Conclusions

While both treatment arms demonstrated long-term effects with acceptable toxicity, this study did not reveal an advantage of the Osi+Ram combination over Osi monotherapy in improving PFS. It’s noteworthy that conducted period during the COVID-19 pandemic, and the suboptimal administration of Ram may have influenced the outcome. jRCT2080224085

Clinical trial identification

jRCT2080224085 2021.11.12.

Legal entity responsible for the study

Thoracic Oncology Research Group (TORG).

Funding

Eli Lilly and Company.

Disclosure

Y. Nakahara: Financial Interests, Personal, Invited Speaker: Ono, Takeda, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Taiho, Chugai; Financial Interests, Personal, Research Grant: JSPS KAKENHI, The Japan Lung Cancer Society; Financial Interests, Institutional, Research Funding: Takeda. T. Kato: Financial Interests, Personal, Advisory Board, speaker, consultancy: AstraZeneca, Eli Lilly, Merck Biopharma, MSD; Financial Interests, Personal, Advisory Board, speaker: Pfizer, Amgen, Janssen; Financial Interests, Personal, Other, consultancy: Daiichi Sankyo, Takeda, Taiho; Financial Interests, Personal, Other, consultancy, speaker: Chugai; Financial Interests, Personal, Invited Speaker: Ono, Novartis, Bristol-Meyers Squibb, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: BeiGene, Glaxo; Financial Interests, Personal, Advisory Board, Steering Committee: Roche; Financial Interests, Personal, Full or part-time Employment, Family member: Eli Lilly; Financial Interests, Institutional, Local PI: Chugai, MSD, Pfizer, Eli Lilly, AbbVie, Regeneron, Novartis, Amgen, Merck Biophama, Haihe Biopharma, Blueprint Medicines, Turning Point, BeiGene, Daiichi Sankyo, Gilead, GSK, Janssen, Bayer, Takeda; Financial Interests, Institutional, Steering Committee Member, Local PI: AstraZeneca. M. Tamiya: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Amgen; Financial Interests, Personal, Advisory Board: Pfizer. K. Yoh: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi sankyo, Lilly, Boehringer Ingelheim, Amgen, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, Lilly, Daiichi sankyo, AbbVie, Taiho, MSD, Takeda, Amgen, Boehringer Ingelheim, Chugai; Financial Interests, Personal, Steering Committee Member: AstraZeneca. N. Furuya: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan, AstraZeneca, Boehringer Ingelheim Japan, Chugai, Bristol Myers Squibb, Taiho, Pfizer Japan, Novartis. A. Ono: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Local PI: Janssen Research & Development. Y. Takiguchi: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical, AstraZeneca, Chugai Pharma, Boehringer Ingelheim, Daiichi Sankyo, Taiho Pharmaceutical, Bristol-Myers Squibb Japan, Lilly, Pfizer, Novartis, Kyowa Kirin International, MSD, Eisai, Takeda, Amgen; Financial Interests, Personal, Other, Member of Ethics Committee: Oncolys BioPharma; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim, Lilly, Chugai Pharma, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: MSD Oncology, AstraZeneca, AbbVie. S. Ikeda: Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, Ono, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Ono, Bristol Myers Squibb, Taiho, Eli Lilly, Pfizer, Boehringer Ingelheim, Takeda; Financial Interests, Research Grant: AstraZeneca, Chugai. K. Watanabe: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, BMS, Boehringer Ingelheim, Merck, MSD, Takeda Pharmaceutical. T. Tokito: Financial Interests, Personal, Invited Speaker: AstraZeneca, Ono Pharmaceutical, MSD Oncology, Bristol Myers Squibb, Boehringer Ingelheim; Financial Interests, Personal, Other, lecture fee: Chugai Pharma, Nippon Kayku. N. Seki: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Eli Lilly, AstraZeneca, MSD, Taiho Pharmaceutical, Pfizer, Ono Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Daiichi Sankyo, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Kyowa Kirin, Merck; Financial Interests, Institutional, Research Grant: Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer, Ono Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Boehringer Ingelheim, Eisai, Daiichi Sankyo, Shionogi. T. Shukuya: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Novartis, Amgen, Pfizer, Bristol-Myers squibb, Boehringer Ingelheim, Daiichi Sankyo, Ono Pharmaceutical, Otsuka pharmaceutical, Eisai, Kyowa Kirin, Life technologies, Eli Lilly, Takeda Pharmaceutical, Nippon Kayaku; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis, MSD; Financial Interests, Institutional, Coordinating PI: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. Y. Shibata: Financial Interests, Personal, Other, Honoraria: Pfizer, Takeda, Bristol-Myers Squibb, Merck, AstraZeneca, Chugai, Ono, Eli Lilly; Financial Interests, Institutional, Local PI: MSD, Novartis, Blueprint Medicines, Chugai. T. Kozuki: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., MSD, Pfizer Japan, Kyowa Hakko Kirin, Nippon Beohringer Ingelheim, Merck Biophama, Nippon Kayaku, Novartis, Takeda Pharmaceutical Co., Bayer, Sawai, Amgen; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, AbbVie; Financial Interests, Institutional, Local PI: Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Ono Pharmaceutical Co., MSD, Kyowa Hakko Kirin, Merck Biophama, Daiichi Sankyo, Amgen, AbbVie, Sanofi, Eisai, Pfizer, Labcorp Development Japan. H. Okamoto: Financial Interests, Institutional, Research Grant: MSD, Taiho, Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Background

Osimertinib (osi) is the current first-line therapy for patients (pts) with metastatic EGFR-mutant NSCLC. Combination of anti-VEGF with EGFR inhibitors has a potential to prolong progression-free survival (PFS).

Methods

The RAMOSE trial (NCT03909334, HCRN LUN-18-335) is a randomized, open-label phase 2 study comparing osi 80mg PO daily + ramucirumab 10 mg/kg IV q3 weeks (Arm A) to osi alone (Arm B) for initial treatment of metastatic EGFR-mutant NSCLC with 2:1 randomization. The primary endpoint is PFS by investigators, secondary endpoints include best response rates (BRR), disease control rate (DCR), overall survival (OS), and safety. The stratification criteria for randomization were EGFR mutation type and presence of CNS metastasis.

Results

At data cut-off Aug 29, 2023, 160 pts consented, 147 pts received treatment, and 139 pts had at least one efficacy scan. The median follow up was 16.6 months (range 1.4-46.1). Among the 139 pts, 57 PFS events (37 progressions and 20 progressions followed by death) were observed, 32 in A and 25 in B. The median PFS was 24.8 (A) vs 15.6 (B) months (HR=0.55; 95%CI: 0.32-0.93; Log Rank p=0.023), 12-mon PFS rate was 76.7% (A) vs. 61.9% (B, p=0.026). BRRs and DCRs had no difference. For high risk gorup of 43 (31%) pts with L858R, PFS was 24.8 (A) vs 18.4 months (B, p=0.388); for 64 (46%) pts with CNS metastasis, PFS was 17.9 (A) vs 13.8 months (B, p=0.225). Any-grade (G) AEs occurred in 93% (A) and 87% (B) of pts. There were no G5 treatment-related AE (TRAE), one G4 TRAE (hyponatremia, A), 46% (A) vs. 35% (B) G3 TRAEs, including G3 hypertension at 28% (A) vs 7% (B) and decreased neutrophils at 21% (A) vs 23% (B). AE-related discontinuation was observed in13 pts (9.7% in A, 8.7% in B). Table: LBA71

Conclusions

Ramucirumab + osi significantly prolonged PFS compared to osi alone in EGFR-mutant NSCLC pts. The RAMOSE seems to be as efficacious as FLAURA2. Safety profile was in line with known safety of each drug.

Clinical trial identification

NCT03909334.

Legal entity responsible for the study

The authors.

Funding

Eli Lilly.

Disclosure

X. Le: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck KGaA, Spectrum Pharmaceutics, Novartis, Boehringer Ingelheim, Eli Lilly, Hengrui, Janssen, Blueprint, Daiichi Sankyo, Regeneron, ArriVent, Abion, Pinetree therapeutics, AbbVie; Financial Interests, Institutional, Invited Speaker: Eli Lilly, EMD Serono, Regeneron, Janssen; Financial Interests, Institutional, Research Grant: Arrivent; Financial Interests, Institutional, Funding: Teligene. J.V. Heymach: Financial Interests, Personal, Advisory Board: Genentech, Mirati Therapeutics, Eli Lilly & Co., Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca, BioAlta, Sanofi, Spectrum Pharmaceuticals, GSK, Spectrum; Financial Interests, Personal, Full or part-time Employment: MD Anderson Cancer Center; Financial Interests, Institutional, Other, International PI for clinical trials: AstraZeneca; Financial Interests, Institutional, Other, International PI for two clinical trials: Boehringer-Ingelheim; Financial Interests, Personal and Institutional, Other, Developed a drug: Spectrum; Financial Interests, Institutional, Coordinating PI: Takeda. All other authors have declared no conflicts of interest.

Background

Eftilagimod alpha (E), a soluble LAG-3 protein, acts as an MHC class II agonist triggering activation of antigen-presenting cells (APC). Subsequently downstream T-cells (e.g. CD4/CD8) are recruited, possibly leading to stronger anti-tumor responses than with pembrolizumab (P) alone, especially in tumors non-overexpressing PD-L1. We hereby report initial overall survival (OS) results of the 1st line non-small cell lung carcinoma (NSCLC) cohort in TACTI-002.

Methods

Patients (pts) with measurable 1st line metastatic NSCLC unselected for PD-L1 were recruited. Primary endpoint (EP) was objective response rate (ORR) by iRECIST. Secondary EPs included OS, ORR by RECIST 1.1, duration of response (DoR), progression free survival (PFS), safety & biomarkers. Pts received 30 mg E SC q2w for 8 cycles (1 cycle= 3 weeks) & then q3w up to 1 yr with P 200 mg IV q3w up to 2 yrs. Imaging was done q9w & assessed by investigator. PD-L1 was centrally assessed (22C3). The study was powered (80%) with a 1-sided alpha of 2.5% to detect an ORR increase from 23% (historical results for P) to 35%.

Results

From Mar 2019-Nov 2021, 114 pts enrolled using modified Simon’s two-stage design. Median follow up of 20.4 mo (cut-off Mar 31, 2023). Median age was 67 (44–85) & 74% were male. ECOG PS was 0 & 1 in 37% & 63% of pts. Pts had squamous (35%) or non-squamous (63%) carcinoma. All PD-L1 subgroups were represented; 77.8% had TPS <50%. Pts received median 9 (1–35) P & 13 (1–22) E doses. Median (m) OS unselected for PD-L1 was 22.6 mo (52.6% events) & mDoR was 21.6 mo. Onset of responses was quick (median: 2.1 mo). Comparable results by RECIST 1.1. Efficacy by PD-L1 shown in the table. Safety was presented prior at SITC 2022.

Table: 1312MO

Conclusions

E + P shows encouraging OS results in line with excellent ORR, PFS and DOR in 1st line NSCLC overall and in all PD-L1 subgroups. This combination warrants further late-stage clinical investigation.

Legal entity responsible for the study

Immutep S.A.

Funding

Immutep S.A.

Disclosure

E. Carcereny: Other, Consultant or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novartis, Roche, Takeda; Other, Speaking: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda; Other, Grant: Merk; Other, N/A: :Bristol Myers Squibb, Pfizer, Roche, Takeda. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. M. Majem: Financial Interests, Personal, Advisory Board: Amgen, Roche, AstraZeneca, Takeda, Janssen, Cassen Recordati, BMS; Financial Interests, Personal, Invited Speaker: Amgen, Roche, AstraZeneca, Pfizer, Takeda, Helsinn; Financial Interests, Institutional, Funding: BMS, AstraZeneca, Roche. T.D. Clay: Other, Honoraria: Specialised Therapeutics, Wiley, Lilly, Roche; Other, Stock and Other Ownership Interests: ClinicIQ; Other, Consulting or Advisory Role: AstraZeneca/MedImmune, Cipla, Foundation Medicine, Takeda, Merck KGaA, Merck/Pfizer, Ipsen; Other, Speakers' Bureau: AstraZeneca/MedImmune, MSD; Other, Travel, Accommodations, Expenses: AstraZeneca; Other, Research Funding: Exelixis, Immutep, Clovis Oncology, MSD Oncology, Pfizer, Amgen, Daiichi Sankyo/AstraZeneca, AbbVie, Janssen Oncology, BeiGene, Bayer, BridgeBio Pharma, BMS GmbH & Co. KG. J. Peguero: Other, Employment: Oncology Consultants; Other, Leadership: Director, Research Department. M.D. Forster: Other, Consulting or Advisory Role: Achilles Therapeutics; AstraZeneca; Bayer; Bristol Myers Squibb; Celgene; Guardant Health; Lilly; Merck Sharp & Dohme; Nanobiotix; Novartis; Oxford VacMedix; Pfizer; PharmaMar; Roche; Takeda; Other, Research Funding: AstraZeneca (Inst); Boehringer Ingelheim (Inst); Merck Serono (Inst); MSD Oncology (Inst); Other, Travel, Accommodations, Expenses: AstraZeneca; Bristol Myers Squibb; Celgene; Guardant Health; MSD Oncology; Roche. E. Kalinka: Financial Interests, Personal, Advisory Board, advisory board member, clinical trial and lectures honoraria: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker, lectures and clinical trial honoraria: Merck Sharp and Dohme; Financial Interests, Personal, Invited Speaker, lectures honoraria: GSK, Roche; Financial Interests, Personal, Invited Speaker, lectures honoraria and writing engagement: Sanofi, Regeneron; Financial Interests, Personal, Advisory Board, advisory role, clinical trials honoraria: AstraZeneca; Financial Interests, Personal, Invited Speaker: Gilead, Amgen; Financial Interests, Personal, Ownership Interest: Instytut MSF Sp zoo; Financial Interests, Personal and Institutional, Local PI: AstraZeneca, Roche, Bristol Myers Squibb, Gilead; Financial Interests, Personal, Local PI: Merck Sharp Dohme. G.M. Garcia Ledo: Other, Employment: Roche Farma; Other, Stock or Ownership: AbbVie; Other, Honoraria: BMS, MSD; Other, Consulting or Advisory Role: Natera. L. Vila Martinez: Other, Consulting or Advisory Role: Boehringer Ingelheim; Other, Honoraria: Roche, Bristol Myers Squibb/Pfizer, Pfizer, AstraZeneca Spain. W. Iams: Financial Interests, Personal, Advisory Board: Tempus, EMD Serono, Amgen, Sanofi, NovoCure, Genentech, AstraZeneca, Catalyst, Jazz Pharma, Elevation Oncology, Bristol Myers Squibb, Janssen, Takeda, Mirati, G1 Therapeutics. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Advisory Board: AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Carrick, Janssen, Pyramid Biosciences; Financial Interests, Institutional, Local PI: Blueprint, Astex, Bayer, BerGenBio, Immutep, Novartis, Nurix, Nuvalent, Roche, Seattle Genetics, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Travel expenses for congress: Immutep, Janssen; Other, Travel expenses: Roche. K. Efthymiadis: Other, Honoraria: Amgen Hellas, MSD Greece, Pfizer Hellas, Roche Hellas; Other, Advisory Boards: Faran SA; Other, Travel & Educational Grants: Amgen Hellas, DEMO SA, Innovis Pharma SA, Merck Greece, MSD Greece, Novartis Greeve, Pfizer Hellas, Roche Hellas, Sanofi Greece, Specifar SA. C. Mueller: Other, Employment: Immutep; Other, Stock and Other Ownership Interests: Immutep. F. Triebel: Other, Employment: Immutep SAS; Other, Stock and Other Ownership Interests: Immutep Ltd; Other, Patents, Royalties, Other Intellectual Property: Being an inventor on patents on LAG-3 owned by Immutep SAS. All other authors have declared no conflicts of interest.

Background

AZD7789 is a monovalent, bispecific, humanised IgG1 that blocks PD-1 and T cell immunoglobulin and mucin domain 3 (TIM-3), receptors that regulate antitumour T cell activity and myeloid activation. Dual blockade of PD-1 and TIM-3 may overcome or delay anti-PD-(L)1 resistance. Here we report dose escalation results from a phase 1/2a, first-in-human, multicentre, open-label trial of AZD7789 monotherapy in pts with stage IIIB–IV NSCLC with ≥1 prior line of systemic therapy including ≥1 anti-PD-(L)1 agent.

Methods

Eligible pts were ≥18 yr old with ECOG PS 0–1. Dose cohorts ranged from 2–2000 mg IV Q3W: 2–225 mg in an accelerated titration design, and 750–2000 mg using mTPI-2. The primary objective was safety, including dose-limiting toxicities (DLTs). Secondary/exploratory objectives included efficacy, pharmacokinetics (PK), PD-1 receptor occupancy (RO), and immunogenicity. Data cutoffs were 13 Feb 2023 for safety and 11 Jan 2023 for efficacy.

Results

In total, 39 pts received AZD7789 2–2000 mg; median age 66 yr, 56% male, 36% PD-L1 status <1%, 33% PD-L1 1–49%, and 28% PD-L1 ≥50%, and 80% had acquired resistance to prior anti-PD-(L)1 therapy (≥6 mo of treatment exposure). Treatment emergent AEs (TEAEs) occurred in 82% of pts and were Grade (Gr) ≥3 in 23%. The most common TEAE was increased blood creatinine (18%); no TEAE led to discontinuation. Treatment related AEs (TRAEs) occurred in 41% of pts; the most common was asthenia (8%). There were no DLTs or Gr ≥3 TRAEs. On-treatment scans were available for 19 pts: 7 had stable disease, including 2 with unconfirmed partial responses, 11 had progression, and 1 was not evaluable. Target lesion shrinkage was observed in 8 pts. PK was generally dose proportional, with t_½ ∼7 days; antidrug antibodies had limited impact on PK. Doses ≥225 mg led to durable PD-1 RO >90% on peripheral T cells. As of 13 Feb 2023, 24 pts remained on AZD7789; updated data will be presented.

Conclusions

AZD7789 has manageable safety and shows preliminary efficacy at tolerable doses. Evaluation is ongoing in immunotherapy-naive pts with NSCLC and pts with acquired resistance to immunotherapy.

Clinical trial identification

NCT04931654; June 18, 2021.

Editorial acknowledgement

Medical writing support for this abstract was provided by Eric Exner of Ashfield MedComms (Milwaukee, WI, USA), an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. S. Cousin: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, MSD, Takeda. G. Ruiter: Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca, AbbVie, Daiichi Sankyo, Cullinan Oncology, Boehringer Ingelheim, Merus, Bayer. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. E. Castanon Alvarez: Financial Interests, Personal, Advisory Board: MSD, Roche, BMS; Financial Interests, Personal, Invited Speaker: GSK; Non-Financial Interests, Principal Investigator: AZ, BMS, Roche, MSD, GSK, ARC. S.S. Ramalingam: Financial Interests, Personal, Other, Editor in Chief, CANCER journal: American Cancer Society; Financial Interests, Research Grant: Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK. C.D. Rolfo: Financial Interests, Personal, Invited Speaker, Egypt event: AstraZeneca; Financial Interests, Personal, Invited Speaker, Foundation One Liquid Biopsy: Roche; Financial Interests, Personal, Invited Speaker, Middle East: MSD; Financial Interests, Personal, Advisory Board, NGS Lung: Inivata, Archer; Financial Interests, Personal, Advisory Board, Lung: Boston Pharmaceuticals, Novartis; Financial Interests, Personal, Advisory Board, Lung pipeline: MD Serono; Financial Interests, Institutional, Invited Speaker, Lung: COR2ED, Daiichi Sankyo, Physicians Education Resource; Financial Interests, Institutional, Advisory Board, Lung: Regeneron, Intellisphere, CEA, Bayer U.C. LLC, General Dynamics, MedStar, Imagene; Financial Interests, Institutional, Coordinating PI, Empower me study Grant by LCRF and Pfizer: Pfizer- Lung Cancer research Foundation; Financial Interests, Institutional, Coordinating PI, Global PI LUNG itrapid@024 trial: MD Serono; Non-Financial Interests, Institutional, Other, Analysis of Liquid Biopsies in Lung Cancer Trial: Guardant Health; Non-Financial Interests, Other, Faculty ESMO NSCLC Metastatic 2021-2025: ESMO; Non-Financial Interests, Leadership Role, Vice-President: ISLB International Society of Liquid Biopsy; Non-Financial Interests, Leadership Role, Scientific Board member: ESO European School of Oncology; Non-Financial Interests, Leadership Role, Deputy Chair Educational Committee: IASLC International Association for Study of Lung Cancer; Non-Financial Interests, Leadership Role, Educational chair: OLA Oncology Latin American Association; Non-Financial Interests, Other, Editor in Chief of the Journal: CROH Critical Reviews in Oncology Hematology; Non-Financial Interests, Other, Associate Editor: ESMO Open. D.R. Spigel: Financial Interests, Institutional, Other, Consulting: AstraZeneca, BeiGene, Bristol Myers Squibb, Evidera, GSK, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Pfizer, Regeneron, Sanofi-Aventis, AbbVie, Novocure, Roche/Genentech; 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, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GSK, GRAIL, Hutchinson MediPharma, ImClone Systems, Ipsen, Janssen, Loxo, MacroGenics, MedImmune, Merck, Nektar, Neon Therapeutics, Novartis, Novocure, Rgenix, SeaGen, Taiho Oncology, Tarveda, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Arcus Biosciences, Molecular Template, Cyteir Therapeutics, BioNTech, Apollomics, Pure Tech Health, Elevation Oncology, Repare Therapeutics, Razor Genomics, Denovo Biopharma, Erasca, Kronos Bio, Zai Laboratory, Faeth Therapeutics, Ascendis Pharma, Lyell Immunopharma, Synthekine, Shenzhen Chipscreen Biosciences, AbbVie, AnHeart Therapeutics, Calithera, Endeavor, FujiFilm Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Millennium Pharmaceuticals, Moderna, Monte Rosa Therapeutics, Peloton Therapeutics, Stemline Therapeutics, Tango Therapeutics, Tesaro. D. Andrew, S. Cho, T. Collins, R. Kurek, N. Ceaicovscaia, M. Petruzzelli, E.J. Dean: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Hansen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. G. Hawkins: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Member: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca. A. Sacher: Financial Interests, Institutional, Coordinating PI: Genentech-Roche, BMS, AstraZeneca; Financial Interests, Institutional, Local PI: Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly.

Background

Once targeted therapies and platinum-based chemotherapy (PBC) become ineffective in patients (pts) with advanced/metastatic (a/m) NSCLC with AGAs, few treatments with limited benefit are available. Dato-DXd is an antibody-drug conjugate composed of a TROP2 directed monoclonal antibody covalently linked to a highly potent cytotoxic payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. We report primary results from the global, open-label, phase 2 TROPION-Lung05 trial (NCT04484142) evaluating Dato-DXd in pts with a/m NSCLC with AGAs progressing on or after ≥1 AGA-specific therapy and PBC.

Methods

Dato-DXd 6 mg/kg was given every 21 days to pts with a/m NSCLC, ECOG status 0 or 1, and ≥1 documented AGA in EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET. The primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DOR) and disease control rate (DCR) by BICR, and safety.

Results

A total of 137 pts received ≥1 dose and had a median age of 61.0 y; 71.5% had ≥3 prior lines of therapy for a/m NSCLC; 56.9% had EGFR mutations. As of 14 Dec 2022, 85.4% discontinued therapy, 63.5% had disease progression, and 49.6% died. Median pt duration on study was 15.2 months (mo); cORR was 35.8%, DCR, 78.8%, and median DOR, 7.0 mo; similar response was seen in pts with EGFR mutations (Table). The most common grade ≥3 TEAEs were stomatitis (9.5%), anemia (5.8%), and increased amylase (5.8%). Table: 1314MO

Primary results (N=137)

Conclusions

Dato-DXd showed encouraging antitumor activity, with a clinically meaningful and durable response, in heavily pretreated pts with NSCLC with AGAs. The safety profile was manageable and consistent with prior safety observed with Dato-DXd. These data support inclusion of pts with AGAs in the TROPION-Lung01 study (NCT04656652).

Clinical trial identification

NCT04484142.

Editorial acknowledgement

Medical writing support was provided by Kristie Garza, PhD, of SciMentum, Inc, a Nucleus Holdings Ltd company, and was funded by Daiichi Sankyo, Inc. Editorial support was provided in accordance with good publication practice guidelines.

Legal entity responsible for the study

Daiichi Sankyo, Inc.

Funding

Daiichi Sankyo, Inc.

Disclosure

L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, BeiGene, Daiichi, 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, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme Corp, BMS, Janssen-Cilag International NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President. ASEICA (Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation president: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group. M. Ahn: Financial Interests, Personal, Advisory Role: AstraZeneca, Merck, Yuhan, Amgen, Roche, Pfizer, Alpha Pharmaceuticals, Takeda, Voronoi, Eutilex, Daiichi Sankyo; Financial Interests, Personal and Institutional, Advisory Role: Arcus. A.E. Lisberg: Financial Interests, Personal, Full or part-time Employment, Immediate Family Member: Boston Scientific; Financial Interests, Personal, Stocks or ownership, Immediate Family Member: Boston Scientific; Financial Interests, Personal, Other, Honoraria; Consulting or advisory role: AstraZeneca, Bristol Myers Squibb, Leica Biosystems, Jazz Pharmaceuticals, Novocure, Pfizer, Eli Lilly, Novartis, Regeneron, Janssen oncology , Sanofi group of companies; Financial Interests, Personal, Other, HoHonoraria; Consulting or advisory rolenoraria: MorphoSys; Financial Interests, Institutional, Research Funding: Daiichi Sankyo, Calithera Biosciences, AstraZeneca, Dracen Pharmaceuticals , WindMIL, eFFECTOR Therapeutics. S. Kitazono: Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Ono Pharmaceutical Co, Chugai Pharmaceutical Co., Ltd. B.C. Cho: Financial Interests, Personal, Stocks or ownership: TheraCanVac Inc, Gencurix Inc, BridgeBio therapeutics, Kanaph Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., J Ints Bio; Financial Interests, Personal and Institutional, Royalties: Champions Oncology, Crown Bioscience, Imagen; Financial Interests, Institutional, Research Grant: MOGAM Institute, LG Chem, Oscotec, Interpark , Bio Convergence Corp, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Onoclogy, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, BridgeBio therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center. E. Shum: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Blueprint Medicines; Financial Interests, Institutional, Research Funding: Delfi Diagnostics. E. Pons-Tostivint: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, BMS, Sanofi; Financial Interests, Institutional, Local PI: AstraZeneca, BMS, Daiichi Sankyo, Sanofi, PDC line, Takeda, Amgen. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fisher; Financial Interests, Personal, Other, Travel Grant: Daiichi Sankyo; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Preferred Network; Financial Interests, Personal and Institutional, Coordinating PI: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network; Financial Interests, Institutional, Coordinating PI: Guardant Health; Non-Financial Interests, Member of Board of Directors: Cancer Net Japan, JAMT. K. Yoh: Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Amgen, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, Lilly, Daiichi Sankyo, AbbVie, Taiho, MSD, Takeda, Amgen, Boehringer Ingelheim, Chugai; Financial Interests, Personal, Steering Committee Member: AstraZeneca. R. Heist: Financial Interests, Institutional, Research Funding: AbbVie, Agios, Corvus, Daiichi Sankyo, Erasca, Lilly, Mirati, Novartis, Turning Point; Financial Interests, Personal, Advisory Board, Consulting fees: AbbVie, Daiichi Sankyo, EMD Serono, Lilly, Novartis, Regeneron, Sanofi. P. Baas: Financial Interests, Institutional, Speaker, Consultant, Advisor: BMS; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Institutional, Advisory Role: Amheart, BeiGene; Financial Interests, Institutional, Research Funding: AstraZeneca. M. Pérol: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, Lilly, Novartis, Takeda, Gritstone, Sanofi, Pfizer, Amgen, Janssen, GSK, Eisai, Ipsen; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, BMS, Boehringer Ingelheim, Takeda, Illumina, Pfizer, Medscape; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Takeda, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Roche; Financial Interests, Personal, Other, DMSB: Roche. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. W. Su: Financial Interests, Personal, Other, Consulting or advisory role: Merck, MSD, Bayer, Roche; Financial Interests, Personal, Other, Honoraria; Consulting or advisory role: Lilly. H. Zebger-Gong: Financial Interests, Personal and Institutional, Full or part-time Employment, Full-time employment: Daiichi Sankyo; Financial Interests, Personal and Institutional, Stocks or ownership, Stock options: Daiichi Sankyo; Financial Interests, Personal, Stocks or ownership, Stocks: Bayer. C. Liu: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. J. Sands: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, Takeda, Jazz Pharmaceuticals, Pharma Mar, Sanofi, Merck, Guardant, Medtronic, Amgen; Financial Interests, Personal, Advisory Board: Curadev; Financial Interests, Institutional, Local PI: Genentech, Merck, Pharma Mar, Legend, Amgen, Daiichi Sankyo, Lilly; Financial Interests, Institutional, Member: Phanes. All other authors have declared no conflicts of interest.

Background

NRG1 fusions are rare oncogenic drivers of NSCLC and other solid tumors. These chimeric proteins bind HER3, leading to HER2/HER3 heterodimerization and oncogenic transformation. Zenocutuzumab (MCLA-128; Zeno) is a bispecific antibody that overcomes HER3-mediated NRG1 signaling in NRG1+ cancer. Zeno is being evaluated in the ongoing pivotal phase 2 eNRGy study and early access program (EAP). Updated NRG1+ NSCLC data are presented.

Methods

Patients (pts) with advanced NRG1+ NSCLC determined by NGS, previously treated with or not candidate for standard therapy, age ≥ 18 y, ECOG PS ≤ 2, and measurable (RECIST v1.1) or evaluable disease were enrolled. Zeno (750 mg IV Q2W) was administered until disease progression or unacceptable toxicity. Tumor imaging was conducted Q8W. The primary endpoint is investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include duration of response (DOR) and safety.

Results

As of 01 Feb 2023, 85 pts with NRG1+ NSCLC (78 eNRGy/7 EAP) were enrolled. Efficacy was assessed in 65 pts who received ≥ 1 dose of Zeno and were enrolled by 01 Aug 2022 to allow for the opportunity for ≥ 6 months (mo) follow-up and met the criteria for the primary efficacy population. The median age was 64 y (range 32-86), 65% were female, 29%/63%/5% pts had ECOG PS 0/1/2 (missing 2 pts). Most were Asian (52%) or White (37%), 77% had visceral metastases, 98% had adenocarcinoma histology, and 1 pt had non-measurable disease. Common fusion partners were CD74 (52%) and SLC3A2 (23%). Pts received a median of 2 prior systemic therapies (range 0-6), 78% with platinum-based chemotherapy; 12% were treatment naïve. In the 64 pts with measurable disease, the confirmed ORR was 34% (22/64; 95% CI 23-47). 50/64 (78%) pts had target lesion reduction. Median DOR was 12.9 mo with responses ongoing in 11/22 (50%) pts. Kaplan-Meier estimate of 6-mo DOR rate was 79%. Among 85 pts treated with Zeno, Grade ≥ 3 individual AEs irrespective of causality occurred in < 4% pts. No pt discontinued Zeno for a treatment related AE.

Conclusions

In this updated analysis, Zeno provides robust and durable efficacy in advanced NRG1+ NSCLC, with a well-tolerated safety profile.

Clinical trial identification

NCT02912949.

Editorial acknowledgement

Medical writing support was provided by Sarah Mackenzie of Merus, N.V.

Legal entity responsible for the study

Merus N.V.

Funding

Merus N.V.

Disclosure

A. Schram: Financial Interests, Institutional, Writing Engagement, & funding to institution as part of participation in the clinical study: Merus ; Financial Interests, Institutional, Research Funding: AstraZeneca, ArQule, BeiGene/Springworks, Black Diamond Therapeutics, Elevation Oncology, Kura, Lilly, Merus, Northern Biologics, Pfizer, PMV Pharma, Relay Therapeutics, Repare Therapeutics, Revolution Medicine, Surface Oncology; Financial Interests, Institutional, Advisory Board: Relay Therapeutics, Mersana, Blueprint Bio; Financial Interests, Institutional, Advisory Board, Payment to me for participation including travel to event: Merus. K. Goto: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Amgen K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Amoy Diagnostics Co., Ltd., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb K.K., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Guardant Health Inc., Merck Biopharma Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K., Medpace Japan K.K.; Financial Interests, Personal and Institutional, Funding: Amgen Inc., Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta,Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical ＆ Biological Laboratories Co., LTD., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics,Inc., Amgen Astellas BioPharma K.K., Bayer Yakuhin, Ltd., Blueprint Medicines Corporation., Life Technologies Japan Ltd., NEC Corporation., Novartis Pharma K.K.; Non-Financial Interests, Member: American Society of Clinical Oncology, The Japan Lung Cancer Society, Japanese Society of Medical Oncology, The Japanese Cancer Association. D. Kim: Financial Interests, Personal, Invited Speaker: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Taiwan Lung Cancer Society, Japan Cancer Association; Financial Interests, Personal, Other, Scientific Advisor: Health Insurance Review & Assessment Service, Korea; Financial Interests, Personal, Writing Engagement, Medical writing assistance: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, Daiichi Sankyo, GSK, Pfizer, MSD, Merck, Novartis, Roche, Takeda, Yuhan; Financial Interests, Institutional, Local PI, Clinical Trial Funding: Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer Ingelheim, Daiich-Sankyo, Hanmi, Janssen, Merus, MIrati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Bridge BioTherapeutics, GSK; Financial Interests, Institutional, Coordinating PI, Clinical Trial Funding: Chong Keun Dang; Financial Interests, Institutional, Research Grant, Laboratory research funding to my institution: InnoN; Non-Financial Interests, Advisory Role: Amgen, BMS / ONO Pharmaceuticals, Daiich-Sankyo, Janssen, GSK, Pfizer, AstraZeneca, SK Biopharm, Takeda, Yuhan; Non-Financial Interests, Member of Board of Directors: Korean Cancer Association, Korean Society of Medical Oncology, Korean Association for Lung Cancer, Asian Thoracic Oncology Research Group; Other, Travel support for advisory board meeting attendance: Amgen, Daiichi Sankyo; Other, Clinical trial research funding to my institution: Asian Thoracic Oncology Research Group. A. Hollebecque: Financial Interests, Personal, Invited Speaker: Servier, Incyte, Eisai; Financial Interests, Personal, Advisory Board: Basilea, Tahio, Relay Theraeutics, QED Therapeutics, Debiopharm, MSD, Boehringer Ingelheim; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Principal Investigator, M19-345: AbbVie; Non-Financial Interests, Principal Investigator, CO42216 ; WP42627 ; CO40939: Roche; Non-Financial Interests, Principal Investigator, MCLA-158: Merus; Non-Financial Interests, Principal Investigator, SGNB6A: Seatle Genetics; Non-Financial Interests, Principal Investigator, TAS-120-202: Tahio; Non-Financial Interests, Principal Investigator, Krystal-10: Mirati; Non-Financial Interests, Principal Investigator, ADP-0033: Adaptimmune; Non-Financial Interests, Principal Investigator, ACT16902: Sanofi; Non-Financial Interests, Principal Investigator, C4201002: Pfizer; Non-Financial Interests, Principal Investigator, RLY-4008: Relay Therapeutics; Non-Financial Interests, Principal Investigator, CC-90011: Celgene/BMS; Non-Financial Interests, Principal Investigator, Loxo-IDH: Loxo/Lilly; Non-Financial Interests, Principal Investigator: AstraZeneca; Non-Financial Interests, Principal Investigator, SN-201 study: Sotio; Non-Financial Interests, Principal Investigator, Tropics-03: Gilead; Non-Financial Interests, Principal Investigator, BI1403: Boehringer Ingelheim. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clincal trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: zy,meworks; Financial Interests, Institutional, Local PI, drug supply for clinical trial: BeiGene; Financial Interests, Coordinating PI, Drug supply for clinical trial: Incyte. K. Nishino: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., NSD, Amgen, Janssen Pharmaceutical K.K., Novartis Pharmaceuticals, Eli Lilly Japan, Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Nippon Kayaku; Financial Interests, Institutional, Other, Research grant: Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD, AbbVie, Daiichi Sankyo Company, Limited, Amgen, Sanofi K.K., Janssen Pharmaceutical K.K., Novartis Pharmaceuticals, Pfizer, Eli Lilly, Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical, Merus, AstraZeneca; Financial Interests, Institutional, Other, Research grant: Eisai Co., Ltd.; Financial Interests, Personal, Invited Speaker, Advisary Board: Pfizer; Financial Interests, Personal, Invited Speaker, Advisory Board: Merck Biopharma Co., Ltd., AstraZeneca. M. Duruisseaux: Financial Interests, Institutional, Advisory Role: BMS, GSK, Sanofi, MSD, AstraZeneca, AbbVie, Takeda, Boehringer Ingelheim, Amgen, Guardant, Pfizer, Mirati; Financial Interests, Institutional, Speaker, Consultant, Advisor: Roche; Financial Interests, Institutional, Advisory Board: BMS, MSD, AstraZeneca, AbbVie, Takeda, Boehringer Ingelheim, Gamamabs Pharma, Pfizer, NanoString, Lilly, Blueprint, Merus; Financial Interests, Institutional, Research Grant: Takeda. J.O. Park: Financial Interests, Personal, Advisory Board: MedPacto, BMS (Celgene), Servier, MediRama, Adicet Bio, AstraZeneca, Merck Sereno; Financial Interests, Personal, Other, Travel support for a poster presentation at ASCO GI 2023 : Minneamrita Therapeutics LLC; Financial Interests, Personal, Research Grant, Clinical research grant: MedPacto, Servier, BMS (Celgene); Financial Interests, Personal, Research Grant: Eutilex, ABL Bio. N. Leighl: Financial Interests, Personal, Other, CME/independent lectures: MSD, BMS, Hoffmann LaRoche, EMD Serono; Financial Interests, Personal, Invited Speaker, independent lectures: Novartis, Takeda; Financial Interests, Personal, Advisory Board: Puma Biotechnology; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Array, Bayer, EMD Serono, Guardant Health, Lilly, MSD, Pfizer, Roche, Takeda, Janssen. T. Macarulla: Financial Interests, Personal, Advisory Board: Ability Pharmaceutical, SL, AstraZeneca, Basilea Pharma, Batxer, BioLineRX Ltd, Celgene SLU, Eisai, Ipsen Pharma, Incyte; Financial Interests, Personal, Other, Direct research fund: Servier, Merck, Sharp and Dhome, Novocure, QED Therapeutics Inc, Roche, Sanofi-Aventis, Zymeworks; Financial Interests, Personal, Invited Speaker: Lilly, Janssen; Financial Interests, Institutional, Research Grant: Amc Medical Research, Armo Biosciences, Basilea, Biokeralty Research Institute, Merck Sharp & Dohme, Oncomed Pharmaceuticals, QED Therapeutics, VCN Biosciences, AbbVie Farmaceútica, Ability Pharmaceuticals, Agios, Amgen, Aslan, AstraZecena, Bayer, BeiGene, Biolinerx, Blueprint Medicines, Boston Biomedical, Bristol Myers Squibb (BMS), Cantargia, Celgene, Eisai, Erytech Pharma, F. Hoffmann-la Roche, Fibrogen, Genentech, Hallozyme, Immunomedics, Incyte, Ipsen, Lab. Menarini, Lilly, Loxo Oncology, Medimmune, Merimarck, Millenim, Nelum, Novartis, Novocure, Zymeworks, Pfizer, Pharmacyclics, Roche; Non-Financial Interests, Member: American Society of Clinical Oncology - ASCO, “Sociedad Española de Oncología Médica” – SEOM, Sociedad Europea de Oncología Médica - ESMO. S.V. Liu: Financial Interests, Personal, Advisory Board, Consultant: AstraZeneca, Elevation Oncology, Genentech / Roche, Janssen, Jazz Pharmaceuticals, Novartis, Regeneron, Sanofi, Turning Point Therapeutics; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Catalyst, Eisai, Gilead, Guardant Health, Merus, Takeda; Financial Interests, Personal, Other, Consultant: Daiichi Sankyo, Merck; Financial Interests, Institutional, Local PI: Alkermes, Elevation Oncology, Gilead, Merck, Merus, Nuvalent, RAPT, Turning Point Therapeutics; Financial Interests, Institutional, Steering Committee Member, Local PI: Genentech; Non-Financial Interests, Member: ASCO, IASLC. M.N. Al-Hallak: Financial Interests, Personal, Speaker’s Bureau: Ipsen, AstraZeneca, Guardant Health; Non-Financial Interests, Personal, Advisory Board: Karmanos Cancer Institute DSMB; Non-Financial Interests, Personal, Member of Board of Directors: Michigan Society of Hematology-Oncology (MSHO); Foundation Board Member. J. Cleary: Financial Interests, Personal, Research Grant: Merck, Tesaro; Financial Interests, Personal, Other, Travel: Incyte; Financial Interests, Personal, Advisory Board: Incyte Pharma, Blueprint, Syros; Financial Interests, Personal, Other, Receipt of equipment, materials, drugs, medical writing, gifts or other services: Bayer, AstraZeneca, Esperas Pharma, Arcus, Apexigen, Merus, Roche, Servier, BMS. C. Neuzillet: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, AstraZeneca, Baxter, Bristol Myers Squibb, Fresenius Kabi, Incyte Biosciences, Merck, MSD, MundiPharma, Mylan, Novartis, Nutricia, OSE Immunotherapeutics, Pierre Fabre, Roche, Sanofi, Servier, Viatris; Financial Interests, Personal, Research Funding: AstraZeneca, Bristol Myers Squibb, Fresenius Kabi, Nutricia, OSE Immunotherapeutics, Roche, Servier, Viatris. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fisher; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Preferred Network; Financial Interests, Personal and Institutional, Coordinating PI: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network; Financial Interests, Institutional, Coordinating PI: Guardant Health. A.K. Joe: Financial Interests, Institutional, Other, Employee: Merus. S. Adeyemi: Financial Interests, Institutional, Other, Employee: Merus . S. Jauhari: Financial Interests, Institutional, Other, Employee: Merus. A. Drilon: Financial Interests, Personal, Advisory Board: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem Oncology, More Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Amgen, Janssen, EcoR1, Monte Rosa; Financial Interests, Personal, Other, CME: Medscape, Onclive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, PeerView Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Options, AiCME; Financial Interests, Personal, Other, CME, Consulting: Axis; Financial Interests, Personal, Other, Consulting: Nuvalent, Merus, EPG Health, mBrace, Harborside Nexus, Ology, TouchIME, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Remedica Ltd, RV More; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, GSK, Teva, Taiho, PharmaMar; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Member: ASCO, AACR, IASLC; Other, Food/Beverage: Merck, Puma, Merus; Other: Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background

BL-B01D1 is a first-in-class novel antibody drug conjugate (ADC) consisting of an EGFRxHER3 bispecific antibody bounded to a novel TOP-I inhibitor payload via a cleavable linker. We now report updated safety/efficacy results from the NSCLC patients (pts) of the BL-B01D1 phase I study.

Methods

This study enrolled pts with locally advanced or metastatic NSCLC and tested doses of 2.5, 3.0, and 3.5 mg/kg administered on D1D8Q3W, as well as doses of 5.0 and 6.0 mg/kg administered on D1Q3W.

Results

As of Mar 31^st, 2023, 114 NSCLC pts who failed standard treatment were enrolled and received at least one dose of BL-B01D1. The most common TRAEs (>10%, all grade/≥ G3) were anemia (59%/25%), leukopenia (59%/28%), neutropenia (51%/32%), thrombocytopenia (48%/23%), nausea (36%/<1%), vomiting (34%/2%), alopecia (27%/0%), decreased appetite (24%/<1%), asthenia (23%/0%), mouth ulceration (21%/0%), diarrhea (20%/<1%), hypophagia (19%/0%), hypokalemia (15%/0%), hypoalbuminemia (12%/0%), rash (11%/0%). No ILD was observed. 88 pts were evaluable for efficacy (at least 1 post-baseline tumor assessment), mPFS for EGFRmut and EGFRwt NSCLC was 6.9 (4.3, ∼) and 5.2 (3.9, ∼) months, respectively, although these results are still considered immature. The study is currently ongoing and further updates regarding DoR, mPFS, and other results will be provided during the meeting. Table: 1316MO

Conclusions

BL-B01D1 demonstrated encouraging efficacy in heavily pretreated metastatic/locally advanced NSCLC, especially in pts with EGFRmut. The observed toxicity is deemed acceptable.

Clinical trial identification

NCT05194982.

Legal entity responsible for the study

Sichuan Baili Pharmaceutical Co., Ltd.

Funding

Sichuan Baili Pharmaceutical Co., Ltd.

Disclosure

L. Zhang: Financial Interests, Institutional, Research Grant, research grant & Trial Chair: AZ; Financial Interests, Institutional, Research Grant: BMS, Roche; Financial Interests, Institutional, Trial Chair: QiLu pharm, Henrui Pharm, Novartis, Hansoh Pharma, China Shiyao Pharma, Kelun Pharm. J. Wang: Financial Interests, Personal, Full or part-time Employment: Baili-Bio Pharmaceutical Co. Ltd. S. Xiao: Financial Interests, Personal, Full or part-time Employment: Baili-Bio (Chengdu) Pharmaceutical Co., Ltd.; Financial Interests, Personal, Stocks/Shares: Baili-Bio (Chengdu) Pharmaceutical Co., Ltd.. H. Wang: Financial Interests, Personal, Full or part-time Employment: Systimmune Inc. H. Zhu: Financial Interests, Personal, Full or part-time Employment: SystImmune Inc; Financial Interests, Personal, Stocks/Shares: SystImmune Inc. M.S. Olivo: Financial Interests, Institutional, Officer, I'm the CMO of the company: SystImmune; Financial Interests, Institutional, Stocks/Shares: SystImmune. Y. Zhu: Financial Interests, Personal, Full or part-time Employment: SystImmune Inc; Financial Interests, Personal, Ownership Interest: SystImmune Inc, Baili Pharmaceutical. All other authors have declared no conflicts of interest.