Browsing Over 268 Presentations
10P - Clinical and laboratory predictors of immune checkpoint inhibitor efficacy in non-small cell lung cancer (ID 245)
- P. Christopoulos (Heidelberg, Germany)
- P. Christopoulos (Heidelberg, Germany)
- J. Kohlhäufl (Heidelberg, Germany)
- F. Bozorgmehr (Heidelberg, Germany)
- J. Kuon (Heidelberg, Germany)
- M. Schneider (Heidelberg, Germany)
- O. Neumann (Heidelberg, Germany)
- S. Liersch (Heidelberg, Germany)
- C. Heussel (Heidelberg, Germany)
- H. Winter (Heidelberg, Germany)
- F. Herth (Heidelberg, Germany)
- S. Rieken (Heidelberg, Germany)
- T. Muley (Heidelberg, Germany)
- M. Meister (Heidelberg, Germany)
- H. Bischoff (Heidelberg, Germany)
- F. Lasitschka (Heidelberg, Germany)
- A. Stenzinger (Heidelberg, Germany)
- M. Thomas (Heidelberg, Germany)
Abstract
Background
Treatment with immune checkpoint inhibitors (ICI) prolongs overall survival (OS) and confers long-term disease control in 15-20% of non-small cell lung cancer (NSCLC) patients. Patient selection currently depends on the levels of PD-L1 expression, but correlation with outcome is weak.
Methods
We retrospectively analyzed the clinical course of ICI-treated stage IV NSCLC patients at our institution.
Results
A total of 453 patients were identified with a median age of 64 years having received nivolumab (57%), pembrolizumab (35%), PD-L1 inhibitors (7%) or PD1 blockade in combination with chemotherapy or CTLA4 inhibitors (1%). Progression-free survival (PFS) under ICI was significantly longer for patients receiving ICI in the first (21%, 7 months in median) compared to second (47%, 4 months in median) and later treatment lines (2 months in median, p < 0.001), for current and ex-smokers (91% of cases, p = 0.034), in case of adenocarcinoma (66%) compared to squamous cell carcinoma (28%) and other histologies (9%, p < 0.001), while age, sex and ECOG status at initial diagnosis had no influence. The total number of metastatic sites and the presence of liver metastases at start of IO treatment were associated with shorter ICI responses (p = 0.018 and p = 0.005, respectively), while metastases to other organs, especially brain, did not play a role. Blood markers, like the Lymphocyte-to-Neutrophile-Ratio (LNR) as well as CRP and LDH as indicators of inflammation and tumor load, had the highest discriminatory value (≥ 2x longer median PFS for cases with higher LNR or lower CRP or LDH, p < 0.0001 for each), while the occurrence of immune-related adverse events (irAE) conferred longer PFS (p < 0.001) as well as overall survival (OS) from the start of IO treatment (p < 0.01). PFS under ICI was similar for cases with PD-L1 <1% vs. 1-49% (14% and 34%, respectively), while cases with PD-L1 expression >50% had an ICI-PFS twice as long (p = 0.011).
Conclusions
Several clinical and blood parameters appear to correlate with ICI benefit better than tissue PD-L1 expression levels in NSCLC patients and could be used along with molecular markers to improve predictive tools for lung cancer immunotherapy.
Legal entity responsible for the study
Thoraxklinik Heidelberg.
Funding
Has not received any funding.
Disclosure
F. Bozorgmehr: Research funding: BMS; Travel grants: BMS, MSD. J. Kuon: Research funding: AstraZeneca, Celgene. C. Heussel: Consultation, lecture and other fees: Novartis, Siemens, Chiesi, Intermune, MEDA Pharma, Bracco, Pfizer, MSD, Roche, Lilly, AstraZeneca, Schering-Plough, Essex, Gilead; Ownership of GSK stocks. F. Herth: Advisory board fees and honoraria: Lilly, Roche, AstraZeneca, Novartis, Boehringer, Chiesi, Teva, Pulmonx BTG, Olympus; Research funding: Lilly, Roche, AstraZeneca, Novartis, Boehringer, Chiesi, Teva. T. Muley: Research funding, patents: Roche. A. Stenzinger: Advisory board honoraria: BMS, AstraZeneca, ThermoFisher, Novartis; Speaker’s honoraria: BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche; Research funding: Chugai. M. Thomas: Advisory board honoraria: Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer; Speaker’s honoraria: Lilly, MSD, Takeda; Research funding: AstraZeneca, BMS, Celgene, Novartis, Roche. All other authors have declared no conflicts of interest.
46P - Inflamed human oropharyngeal cancers with ongoing tumor-specific T cell responses comprise a different type of immune suppressive T cells (ID 259)
- S. J. Santegoets (Leiden, Netherlands)
- S. J. Santegoets (Leiden, Netherlands)
- C. L. Duurland (Leiden, Netherlands)
- E. S. Jordanova (Leiden, Netherlands)
- V. J. Van Ham (Leiden, Netherlands)
- I. Ehsan (Leiden, Netherlands)
- M. J. Welters (Leiden, Netherlands)
- S. H. Van der Burg (Leiden, Netherlands)
Abstract
Background
Recent studies have shown that for optimal immune suppression regulatory T cells (Tregs) are required to adopt a transcriptional profile similar to that of the type of T cells they aim to suppress. For instance, Foxp3+ Tregs upregulate the Th1-associated transcription factor Tbet to control a type 1 cytokine-mediated inflammatory response in order to prevent unwanted tissue destruction and immunopathology. However, little is known about the existence and function of such Treg cells in cancer patients.
Methods
To study the presence and potential impact of Tbet-expressing Foxp3+ (Foxp3+Tbet+) Tregs in human cancer, we applied three-color immunofluorescence staining and 12-parameter flow cytometry on the tumor microenvironment (TME) of human papilloma virus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) patients.
Results
Our data revealed that Foxp3+Tbet+ Tregs accumulate and dominate in the tumor cell nests of patients with a concomitant HPV-specific and type 1-oriented intratumoral T cell infiltrate. Moreover, these CD4+CD25+CD127–Foxp3+Tbet+ Tregs exhibited an activated phenotype and co-expressed high levels of CTLA4 and Helios. Assessment of the methylation status of the FoxP3 gene locus TSDR of flow cytometry-sorted Foxp3+Tbet+ and Foxp3+Tbet - Tregs revealed that it was maximally demethylated, indicating that these Tregs have the full capacity to suppress immune cells. Interestingly, OPSCC patients with high intratumoral frequencies of Foxp3+Tbet+ Tregs, but not Foxp3+Tbet– Tregs, displayed prolonged disease-specific survival, suggesting that the presence of Foxp3+Tbet+ Tregs is a reflection of a strong and clinically favorable local tumor-specific type 1 immune response.
Conclusions
In conclusion, bona fide Foxp3+Tbet+ regulatory T cells accumulate in HPV16-driven tumors that are highly infiltrated with type 1 tumor-specific T cells, at levels enough to impede full spontaneous immune-mediated tumor control.
Legal entity responsible for the study
Sjoerd H. van der Burg.
Funding
The Dutch Cancer Society.
Disclosure
All authors have declared no conflicts of interest.
84P - Safety and clinical outcome in patients with microsatellite-stable, metastatic colorectal or pancreatic cancer treated with the CXCL12 inhibitor NOX-A12 in combination with PD-1 checkpoint inhibitor pembrolizumab (ID 463)
- N. Halama (Heidelberg, Germany)
- N. Halama (Heidelberg, Germany)
- U. Prüfer (Heidelberg, Germany)
- A. Frömming (Berlin, Germany)
- D. Beyer (Berlin, Germany)
- D. Eulberg (Berlin, Germany)
- J. Jungnelius (Berlin, Germany)
- A. Mangasarian (Berlin, Germany)
Abstract
Background
NOX-A12 is an inhibitor of the chemokine CXCL12 for treatment of solid tumors. Binding of CXCL12 by NOX-A12 prevents receptor engagement and blocks the ability of CXCL12 to form a chemotactic concentration gradient. The Opera study (NCT03168139) is a Phase 1/2 study to evaluate pharmacodynamic effects and safety of monotherapy with NOX-A12 as well as safety and efficacy of a combination of NOX-A12 with pembrolizumab in metastatic microsatellite-stable colorectal (CRC) and pancreatic (PaC) cancer.
Methods
Patients received 300 mg NOX-A12 twice weekly during the two-week monotherapy phase. Biopsies were taken from liver metastases before treatment and after NOX-A12 monotherapy for analysis of immune cell infiltration and cytokine signature. In the combination phase, patients received repeated 21-day cycles of 300 mg NOX-A12 and 200 mg pembrolizumab.
Results
20 patients were recruited, thereof 11 with CRC and 9 with PaC. 15 of the patients (75%) are male, with a median age of 62 (CRC) and 68 years (PaC). Patients were heavily pretreated with a median of 5 (CRC) and 3 lines (PaC) of prior treatment. Known best responses to last prior treatment was PD for 16 out of 20 patients. The AE profile was comparable with the pembrolizumab profile or typical for the underlying diseases. Thus far, 5 of the patients (25%) achieved a stable disease (3 CRC and 2 PaC). Interestingly, some of the patients with SD or clinical benefit also showed a favorable tissue cytokine response upon NOX-A12 monotherapy. Higher changes of CXCL12 levels in tissue observed upon monotherapy – indicating more complete CXCL12 neutralization – correlated with a favorable cytokine profile.
Conclusions
NOX-A12 alone and combined with pembrolizumab was safe and well tolerated. Changes in the cytokine signature in tumor tissue suggest that NOX-A12 modulates the tumor microenvironment and induces an immune-stimulatory Th1-like signature in multiple patients of which some show signs of disease stabilization or clinical benefit. The observed time of treatment compares favorably with the expected clinical course of such end-stage and heavily pre-treated patient population.
Clinical trial identification
EudraCT: 2016-003657-15.
Legal entity responsible for the study
Noxxon Pharma.
Funding
Noxxon Pharma AG.
Disclosure
N. Halama, U. Prüfer: Research funded by Noxxon Pharma AG. A. Frömming, D. Beyer, D. Eulberg, J. Jungnelius, A. Mangasarian: Employee of Noxxon Pharma AG.
New directions in CAR therapy (ID 12)
- F. Thistlethwaite (Manchester, United Kingdom)
- F. Thistlethwaite (Manchester, United Kingdom)
LBA4 - Long-term follow-up in the KEYNOTE-010 study of pembrolizumab (pembro) for advanced NSCLC, including in patients (pts) who completed 2 years of pembro and pts who received a second course of pembro (ID 479)
- R. Herbst (New Haven, CT, United States of America)
- R. Herbst (New Haven, CT, United States of America)
- E. B. Garon (Santa Monica, CA, United States of America)
- D. Kim (Seoul, Korea, Republic of)
- B. Chul Cho (Seoul, Korea, Republic of)
- J. Pérez Gracia (Pamplona, Spain)
- J. Han (Goyang-si, Korea, Republic of)
- C. Dubos Arvis (Caen, France)
- M. Majem (Barcelona, Spain)
- M. Forster (London, United Kingdom)
- I. Monnet (Créteil, France)
- S. Novello (Orbassano, Italy)
- Z. Szalai (Gyor, Hungary)
- M. A. Gubens (San Francisco, CA, United States of America)
- W. Su (Tainan, Taiwan)
- G. L. Ceresoli (Bergamo, Italy)
- A. Samkari (Kenilworth, NJ, United States of America)
- E. Jensen (Kenilworth, NJ, United States of America)
- G. M. Lubiniecki (Kenilworth, NJ, United States of America)
- P. Baas (Amsterdam, Netherlands)
Abstract
Background
In the global, open-label, phase 2/3 study KEYNOTE-010, pembro 10 mg/kg or 2 mg/kg Q3W improved OS vs docetaxel in pts with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1% (coprimary analyses) at median follow-up of 13.1 mo. We present long-term results overall, in pts who completed 35 cycles (∼2 y) of pembro, and in pts who received a second course of pembro.
Methods
Pts aged >18 y with previously treated advanced NSCLC with PD-L1 TPS ≥1% were randomized 1:1:1 to pembro 10 mg/kg or 2 mg/kg Q3W, or docetaxel 75 mg/m2 Q3W. Pts received pembro for 35 cycles, until disease progression/intolerable toxicity. Response was assessed every 9 wk (RECIST 1.1 by independent central review), and survival every 2 mo posttreatment. There was no difference between pembro doses in the primary analysis, thus doses were pooled in this analysis.
Results
As of March 16, 2018, median (range) follow-up was 42.6 (35.2–53.2) mo overall (N = 1033). Pembro improved OS vs docetaxel in pts with PD-L1 TPS ≥50% (HR, 0.53; 95% CI, 0.42–0.66; P < 0.00001) and TPS ≥1% (HR, 0.69; 95% CI, 0.60–0.80; P < 0.00001). In pts with PD-L1 TPS ≥50%, median (95% CI) OS was 16.9 (12.3–21.4) mo with pembro vs 8.2 (6.4–9.8) mo with docetaxel; 36-mo OS rates were 35% vs 13%, respectively. Similar to the primary analysis, 16% of pembro pts and 36% of docetaxel pts had grade 3–5 treatment-related AEs. 79 of 690 pembro pts received 35 treatment cycles (∼2 y). 36-mo OS rate among these 79 pts was 99% and 75 (95%) had PR/CR as best response; 72 pts (91%) remained alive. 48 pts (64%) had an ongoing response; median duration of response was not reached (range, 4–46+ mo). 25 of 79 pts (32%) had PD (investigator review) after stopping 35 cycles of pembro. 14 pts received second course pembro, 5 of whom completed 17 cycles; 6 (43%) had PR, 5 (36%) had SD, and 11 (79%) remained alive.
Conclusions
At 43-mo follow-up, pembro continued to prolong OS vs docetaxel in pts with previously treated, PD-L1–expressing advanced NSCLC, with manageable long-term safety. Most pts who completed 35 cycles (∼2 y) of pembro had durable response. The majority of pts with PD by investigator review who received second course pembro had either PR or SD and remained alive.
Editorial acknowledgement
Medical writing and editorial assistance was provided by C4 MedSolutions, LLC (Yardley, PA), a CHC Group company. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Clinical trial identification
NCT01905657.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
R.S. Herbst: Consulting role: Eli Lilly, Genentech/Roche, Merck, NextCure, Novartis, Pfizer; Research support: AstraZeneca, Eli Lilly, Merck. E.B. Garon: Funding to institution: Merck & Co., Inc., AstraZeneca, Eli Lilly, Genentech, Bristol-Myers Squibb, Pfizer, Novartis, Mirati. B. Chul Cho: Honoraria: AstraZeneca, Roche, Boehringer Ingelheim; Research funding: Bayer, AstraZeneca, Yuhan, Novartis; Consultant or advisor: AstraZeneca, Roche, Boehringer Ingelheim; Speakers’ bureau: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis. J.L. Pérez Gracia: Grants: Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Lilly; Advisor, speakers’ bureau: Bristol-Myers Squibb, Roche. J-Y. Han: Honoraria: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme; Research funding: Roche; Consultant or advisor: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Eli Lilly. M. Majem: Consultant or advisor: AstraZeneca, Roche, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis. M. Forster: Research grants: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck; Honoraria for advisory and consultancy roles: Achilles, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche. I. Monnet: Congress invitations: Roche, AstraZeneca. S. Novello: Funding to institution: Merck Sharp & Dohme; Speakers bureau: Eli Lilly, Takeda, Roche, AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim. M.A. Gubens: Research grant to institution: Merck & Co., Inc.; Personal fees for consulting: AbbVie, Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera, Clovis, Genentech-Roche, Mersana, Nektar, Novartis, Pfizer. A. Samkari, E. Jensen, G.M. Lubiniecki: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. P. Baas: Consulting role: Genentech/Roche, Merck, Bristol-Myers Squibb, Pfizer; Research support: Bristol-Myers Squibb, Roche, Merck. All other authors have declared no conflicts of interest.
Session DOI (ID 515)
Self and viral antigens-HPV vaccine for therapy (ID 67)
- M. J. Welters (Leiden, Netherlands)
- M. J. Welters (Leiden, Netherlands)
When 1+1 = 3: Unlocking the potential of the IL-2 pathway with NKTR-214 in combination treatment (ID 103)
- J. Zalevsky (San Francisco, United States of America)
- J. Zalevsky (San Francisco, United States of America)
49O - IMpower133: Patient-reported outcomes (PROs) in a ph1/3 study of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide (CP/ET) in extensive-stage SCLC (ES-SCLC) (ID 316)
- A. Mansfield (Rochester, MN, United States of America)
- R. Califano (Manchester, United Kingdom)
- A. Każarnowicz (Olsztyn, Poland)
- N. Karaseva (St Petersburg, Russian Federation)
- A. Sánchez (Seville, Spain)
- S. V. Liu (Washington DC, MD, United States of America)
- L. Horn (Nashville, TN, United States of America)
- C. Quach (South San Francisco, CA, United States of America)
- W. Yu (South San Francisco, CA, United States of America)
- F. Kabbinavar (South San Francisco, CA, United States of America)
- S. Lam (South San Francisco, CA, United States of America)
- A. Mansfield (Rochester, MN, United States of America)
Abstract
Background
In IMpower133 (NCT02763579), 1L treatment (tx) with atezo + CP/ET for ES-SCLC provided a significant improvement in survival v placebo (PBO) + CP/ET and no unexpected safety signals. PROs were assessed to inform the overall tx benefit of adding atezo to CP/ET.
Methods
Patients (pts) were randomised to atezo + CP/ET (1200 mg + AUC 5/100 mg/m2) (N = 201) or PBO + CP/ET (N = 202) IV q3w x 12 wks, then maintenance atezo or PBO q3w until progression/intolerable toxicity/clinical benefit loss. Descriptive analyses of EORTC QLQ-C30 and QLQ-LC13 scales (score range 0–100) included change from baseline (BL), cumulative distribution function curves of change at wk 12 and time to deterioration (TTD). A ≥ 10-point change from BL was prespecified as clinically meaningful.
Results
Completion rates were ≥85% at BL and ≥70% to wk 75 in both arms; BL PRO scores were comparable. At wks 27 and 54, 108 and 34 pts remained on study and eligible to complete assessments, respectively. Pts in both arms reported early, notable lung cancer (LC) symptom palliation (Table) with numeric trends of greater improvement with atezo + CP/ET. Higher proportions of atezo + CP/ET pts reported LC symptom relief at wk 12 v PBO + CP/ET. No apparent differences in TTD of cough or chest pain were seen; a numeric delay in TTD of dyspnoea favoured atezo + CP/ET (HR 0.75; 95% CI 0.55–1.02). Atezo + CP/ET pts reported improved physical function above BL until wk 51 and clinically meaningful health-related quality of life (HRQoL) improvements that persisted at most visits through wk 54. Changes in tx-related symptoms (diarrhoea, nausea/vomiting) were similar across arms.Mean score change from BL at wk 12 (negative value reflects improvement) Atezo + CP/ET (n = 124) PBO + CP/ET (n = 131) Arm/shoulder pain −7.0 −2.5 Chest pain –7.8 –4.1 Cough –14.8 –15.5 Dyspnoea –6.5 –2.3
Conclusions
Atezo + CP/ET tx provided a significant improvement in survival as well as immediate and tangible improvements in pt-reported LC symptoms. PROs indicating sustained function and improved HRQoL with minimal impact from tx toxicities further support the positive benefit:risk of atezo + CP/ET in 1L ES-SCLC.
Editorial acknowledgement
Support for third-party writing assistance for this abstract, furnished by Daniel Clyde, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Clinical trial identification
NCT02763579, May 5, 2016.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd/Genentech, Inc.
Funding
F. Hoffmann-La Roche Ltd/Genentech, Inc.
Disclosure
R. Califano: Honoraria for consultancy, speaker bureau and advisory board: Roche. S.V. Liu: Research grant (institution): AZ, Bayer, Blueprint, Clovis, Corvus, Esanex, Genentech, Lilly, Lycera, Merck, Molecular Partners, OncoMed, Pfizer, Threshold; Consultant: AZ, BMS, Celgene, Genentech, Heron, Lilly, Pfizer, Regeneron, Taiho (DSMB), Takeda. L. Horn: Consultancy: AbbVie, AstraZeneca, Merck, Incyte, Xcovery, Genentech, EMD Serono. C. Quach, F. Kabbinavar, S. Lam: Employment and stock: Roche/Genentech. W. Yu: Employment: Genentech. A. Mansfield: Honoraria for participation in advisory boards (institution): Genentech, AbbVie, BMS; Grants: Novartis, Verily. All other authors have declared no conflicts of interest.
37P - Pooling signaling and costimulatory domains in a flexible CARpool design (ID 333)
- L. Springuel (Mont Saint Guibert, Belgium)
- L. Springuel (Mont Saint Guibert, Belgium)
- J. Bolsée (Mon-Saint-Guibert, Belgium)
- A. Velghe (Mon-Saint-Guibert, Belgium)
- S. Agaugué (Mon-Saint-Guibert, Belgium)
- D. Gilham (Mon-Saint-Guibert, Belgium)
Abstract
Background
Chimeric Antigen Receptors (CARs) consist of a target binding moiety fused to an extracellular spacer, a transmembrane region and an intracellular signaling tail comprising a tandem alignment of co-stimulatory and activatory domains. This linear configuration displays rigid spatial orientation and ratio of co-stimulation to activation domains. We have developed a novel mix and match approach (CARpool) where the costimulatory signal is provided in trans on accessory proteins that associate with the antigen binding chain via transmembrane interactions.
Methods
Several CD3ζ-containing CAR chains were designed using the transmembrane and cytoplasmic domains of NKG2D or NKp44, associating with DAP10 and DAP12 respectively. Each CAR contained a B7H6-targeting scFv and was co-expressed with corresponding accessory protein using a 2A site. Primary human T cells engineered with the diverse constructs were screened for CAR expression, phenotype and in vitro function.
Results
NKG2D-based CAR complexes were moderately expressed at the cell surface but bound B7H6 and led to potent cells. Modification of the position of the charged residue within the transmembrane domain of the CAR is being used to modulate the surface expression and thus their potency. NKp44-based CAR complexes were more frequently expressed on primary T cells and bound B7H6, though functionality appears to be dependent on the nature of the extracellular spacer.
Conclusions
These studies provide proof-of-concept for a novel CAR design where it is possible to incorporate or interchange costimulatory domain(s) in a stoichiometrically controlled way. Recapitulating physiological TCR activation by providing co-stimulation in trans within the CARpool may result in optimal downstream signaling, thereby enhancing anti-tumoral activity.
Legal entity responsible for the study
Celyad SA.
Funding
Celyad SA.
Disclosure
L. Springuel, J. Bolsée, A. Velghe, S. Agaugué, D. Gilham: Employee of Celyad SA.
75P - Cemiplimab, a human PD-1 monoclonal antibody, in patients (pts) with recurrent or metastatic cervical cancer: Interim data from phase I cohorts (ID 434)
- D. Rischin (Melbourne, Australia)
- D. Rischin (Melbourne, Australia)
- M. Gil-Martin (Barcelona, Spain)
- A. González-Martin (Madrid, Spain)
- I. Brana (Barcelona, Spain)
- J. Y. Hou (New York, NY, United States of America)
- D. Cho (New York, NY, United States of America)
- G. Falchook (Denver, CO, United States of America)
- S. Formenti (New York, NY, United States of America)
- S. Jabbour (New Brunswick, NJ, United States of America)
- K. Moore (Oklahoma City, OK, United States of America)
- A. Naing (Houston, TX, United States of America)
- K. P. Papadopoulos (San Antonio, TX, United States of America)
- J. Baranda (Fairway, KS, United States of America)
- A. Weise (Detroit, MI, United States of America)
- M. G. Fury (Tarrytown, NY, United States of America)
- M. Feng (Basking Ridge, NJ, United States of America)
- J. Li (Basking Ridge, NJ, United States of America)
- I. Lowy (Tarrytown, United States of America)
- M. Mathias (Tarrytown, NY, United States of America)
Abstract
Background
For pts who progress after first-line platinum based therapy for recurrent/metastatic cervical cancer, there are no therapies available that have been demonstrated to improve survival or quality of life. Cemiplimab (REGN2810), a human monoclonal antibody to PD-1, exhibited encouraging efficacy and acceptable tolerability in a phase 1 dose escalation study. The present report focuses on interim data from the phase 1 cervical cancer expansion cohorts (ECs) of cemiplimab as a monotherapy (EC 23) or in combination with hypofractionated radiotherapy (hfRT) (EC 24) (NCT02383212).
Methods
Pts with recurrent or metastatic cervical cancer resistant to or intolerant of platinum and taxane doublet therapy received cemiplimab 3 mg/kg Q2W IV for up to 48 weeks, in ECs 23 and 24, and hfRT (9 Gy x 3 times/week given 1 week after first dose of cemiplimab) in EC 24. The co-primary objectives were to evaluate the safety, tolerability, and efficacy of cemiplimab monotherapy or in combination with hfRT. Tumour response assessments (in non-irradiated target lesions) were performed by RECIST 1.1 Q8W.
Results
As of 1 Sept, 2017, these ECs were fully enrolled with 20 pts (EC 23, n = 10, EC 24, n = 10). Median (range) age was 55.0 (31–76) years (EC 23) and 51.5 (29–65) years (EC 24). ECOG performance status 1 vs. 0 was 60% vs. 40% and 80% vs. 20%, respectively, for EC 23 and EC 24. Investigator-assessed overall response rate (ORR; complete response [CR] + partial response [PR]) was 10.0% (0 CR and 1 PR) in each of EC 23 and EC 24. At the time of data cut-off, both responses were ongoing with durations of 3.7+ months. The most common treatment-emergent adverse events (TEAEs) of any grade were diarrhoea (40.0%), fatigue, hypokalaemia and pain in extremity (each 30.0%) in EC 23, and diarrhoea and urinary tract infection (each 30.0%) in EC 24. There was no grade ≥3 TEAE reported in > 1 patient in either cohort.
Conclusions
Cemiplimab as monotherapy and in combination with hfRT demonstrated antitumour activity with an acceptable safety profile in pts with metastatic or recurrent cervical cancer. Cemiplimab monotherapy vs. chemotherapy in ≥ 2nd line cervical cancer is currently being evaluated in a global randomised phase 3 study (NCT03257267).
Editorial acknowledgement
Medical writing support under the direction of the authors was provided by Emmanuel Ogunnowo, PhD, of Prime (Knutsford, UK) and funded by Regeneron Pharmaceuticals, Inc. and Sanofi according to Good Publication Practice guidelines.
Clinical trial identification
NCT02383212.
Legal entity responsible for the study
Regeneron Pharmaceutical Inc. and Sanofi.
Funding
Regeneron Pharmaceutical Inc. and Sanofi.
Disclosure
D. Rischin: Research funding: Genentech/Roche, Merck, Amgen, Regeneron, Bristol-Myers Squibb. A. González-Martin: Consulting, advisory, speakers’ bureau, travel accommodation expenses: AstraZeneca, Tesaro, Roche, Pharmamar. J.Y. Hou: Consultant and fees: Foundation Medicine, Massive Bio, Inc. D. Cho: Consulting fees: Pfizer, BMS, Exelixis, Genentech, Prometheus. G. Falchook: Funding for trial for submitted work. S. Jabbour: Research funding grants: Merck, Nestle outside of the submitted work. K. Moore: KInstitutional consultancy (honorarium and ad board) fees: Tesaro, Genentech Roche, Clovis, AstraZeneca (for agents not involved in the SOLO-1 study), Immunogen, VBL Therapeutics, Janssen. M.G. Fury: Employee and shareholder: Regeneron Pharmaceuticals, Inc.; Patents, royalties, other intellectual property: Regeneron Pharmaceuticals, Inc. M. Feng: Employee and shareholder: Regeneron Pharmaceuticals, Inc., Bayer. J. Li: Employee and shareholder: Regeneron Pharmaceuticals, Inc., Novartis. I. Lowy: Employee, shareholder, fees for travel and accommodation expenses, leadership: Regeneron Pharmaceuticals, Inc. M. Mathias: Employee and shareholder: Regeneron Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.
107TiP - Phase I safety and pharmacokinetics of ADU-1604, an anti-CTLA-4 antibody, in adults with metastatic melanoma (ID 265)
- M. Hendriks (Oss, Netherlands)
- M. Hendriks (Oss, Netherlands)
- E. De Cock (Oss, Netherlands)
- K. Maplestone (Oss, Netherlands)
- H. Namini (Oss, Netherlands)
- A. Van Elsas (Oss, Netherlands)
Abstract
Background
ADU-1604 is a humanized IgG1 monoclonal antibody in development for use as monotherapy or in combination with other anti-cancer therapies. It targets a novel epitope on the validated inhibitory receptor, CTLA-4. ADU-1604 was characterized in vitro and shown to bind to human CTLA-4, block binding of CD80 and CD86 to CTLA-4, and stimulate IL-2 production by activated lymphocytes. ADU-1604 enhanced T cell dependent hepatitis B surface antigen vaccine-induced antibody responses in cynomolgus monkeys and demonstrated anti-tumor activity in a non-small cell lung cancer patient-derived xenograft humanized mouse model. The primary objective of the first-in-human study is to determine the recommended phase 2 dose (RP2D) by evaluating the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ADU-1604 administered as an intravenous (IV) infusion.
Trial design
This first-in-human, open-label, multicenter, dose-escalation study is conducted in adults with metastatic melanoma without further established treatment options. The study includes two parts: 1) Dose Escalation starts with 0.3 mg/kg of ADU-1604 IV infusion in 3-6 subjects and dosing is escalated until the RP2D is defined (represented by the dose tolerated while not exceeding the maximum tolerated dose or maximum dose (10 mg/kg)). 2) In Dose Confirmation, 7-10 additional subjects receive ADU-1604 at the RP2D until the maximum number of planned doses are administered (4 treatment cycles), disease progression is confirmed, or consent is withdrawn, whichever occurs first. The end of the study is defined as the date when all subjects have completed the final protocol-specified safety assessment and/or discontinued study participation. Primary endpoints include incidence of dose limiting toxicity, treatment-emergent adverse events (TEAEs), and changes from baseline in safety parameters. Secondary endpoints include severity of TEAEs, serious adverse events, changes from baseline in safety assessments, serum concentration-time profiles and PK parameters (including Cmax, AUC), and incidence of anti-ADU-1604 antibodies. This study is designed to provide the RP2D of ADU-1604 based on the totality of PK-PD, as well as clinical responses and safety.
Clinical trial identification
NCT03674502.
Legal entity responsible for the study
Aduro Biotech Europe.
Funding
Aduro Biotech Europe.
Disclosure
M. Hendriks, E. de Cock, K. Maplestone, H. Namini, A. van Elsas: Employee of and holds stock in Aduro Biotech Europe at the time of this work.