Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial.

Background: Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Patients and Methods: Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT).
Results: A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed.
Conclusions: Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents.
Clinical Trial Registration: ClinicalTrials.govNCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491.
Competing Interests: Disclosure JRA reports nonfinancial support and reasonable reimbursement for travel from the European Society for Medical Oncology; has received travel and accommodation expenses from Ellipses Pharma, IONCTURA, Kelun Pharmaceuticals/KLUS Pharma, Molecular Partners, and Peptomyc; has served in consulting or advisory roles for Boxer Capital, Chinese University of Hong Kong, Ellipses Pharma, IONCTURA (including serving on a scientific advisory board), Kelun Pharmaceuticals/KLUS Pharma, Molecular Partners, Peptomyc, Vall d’Hebron Institute of Oncology/Ministerio De Empleo Y Seguridad Social, and Tang Advisors; has received research funding from Black Diamond Therapeutics, Blueprint Medicines, Hummingbird, MSD, Vall d’Hebron Institute of Oncology/Cancer Core Europe, and Yingli; and has served as investigator in clinical trials with Aadi Bioscience, Amgen, Bayer, BioAtla, BioMed Valley Discoveries, Bicycle Therapeutics, Cancer Core Europe, Cellestia, Curis, CytomX, Deciphera, Fore Biotherapeutics, Genmab, GSK, Hummingbird, Hutchison MediPharma, IDEAYA, Kelun-Biotech, Loxo Oncology, Merus, Mirati Linnaeus Therapeutics, Novartis, Nuvation, Pfizer, Roche Pharmaceuticals, Spectrum Pharmaceuticals, Symphogen, Taiho, Takeda-Millennium, Tango Therapeutics, and Yingli. DSWT has received institutional research funding from AstraZeneca, GSK, and Novartis; has received honoraria from BMS, Novartis, Pfizer, Roche, and Takeda; has served in consulting or advisory roles for AstraZeneca, Loxo, MSD, Novartis, Pfizer, and Roche; and has received travel and accommodation expenses from Boehringer Ingelheim, Pfizer, and Roche. IGL has served in consulting or advisory roles for Array BioPharma, Eisai, Jazz Pharmaceuticals, Kanaph, OncXerna, SOTIO, and Sumitomo; and has received institutional research funding from ARMO BioSciences, Bayer, BMS, BridgeBio, GSK, Glenmark, Halozyme, Ignyta, Incyte, Lilly, MedImmune, NewLink Genetics, Novartis, OncoMed, and Pfizer. WH has received research funding from AI Therapeutics. JTB has received research funding from Novartis and Pfizer. NB has served in consulting or advisory roles for AstraZeneca, BMS, Celgene, and Exelixis. ZZ reports stock and other ownership interests in and was employed by Pfizer at the time of study. SD, KK, CW, and RJL report employment by and stock and other ownership interests in Pfizer. NP reports stock and other ownership interests in and was employed by Pfizer at the time of study. WAM has served in consulting or advisory roles for Five Prime Therapeutics (DMSC), Zymeworks (DMSC), and QED Therapeutics (DMSC); and has received institutional research funding from ALX Oncology, AstraZeneca, BeiGene, EDDC/D3, Exelixis, Fate Therapeutics, Pfizer, Roche/Genentech, and Takeda. AB, SR, NK have declared no conflicts of interest. Data sharing Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. Ethics approval and consent to participate The trial was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation Guideline for Good Clinical Practice, and the International Ethical Guidelines for Biomedical Research Involving Human Subjects. All patients provided written informed consent before enrollment. The protocol, amendments, and informed consent forms were approved by the institutional review board or independent ethics committee at each center.
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