Zolbetuximab with gemcitabine + nab-paclitaxel (GN) in first-line treatment of Claudin 18.2–positive metastatic pancreatic cancer (mPC): Phase II, open-label, randomized study

BackgroundGN is a standard-of-care first-line treatment option for patients (pts) with mPC. Poor prognosis and a low 5-year survival rate (<5%) in mPC highlight the need for new regimens. Claudin 18.2 (CLDN18.2) is a tight junction protein not normally expressed in the pancreas but frequently expressed in pancreatic adenocarcinoma. Zolbetuximab binds to CLDN18.2 and mediates tumor cell death via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.Trial designThis phase 2 study (NCT03816163) is assessing safety and efficacy of zolbetuximab + GN vs GN alone in pts with CLDN18.2-positive mPC (moderate to strong membranous CLDN18 staining in ≥75% of tumor cells). Preliminary screening data indicate that 2548 pts with mPC were screened. A total of 2113 screened pts had valid CLDN18.2 immunohistochemistry results, and 27.7% (585/2113) had CLDN18.2-positive tumors; 624 pts had screen failures due to other reasons. As of April 2024, 396 pts are enrolled vs the protocol-defined enrollment of approximately 369 pts. The study design included a safety lead-in enrolling 3–12 pts to assess safety/tolerability of zolbetuximab (n=3 at 1000 mg/m2 on Cycle [C] 1 Day [D] 1, then 600 mg/m2 Q2W, with the potential to expand/de-escalate [3+3 design]) + GN and to confirm the recommended phase 2 dose (RP2D). Specified zolbetuximab-related dose-limiting toxicities (DLTs) were to be assessed after C1 (28 days). Pts were to be randomly assigned in a 2:1 ratio to receive zolbetuximab (RP2D; D1 and 15 of each C) + GN (D1, 8, and 15 of each C) in Arm 1 or GN alone in Arm 2, with imaging (CT/MRI) every 8 weeks until disease progression per investigator (RECIST v1.1) or the start of another systemic anticancer treatment. In Japan, DLTs were to be evaluated in ≤6 pts receiving the RP2D in Arm 1. The primary objectives of the study are to confirm the RP2D, assess overall survival in Arm 1 vs Arm 2, and establish safety/tolerability of zolbetuximab + GN. Secondary endpoints include progression-free survival, objective response rate, duration of response, pharmacokinetics, and health-related quality of life (per amended protocol).Clinical trial identificationNCT03816163.Editorial acknowledgementMedical writing/editorial support was provided by Rachel O’Keefe, PhD, Pamela Barendt, PhD, and Cheryl Casterline, MA, from Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA.Legal entity responsible for the studyAstellas Pharma, Inc.FundingAstellas Pharma, Inc.DisclosureW. Park: Financial Interests, Personal, Other, Consultancy: Astellas; Financial Interests, Personal, Advisory Board: EXACT Therapeutics; Financial Interests, Personal, Invited Speaker, Continuing Medical Education: American Physician Institute, Integrity; Financial Interests, Institutional, Research Grant: Merck, Break Through Cancer, Parker Institute for Cancer Immunotherapy, The Society of MSK, National Institute of Health - National Cancer Institute; Financial Interests, Institutional, Local PI: Astellas, Miracogen, Amgen, Revolution Medicines. E.M. O'Reilly: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, BioNTech, Merck, AstraZeneca, Novartis, FibroGen, Astellas, Tempus, Merus, BMS, Berry Genomics, Exelixis, Incyte, Neogene, Sevier, Thetis, Vector, Yiviva; Financial Interests, Personal, Advisory Board, +Spouse: Ipsen; Financial Interests, Personal, Advisory Board, Spouse: Genentech/Roche, Eisai; Financial Interests, Personal, Advisory Board, + spouse: Autem; Financial Interests, Institutional, Local PI: Genentech/Roche, Arcus, Elicio; Financial Interests, Personal and Institutional, Coordinating PI: BioNTech; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Pertzye; Financial Interests, Institutional, Research Grant: Parker Institute; Non-Financial Interests, Other, Scientific and Medical Advisory Board: Pancreas Cancer Action Network; Non-Financial Interests, Member of Board of Directors: National Pancreas Foundation; Other, Editor: American Society of Clinical Oncology, American Association of Cancer Research (AACR). D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, Aslan, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, AbbVie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna, Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Astellas, Bayer, BMS, Boehringer Ingelheim, Esteve, Hutchmed, Ipsen, Midatech Pharma, MSD, Novartis, PharmaMar, Servier, Takeda; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Non-Financial Interests, Leadership Role, Chair elect: European Neuroendocrine Tumor Society (ENETS); Non-Financial Interests, Leadership Role, Past presidente, Member of the Executive Committee: Grupo Español de Tumores Neuroendocrinos (GETNE); Other, Honoraria received by spouse for advisory board or invited speaker roles: ABBIE, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. G. Roth: Financial Interests, Personal, Advisory Board: Servier, AstraZeneca, MSD, BMS, Ipsen, Viatris; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Institutional, Coordinating PI: Genoscience Pharma; Financial Interests, Personal and Institutional, Coordinating PI: Netris Pharma, Alpha Tau. T. Nakajima: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma, Inc. D. Moran, J. Yang: Non-Financial Interests, Institutional, Sponsor/Funding: Astellas; Non-Financial Interests, Institutional, Writing Engagement: OPEN Health. F. Kunieda: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma, Inc. All other authors have declared no conflicts of interest.