2392 - GLOW: Randomized Phase 3 Study of Zolbetuximab + CAPOX Compared With Placebo + CAPOX as First-line Treatment of Patients With CLD18.2⁺/HER2⁻ Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

Background

Despite treatment advances, gastric cancer (GC) remains a leading cause of cancer-related death worldwide. Standard first-line chemotherapeutic regimen for advanced GC consists of fluoropyrimidine with platinum-based combinations, such as capecitabine + oxaliplatin (CAPOX). Recently, CLDN18.2 has emerged as a promising targetable biomarker. In healthy tissue, CLDN18.2 is confined to gastric mucosa tight junctions. Upon malignant transformation, cell polarity perturbations lead to exposure of CLDN18.2 on the cell surface. Zolbetuximab is a chimeric IgG1 monoclonal antibody that specifically binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In a randomized phase II study (NCT01630083), patients (pts) with CLDN18.2⁺advanced GC/GEJ treated with zolbetuximab + epirubicin, oxaliplatin, and capecitabine (EOX) showed prolonged survival compared to EOX alone.

Trial design

This global, phase III, double-blind, placebo-controlled study (NCT03653507) will enroll ∼500 adult pts with CLDN18.2⁺/HER2^– locally advanced unresectable or metastatic GC or GEJ not previously treated with chemotherapy for advanced/metastatic disease. Patients will be randomized 1:1 to receive zolbetuximab + CAPOX or placebo + CAPOX. Zolbetuximab will be administered by IV infusion as an 800 mg/m² loading dose (Cycle 1, Day 1) followed by 600 mg/m² Q3W in combination with CAPOX. Tumor tissue will be collected at screening to determine CLDN18.2 and HER2 status (if unknown) by central testing; pts will be considered CLDN18.2⁺ if ≥ 75% of tumor cells demonstrate moderate-to-strong membranous IHC staining. The primary objective is to compare progression-free survival of zolbetuximab + CAPOX vs placebo + CAPOX; secondary efficacy objectives include comparison of overall survival, objective response rate, and duration of response. The safety/tolerability profile, effects on health-related quality-of-life, PK profile, and immunogenicity of zolbetuximab are other secondary endpoints.

Clinical trial identification

NCT03653507.

Editorial acknowledgement

Patrick Tucker of OPEN Health Medical Communications.

Legal entity responsible for the study

Astellas Pharma, Inc.

Funding

Astellas Pharma, Inc.

Disclosure

J.A. Ajani: Advisory / Consultancy, Research grant / Funding (self): Astellas. S. Al-Batran: Advisory / Consultancy: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: Servier; Speaker Bureau / Expert testimony: Nordic Bioscience; Research grant / Funding (institution): Hospira; Research grant / Funding (institution): Medac; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Vifor Pharma; Research grant / Funding (self): Roche Pharma AG. Y. Bang: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Merck Serano; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Taiho; Advisory / Consultancy: Daiich-Sankyo; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): FivePrime; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Ono; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): BieGene; Advisory / Consultancy, Research grant / Funding (institution): GreenCross; Advisory / Consultancy, Research grant / Funding (institution): Genexine; Advisory / Consultancy: Samyang Biopharm; Advisory / Consultancy: Hanmi; Research grant / Funding (institution): CKD Pharma. D.V. Catenacci: Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): Gritstone; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self), Advisory / Consultancy: Genentech/Roche; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo. P. Enzinger: Advisory / Consultancy: Merck; Advisory / Consultancy: Astellas; Advisory / Consultancy: Celgene; Advisory / Consultancy: Lilly; Advisory / Consultancy: Loxo; Advisory / Consultancy: Taiho. D. Ilson: Advisory / Consultancy: Astellas. S. Kim: Honoraria (self): Merck. F. Lordick: Honoraria (self): Astellas; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self): AstraZeneca; Advisory / Consultancy: Biontech; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): Elsevier; Travel / Accommodation / Expenses: Infomedica; Honoraria (self): Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self): Servier; Honoraria (self): Amgen; Honoraria (self): Nordic Group; Honoraria (self): Ganymed Pharma; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Fresenius Biotech; Travel / Accommodation / Expenses: Taiho Pharma. K. Shitara: Advisory / Consultancy, Research grant / Funding (institution): Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (institution): Novartis; Honoraria (institution): AbbVie; Honoraria (institution): Yakult; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Chugai pharma; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): Medi Science. E. Van Cutsem: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Incyte; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution): Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen. A. Arozullah: Full / Part-time employment: Astellas Pharma Global Development. J.W. Park: Full / Part-time employment: Astellas Pharma Global Development. All other authors have declared no conflicts of interest.