Fluorouracil, folinic acid, and oxaliplatin (mFOLFOX6) is accepted first-line therapy for advanced/metastatic G/GEJ. Claudin (CLDN)18.2, a tight junction protein and new molecular target, is confined to gastric mucosa (ie, cells in the pit and base regions of the gastric glands) in healthy tissue. Upon malignant transformation, structural loss in G/GEJ cells may allow antibodies more access to previously unavailable CLDN18.2. Zolbetuximab (zolbe), a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Phase II (NCT01630083) results showed prolonged survival of patients (pts) with CLDN18.2+ advanced G/GEJ treated with zolbe + epirubicin, oxaliplatin, and capecitabine (EOX) vs EOX alone.
SPOTLIGHT (NCT03504397) is enrolling ∼550 pts from global sites including China, Japan, Korea, and Taiwan. Eligible pts should have locally advanced unresectable or metastatic G/GEJ that is CLDN18.2+/human epidermal growth factor receptor 2-negative (HER2–) and radiologically evaluable lesions per RECIST v1.1. Prior chemotherapy for advanced/metastatic G/GEJ is not permitted. Patients will be randomized 1:1 to zolbe + mFOLFOX6 or placebo + mFOLFOX6. Randomization will be stratified by region (Asia vs non-Asia), number of metastatic sites (0 to 2 vs ≥3), and prior gastrectomy (yes vs no). Patients will receive zolbe 800 mg/m2 IV on Cycle 1 Day 1 (loading dose), then 600 mg/m2 IV every 3 weeks; mFOLFOX6 will be administered on Days 1, 15, and 29 of each 42-day cycle (4 cycles). Central tumor tissue testing will determine CLDN18.2/HER2 status (if unknown); pts are considered CLDN18.2+ if ≥75% of tumor cells show moderate-to-strong immunohistochemical staining. Primary endpoint: progression-free survival per independent review committee. Key secondary endpoint: overall survival. Other secondary endpoints: objective response rate; duration of response; safety/tolerability, pharmacokinetics, and immunogenicity of zolbe. As of June 30, 2020, 190 sites have been initiated.
NCT03504397.
Medical writing/editorial support was provided by Patrick Tucker, PhD, Cathy R. Winter, PhD, and Elizabeth Hermans, PhD, from OPEN Health Medical Communications, Chicago, IL.
Astellas Pharma, Inc.
This study was funded by Astellas Pharma, Inc.
K. Shitara: Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Ono Pharmaceutical; Research grant/Funding (institution): Dainippon Sumitomo Pharma; Advisory/Consultancy, Research grant/Funding (institution): MSD; Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Taiho Pharmaceutical; Research grant/Funding (institution): Chugai Pharm; Advisory/Consultancy, Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Medi Science; Honoraria (institution), Advisory/Consultancy: Novartis; Honoraria (institution), Advisory/Consultancy: AbbVie; Honoraria (institution): Yakult; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Takeda; Advisory/Consultancy: Pfizer; Advisory/Consultancy: GlaxoSmithKline. S-E. Al-Batran: Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Celgene; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Nordic Pharma; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: MSD Sharp & Dohme; Speaker Bureau/Expert testimony: AIO gGmbH; Speaker Bureau/Expert testimony: MCI; Speaker Bureau/Expert testimony: promedicis; Speaker Bureau/Expert testimony: Forum für Medizinische Fortbildung; Officer/Board of Directors: IKF Klinische Krebsforschung GmbH; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Vifor; Research grant/Funding (institution): Medac; Research grant/Funding (institution): Hospira; Research grant/Funding (institution): German Cancer Aid (Krebshilfe); Research grant/Funding (institution): German Research Foundation; Research grant/Funding (institution): Federal Ministry of Education and Research. Y-J. 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; Advisory/Consultancy, Research grant/Funding (institution): Taiho; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Astellas; Advisory/Consultancy, Research grant/Funding (institution): BeiGene; Advisory/Consultancy, Research grant/Funding (institution): GreenCross; Advisory/Consultancy: Samyang Biopharm; Advisory/Consultancy: Hanmi; Advisory/Consultancy, Research grant/Funding (institution): Genexine; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Boeringer Ingelheim; Research grant/Funding (institution): MacroGenics. D. Catenacci: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: Merck; Advisory/Consultancy: BMS; Advisory/Consultancy: Lilly; Advisory/Consultancy: Gritstone; Advisory/Consultancy: Taiho; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Daichii Sankyo. P.C. Enzinger: Advisory/Consultancy: Merck; Advisory/Consultancy: Astellas; Advisory/Consultancy: Celgene; Advisory/Consultancy: Lilly; Advisory/Consultancy: Loxo; Advisory/Consultancy: Taiho; Advisory/Consultancy: Zymeworks. D.H. Ilson: Advisory/Consultancy: Astellas Pharma. S. Kim: Travel/Accommodation/Expenses: Astellas Pharma. F. Lordick: Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol Myers Squibb; Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Eli Lilly; Travel/Accommodation/Expenses: Elsevier; Travel/Accommodation/Expenses: Biontech GmbH; Travel/Accommodation/Expenses: Excerpta Medica; Travel/Accommodation/Expenses: Medscape; Travel/Accommodation/Expenses: E-Cancer; Travel/Accommodation/Expenses: Servier; Travel/Accommodation/Expenses: Merck Serono; Travel/Accommodation/Expenses: Merck Sharpe Dohme; Travel/Accommodation/Expenses: Springer Nature Verlag GmbH. 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; Advisory/Consultancy, Research grant/Funding (institution): Celgene; Advisory/Consultancy: Incyte; Advisory/Consultancy, Research grant/Funding (institution): Lilly; 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; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Ipsen. R-H. Xu: Honoraria (institution): Merck; Honoraria (institution): Roche. A. Arozullah: Full/Part-time employment: Astellas Pharma. J.W. Park: Full/Part-time employment: Astellas Pharma. J.A. Ajani: Advisory/Consultancy, Research grant/Funding (institution): Astellas Pharma. All other authors have declared no conflicts of interest.