First-line (1L) zolbetuximab + chemotherapy in patients (pts) with claudin 18.2 (CLDN18.2) +, HER2-, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: A pooled final analysis of SPOTLIGHT + GLOW

BackgroundSPOTLIGHT and GLOW showed improved progression-free and overall survival (PFS, OS) with 1L zolbetuximab + chemotherapy vs placebo + chemotherapy in pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma at interim and updated analyses. Here we present the pooled final OS analysis.MethodsPts were randomly assigned 1:1 to zolbetuximab IV (800 mg/m2 cycle 1 day 1, then 600 mg/m2 every 3 weeks) + chemotherapy (SPOTLIGHT, mFOLFOX6: folinic acid, fluorouracil, oxaliplatin IV every 2 weeks; GLOW, CAPOX: capecitabine twice daily days 1–14, oxaliplatin IV every 3 weeks) or placebo + chemotherapy for four 42-day cycles (SPOTLIGHT) or eight 21-day cycles (GLOW). Pts continued zolbetuximab/placebo, + capecitabine (GLOW) or + folinic acid + fluorouracil (SPOTLIGHT) per investigator decision, until progressive disease (PD) or discontinuation criteria were met. Endpoints included PFS (primary), OS (key secondary), and objective response rate (ORR)/safety (secondary).ResultsThe addition of zolbetuximab continued to improve both PFS and OS at final analysis (n=1072; Table). The most common treatment-emergent adverse events (TEAEs) with zolbetuximab + chemotherapy were nausea (76.0% vs 56.2% in zolbetuximab vs placebo arms), vomiting (66.8% vs 34.2%), and decreased appetite (45.2% vs 34.7%); serious TEAEs (48.0% vs 48.4%), grade ≥3 TEAEs (80.7% vs 74.8%), and drug-related TEAEs leading to death (2.1% vs 2.3%) were similar in both arms. Table: 1438P Zolbetuximab + chemotherapy Placebo + chemotherapy PFS Median, mo (95% CI) 9.2 (8.4–10.4) 8.2 (7.6–8.4) HRa (95% CI); 1-sided P value 0.71 (0.61–0.83); <0.0001 Median follow-up, months 18.2 17.9 Events, n/n (%) 312/537 (58.1) 369/535 (69.0) OS Median, mo (95% CI) 16.4 (15.0–17.9) 13.7 (12.3–15.3) HRa (95% CI); 1-sided P value 0.77 (0.67–0.89); 0.0002 2-year OS rate (%) 33.7 24.4 Median follow-up, months 32.7 31.8 Events, n/n (%) 377/537 (70.2) 424/535 (79.3) ORR, pts with measurable lesions n/n 233/406 229/414 % (95% CI) 57.4 (52.4–62.3) 55.3 (50.4–60.2) aZolbetuximab vs placebo arms. ConclusionsZolbetuximab + chemotherapy continued to demonstrate statistically significant and clinically meaningful improvement in PFS and OS vs placebo + chemotherapy, with no new safety signals—supporting zolbetuximab + chemotherapy as a new standard for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma.Clinical trial identificationNCT03504397; NCT03653507.Editorial acknowledgementMedical writing support was provided by Ann Ferguson, PhD, of Oxford PharmaGenesis Inc.Legal entity responsible for the studyAstellas Pharma Inc.FundingAstellas Pharma Inc.DisclosureY. Kang: Financial Interests, Personal, Advisory Board: ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncology, BMS, Merck, Roche, Liscure. M.A. Shah: Financial Interests, Personal, Funding: Merck, Bristol Myers Squibb, Oncolys Biopharma. K. Shitara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Takeda, Ono Pharmaceutical, MSD, Novartis, Daiichi Sankyo, Amgen, Guardant Health Japan Corp, Astellas Pharma Inc., Astellas, Bayer, AstraZeneca, Zymeworks Biopharmaceuticals Inc., ALX Oncology Inc.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Janssen, AstraZeneca, Eli Lilly, Astellas, Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Eisai, Amgen, PRA Health Sciences. J.A. Ajani: Financial Interests, Personal, Advisory Board: BMS, Gilead, Astellas, AZ, Jazz, KirinKyowa, Servier, BeiGene, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI, My institution receives funding: BMS; Financial Interests, Institutional, Coordinating PI: Merck, Jazz, Astellas, DeltaFly, Gilead, Roche. F. Lordick: Financial Interests, Personal, Advisory Board: Amgen, Astellas, BMS, Bayer, BeiGene, BioNTech, Eli Lilly, Elsevier, MSD, Novartis, Roche, Daiichi Sankyo, PAGE; Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Eli Lilly, Imedex, Incyte, MSD, MedUpdate, Medscape, Merck Serono, Roche, Servier, StreamedUp!, Daiichi Sankyo, Novartis, Art Tempi; Financial Interests, Personal, Writing Engagement: Deutscher Ärzteverlag, Iomedico, Springer-Nature; Financial Interests, Institutional, Research Grant: BMS, Gilead. E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, Agenus, ALX, Arcus Biosciences, Astellas, AstraZeneca, Bayer, BeiGene, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Debiopharm, Elmedix, Eisai, GSK, Hoopika Biotech, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Seattle Genetics, Servier, Simcere, Takeda, Taiho, Terumo; Financial Interests, Personal, Invited Speaker: Amgen, Pfizer. S.J. Klempner: Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Merck, Bristol Myers Squibb, Astellas, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, One Time Advisory Board: Natera; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x 1, 2023: Mersana; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x 1: Sanofi-Aventis; Financial Interests, Personal, Advisory Board, Stomach Cancer consulting, ended in 1/2024: Novartis; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x1 in 1/2024: AstraZeneca; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x1 in 3/2024: I-Mab Therapeutics; Financial Interests, Personal, Advisory Board, Stomach cancer consulting, <$1,500 USD in 2023: Taiho Oncology; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x1, planned for 6/2024: Eisai; Financial Interests, Personal, Stocks/Shares, Stock Ownership, ended in 6/2022: Turning Point Therapeutics; Financial Interests, Personal, Stocks/Shares, Early investor, company is not public: MBrace; Financial Interests, Institutional, Coordinating PI, National PI for trial: Leap Therapeutics; Financial Interests, Personal and Institutional, Local PI, Local PI for trial, also served on advisory board as noted above: Astellas; Financial Interests, Institutional, Local PI, Ended in 2022: Macrogenics; Financial Interests, Institutional, Coordinating PI, Trial PI, ended in 2023: Silverback; Financial Interests, Institutional, Local PI, Site PI for phase III trials: Arcus; Financial Interests, Personal and Institutional, Local PI, Site PI for trial, as disclosed above was a one-time advisory board participant, <$5,000 USD: I-Mab; Non-Financial Interests, Advisory Role, Medical-Scientific Advisory Board Member: Debbies Dream Foundation; Non-Financial Interests, Advisory Role, Member of Scientific Advisory Board: Hope for Stomach Cancer; Non-Financial Interests, Other, Member of Gastric and Esophageal NCCN Guideline Committees: NCCN; Other, Participant in gastroesophageal CME activities, compensated, last in 3/2024: Research to Practice. K. Yamaguchi: Financial Interests, Personal, Expert Testimony: Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K. Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. Bristol Myers Squibb K.K., Takeda Pharmaceutical Co., Ltd. T. Nakajima, Y.J. Cao, R. Li, R.R. Pophale: Financial Interests, Personal, Full or part-time Employment: Astellas. R. Xu: Financial Interests, Personal, Invited Speaker: BMS, MSD, Hutchison Pharm; Financial Interests, Personal, Advisory Board: Henrui, BeiGene, Astalas, Merck, Junshi, Innovent, Keymed Biosience. All other authors have declared no conflicts of interest.