135MO - Updated efficacy and safety results from phase III SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients with claudin-18 isoform 2-positive (CLDN18.2+), HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma

Background

The phase 3 SPOTLIGHT study showed statistically significant improvement with 1L zolbetuximab + a modified folinic acid, 5-FU, and oxaliplatin regimen (mFOLFOX6) vs placebo (PBO) + mFOLFOX6 in PFS (final; median 10.6 vs 8.7 mo, HR 0.75 [95% CI 0.60, 0.94], P = 0.0066) and OS (interim; median 18.2 vs 15.5 mo, HR 0.75 [95% CI 0.60, 0.94], P = 0.0053) in patients (pts) with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. We present an updated efficacy and safety analysis with 9.7 mo additional follow-up from the primary analysis.

Methods

Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m² (cycle 1, day [D] 1) followed by 600 mg/m² (every 3 weeks) + mFOLFOX6 IV (D1, 15, 29) for four 42-day cycles or to PBO + mFOLFOX6; pts without progressive disease (PD) continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator’s discretion, until PD or discontinuation criteria were met. Primary endpoint was PFS per RECIST v1.1 by IRC; OS was a key secondary endpoint.

Results

At data cutoff (June 29, 2023), 565 pts were assigned to zolbetuximab + mFOLFOX6 (n = 283) or PBO + mFOLFOX6 (n = 282). In zolbetuximab vs PBO arms, median follow-up was 17.9 vs 15.2 mo for PFS and 31.1 vs 29.6 mo for OS, respectively. Median PFS was 11.0 vs 8.9 mo (HR 0.73 [95% CI 0.59, 0.91], P = 0.0022). Median OS was 18.2 vs 15.6 mo (HR 0.78 [95% CI 0.64, 0.95], P = 0.0067), with follow-up ongoing until final analysis; 24-mo OS rate was 37.7% vs 29.1%. Most common TEAEs with zolbetuximab + mFOLFOX6 were nausea (zolbetuximab arm: 82.4% vs PBO arm: 61.5%), vomiting (67.4% vs 36.3%), and decreased appetite (48.7% vs 34.9%); incidences of serious TEAEs were similar between arms (47.0% vs 46.4%).

Conclusions

With longer follow-up, zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant improvement in PFS and OS compared with PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a potential new option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma.

Clinical trial identification

NCT03504397.

Editorial acknowledgement

Medical writing support, conducted in accordance with Good Publication Practice (GPP 2022) and the International Committee of Medical Journal Editors (ICMJE) guidelines, was provided by Ann Ferguson, PhD, of Oxford PharmaGenesis Inc.

Legal entity responsible for the study

Astellas Pharma Inc.

Funding

Astellas Pharma Inc.

Disclosure

J.A. Ajani: Financial Interests, Personal, Research Funding: Astellas Pharma Inc., Bristol Myers Squibb, Merck & Co., Zymeworks, Taiho Pharmaceutical, Delta-Fly Pharma, Inc., ProLynx Inc, Daiichi Sankyo, Leap Therapeutics, Inc., Turning Point Therapeutics, Inc., Lanova Pharma, and Gilead Sciences, Inc; Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Merck & Co., Astellas Pharma Inc., Taiho Pharmaceutical, Zymeworks, BeiGene, AstraZeneca, Amgen, Novartis, Gilead Sciences, Inc., Servier Laboratories, Arcus Biosciences, and GRAIL; Financial Interests, Personal, Other, travel: Daiichi Sankyo, Bristol Myers Squibb, Aadi Bioscience, and Merck & Co. 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. Y. Bang: Financial Interests, Personal, Research Funding: Astellas Pharma Inc., Genentech, Roche Holding AG, Merck Serono, Daiichi Sankyo, MSD, Amgen, and BeiGene; Financial Interests, Personal, Speaker, Consultant, Advisor: MSD, Daiichi Sankyo, ALX Oncology, Hanmi Pharmaceutical, Merck Serono, Astellas Pharma Inc., Samyang Biopharm Corporation, and Daewoong Pharmaceutical. P.C. Enzinger: Financial Interests, Personal, Research Funding: Astellas Pharma Inc.; Financial Interests, Personal, Speaker, Consultant, Advisor: ALX Oncology, Arcus Biosciences, Astellas Pharma Inc., AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, Chimeric Therapeutics, Celgene, Coherus BioSciences, Daiichi Sankyo, Five Prime Therapeutics, Inc., IDEAYA Biosciences, Istari Oncology, Legend. D.H. Ilson: Financial Interests, Personal, Research Funding: Astellas Pharma Inc.; Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, Bayer, Astellas Pharma Inc., Merck & Co., Daiichi Sankyo, Natera Inc, Taiho Pharmaceutical, Bristol Myers Squibb, Eli Lilly and Company, Roche Holding AG, and AstraZeneca; Financial Interests, Personal, Advisory Board: MacroGenics, and Merck & Co. M.A. Shah: Financial Interests, Personal, Research Funding: Astellas Pharma Inc., Merck & Co., Bristol Myers Squibb, and Oncolys BioPharma; Financial Interests, Personal, Leadership Role: ASCO Leadership Council. E. van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. R. Xu: Financial Interests, Personal, Invited Speaker: BMS, MSD; Financial Interests, Personal, Advisory Board: Henrui, BeiGene, Astellas, Merck, Junshi. G. Aprile: Financial Interests, Personal, Research Funding: Astellas Pharma Inc.; Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, AstraZeneca, Bristol Myers Squibb, Merck & Co., MSD, and Novartis; Financial Interests, Personal, Financially compensated role: Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, Merck & Co., MSD, and Novartis. J. Xu: Financial Interests, Personal, Research Funding: Astellas Pharma Inc. R.A. Pazo Cid: Financial Interests, Personal, Advisory Board: Roche, BMS, Servier, Ipsen, Lilly, AstraZeneca; Financial Interests, Personal, Invited Speaker: Servier, BMS, Roche, Eisai; Financial Interests, Personal and Institutional, Local PI, Support for manuscript presentation (funding, provision of study materials, medical writing, article processing charges): Ipsen, Astellas. Y. Kang: Financial Interests, Personal, Advisory Board: ALX Oncology, Zymeworks, Amgen, Novartis, Macrogenics, Daehwa, Blueprint, Surface Oncology, BMS, Merck, Roche, Liscure. J. Yang: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Inc. D. Moran, P. Bhattachary: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Inc. M. Matsangou: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Global Development, Inc. A. Arozullah: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Inc.; Financial Interests, Personal, Stocks/Shares: Astellas Pharma Inc. J.W. Park: Financial Interests, Personal, Full or part-time Employment: Astellas Pharma Inc. K. Shitara: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono, MSD, Taiho, Novartis, AbbVie, GSK, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan Corp, Astellas Pharma Inc.; Financial Interests, Personal, Invited Speaker: Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Research Grant: Astellas, Ono, Daiichi Sankyo, Taiho, Chugai, MSD, Eisai, Amgen.