128MO - Final overall survival for the phase III, KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ advanced, unresectable or metastatic G/GEJ adenocarcinoma

Background

In a prior analysis of the phase III KEYNOTE-811 study (NCT03615326), first-line pembrolizumab (pembro)/trastuzumab and chemotherapy (chemo) provided superior PFS, and improved ORR with durable responses vs placebo (pbo)/trastuzumab and chemo in unresectable, HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) cancer, notably in PD-L1 CPS ≥1 tumors; overall survival (OS) was immature. These data supported approval of pembro/trastuzumab and chemo for first-line HER2+ mG/GEJ cancer with PD-L1 CPS ≥1. We present results of the final analysis of OS for KEYNOTE-811.

Methods

Eligible patients (pts) aged ≥18 years with treatment-naive unresectable, HER2+ mG/GEJ adenocarcinoma irrespective of PD-L1 status were randomized 1:1 to pembro 200 mg IV Q3W or pbo IV Q3W plus chemo (5-FU and cisplatin [FP] or capecitabine and oxaliplatin [CAPOX] and trastuzumab [SOC]). Randomization was stratified by region, PD-L1 status, and chemo choice. Dual primary end points were PFS (RECIST v1.1, BICR) and OS. Data cut-off at final analysis was 20 Mar 2024.

Results

A total of 698 pts were randomized (350 to pembro + SOC; 348 to pbo + SOC). Median follow-up was 50.2 mo. In all pts, PFS continued to be longer with pembro + SOC vs pbo + SOC (median 10.0 vs 8.1 mo; HR 0.73; 95% CI, 0.61-0.87). In pts with PD-L1 CPS ≥1, median PFS was 10.9 vs 7.3 mo (HR 0.72; 95% CI, 0.60-0.87). At final analysis, OS was significantly improved with pembro + SOC (median 20.0 vs 16.8 mo; HR 0.80; 95% CI, 0.67-0.94; p=0.0040 [less than prespecified boundary 0.0201) vs pbo + SOC. In pts with PD-L1 CPS ≥1, median OS was 20.1 vs 15.7 mo (HR 0.79; 95% CI, 0.66-0.95). ORR was 72.6% vs 60.1% with pembro + SOC vs pbo + SOC. Grade ≥3 drug-related AE rates were 59% vs 51%.

Conclusions

First-line pembro plus trastuzumab and chemo provided a statistically significant and clinically meaningful improvement in OS vs pbo plus trastuzumab and chemo in all pts with unresectable, HER2+ mG/GEJ cancer. OS was longer in pts with PD-L1 CPS ≥1. These data support the approval of pembro plus trastuzumab and chemo in pts with HER2+ mG/GEJ cancer and confirm this regimen as SOC in the first-line setting.

Clinical trial identification

NCT03615326, first posted 2018-10-05.

Editorial acknowledgement

Luana Atherly-Henderson of Merck & Co., Inc., Rahway, NJ USA provided writing support.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ USA.

Disclosure

S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas, beringer Ingelheim; Financial Interests, Personal, Invited Speaker: MSD, Daiichi Sankyo; Financial Interests, Personal, Steering Committee Member: Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Personal, Other, Durg supply for clinical trial: Merck; Financial Interests, Institutional, Coordinating PI, Drug supply for clincal trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: zy,meworks; Financial Interests, Institutional, Local PI, drug supply for clincial trial: Beigine; Financial Interests, Personal, Local PI: roche. A. Kawazoe: Financial Interests, Personal, Advisory Board: Zymeworks, Merck & Co.; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eli Lilly, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd. Y. Bai, J. Xu: Financial Interests, Institutional, Research Funding: MSD. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Astellas, GSK, Takeda, Bayer, Rottapharm; Financial Interests, Personal, Invited Speaker: Pierre Fabre, GSK, Roche, Servier, Amgen, Bristol Myers Squibb, Incyte, Lilly, Merck Serono, MSD, Astra-Zeneca; Financial Interests, Institutional, Coordinating PI: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb; Non-Financial Interests, Personal, Member of Board of Directors, Italian No-Profit Oncology Research Foundation supporting academic Clinical trials: GONO Foundation. J. Metges: Financial Interests, Institutional, Research Grant: MSD , BMS, Zymeworks, Daiichi, Astellas, Bayer; Financial Interests, Personal, Invited Speaker: MSD, Astellas, Bayer, BMS; Financial Interests, Personal, Other, support for attending meetings and/or travel: MSD , Daiichi, BMS. P.E. Yanez Weber: Financial Interests, Institutional, Research Funding: MSD. L.S. Wyrwicz: Financial Interests, Personal, Advisory Board: BMS, Servier; Financial Interests, Personal and Institutional, Local PI: BMS, MSD, Servier, Beigene, Roche, AstraZeneca; Financial Interests, Personal, Steering Committee Member: AstraZeneca. L. Shen: Financial Interests, Personal, Advisory Board: MSD, BI, Servier, AZ, Transcenta Holding Limited; Financial Interests, Institutional, Funding: Beigene, Ltd.; Financial Interests, Institutional, Trial Chair: Rongchang Pharmaceutical, Roche, Innovent, Beigene, Ltd., NovaRock Biotherapeutics Limited. Y.V. Ostapenko: Financial Interests, Institutional, Research Funding: MSD . M. Bilici: Financial Interests, Institutional, Research Funding: MSD. H.C. Chung: Financial Interests, Personal and Institutional, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Ono, Y-Biologics, Seagen, MD Biopharm. 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. M. Mahave: Financial Interests, Institutional, Research Funding: MSD . E. van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, Agenus, ALX, Arcus Biosciences, Astellas, AstraZeneca, Bayer, Beigene, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi, Debiopharma, 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. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics, CARSgen Therapeutics, hC Bioscience Inc, Takeda Pharmaceuticals International AG, Alentis Therapeutics, Immodulon Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Advisory Board: Cardiff Oncology, Aveo Oncology; Financial Interests, Personal, Other, scientific consultancy: Ono Pharma USA Inc; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics, 1TRIALSP, Alentis Therapeutics, Pangaea Oncology; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Personal, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Personal, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Personal, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Personal, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Personal, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Personal, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Personal, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Personal, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Personal, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Personal, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Personal, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc; Non-Financial Interests, Personal, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. 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Bhagia: Financial Interests, Personal, Full or part-time Employment, United States: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. Y.Y. Janjigian: Financial Interests, Personal, Advisory Board: AbbVie, Arcus Biosciences, Ask- Gene Pharma, Inc., AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Inc., Eli Lilly, GSK, Guardant Health, Inc., Imugene, Lynx Health, Merck, Sanofi Genzyme, Seagen, Zymeworks Inc.; Financial Interests, Personal, Other, Consulting: Amerisource Bergen, Astellas, Basilea Pharmaceutica, Geneos Therapeutics, Imedex, Inspirna, Mersana Therapeutics, Paradigm Medical Communications, Pfizer, Silverback Therapeutics; Financial Interests, Personal, Other, Consulting and Invited Speaker: Arcus Biosciences, AstraZeneca, Clinical Care Options, HMP Education, Merck Serono, PeerView Institue, Research to Practice; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Ed MedResources (OncInfo), H.C. 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