1511O - Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Survival results from the phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study

Background

In a previous analysis of the phase III KEYNOTE-811 study, pembrolizumab (pembro)/trastuzumab and chemotherapy (chemo) vs placebo (pbo)/trastuzumab and chemo provided an ORR of 74% vs 52% in the first 264 pts. These data led to FDA approval of first-line pembro/trastuzumab and chemo for HER2+ mG/GEJ adenocarcinoma. We present results of a prespecified interim analysis of PFS.

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. Treatment continued for ≤2 years or until disease progression or intolerable toxicity. Dual primary end points were PFS (RECIST v1.1, BICR) or OS. Data cut-off for this interim analysis was May 25, 2022. Per the DSMC, OS assessment is ongoing.

Results

At data cut-off, 698 pts were randomized (350 to pembro + SOC; 348 to pbo + SOC). Median follow-up was 28.4 mo. In all pts, pembro + SOC vs pbo + SOC significantly improved PFS (median 10.0 vs 8.1 mo; HR 0.72; 95% CI 0.60-0.87; p=0.0002). In pts with PD-L1 CPS ≥1, median PFS was 10.8 vs 7.2 mo (HR 0.70; 95% CI, 0.58-0.85). 24-mo PFS rates were 27% vs 13%. At data cut-off, 75% of required OS events had occurred. OS follow-up is ongoing. ORR was 72.6% vs 59.8% with pembro + SOC vs pbo + SOC (73.2% vs 58.4% [PD-L1 CPS ≥1]); median (range) DOR was 11.2 mo (1.1+ to 40.1+) vs 9.0 mo (1.4+ to 38.3+). Approximately 31% vs 19% of responders had a response duration ≥24 mo. Grade ≥3 drug-related AE rates were 58% vs 51%. Grade 5 drug-related AEs occurred in 4 (1.1%) vs 3 (0.9%) pts, respectively.

Conclusions

First-line pembro plus trastuzumab and chemo provided superior PFS, and improved ORR with durable responses vs pbo plus trastuzumab and chemo in pts with unresectable, HER2+ mG/GEJ adenocarcinoma, notably in pts with PD-L1 CPS ≥1. These efficacy and safety data continue to support use of this regimen in the first-line setting.

Clinical trial identification

NCT03615326.

Editorial acknowledgement

Editorial assistance provided by Luana Atherly-Henderson, an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

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

Y.Y. Janjigian: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Merck; Financial Interests, Personal, Advisory Board: RGENIX, Eli Lilly, Daiichi Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks Inc., Seagen, Basilea Pharmaceutica, AstraZeneca; Financial Interests, Personal, Other, Consulting: Michael J. Hennessy Associates, Paradigm Medical Communications, Amerisource Bergen, Arcus Biosciences, Geneos Therapeutics, GSK, Imedex, Lynx Health, Mersana Therapeutics, PeerView Institue, Reasearch to Practice, Silverback Therapeutics; Financial Interests, Personal, Stocks/Shares: RGENIX; Financial Interests, Personal and Institutional, Research Grant: NCI, Department of Defense, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genentech/Roche, Bristol Myers Squibb, Eli Lilly, Merck. A. Kawazoe: Financial Interests, Personal, Advisory Board: Zymeworks; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo, Eli Lilly, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Expert Testimony: Merck & Co. Y. Bai, J. Xu: Financial Interests, Institutional, Research Grant: MSD. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre Fabre, GSK, Roche, Astellas; Financial Interests, Institutional, Invited Speaker: Amgen, Merck, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. J. Metges: Financial Interests, Personal, Research Grant: MSD, Bristol Myers Squibb, Zymeworks, Daisshi, Astellas, Bayer; Financial Interests, Personal, Speaker’s Bureau, honoraria: MSD, Astellas, Bayer; Financial Interests, Personal, Other, travel fees: MSD, Daiishi, Bristol Myers Squibb. P.E. Yanez Weber: Financial Interests, Institutional, Research Grant: 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, Invited Speaker: AstraZeneca. L. Shen: Financial Interests, Institutional, Funding: Astellas; Financial Interests, Personal, Writing Engagement: Oxford PharmaGenesis; Financial Interests, Personal, Research Grant: Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), Beihai Kangcheng (Beijing) Medical Technology, Yaojie Ankang (Nanjing) Technology Co., Ltd., Baiji Shenzhou (Beijing) Biotechnology Co., Ltd, Jacobio Pharmaceuticals; Financial Interests, Personal, Speaker, Consultant, Advisor: Mingji Biopharmaceutical, Haichuang Pharmaceutical, Harbour BioMed; Financial Interests, Personal, Speaker’s Bureau: Hutchison Whampoa, Hengrui, ZaiLab, CStone Pharmaceutical; Financial Interests, Personal, Advisory Board: MSD, Merck, Bristol Myers Squibb, BI, Sanofi, Roche, Servier, AstraZeneca. Y.V. Ostapenko: Financial Interests, Institutional, Other, Principal Investigator: Jounce Therapeutics. M. Bilici: Financial Interests, Institutional, Research Grant: MSD. H.C. Chung: Financial Interests, Institutional, Funding: MSD. K. Shitara: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, 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 Pharmaceutical, Daiichi Sankyo, Taiho, Chugai Pharmaceutical, MSD, Eisai, Amgen. S. Qin: Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal and Institutional, Principal Investigator: China. E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, 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. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex/HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; 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, Array Biopharma 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, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer - AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, 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, 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, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Taiho Pharma USA Inc, Janssen-Cilag International NV, Servier; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Janssen-Cilag International NV, Merus NV, Hutchinson Medipharma, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer-EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. K. Li, C. Shih, P. Bhagia: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Daiichi Sankyo, Amgen; Financial Interests, Institutional, Funding: MSD, Lilly; Financial Interests, Institutional, Research Grant: BMS, Daiichi Sankyo; Financial Interests, Institutional, Local PI: Indivumed, AstraZeneca; Financial Interests, Other, Drug supply for clinical trial: Merck; Financial Interests, Institutional, Invited Speaker, Drug supply for clinical trial: MSD; Financial Interests, Institutional, Local PI, drug supply for clinical trial: Zymeworks; Financial Interests, Institutional, Local PI, drug supply for clinical trial: BeiGene; Financial Interests, Invited Speaker, Drug supply for clinical trial: Incyte.