130O - The phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma

Background

In a prior analysis of the phase 3 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.

Methods

Eligible patients (pts) aged ≥18 years with first-line, locally-advanced unresectable or metastatic HER2+ mG/GEJ adenocarcinoma irrespective of PD-L1 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 Mar 29, 2023.

Results

At data cut-off, 698 pts were randomized (350 pembro + SOC; 348 pbo + SOC). Median follow-up was 38.5 mo. In all pts, pembro + SOC vs pbo + SOC significantly improved PFS (median 10.0 vs 8.1 mo; HR 0.73; 95% CI 0.61-0.87; p=0.0002). In pts with PD-L1 CPS ≥1, median PFS was 10.9 vs 7.3 mo (HR 0.71; 95% CI, 0.59-0.86). OS was longer with pembro + SOC vs pbo + SOC in all pts (median 20.0 vs 16.8 mo; HR 0.84; 95% CI, 0.70-1.01), and in pts with PD-L1 CPS ≥1 (median 20.0 vs 15.7; HR 0.81; 95% CI, 0.67-0.98). As the prespecified criteria for significance was not met, OS continued to final analysis. ORR was 72.6% vs 60.1% with pembro + SOC vs pbo + SOC (73.2% vs 58.4% [PD-L1 CPS ≥1]); median DOR was 11.3 mo vs 9.5 mo. Grade ≥3 drug-related AE rates were 59% vs 51%. Grade 5 drug-related AEs occurred in 4 (1%) vs 3 (1%) pts, respectively.

Conclusions

First-line pembro plus trastuzumab and chemo significantly improved PFS, and improved ORR with durable responses vs pbo plus trastuzumab and chemo in pts with unresectable, HER2+ mG/GEJ adenocarcinoma, specifically in pts with PD-L1 CPS ≥1. These data support use of this regimen as a standard option for HER2+ and PD-L1-positive tumors.

Clinical trial identification

NCT03615326.

Editorial acknowledgement

Provided by Luana Atherly-Henderson, PhD, CMPP 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

S.Y. Rha: Financial Interests, Personal, Advisory Board: Indivumed, Amgen, LG biochemical, Astellas; Financial Interests, Personal, Invited Speaker: MSD, Lilly, 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: Zymeworks; Financial Interests, Institutional, Local PI, drug supply for clincial trial: Beigine; Financial Interests, Personal, Coordinating PI, Drug supply for clnical trial: Incyte. A. Kawazoe: Financial Interests, Personal, Advisory Board: Zymeworks, Merck & Co.; Financial Interests, Personal, Invited Speaker: Taiho, Daiichi Sankyo, Eli Lilly, Bristol Myers Squibb, Ono. Y. Bai, J. Xu: Financial Interests, Personal, Funding: 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, Coordinating PI: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol -Myers Squibbb. J. Metges: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, MSD, Astellas, Bayer; Financial Interests, Personal, Research Funding: BMS, MSD, Amgen, Astellas, Bayer. P.E. Yanez Weber: Financial Interests, Personal, 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, Other, Consulting fees: Mingji biopharmaceutical, Haichuang pharmaceutical, Herbour biomed; Financial Interests, Personal, Advisory Board: MSD, Merck, BMS, BI, Sanofi, Roche, Servier, AZ; Financial Interests, Institutional, Funding: Beijing Xiantong Biomedical Technology, Qilu Pharmaceutical, ZaiLab Pharmaceutical (Shanghai), Alphamab Oncology, Yaojie Ankang (Nanjing) Technology Co., Ltd., BeiGene, Ltd., Qiyu Biotechnology (Shanghai) Co., Ltd., BriSTAR immunotech; Financial Interests, Institutional, Local PI: Merck Healthcare KGaA, Roche; Financial Interests, Institutional, Trial Chair: Rongchang Pharmaceutical, Innovent, BeiGene, Ltd., NovaRock Biotherapeutics Limited, Qilu Pharmaceutical. Y.V. Ostapenko: Financial Interests, Institutional, Other, Principal Investigator: Jounce Therapeutics. M. Bilici: Financial Interests, Personal, Funding: MSD. H.C. Chung: Financial Interests, Personal, Speaker, Consultant, Advisor: Taiho, Celltrion, MSD, Lily, BMS/Ono, Serono, Gloria, BeiGene, Amgen, Zymework, Y Biologics, Seagen, MD Biolab; Financial Interests, Institutional, Research Grant: Lily, GSK, MSD, Merck-Serono, BMS/Ono, Taiho, Amgen, BeiGene, Incyte, Zymework. K. Shitara: Financial Interests, Personal, Advisory Board: Lilly, Bristol Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, MSD, Taiho Pharmaceutical, Novartis, AbbVie, GSK, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan Corp, Astellas Pharma Inc.; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Eisai, Amgen; Financial Interests, Personal, Invited Speaker: Janssen Pharmaceutical K.K. S. Qin: Financial Interests, Personal, Funding: MSD. 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. 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 Serono, 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, Debiopharm International SA, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, F. Hoffmann-La Roche Ltd, Merck, Sharp & Dohme de España, SA, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, 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, Personal, Leadership Role, External Scientific Committee: IdiSNA –Universidad de Navarra, Institute for Health Research INCLIVA – Clinical Hospital of Valencia; 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, 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, Principal Investigator, Clinical Trials & Research: AstraZeneca Pharmaceutics LP, Array Biopharma Inc., BeiGene, Boehringer Ingelheim, F. Hoffmann-La Roche Ltd, Debiopharm International SA, Bristol Myers Squibb International Corporation, Celgene International SARL, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Menarini, Janssen-Cilag International NV, MedImmune, 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, 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, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Personal, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Personal, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Personal, Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System; Other, Personal, Other, President: Oncology Master Plan – Catalonia Department of Health. K. Li, C. Shih, P. Bhagia: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme Corp.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc. Y.Y. Janjigian: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Merck Serono; 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 and Institutional, Research Grant: Department of Defense, NCI, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genetech/Roche, Bristol Myers Squibb, Eli Lilly, Merck; Financial Interests, Personal, Stocks/Shares: RGENIX.