Initial data from the phase 3 KEYNOTE-811 study of trastuzumab and chemotherapy with or without pembrolizumab for HER2-positive metastatic gastric or gastroesophageal junction (G/GEJ) cancer

Background Standard-of-care (SOC) first-line therapy for HER2-positive metastatic G/GEJ cancer is trastuzumab plus chemotherapy. Adding pembrolizumab to SOC showed promising efficacy and manageable safety in two phase 2 studies. In the ongoing global, randomized, double-blind phase 3 KEYNOTE-811 study, we are assessing whether adding pembrolizumab to trastuzumab and chemotherapy improves efficacy versus trastuzumab and chemotherapy alone for participants with HER2-positive metastatic G/GEJ cancer (NCT03615326). Methods Eligible participants with previously untreated, unresectable or metastatic HER2-positive G/GEJ cancer and ECOG PS 0 or 1 are allocated 1:1 to receive pembrolizumab 200 mg IV Q3W or placebo IV Q3W for up to 2 years or until intolerable toxicity or PD; all participants also receive trastuzumab and investigator’s choice of 5-fluorouracil and cisplatin (FP) or capecitabine and oxaliplatin (CAPOX) at standard doses. Accrual to the global cohort, planned for 692 participants, is almost complete. Response and PD are assessed per RECIST v1.1 by blinded, independent central review. PFS and OS are the dual primary endpoints. ORR and DOR are secondary endpoints. The protocol-specified first interim analysis was to occur when the first 260 participants had at least 8.5 months follow-up and assessed whether ORR was significantly improved in the pembrolizumab versus placebo arm; the superiority boundary was P = 0.002. The difference in ORR was calculated using the Miettinen and Nurminen method stratified by the randomization stratification factors of geographic region, PD-L1 status, and chemotherapy choice. The efficacy population included the first 264 participants enrolled. The safety population included all enrolled participants who received study treatment as of the June 17, 2020, data cutoff (N = 433). Results In the efficacy population, 133 participants were randomized to pembrolizumab + SOC, 131 to placebo + SOC; CAPOX was chosen for 87.1%, and median study follow-up was 12.0 months (range, 8.5-19.4). Confirmed ORR (95% CI) was 74.4% (66.2-81.6) for pembrolizumab + SOC vs. 51.9% (43.0-60.7) for placebo + SOC (difference, 22.7% [95% CI, 11.2-33.7], P = 0.00006); CR rate was 11.3% vs. 3.1% and DCR was 96.2% vs. 89.3%. Median (range) DOR was 10.6 months (1.1+ to 16.5+) for the pembrolizumab arm and 9.5 months (1.4+ to 15.4+) for the placebo arm; estimated DOR ≥6 months and ≥9 months was 70.3% vs. 61.4% and 58.4% vs. 51.1%, respectively. In the safety population, 217 participants received pembrolizumab + SOC and 216 received placebo + SOC. AEs were grade 3-5 in 57.1% of participants in the pembrolizumab arm vs. 57.4% in the placebo arm, led to death in 3.2% vs. 4.6%, and led to discontinuation of any drug in 24.4% vs. 25.9%. Conclusions The combination of pembrolizumab, trastuzumab, and chemotherapy provides a substantial, statistically significant improvement in ORR compared with placebo, trastuzumab, and chemotherapy as first-line therapy for HER2-positive, metastatic G/GEJ cancer. Along with the durability of responses and the manageable safety profile, these initial data support pembrolizumab plus trastuzumab and chemotherapy as a possible new treatment option for HER2-positive, metastatic G/GEJ cancer. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure Y. Janjigian: Advisory / Consultancy: Bristol-Myers Squibb, Merck Serono, RGENIX, Eli Lilly, Daiichi-Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks, Seattle Genetics, Basilea Pharmaceutica, AstraZeneca Research grant / Funding (institution): NCI, Department of Defense, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genetech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck. K. Shitara: Honoraria (self): Novartis , AbbVie Inc, Yakult Advisory / Consultancy: Astellas Pharma; Bristol-Myers Squibb; Novartis; Taiho Pharmaceutical; Merck Pharmaceutical, Eli Lilly and Company; Pfizer Inc; AbbVie Inc; GlaxoSmithKline; Amgen, Takeda Pharmaceuticals; Ono Pharmaceutical; Daiichi Sankyo; Boehringer Ingelheim Research grant / Funding (institution): Astellas Pharma; Daiichi Sankyo; Merck Pharmaceutical; Medi Science, Ono Pharmaceutical; Taiho Pharmaceutical, Dainippon Sumitomo Pharma; Chugai Pharma; Eisai. E. Van Cutsem: Advisory / Consultancy: Bayer, Lilly, Roche, Servier, Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, Merck KGaA, Novartis, AstraZeneca, Halozyme, Array BioPharma, Biocartis, GlaxoSmithKline, Daiichi Sankyo, Pierre Fabre, Sirtex Medical, Taiho Pharmaceutical, Incyte. Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. J. Tabernero: Honoraria (self): educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER); Advisory / Consultancy: Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. L. Li: Full / Part-time employment: Merck & Co., Inc. C. Shih: Shareholder / Stockholder / Stock options: Merck & Co. Full / Part-time employment: Merck & Co. P. Bhagia: Full / Part-time employment: Merck & Co., Inc. L. Shen: None provided. All other authors have declared no conflicts of interest.