Dr Janjigian on Pembrolizumab/Trastuzumab/Chemotherapy in HER2+ Gastric Cancer

Yelena Y. Janjigian, MD, chief, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, discusses results from the primary progression-free survival (PFS) and interim overall survival (OS) analyses of the phase 3 KEYNOTE-811 trial (NCT03615326) in patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, and contextualizes these findings with previously reported data from this trial.

The initiation of KEYNOTE-811 was supported by a phase 2, investigator-initiated trial (NCT02954536) conducted at Memorial Sloan Kettering Cancer Center that evaluated pembrolizumab (Keytruda) plus trastuzumab (Herceptin) and chemotherapy in patients with HER2-positive, metastatic, esophagogastric adenocarcinoma, Janjigian says. In this single-arm trial, the combination produced an overall response rate (ORR) of 83% (95% CI, 63%-95%). KEYNOTE-811 subsequently investigated the combination vs placebo plus trastuzumab and chemotherapy in this population.

In 2021, the FDA granted accelerated approval to the combination of pembrolizumab, trastuzumab, and placebo for patients with HER2-positive gastric or GEJ adenocarcinoma based on findings from the first interim analysis of KEYNOTE-811. In this analysis, the investigational arm achieved a 22% improvement in ORR vs the control arm.

At the 2023 ESMO Congress, Janjigian presented updated survival data from KEYNOTE-811, which were simultaneously published in The Lancet. These findings demonstrated a PFS improvement with pembrolizumab plus trastuzumab and chemotherapy over the standard of care, regardless of patient PD-L1–status, for the first time in the frontline, HER2-positive gastric cancer setting. At a median follow-up of 28.4 months, the median PFS was 10.0 months (95% CI, 8.6-11.7) in the investigational arm vs 8.1 months (95% CI, 7.0-8.5) in the control arm (HR, 0.72; 95% CI, 0.60-0.87).

The OS data for this trial are still maturing until the final analysis, Janjigian notes. However, the OS data in the third interim analysis look promising, Janjigian emphasizes. At a data cutoff of March 29, 2023, the median OS was 20.0 months (95% CI, 17.8-22.1) in the investigational arm vs 16.8 months (95% CI, 15.0-18.7) in the control arm (HR, 0.84; 95% CI, 0.70-1.01). This difference in OS has not been previously demonstrated with any frontline therapy in gastric cancer, Janjigian explains. Although the population of patients with a combined positive score higher than 1 experienced a meaningful OS improvement, the OS hazard ratio crossed 1 in the intention-to-treat population, so mature data are needed, Janjigian concludes.

Editor’s Note: Dr Janjigian reports advisory/consulting roles with Rgenix (equity), Merck, Serono, BMS, Eli Lilly, Pfizer, Bayer, Imugene, MSD, Daiichi Sankyo, Zymeworks, Seagen, Basilea Pharmaceutical, and AstraZeneca; institutional research funding from MSD, NCI, US Department of Defense, Cycle of Survival, Fred’s Team, Rgenix, Bayer, Genentech/Roche, BMS, and Eli Lilly; and study funding and medical writing assistance from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

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