FDA Approval Summary: Pembrolizumab for the Treatment of HER2-Positive Gastric Cancer.

On May 5, 2021, and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval, respectively, for pembrolizumab plus trastuzumab and platinum-based chemotherapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2) gastric or gastroesophageal junction carcinoma. Both approvals were based on KEYNOTE-811, a randomized, multiregional trial comparing pembrolizumab plus trastuzumab and chemotherapy versus placebo plus trastuzumab and chemotherapy. Accelerated approval (AA) was granted based on the overall response rate (ORR) in the first 264 patients randomized, showing a statistically significant improvement with pembrolizumab (74.4% vs. 51.9%, P = 0.00006). The final overall survival (OS) analysis demonstrated a clinically meaningful improvement, with a median OS of 20.0 months [95% confidence interval (CI), 17.8-22.1] and 16.8 months (95% CI, 14.9-18.7) in the pembrolizumab and placebo arms, respectively [hazard ratio (HR), 0.80 (95% CI, 0.67-0.94); P = 0.004]. However, in exploratory subgroup analyses, treatment benefit seemed to be driven by the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥1 population [85% of patients, with an OS HR of 0.79 (95% CI, 0.66-0.95)], whereas in the PD-L1 CPS <1 subgroup (15% of patients) treatment with pembrolizumab did not show improvement [HR, 1.10 (95% CI, 0.72-1.68)]. These results are consistent with analysis of pembrolizumab and other immune checkpoint inhibitors across multiple clinical trials in patients with gastric cancer. KEYNOTE-811 utilized a "one-trial" approach allowing AA based on the response rate with subsequent conversion to regular approval based on survival outcomes. KEYNOTE-811 also provided data for earlier access to therapies in a first-line metastatic setting, following FDA's Project FrontRunner approach.