Abstract
On May 5, 2021 and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval 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 was granted based on 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% CI 17.8, 22.1) and 16.8 months (95% CI 14.9, 18.7) in the pembrolizumab and placebo arms respectively (HR 0.80 [95% CI 0.67, 0.94]; p= 0.004). However, in exploratory subgroup analyses treatment benefit appeared to be driven by the PD-L1 CPS ≥1 population (85% of patients, with an OS HR of 0.79 [95% CI 0.66, 0.95]), whereas in the 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 accelerated approval based on response rate with subsequent conversion to regular approval based on survival outcomes. KEYNOTE-811 also provided data for earlier access to therapies in a frontline metastatic setting, following FDA's Project Frontrunner approach.