In interim analyses from the phase III KEYNOTE-811 trial reported in The Lancet, Yelena Y. Janjigian, MD, and colleagues found that the addition of pembrolizumab to trastuzumab and chemotherapy in first-line treatment of patients with locally advanced or metastatic HER2-positive gastric/gastroesophageal junction adenocarcinoma significantly improved progression-free survival.
The first interim analysis in the trial supported the May 2021 accelerated approval of pembrolizumab with trastuzumab and chemotherapy in this setting on the basis of objective response rate and duration of response.
Yelena Y. Janjigian, MD
Study Details
In the double-blind trial, 698 patients from sites in 20 countries were randomly assigned between October 2018 and August 2021 to receive pembrolizumab at 200 mg (n = 350) or placebo (n = 348) every 3 weeks plus standard chemotherapy and trastuzumab every 3 weeks for up to 35 cycles or until disease progression or unacceptable toxicity. Trastuzumab was given at 6 mg/kg every 3 weeks following an initial loading dose of 8 mg/kg. Chemotherapy consisted of fluorouracil (800 mg/m² on days 1–5 of each 3-week cycle) plus cisplatin (80 mg/m² once every 3 weeks) or capecitabine (1,000 mg/m² twice daily on days 1–14 of each 3-week cycle) plus oxaliplatin (130 mg/m² once every 3 weeks).
The dual primary endpoints of the trial were progression-free survival and overall survival in the intention-to-treat population.
Key Findings
At second interim analysis, median follow-up was 28.3 months (interquartile range [IQR] = 19.4–34.3 months) in the pembrolizumab group and 28.5 months (IQR = 20.1–34.3 months) in the control group. Median progression-free survival was 10.0 months (95% confidence interval [CI] = 8.6–11.7 months) in the pembrolizumab group vs 8.1 months (95% CI = 7.0–8.5 months) in the control group (hazard ratio [HR] = 0.72, 95% CI = 0.60–0.87, P = .0002). Among 298 patients in the pembrolizumab group and 296 in the control group with a PD-L1 combined positive score (CPS) ≥ 1, median progression-free survival was 10.8 months vs 7.2 months (HR = 0.70, 95% CI = 0.58–0.85). No significant difference was observed among the 52 patients in each group with CPS < 1 (median = 9.5 vs 9.6 months, HR = 1.17, 95% CI = 0.73–1.89).
At second interim analysis, median overall survival was 20.0 months (95% CI = 17.8–23.2 months) vs 16.9 months (95% CI = 15.0–19.8 months) among all patients (HR = 0.87, 95% CI = 0.72–1.06, P = .084). Among patients with PD-L1 CPS ≥ 1, median overall survival was 20.5 months vs 15.6 months (HR = 0.79, 95% CI = 0.64–0.98). No significant difference was observed among patients with CPS < 1 (median = 16.1 vs 22.3 months, HR = 1.61, 95% CI = 0.98–2.64).
At third interim analysis, median follow-up was 38.4 months (IQR = 29.5–44.4 months) in the pembrolizumab group and 38.6 months (IQR = 30.2–44.4 months) in the control group. Median progression-free survival was 10.0 months (95% CI = 8.6–12.2 months) vs 8.1 months (95% CI = 7.1–8.6 months) among all patients (HR = 0.73, 95% CI = 0.61–0.87), and 10.9 vs 7.3 months (HR = 0.71, 95% CI = 0.59–0.86) among patients with CPS ≥ 1. No difference was observed among patients with CPS < 1 (median = 9.5 vs 9.5 months, HR = 1.03, 95% CI = 0.65–1.64). Median overall survival was 20.0 months (95% CI = 17.8–22.1 months) vs 16.8 months (95% CI = 15.0–18.7 months) among all patients (HR = 0.84, 95% CI = 0.70–1.01), and 20.0 vs 15.7 months among those with CPS ≥ 1 (HR = 0.81, 95% CI = 0.67–0.98).
Grade ≥ 3 treatment-related adverse events occurred in 58% of patients in the pembrolizumab group vs 51% of the control group; serious treatment-related adverse events occurred in 25% vs 23%; and treatment-related adverse events led to discontinuation of any study drug in 35% vs 31% of patients, and to death in four (1%) vs three patients (1%).
The investigators concluded, “Compared with placebo, pembrolizumab significantly improved progression-free survival when combined with first-line trastuzumab and chemotherapy for metastatic HER2-positive gastroesophageal cancer, specifically in patients with tumors with a PD-L1 [CPS ≥ 1]. Overall survival follow-up is ongoing and will be reported at the final analysis.”
Dr. Janjigian, of Memorial Sloan Kettering Cancer Center, is the corresponding author for The Lancet article.
Disclosure: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit thelancet.com.
