Esophagus to Small Intestine
Lancet. 2023;402(10418):2197–208
Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastroesophageal junction adenocarcinoma: Interim analyses from the phase 3 KEYNOTE-811 randomized placebo-controlled trial
Background: Evidence for the efficacy of combined programmed cell death 1 (PD-1) and HER2 blockade with chemotherapy on progression-free and overall survival in HER2-positive gastroesophageal cancer is scarce. The first interim analysis of the randomized, phase 3 KEYNOTE-811 study showed a superior objective response with pembrolizumab compared with placebo when added to trastuzumab plus fluoropyrimidine and platinum-based chemotherapy. Here, the authors report results from protocol-specified subsequent interim analyses of KEYNOTE-811.
Methods: The randomized, phase 3 KEYNOTE-811 trial involved 168 medical centers in 20 countries worldwide. Patients aged 18 years or older with locally advanced or metastatic HER2-positive gastroesophageal junction adenocarcinoma, without previous first-line treatment, were randomly assigned (1:1) by an integrated interactive voice-response and web-response system to intravenous pembrolizumab 200 mg or placebo, both to be combined with standard chemotherapy (fluoropyrimidine and platinum-based therapy) plus trastuzumab every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxic effects, or investigator- or participant-initiated withdrawal. Randomization used a block size of 4 and was stratified by region, PD-L1 status, and chemotherapy. Dual primary end points were progression-free and overall survival, analyzed by intention to treat. Safety was assessed in all randomly assigned patients who received at least 1 dose of study treatment according to the treatment received.
Findings: Between October 5, 2018, and August 6, 2021, 698 patients were assigned to pembrolizumab (n = 350) or placebo (n = 348). 564 (81%) were male and 134 (19%) were female. At the third interim analysis, 286 of 350 patients (82%) in the pembrolizumab group and 304 of 346 (88%) in the placebo group who received treatment had discontinued treatment, mostly due to disease progression. At the second interim analysis (median follow-up 28.3 months [interquartile range {IQR}, 19.4–34.3] in the pembrolizumab group and 28.5 months [IQR, 20.1–34.3] in the placebo group), median progression-free survival was 10.0 months (95% confidence interval [CI]: 8.6–11.7) in the pembrolizumab group versus 8.1 months (95% CI: 7.0–8.5) in the placebo group (hazard ratio [HR] = 0.72, 95% CI: 0.60–0.87; p = 0.0002). Median overall survival was 20.0 months (IQR, 17.8–23.2) versus 16.9 months (IQR, 15.0–19.8; HR = 0.87, 95% CI: 0.72–1.06; p = 0.084). At the third interim analysis (median follow-up 38.4 months [IQR, 29.5–44.4] in the pembrolizumab group and 38.6 months [IQR, 30.2–44.4] in the placebo group), median progression-free survival was 10.0 months (IQR, 8.6–12.2) versus 8.1 months (IQR, 7.1–8.6; HR = 0.73, 95% CI: 0.61–0.87), and median overall survival was 20.0 months (IQR, 17.8–22.1) versus 16.8 months (IQR, 15.0–18.7; HR = 0.84, 95% CI: 0.70–1.01), but did not meet prespecified criteria for significance and will continue to final analysis. Grade 3 or worse treatment-related adverse events occurred in 204 of 350 patients (58%) in the pembrolizumab group versus 176 of 346 patients (51%) in the placebo group. Treatment-related adverse events that led to death occurred in 4 patients (1%) in the pembrolizumab group and 3 (1%) in the placebo group. The most common treatment-related adverse events of any grade were diarrhea (165 [47%] in the pembrolizumab group vs. 145 [42%] in the placebo group), nausea (154 [44%] vs. 152 [44%]), and anemia (109 [31%] vs. 113 [33%]).
Interpretation: 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 programmed cell death ligand 1 combined positive score of ≥ 1. Overall survival follow-up is ongoing and will be reported at the final analysis.