In the final analysis of the phase III KEYNOTE-811 trial, the addition of pembrolizumab to trastuzumab and chemotherapy significantly improved overall survival in patients with treatment-naive, unresectable, HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma. The study's findings, presented at the ESMO Congress 2024, establish pembrolizumab plus chemotherapy as a first-line standard of care in PD-L1–positive advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma.
The KEYNOTE-811 trial involved 698 patients randomized to receive either pembrolizumab (n = 350) or placebo (n = 348), in combination with trastuzumab and chemotherapy (capecitabine and oxaliplatin [CAPOX] in 85% and fluorouracil plus cisplatin in the remainder). At a median follow-up of 50.2 months, the pembrolizumab arm demonstrated a median overall survival of 20.0 months compared to 16.8 months in the placebo arm (HR = 0.80; P = .0040). The 36-month overall survival rate was 28% with pembrolizumab and 23% with placebo.
Progression-Free Survival and Overall Response
Progression-free survival data mirrored the interim analysis, with a median progression-free survival of 10.0 months in the pembrolizumab arm versus 8.1 months in the placebo arm (HR = 0.73; 95% CI = 0.61–0.87). The overall response rate was 72.6% with pembrolizumab and 60.1% without it, representing a 12.6% increase with the PD-1 inhibitor. The duration of response was also prolonged, with 11.3 months in the pembrolizumab arm compared to 9.5 months in the placebo arm. At 36 months, responses were ongoing for 24% of patients in the pembrolizumab arm and 15% in the placebo group.
Subgroup Analysis
Subgroup analysis revealed that patients with PD-L1 expression (CPS ≥ 1) experienced a 21% reduction in the risk of death and a 28% reduction in disease progression with pembrolizumab. In contrast, the subset of patients with PD-L1 CPS < 1 did not derive benefit from the addition of immunotherapy. Asian patients, representing 34% of the study population, did not show a significant benefit (HR = 1.05; 95% CI = 0.77–1.43) compared to the non-Asian population (HR = 0.72; 95% CI = 0.59–0.87).
Safety Profile
The adverse event profile remained consistent with previous analyses. Serious adverse events were reported in 26% of the pembrolizumab arm and 23% of the control group. Discontinuation of the drug (or placebo) occurred in 37% and 34% of patients, respectively. The most common treatment-related toxicities were diarrhea, nausea, and anemia, primarily attributed to the chemotherapy component. No new immune-mediated concerns were identified.
Expert Commentary
Filippo Pietrantonio, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, emphasized the clinical significance of the findings, stating, "This is the first time that formal testing has been performed on overall survival, and the fact that patients gained around 3 months is clinically meaningful... Despite the discontinuation of pembrolizumab after 2 years, it provided an absolute gain in long-term survival of at least 5%, and this is on top of the benefit of anti-HER2 therapy."
Cadonilimab Shows Promise in HER2-Negative Gastric Cancer
In a separate study, cadonilimab (PD-1/CTLA-4 bispecific antibody) plus chemotherapy demonstrated a statistically significant improvement in overall survival compared to placebo plus chemotherapy in patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. The median overall survival was 14.1 months in the cadonilimab group versus 11.1 months in the placebo group (HR 0.66; 95% CI 0.54–0.81; P < 0.001).
