As reported in The Lancet Oncology by Sun Young Rha, MD, and colleagues, the phase III KEYNOTE-859 trial has shown that the addition of first-line pembrolizumab to chemotherapy was associated with a statistically significant improvement  in overall survival in patients with HER2-negative advanced gastric/gastroesophageal junction adenocarcinoma.

Sun Young Rha, MD

Study Details

In the double-blind trial, 1,579 patients with locally advanced or metastatic disease from sites in 33 countries were randomly assigned between November 2018 and June 2021 to receive investigator’s choice of chemotherapy with fluorouracil (800 mg/m² per day continuously on days 1–5) and cisplatin (80 mg/m² on day 1 of  3-week cycles) or capecitabine (1,000 mg/m² twice daily on days 1–14) and oxaliplatin (130 mg/m² on day 1 of each 3-week cycle) plus either pembrolizumab at 200 mg (n = 790) or placebo (n = 789) every 3 weeks for up to 35 cycles. Chemotherapy consisted of fluorouracil/cisplatin in 108 vs 108 patients and capecitabine/oxaliplatin in 682 vs 681 patients.

The primary endpoint was overall survival, assessed in the intention-to-treat (ITT) population and the populations with PD-L1 combined positive score (CPS) of ≥ 1 and CPS ≥ 10.

Overall Survival

Median follow-up was 31.0 months (interquartile range = 23.0–38.3 months). In the ITT population, median overall survival was 12.9 months (95% confidence interval [CI] = 11.9–14.0 months) in the pembrolizumab group vs 11.5 months (95% CI = 10.6–12.1 months) in the control group (hazard ratio [HR] = 0.78, 95% CI = 0.70–0.87, P < .0001). Rates at 12 and 24 months were 53% vs 47% and 28% vs 19%, respectively.

Among 618 vs 617 patients with CPS ≥ 1, median overall survival was 13.0 months (95% CI 11.6–14.2 months) in the pembrolizumab group vs 11.4 months (95% CI = 10.5–12.0 months) in the control group (HR = 0.74, 95% CI = 0.65–0.84, P < .0001). Rates at 12 and 24 months were 52% vs 46% and 30% vs 18%, respectively.

Among 279 vs 272 patients with CPS ≥ 10, median progression-free survival was 15.7 months (95% CI = 13.8–19.3 months) in the pembrolizumab group vs 11.8 months (95% CI = 10.3–12.7 months) in the control group (HR = 0.65, 95% CI = 0.53–0.79, P < .0001). Rates at 12 and 24 months were 61% vs 48% and 38% vs 21%, respectively.

Among 172 vs 172 patients with CPS < 1, the hazard ratio for the pembrolizumab group vs the control group was 0.92 (95% CI = 0.73–1.17).

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 59% of patients in the pembrolizumab group vs 49% of the control group, most commonly decreased neutrophils (9% vs 8%) and anemia (8% vs 6%) in both groups. Serious treatment-related adverse events occurred in 23% vs 19% of patients. Treatment-related adverse events led to treatment discontinuation in 26% vs 20% of patients. Grade ≥ 3 immune-mediated adverse events occurred in 5% of the pembrolizumab group, including one grade 5 event (pneumonitis). Treatment-related adverse events led to death in 8 patients (1%) in the pembrolizumab group and 16 patients (2%) in the control group.

The investigators concluded, “Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group. Therefore, pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma.”

Sun Young Rha, MD, of the Department of Internal Medicine, Yonsei Cancer Center, Seoul, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp and Dohme. For full disclosures of the study authors, visit thelancet.com.