As reported in The Lancet by Sun et al, the phase III KEYNOTE-590 trial showed that the addition of first-line pembrolizumab to chemotherapy resulted in improved overall and progression-free survival in patients with advanced esophageal and Siewert type 1 gastroesophageal junction (GEJ) cancers.

The trial supported the March 2021 approval of pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1–5 cm above the GEJ [Siewert type 1]) carcinoma who are not candidates for surgical resection or definitive chemoradiation.

Study Details

In the double-blind trial, 749 patients—irrespective of PD-L1 status—from sites in 26 countries were randomly assigned to receive pembrolizumab at 200 mg (n = 373) or placebo (n = 376) every 3 weeks for up to 35 cycles, both combined with fluorouracil at 800 mg/m² on days 1 to 5 plus cisplatin at 80 mg/m² on day 1 every 3 weeks for up to 6 cycles.

For the pembrolizumab vs control groups, 73% vs 73% had esophageal squamous cell carcinoma (SCC) and 27% vs 27% had adenocarcinoma, including 11% vs 13% with Siewert type 1 GEJ adenocarcinoma. The primary endpoints were overall survival in patients with esophageal SCC and PD-L1 combined positive score (CPS) ≥ 10, as well as overall and progression-free survival in patients with esophageal SCC, PD-L1 CPS ≥ 10, and all randomly assigned patients.

Primary Endpoints

At first interim analysis at a median follow-up of 22.6 months, median overall survival was 13.9 months among 143 patients in the pembrolizumab group vs 8.8 months among 143 patients in the control group with esophageal SCC and PD-L1 CPS ≥ 10 (hazard ratio [HR] = 0.57, 95% confidence interval [CI] = 0.43–0.75, P < .0001).

Among 274 pembrolizumab group vs 274 control group patients with esophageal SCC, median overall survival was 12.6 months vs 9.8 months (HR = 0.72, 95% CI = 0.60–0.88, P = .0006) and median progression-free survival was 6.3 months vs 5.8 months (HR = 0.65, 95% CI = 0.54–0.78, P < .0001).

Among 186 vs 197 patients with PD-L1 CPS ≥ 10, median overall survival was 13.5 months vs 9.4 months (HR = 0.62, 95% CI = 0.49–0.78, P < .0001) and median progression-free survival was 7.5 months vs 5.5 months (HR = 0.51, 95% CI = 0.41–0.65, P < .0001).

Among all randomly assigned patients, median overall survival was 12.4 months vs 9.8 months (HR = 0.73, 95% CI = 0.62–0.86, P < .0001) and median progression-free survival was 6.3 months vs 5.8 months (HR = 0.65, 95% CI = 0.55–0.76, P < .0001). Subsequent anticancer therapy was received by 43% of patients in the pembrolizumab group vs 47% in the control group, including immunotherapy in 6% vs 9%.

Adverse Events

Grade ≥ 3 adverse events occurred in 86% of the pembrolizumab group vs 83% of the control group and were considered treatment-related in 72% vs 68%; the most common treatment-related grade ≥ 3 events in both groups were decreased neutrophil count (23% vs 17%), neutropenia (14% vs 16%), and anemia (12% vs 15%). Adverse events led to treatment discontinuation in 24% vs 20% of patients. Fatal adverse events occurred in 8% vs 10% of patients and were considered related to treatment in 2% vs 1%.

Immune-mediated adverse events and infusion reactions of any grade occurred in 26% vs 12% of patients, with the most common in the pembrolizumab group being hypothyroidism (11% vs 7% in the control group), pneumonitis (6% vs 1%), and hyperthyroidism (6% vs 1%).

The investigators concluded, “Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced esophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with esophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomized patients regardless of histology, and had a manageable safety profile in the total as-treated population.”

Jong-Mu Sun, MD, of Samsung Medical Center, Sungkyunkwan University, Seoul, 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.