As reported in JAMA Oncology by Kohei Shitara, MD, and colleagues, the phase III KEYNOTE-062 trial showed no significant improvement in overall or progression-free survival with first-line pembrolizumab with or without chemotherapy vs chemotherapy alone in patients with PD-L1–positive advanced gastric/gastroesophageal junction cancer. Pembrolizumab alone was noninferior to chemotherapy for overall survival.

Kohei Shitara, MD

Study Details

The partially blinded trial included 763 patients with locally advanced/unresectable or metastatic gastric/gastroesophageal junction cancer with a PD-L1 combined positive score (CPS) ≥ 1 from 200 sites in 29 countries. Patients were randomly assigned 1:1:1 between September 2015 and May 2017 to receive 3-week cycles of pembrolizumab at 200 mg (n = 256); pembrolizumab plus chemotherapy with cisplatin at 80 mg/m²/d on day 1 plus fluorouracil at 800 mg/m²/d on days 1 to 5 or capecitabine at 1,000 mg/m² twice daily (n = 257); or chemotherapy plus placebo (n = 250). The primary endpoints were overall survival and progression-free survival in patients with a PD-L1 CPS ≥ 1 or ≥ 10.

Key Findings

At final analysis, median follow-up was 29.4 months (range = 22.0–41.3 months).

Pembrolizumab alone was noninferior to chemotherapy for overall survival in patients with a CPS of 1 or greater (median = 10.6 vs 11.1 months; hazard ratio [HR] = 0.91, 99.2% confidence interval [CI] = 0.69–1.18, with noninferiority margin of 1.2 for upper boundary). Pembrolizumab was not superior to chemotherapy in this comparison (HR = 0.91, 95% CI = 0.74–1.10).

Median overall survival among patients with a CPS ≥ 10 was 17.4 months with pembrolizumab monotherapy vs 10.8 months with chemotherapy (HR = 0.69, 95% CI = 0.49–0.97), but this difference was not statistically tested due to hierarchical testing criteria.

Median overall survival was 12.5 months with pembrolizumab plus chemotherapy vs 11.1 months with chemotherapy (HR = 0.85, 95% CI = 0.70–1.03; P = .05) among patients with a CPS ≥ 1 and 12.3 months vs 10.8 months (HR = 0.85, 95% CI = 0.62–1.17; P = .16) among those with a CPS ≥ 10.

Median progression-free survival was 2.0 months with pembrolizumab alone vs 6.4 months with chemotherapy (HR = 1.66, 95% CI = 1.37–2.01) among patients with a CPS ≥ 1 and 2.9 vs 6.1 months (HR = 1.10, 95% CI = 0.79–1.51) among those with a CPS ≥ 10. Median progression-free survival was 6.9 months with pembrolizumab plus chemotherapy in patients with CPS ≥ 1 (HR = 0.84, 95% CI = 0.70–1.02; P = .04), but the difference did not meet criteria for superiority.

Adverse Events

Drug-related adverse events of any grade occurred in 54.3% of patients in the pembrolizumab monotherapy group, 94.0% of those in the pembrolizumab plus chemotherapy group, and 91.8% of those in the chemotherapy group, and were grade ≥ 3 in 16.9%, 73.2%, and 69.3%, respectively. Drug-related adverse events resulted in discontinuation of treatment in 3.9%, 27.6%, and 18.0%, respectively. Drug-related grade ≥ 3 immune-mediated adverse events occurred in 5.9%, 5.6%, and 1.6%. Death due to drug-related adverse events occurred in 1.2%, 2.0%, and 1.2% of patients.

The investigators concluded, “This phase III randomized clinical trial found that among patients with untreated, advanced gastric/gastroesophageal junction cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the overall survival and progression-free survival endpoints tested.”

Josep Tabernero, MD, PhD, MSc, of the Medical Oncology Department, Vall d’Hebron University Hospital and Institute of Oncology, Barcelona, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co. For full disclosures of the study authors, visit jamanetwork.com.