As reported in the Journal of Clinical Oncology by Takashi Kojima, MD, and colleagues, the phase III KEYNOTE-181 trial has shown that second-line pembrolizumab improved overall survival vs investigator’s choice of chemotherapy in patients with advanced or metastatic esophageal cancer with a PD-L1 combined positive score (CPS) of ≥10.
The study supported, along with KEYNOTE-180, the July 2019 U.S. Food and Drug Administration approval of pembrolizumab for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 CPS ≥ 10 with disease progression after one or more prior lines of systemic therapy.
Takashi Kojima, MD
Study Details
The open-label trial included 682 patients from sites in 32 countries with advanced or metastatic squamous cell carcinoma or adenocarcinoma of the esophagus that had progressed after one prior therapy. Patients were randomly assigned between December 2015 and June 2017 to pembrolizumab at 200 mg every 3 weeks for up to 2 years (n = 314) or investigator’s choice of chemotherapy with paclitaxel, docetaxel, or irinotecan (n = 314).
The primary endpoints were overall survival in patients with PD-L1 CPS ≥ 10, in patients with squamous cell carcinoma, and in all patients. For the pembrolizumab vs chemotherapy groups, 34% vs 37% had PD-L1 CPS ≥ 10, and 63% vs 65% had squamous cell carcinoma.
Overall Survival
At data cutoff in October 2018, median follow-up from random assignment to first data cutoff or death was 7.1 months (range = 0.5–31.3 months) in the pembrolizumab group and 6.9 months (range = 0.2–32.2 months) in the chemotherapy group.
At final analysis, conducted 16 months after the last patient was randomly assigned, median overall survival was 9.3 months (95% confidence interval [CI] =6.6–12.5 months) in the pembrolizumab group vs 6.7 months (95% CI = 5.1–8.2 months) in patients in the chemotherapy group with PD-L1 CPS ≥ 10 (hazard ratio [HR] = 0.69, 95% CI = 0.52–0.93; P = .0074, with the difference meeting the prespecified superiority boundary [P < .00853]). Overall survival rates at 12 months were 43% vs 20%.
Hazard ratios were 0.64 (95% CI = 0.46–0.90) among 167 patients with squamous histology and 0.93 (95% CI = 0.52–1.65) among 55 with adenocarcinoma. Hazard ratios were 0.59 (95% CI = 0.39–0.90) among 115 patients from Asia and 0.83 (95% CI = 0.55–1.25) among 107 patients from regions other than Asia.
Among patients with squamous cell carcinoma, median overall survival was 8.2 months (95% CI = 6.7–10.3 months) in the pembrolizumab group vs 7.1 months (95% CI = 6.1–8.2 months) in the chemotherapy group (HR = 0.78, 95% CI = 0.63–0.96; P = .0095), with the difference not meeting the prespecified boundary for significance (P < .0077). The 12-month overall survival rates were 39.4% vs 24.9%.
Among all patients, median overall survival was 7.1 months (95% CI = 6.2–8.1 months) in the pembrolizumab group vs 7.1 months (95% CI = 6.3–8.0 months) in the chemotherapy group (HR = 0.89, 95% CI = 0.75–1.05; P = .0560). Overall survival rates at 12 months were 32.4% vs 24.2%.
In patients with PD-L1 CPS ≥ 10, median progression-free survival was 2.6 months vs 3.0 months (HR = 0.73, 95% CI = 0.54–0.97), with 12-month rates of 20.8% vs 6.7%. Median progression-free survival was 2.2 months vs 3.1 months in patients with squamous cell carcinoma (HR = 0.92, 95% CI = 0.75–1.13) and 2.1 months vs 3.4 months among all patients (HR = 1.11, 95% CI = 0.94–1.31).
Objective response rates were 21.5% vs 6.1% among patients with PD-L1 CPS ≥ 10, with median response durations of 9.3 months (range = 2.11–22.61 months) in the pembrolizumab group and 7.7 months (range = 4.3–16.81 months) in the chemotherapy group, with benefit in the pembrolizumab group observed regardless of histology. Objective response rates were 16.7% vs 7.4% among patients with squamous cell carcinoma and 13.1% vs 6.7% among all patients.
Adverse Events
Treatment-related adverse events of any grade occurred in 64% of patients in the pembrolizumab group vs 86% of patients in the chemotherapy group, with those in the chemotherapy group experiencing more fatigue, diarrhea, and hematologic toxicities. Grade ≥ 3 treatment-related adverse events occurred in 18% vs 41%.
The most common events in the pembrolizumab group included asthenia (1.3%) and anemia (1.3%). The most common events in the chemotherapy group included decreased white blood cell count (10%), decreased neutrophils (10%), and anemia (8%).
Treatment-related adverse events led to discontinuation of treatment in 19 patients in each group (6.1% vs 6.4%) and to death in 5 patients in each group (1.6% vs 1.7%). Immune-mediated adverse events and infusion reactions occurred in 23% of the pembrolizumab group vs 7% of the chemotherapy group.
The investigators concluded, “Pembrolizumab prolonged overall survival vs chemotherapy as second-line therapy for advanced esophageal cancer in patients with PD-L1 CPS ≥ 10, with fewer treatment-related adverse events.”
Toshihiko Doi, MD, PhD, of the National Cancer Center Hospital East, Kashiwashi, Chiba, Japan, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit ascopubs.org.
