As reported in the Journal of Clinical Oncology by Takashi Kojima, MD, of the National Cancer Center Hospital East, Kashiwa, Japan, and colleagues, the phase III KEYNOTE-181 trial has shown that second-line pembrolizumab improved overall survival vs the investigator choice of chemotherapy in patients with advanced/metastatic esophageal cancer with PD-L1 combined positive score (CPS) ≥ 10.1
Takashi Kojima, MD
The study supported, along with KEYNOTE-180, the July 2019 approval of pembrolizumab for 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.
In the open-label trial, 682 patients from sites in 32 countries with advanced/metastatic squamous cell carcinoma or adenocarcinoma of the esophagus that had progressed after one prior therapy were randomly assigned between December2015 and June 2017 to pembrolizumab at 200 mg every 3 weeks for up to 2 years (n = 314) or the 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.
At data cutoff in October 2018, median follow-up from random assignment to first of 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 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.
Two patient fatalities were not included in the original data analysis due to a data reporting inconsistency. A subsequent updated overall survival analysis was performed at the October 2018 cutoff date to include these events. In addition, an overall survival analysis was performed with 4 months of additional follow-up (data cutoff in February 2019). The updated analysis showed a hazard ratio of 0.70 (95% CI = 0.52–0.94, P = .00855) in the population with PD-L1 CPS ≥ 10, which did not meet the prespecified boundary for showing superiority (P < .00853). After an additional 4 months of follow-up, the hazard ratio was 0.67 (95% CI = 0.50–0.89).
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%. After the additional 4-month follow-up, the hazard ratio was 0.75 (95% CI = 0.61–0.93).
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%. After the additional 4-month follow-up, the hazard ratio was 0.85 (95% CI = 0.72–1.01).
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-–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 the benefit of 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.
Treatment-related adverse events of any grade occurred in 64% of the pembrolizumab group vs 86% of the chemotherapy group, with patients 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 in the pembrolizumab group included asthenia (1.3%) and anemia (1.3%). The most common 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%).
There were five treatment-related deaths in each group (1.6% vs 1.7%). Causes in the pembrolizumab group were myocarditis, death, and decreased white blood cell count in one patient each and pneumonitis in two patients. Causes in the chemotherapy group were pneumonia, pneumonia aspiration, sepsis, decreased neutrophil count, and hemorrhagic shock in one patient each Immune-mediated adverse events and infusion reactions of any grade 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.”
DISCLOSURE: The study was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co. Dr. Kojima has received honoraria from Oncolys BioPharma and Ono Pharmaceutical; has served in a consulting or advosry role for Astellas Pharma, BMS, Merck, MSD, and Ono Pharmaceutical; and has received institutional research funding from Astellas Amgen BioPharma, MSD, Ono Pharmaceutical, Shionogi, and Taiho Pharmaceutical.