SAN FRANCISCO—Pembrolizumab significantly improves overall survival (OS) compared with chemotherapy as second-line therapy for advanced esophageal cancer patients who are likely to respond to the immunotherapy, with a more favorable safety profile.
Advanced or metastatic esophageal cancer remains among the most common cancers worldwide, and patients with advanced esophageal cancer after first-line chemotherapy experience a poor prognosis and limited treatment options.
“For those who experience disease progression, there is no established standard of care, underscoring the need for improved therapies in the second-line setting,” said lead author Takashi Kojima, MD, Professor at the Department of Gastroenterology and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, at the 209 Gastrointestinal Cancers Symposium.
Kojima presented the results (Abstract 2) of the open-label, randomized, phase III KEYNOTE-181 study of pembrolizumab versus investigator's choice chemotherapy as second-line therapy for 628 patients with advanced/metastatic squamous cell carcinoma and adenocarcinoma of the esophagus or Siewert type I adenocarcinoma of the esophago-gastric junction.
Patients were randomized to pembrolizumab 200 mg every 3 weeks for up to 2 years or investigator's choice chemotherapy of paclitaxel, docetaxel, or irinotecan. Intravenous chemotherapy consisted of docetaxel at 75 mg/m2 on day 1 of each 21-day cycle; paclitaxel at 80 mg to 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle; or irinotecan at 80 mg/m2 on day 1 of each 14-day cycle.
Randomization was stratified by histology and region (Asia vs. rest of world). Some 401 patients had squamous cell carcinoma and 222 patients had a PD-L1 combined positive score (CPS) of 10 or greater. CPS is a robust, reproducible PD-L1 scoring method that predicts response to pembrolizumab.
At a median follow-up of 7.1 months for pembrolizumab and 6.9 months for chemotherapy, patients with PD-L1–positive tumors had median OS of 9.3 months with pembrolizumab as compared with 6.7 months with chemotherapy. The 1-year OS rate for pembrolizumab was 43 percent and for chemotherapy was 20 percent.
For patients with squamous cell carcinoma, the results show a clinically meaningful improvement in median OS with pembrolizumab (8.2 months) as compared with chemotherapy (7.1 months), but this difference was not statistically significant per a pre-specified statistical plan. In the overall intention-to-treat population, there was no difference in OS in both treatment arms, with a median OS of 7.1 months.
For the first time, a study has shown that a PD-1 inhibitor demonstrates an improvement in survival for this patient population. “The significant improvement in OS observed with pembrolizumab in patients with squamous cell carcinoma or adenocarcinoma whose tumors expressed PD-L1 with a CPS of 10 or greater represents an important scientific advancement and has the potential to benefit patients who currently have limited treatment options,” said Kojima.
The safety profile of pembrolizumab was consistent with what has been reported in prior trials, he said. Treatment-related adverse events occurred in 64.3 percent of pembrolizumab patients as compared with 86.1 percent for chemotherapy patients. With pembrolizumab, the most common treatment-related adverse events were fatigue (11.8%), hypothyroidism (10.5%), decreased appetite (8.6%), asthenia (7.0%), nausea (7.0%), and diarrhea (5.4%). Grade 3-5 treatment-related adverse events occurred in 57 patients (18.2%) who received pembrolizumab as compared with 121 patients (40.9%) on chemotherapy. Five treatment-related deaths occurred in each group.
In conclusion, Kojima noted: “These data support pembrolizumab as a new second-line standard of care for esophageal cancer with PD-L1 CPS of 10 or greater.” He stated that the phase III KEYNOTE-590 study of pembrolizumab plus chemotherapy as first-line therapy for advanced esophageal cancer is ongoing.
The results suggest that pembrolizumab may not be indicated in unselected patients in this setting, but that patients with higher PD-L1 expression can benefit.
Mark L. Fuerst is a contributing writer.