Manish A. Shah
Pembrolizumab induced durable antitumor activity among patients with advanced, metastatic esophageal cancer whose disease progressed after two or more lines of treatment, according to results of the open-label, phase 2 KEYNOTE-180 study published in JAMA Oncology.
“In the first- and second- line setting, conventional chemotherapy is largely palliative, with limited evidence of durable benefit,” Manish A. Shah, MD, medical oncologist in the division of hematology and medical oncology in the department of medicine at Weill Cornell Medicine and NewYork-Presbyterian Hospital, and colleagues wrote. “Few patients whose disease progresses after two or more lines of therapy receive treatment, and there is a lack of clinical data in this setting.”
The study included 121 patients (median age, 65 years; range 33-87; men, n = 100) from 57 sites in 10 countries. Among the patients, 18 (14.9%) underwent three or more prior therapies, 63 (52.1%) had esophageal squamous cell carcinoma, and 58 (47.9%) had tumors positive for programmed death ligand-1 (PD-L1).
All patients received 200 mg of pembrolizumab (Keytruda, Merck) every 3 weeks for up to 2 years until disease progression, unacceptable adverse events or withdrawal of consent. Median duration of treatment was 2 months (range, 0.03-17 months) with a median of four treatments (range 1-26).
Objective response rate — assessed per Response Evaluation Criteria in Solid Tumors version 1.1 by central review every 9 weeks — served as the primary endpoint. Secondary endpoints included duration of response, PFS and OS.
Median follow-up was 5.8 months (range, 0.2-18.3).
Results showed an ORR of 9.9% (95% CI, 5.2-16.7), with 12 patients demonstrating a partial response. They included nine of 63 patients (14.3%; 95% CI, 6.7-25.4) with esophageal squamous cell carcinoma and three of 58 patients (5.2%; 95% CI, 1.1-14.4) with adenocarcinoma.
Researchers observed an ORR of 13.8% (95% CI, 6.1-25.4) among patients with PD-L1-positive tumors vs. 6.3% (95% CI, 1.8-15.5) among those with PD-L1 negative tumors.
Median duration of response among the 12 responders was not reached (range, 1.9-14.4 months). Researchers estimated that four patients had responses lasting 6 months or longer.
Median PFS was 2 months (95% CI, 1.9-2.1), with a 6-month PFS rate of 16% (95% CI, 10-23) and 9-month PFS rate of 9% (95% CI, 5-16).
Researchers reported median OS of 5.8 months (95% CI, 4.5-7.2), with a 6-month OS rate of 49% (95% CI, 40-57) and 12-month OS rate of 28% (95% CI, 20-37).
PFS was similar among all the subgroups, whereas OS appeared higher among patients who had esophageal squamous cell carcinoma and PD-L1-positive tumors.
Treatment-related adverse events occurred in 70 patients (57.9%) and included fatigue (10.7%), rash (7.4%), pruritus (6.6%), hypothyroidism (5.8%) and diarrhea (5%). Fifteen patients (12.4%) experienced grade 3 to grade 5 adverse events.
Immune-related adverse events among 25 patients (20.7%) included hypothyroidism (7.4%) and pneumonitis (7.4%).
Five patients discontinued treatment due to adverse events. One patient died of pneumonitis attributable to treatment.
Limitations to the study included the fact that it was not a randomized trial.
“Where effective treatment options are an unmet need, pembrolizumab provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer,” Shah and colleagues wrote. “Phase 3 studies evaluating pembrolizumab vs. standard therapy for patients with esophageal cancer progressing after first-line therapy or in combination with chemotherapy as first-line therapy for patients with locally advanced unresectable or metastatic esophageal cancer are ongoing.”– by John DeRosier
Disclosures: Merck funded the study. Shah reports research funding from Boston Biomedical, Merck, the NIH and Stand Up To Cancer. Please see the study for all other authors’ relevant financial disclosures.