Efficacy and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-180 Study

Abstract

Importance: Effective treatment options are limited for patients with advanced, metastatic esophageal cancer progressing after 2 or more lines of systemic therapy.

Objective: To evaluate the efficacy and safety of pembrolizumab for patients with advanced, metastatic esophageal squamous cell carcinoma (ESCC) or advanced, metastatic adenocarcinoma of the esophagus and gastroesophageal junction that progressed after 2 or more lines of systemic therapy.

Design, setting, and participants: This phase 2, open-label, interventional, single-arm study, KEYNOTE-180, enrolled 121 patients from January 12, 2016, to March 21, 2017, from 57 sites in 10 countries. Patients had advanced, metastatic esophageal cancer that progressed after 2 or more lines of therapy and had evaluable tumor samples for biomarkers.

Interventions: Pembrolizumab, 200 mg, was administered intravenously every 3 weeks until disease progression, unacceptable toxic effects, or study withdrawal, for up to 2 years.

Main outcomes and measures: Primary end point was objective response rate per the Response Evaluation Criteria in Solid Tumors by central imaging review for all patients.

Results: As of September 18, 2017, of 121 enrolled patients (100 men and 21 women; median age, 65 years [range, 33-87 years]), 18 (14.9%) had undergone 3 or more prior therapies, 63 (52.1%) had ESCC, and 58 (47.9%) had tumors positive for programmed death ligand-1 (PD-L1), defined as a combined positive score of 10 or higher assessed by immunohistochemistry. Median duration of follow-up was 5.8 months (range, 0.2-18.3 months). Objective response rate was 9.9% (95% CI, 5.2%-16.7%) among all patients (12 of 121), and median duration of response was not reached (range, 1.9-14.4 months). Objective response rate was 14.3% (95% CI, 6.7%-25.4%) among patients with ESCC (9 of 63), 5.2% (95% CI, 1.1%-14.4%) among patients with adenocarcinoma (3 of 58), 13.8% (95% CI, 6.1%-25.4%) among patients with PD-L1-positive tumors (8 of 58), and 6.3% (95% CI, 1.8%-15.5%) among patients with PD-L1-negative tumors (4 of 63). Overall, 15 patients (12.4%) had treatment-related grade 3 to 5 adverse events. Only 5 patients (4.1%) discontinued treatment because of adverse events. There was 1 treatment-related death from pneumonitis.

Conclusions and relevance: Where effective treatment options are an unmet need, pembrolizumab provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer. 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.

Trial registration: ClinicalTrials.gov identifier: NCT02559687.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Shah reports receiving research funding from Stand Up 2 Cancer, Boston Biomedical, Merck, and the National Institutes of Health. Dr Kojima reports receiving research funding from Oncolys BioPharma; Ono Pharmaceutical; Merck, Sharp & Dohme (MSD); Oncolys BioPharma; Astellas; Shinogi Pharma; and Amgen BioPharma. Dr Hochhauser reported ownership of stock in Novartis and Roche and receiving reimbursement for travel and accommodations from Celgene. Dr Enzinger reported serving in consulting and advisory roles for Astellas, Beigene, Celgene, Five Prime, Lilly, and Merck. Dr Hollebecque reported receiving personal fees from Servier and Gritstone Oncology and receiving reimbursement for travel and accommodations from Amgen. Dr Lordick reported receiving grants and personal fees from Bristol Myers Squibb and receiving personal fees from Astellas, Astra Zeneca, Eli Lilly, Elsevier, Biontech GmbH, Excerpta Medica, Medscape, E-Cancer, Servier, Merck Serono, MSD, and Springer Verlag GmbH. Dr Kato reported receiving research funding from MSD, Ono Pharmaceuticals, Shionogi, and Merck Serono. Dr Liu, Dr Lunceford, Dr Kang, and Dr Bhagia are employees of MSD and hold stock in MSD. No other disclosures were reported.

Figures

Figure.. Enrollment and Disposition of the KEYNOTE-180 Study

Eligible patients were 18 years or older; had histologically confirmed advanced and metastatic adenocarcinoma, squamous cell carcinoma of the esophagus, or advanced and metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction; and had disease progression after at least 2 prior lines of therapy. aA total of 31 patients in the study are being followed up.