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Brief Report
December 20, 2018

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

Author Affiliations
  • 1Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York
  • 2Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
  • 3Department of Oncology, University College London Hospitals National Health Service Foundation Trust, London, United Kingdom
  • 4Center for Esophageal and Gastric Cancer, Dana Farber Cancer Institute, Boston, Massachusetts
  • 5Department of Medical Oncology, Institut de Cancérologie de l’Ouest, St Herblain, Nantes, France
  • 6Department of Adult Medicine, Institut Gustave Roussy, Villejuif, France
  • 7Department of Oncology, Hematology, and Hemostaseology, University Cancer Center Leipzig, Leipzig, Germany
  • 8Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
  • 9Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan
  • 10Lung Cancer Branch, National Cancer Center, Goyang, South Korea
  • 11Department of Medical Oncology, Washington University School of Medicine in St Louis, St Louis, Missouri
  • 12Drug Development Program, Sarah Cannon Research Institute, University College, London, United Kingdom
  • 13Department of General Cancer, Centre Oscar-Lambret, Lille, France
  • 14Department of Medical Oncology and Hematology, Sansum Clinic, Santa Barbara, California
  • 15Department of Oncology, Odense University Hospital, Odense, Denmark
  • 16Clinical Research, Merck & Co Inc, Kenilworth, New Jersey
  • 17Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
JAMA Oncol. Published online December 20, 2018. doi:10.1001/jamaoncol.2018.5441
Key Points

Question  Is pembrolizumab effective and safe for patients with advanced, metastatic esophageal cancer that has progressed after 2 or more lines of systemic therapy?

Findings  Among 121 heavily pretreated patients with advanced, metastatic esophageal cancer enrolled in the phase 2 KEYNOTE-180 study, patients treated with pembrolizumab had an objective response rate of 9.9%, with partial responses observed in 12 patients per the Response Evaluation Criteria in Solid Tumors, version 1.1, by central imaging review. The safety profile was manageable and similar to that seen previously with pembrolizumab.

Meaning  These data suggest that pembrolizumab has modest activity in patients with heavily pretreated, metastatic esophageal cancer.


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