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

Manish A. Shah, Takashi Kojima, Daniel Hochhauser, Peter Enzinger, Judith Raimbourg, Antoine Hollebecque, Florian Lordick, Sung Bae Kim, Masahiro Tajika, Heung Tae Kim, Albert Lockhart, Hendrik Tobias Arkenau, Farid El-Hajbi, Mukul Gupta, Per Pfeiffer, Qi Liu, Jared Lunceford, S. Peter Kang, Pooja Bhagia, Ken Kato

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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.

Original languageEnglish (US)
JournalJAMA oncology
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Shah, M. A., Kojima, T., Hochhauser, D., Enzinger, P., Raimbourg, J., Hollebecque, A., Lordick, F., Kim, S. B., Tajika, M., Kim, H. T., Lockhart, A., Arkenau, H. T., El-Hajbi, F., Gupta, M., Pfeiffer, P., Liu, Q., Lunceford, J., Kang, S. P., Bhagia, P., & Kato, K. (Accepted/In press). 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. JAMA oncology. https://doi.org/10.1001/jamaoncol.2018.5441