Manish A Shah1, Takashi Kojima2, Daniel Hochhauser3, Peter Enzinger4, Judith Raimbourg5, Antoine Hollebecque6, Florian Lordick7, Sung-Bae Kim8, Masahiro Tajika9, Heung Tae Kim10, A Craig Lockhart11, Hendrik-Tobias Arkenau12, Farid El-Hajbi13, Mukul Gupta14, Per Pfeiffer15, Qi Liu16, Jared Lunceford16, S Peter Kang16, Pooja Bhagia16, Ken Kato17. 1. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York. 2. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. 3. Department of Oncology, University College London Hospitals National Health Service Foundation Trust, London, United Kingdom. 4. Center for Esophageal and Gastric Cancer, Dana Farber Cancer Institute, Boston, Massachusetts. 5. Department of Medical Oncology, Institut de Cancérologie de l'Ouest, St Herblain, Nantes, France. 6. Department of Adult Medicine, Institut Gustave Roussy, Villejuif, France. 7. Department of Oncology, Hematology, and Hemostaseology, University Cancer Center Leipzig, Leipzig, Germany. 8. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 9. Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, Japan. 10. Lung Cancer Branch, National Cancer Center, Goyang, South Korea. 11. Department of Medical Oncology, Washington University School of Medicine in St Louis, St Louis, Missouri. 12. Drug Development Program, Sarah Cannon Research Institute, University College, London, United Kingdom. 13. Department of General Cancer, Centre Oscar-Lambret, Lille, France. 14. Department of Medical Oncology and Hematology, Sansum Clinic, Santa Barbara, California. 15. Department of Oncology, Odense University Hospital, Odense, Denmark. 16. Clinical Research, Merck & Co Inc, Kenilworth, New Jersey. 17. Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
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.
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.
Authors: Pier Luigi Zinzani; Vincent Ribrag; Craig H Moskowitz; Jean-Marie Michot; John Kuruvilla; Arun Balakumaran; Yayan Zhang; Sabine Chlosta; Margaret A Shipp; Philippe Armand Journal: Blood Date: 2017-05-10 Impact factor: 22.113
Authors: Lindsey A Torre; Freddie Bray; Rebecca L Siegel; Jacques Ferlay; Joannie Lortet-Tieulent; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2015-02-04 Impact factor: 508.702
Authors: Peter C Enzinger; Barbara Ann Burtness; Donna Niedzwiecki; Xing Ye; Kathe Douglas; David H Ilson; Victoria Meucci Villaflor; Steven J Cohen; Robert J Mayer; Alan Venook; Al Bowen Benson; Richard M Goldberg Journal: J Clin Oncol Date: 2016-07-05 Impact factor: 44.544