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Original Investigation
April 30, 2020

A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer

Author Affiliations
  • 1Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida
  • 2Department of Medical Oncology and Therapeutics Research, City of Hope, Duarte, California
  • 3Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
  • 4Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, Florida
  • 5Department of Oncology, Mayo Clinic, Rochester, Minnesota
  • 6Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, Florida
  • 7Department of Pathology, Korea University Guro Hospital, Seoul, Korea
JAMA Oncol. Published online April 30, 2020. doi:10.1001/jamaoncol.2020.0930
Key Points

Question  What is the clinical activity of nivolumab in patients with advanced refractory biliary tract cancer?

Findings  In this multicenter phase 2 study of 54 patients with advanced refractory biliary tract cancer, 10 patients achieved an objective response with a disease control rate of 59% by investigator assessment. Five patients experienced an objective response with a disease control rate of 50% by blinded central independent radiologic review.

Meaning  Further exploration of nivolumab is warranted for patients with advanced refractory biliary tract cancer.


Importance  Currently, there is no established second-line systemic treatment for biliary tract cancer (BTC). Preclinical data have demonstrated that the presence of tumor-infiltrating CD8 T cells and programmed cell death 1 ligand 1–expressing tumor cells in the tumor microenvironment of BTC supports the rationale of using programmed cell death 1 protein blockade immunotherapy in BTC.

Objective  To evaluate anticancer activity of nivolumab in patients with advanced refractory BTC.

Design, Setting, and Participants  In this single-group, multicenter phase 2 study of nivolumab, 54 patients with histologically confirmed BTC whose disease progressed while undergoing treatment with at least 1 line but no more than 3 lines of systemic therapy were enrolled between October 5, 2016, and December 26, 2018. Analysis was performed on an intention-to-treat basis.

Interventions  Nivolumab, 240 mg, was delivered intravenously every 2 weeks for 16 weeks, and then 480 mg was delivered intravenously every 4 weeks until disease progression or unacceptable toxic effects occurred.

Main Outcomes and Measures  The primary end point was investigator-assessed objective response rate, and the secondary end points were progression-free survival, overall survival, and incidence of adverse events.

Results  A total of 54 patients (27 men and 27 women; median age, 65 years [range, 28-86 years]) enrolled, and 46 (22 men and 24 women; median age, 65 years [range, 28-86 years]) were examined for objective response with radiologic imaging. The investigator-assessed objective response rate was 22% (10 of 46), including 1 unconfirmed partial response, with a disease control rate of 59% (27 of 46). Central independent review found an objective response rate of 11% (5 of 46), including 1 unconfirmed partial response, with a disease control rate of 50% (23 of 46). All patients who responded to treated (hereafter referred to as responders) had mismatch repair protein–proficient tumors. The median duration of investigator-assessed response was not reached, with a median follow-up of 12.4 months. Among the intention-to-treat population, median progression-free survival was 3.68 months (95% CI, 2.30-5.69 months) and median overall survival was 14.24 months (95% CI, 5.98 months to not reached). Programmed cell death 1 ligand 1 expression in tumors was associated with prolonged progression-free survival (hazard ratio, 0.23; 95% CI, 0.10-0.51; P < .001). The most common treatment-related grade 3 or 4 toxic effects were hyponatremia (3 of 54 [6%]) and increased alkaline phosphatase (2 of 54 [4%]).

Conclusions and Relevance  This study found that nivolumab was well tolerated and showed modest efficacy with durable response in patients with refractory BTC. Further studies are warranted to verify the findings and evaluate biomarkers for improved treatment selection for patients.

Trial Registration  ClinicalTrials.gov Identifier: NCT02829918

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