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Original Investigation
July 30, 2020

Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial

Author Affiliations
  • 1Department of Medical Oncology, Austin Health, Melbourne, Australia
  • 2Olivia Newton-John Cancer Research Institute, Melbourne, Australia
  • 3Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
  • 4Blacktown Hospital and the University of Sydney, Sydney, Australia
  • 5Department of Medical Oncology, Monash Health, Melbourne, Australia
  • 6Monash University, Melbourne, Australia
  • 7Albury-Wodonga Regional Cancer Centre, Albury-Wodonga, Australia
  • 8Department of Anatomical Pathology, Austin Health, Melbourne, Australia
  • 9School of Cancer Medicine, La Trobe University, Australia
  • 10Department of Surgery, University of Melbourne, Melbourne, Australia
JAMA Oncol. Published online July 30, 2020. doi:10.1001/jamaoncol.2020.2814
Key Points

Question  Is combination immunotherapy with nivolumab and ipilimumab associated with positive outcomes in patients with advanced biliary tract cancers?

Findings  In this subgroup analysis of a phase 2 nonrandomized clinical trial of 39 patients with advanced biliary tract cancers, 33 of whom had undergone previous systemic therapy, an objective response rate of 23% and a disease control rate of 44% was observed. Most of the responses were durable and limited to patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma.

Meaning  These data indicate that nivolumab and ipilimumab combination treatment has significant activity in a subset of patients with advanced biliary tract cancers.


Importance  Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies.

Objective  To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers.

Design, Setting, and Participants  The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research.

Interventions  Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events.

Main Outcomes and Measures  The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1.

Results  Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events.

Conclusions and Relevance  This subgroup analysis of a phase 2 clinical trial found that combination immunotherapy with nivolumab and ipilimumab was associated with substantial positive outcomes patients with advanced biliary tract cancers. This treatment compares favorably to single-agent anti–programmed cell death protein 1 (anti–PD-1) therapy and warrants further investigation. Ongoing translational research is focused on identifying biomarkers that can predict treatment response.

Trial Registration  ClinicalTrials.gov Identifier: NCT02923934

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