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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Klein reports speaker fees from Bristol-Myers Squibb and MSD, travel support and personal fees from Bristol-Myers Squibb, personal fees from MSD Australia outside the submitted work, and grants from the Federal Department of Health Australia during the conduct of the study; Dr Kee reports honoraria/advisory board fees and personal fees from Novartis and travel and other support from Bristol-Myers Squibb outside the submitted work; Dr Nagrial reports personal fees from Bristol-Myers Squibb, MSD, Roche, and AstraZeneca outside the submitted work. Dr Markman reports honoraria/advisory board fees from Novartis and Amgen and nonfinancial support from Akesobio outside the submitted work; Dr Underhill reports grants from Border Medical Oncology Research Unit during the conduct of the study; Dr Palmer reports support from the Olivia Newton-John Cancer Research Institute during the conduct of the study; Dr Tebbutt reports personal fees from Bristol-Myers Squibb outside the submitted work; Dr Carlino reports personal fees from Bristol-Myers Squibb, MSD, personal Novartis, Amgen, Pierre Fabre, Merck Serono, Sanofi, Ideaya, Nektar, and Eisai and honoraria/advisory board fees from Bristol-Myers Squibb, Amgen, Novartis, MSD, Roche, Pierre Fabre, Ideaya, Sanofi, Merck, and Nektar outside the submitted work. Dr Cebon reported grants from Bristol-Myers Squibb during the conduct of the study and honoraria/advisory board fees from Bristol-Myers Squibb, Amgen, Novartis, and MSD outside the submitted work. No other disclosures are reported.

Figures

Figure.. Kaplan-Meier Curve of Overall Survival and Progression Free Survival for the Entire Cohort (A, B) and Previously Treated Patients (C, D)