Oliver Klein, MD1,2; Damien Kee, MD1,3; Adnan Nagrial, MD4; etalBen Markman, MD5,6; Craig Underhill, MD7; Michael Michael, MD3; Louise Jackett, MD8; Caroline Lum, MD5; Andreas Behren, PhD2,9; Jodie Palmer, PhD2,9; Niall C. Tebbutt, MD1,10; Matteo S. Carlino, PhD4; Jonathan Cebon, PhD1,2,9
Author Affiliations
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.
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
