Randomized phase 2 study of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy in pretreated patients with metastatic biliary tract cancer.

545 Background: The treatment options for patients with biliary tract cancer (BTC) are limited. The aim of this study was to evaluate the clinical benefit of nivolumab with or without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with BTC. Methods: In this phase 2 study with a Simon’s 2-stage optimal design, patients with BTC refractory to at least one line of prior chemotherapy were randomized 1:1 to receive SBRT of 15 Gy combined with nivolumab or nivolumab/ipilimumab stratified by performance status. Signed informed consent was obtained from all patients. The primary endpoint was clinical benefit rate (CBR) defined as the proportion of patients with stable disease, partial response (PR), or complete response according to RECIST 1.1. Decision on expansion independently for both arms was pending on CBR from the first stage. Secondary endpoints included overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Between September 2018 and January 2022, 61 patients (19 SBRT/nivolumab and 42 SBRT/nivolumab/ipilimumab) received at least one treatment. Forty-eight patients (79%) had cholangiocarcinoma (intrahepatic 41, perihilar 2, distal 4, unspecified 1) and 13 patients (21%) had gallbladder cancer. No responses were observed in SBRT/nivolumab arm and this cohort was closed for inclusion after first stage based on CBR of 11% (95% confidence interval (CI) 1-33). SBRT/nivolumab/ipilimumab resulted in CBR of 31% (95% CI 18-47) and an overall response rate of 11.9% (95% CI 4.0-25.6). Of the five patients that achieved a PR, the median duration of response was 4.4 months (95% CI 0.0-9.2). A median PFS of 1.7 months (95% CI 1.6-1.7) and 1.7 months (95% CI 1.6-1.8), and a median OS of 4.7 months (95% CI 3.2-6.2) and 5.0 months (95% CI 2.1-7.9) were observed for patients receiving SBRT/nivolumab and SBRT/nivolumab/ipilimumab, respectively. Treatment-related adverse events grade 3 or higher occurred in 3 (16%) patients in the SBRT/nivolumab arm and 13 (31%) patients in the SBRT/nivolumab/ipilimumab arm. One patient died due to hepatitis in the combination arm. Conclusions: The combination of SBRT/nivolumab/ipilimumab demonstrated anti-tumor activity and acceptable toxicities in patients with advanced BTC. Further studies are warranted. Clinical trial information: NCT02866383 .