A Phase II multi institutional study of nivolumab in patients with advanced refractory biliary tract cancers (BTC)

Abstract

Introduction: Biliary tract cancers (BTC) typically include intra and extrahepatic cholangiocarcinoma and cancers of the gallbladder. There is no established second line option for patients with advanced BTC who have failed one prior systemic therapy. There are pre-clinical and small series of clinical data which supports the usage of immune modulatory agents in BTC. Therefore we propose to evaluate the anti-PD1 agent nivolumab in advanced, refractory BTC. Methods: Pts with histologically proven BTC who progressed on at least one line of systemic therapy received nivolumab 240mg IV q2weeks for 16 weeks and then 480 mg IV every 4 weeks until disease progression or unacceptable toxicity The Simon two staged design was used to assess objective response rate (ORR) by RECIST 1.1 every 8 weeks as a primary endpoint. In the first stage, 18 patients were accrued and if one response was seen, the plan was to accrue additional 14 patients for total of 32 patients. Secondary endpoints were PFS, OS and safety profile. Results: Median age was 64.5 (range: 28-86) years and the primary sites of tumor were intrahepatic cholangiocarcinoma 64.7%, extrahepatic 2.9%, and gallbladder 32.4%. 17 (50.0%) of the patients were female. Twenty pts (59%) failed 1 line of therapy and 14 pts (41%) failed more than one line of therapy. Thirty-four pts received at least 1 dose of nivolumab of whom 29 pts (1 pt withdrew consent and 4 pts came off the study due to clinical progression) were evaluable for response rate. Out of 29 pts, 5 pts (17%) achieved PR and 11 pts (38%) achieved SD. DCR was 55%. Four patients who responded were all microsatellite stable and still remain on treatment (2 pts have durations of response > 12 months). For all 34 pts with median follow up of 8 months, median PFS was 3.5 months (95% CI: 2.1-7.6) and the median OS has not been reached. 6-month OS was 76.3%. Most common treatment related AEs(TRAE) were fatigue (23.5%) and elevated AST and ALT (15% and 11%). Grade III TRAEs were seen in 7pts (21%); most common were elevated bilirubin (3%) and elevated alkaline phosphatase (6%). There were no grade IV or V toxicities reported. Tissue samples were collected in all pts with planned correlative studies underway. Conclusion: The primary endpoint of ORR was met. Nivolumab was well tolerated and has shown promising efficacy in refractory BTC including durable responses lasting over 1 year. Further randomized trial is warranted in refractory BTC.