Impaired chromatin remodeling predicts better survival to modified gemcitabine and S-1 plus nivolumab in advanced biliary tract Cancer: A phase II T1219 study

[[abstract]]PURPOSE: Modified Gemcitabine and S-1 is an active regimen for patients with advanced biliary tract cancer (ABTC) in our previous study. Herein, we report the results of a single-arm phase II of Nivolumab plus modified GS (NGS) as first-line treatment in ABTC. PATIENTS AND METHODS: Patients received Nivolumab 240 mg and 800 mg/m2 Gemcitabine on day 1 plus daily 80/100/120 mg of S-1 (based on body surface area) on days 1-10, in a 2-week cycle. The primary endpoint was the objective response rate (ORR). The correlation between therapeutic efficacy and genetic alterations with signatures identified by targeted next-generation sequencing panels was explored. RESULTS: Between December 2019 and December 2020, 48 eligible patients were enrolled. After a median of 17.6 months of follow-up, the ORR was 45.9% (95% confidence interval [CI], 31.4%-60.8%). The median progression-free survival (PFS) and overall survival (OS) was 9.1 (95% CI, 5.8-9.6) and 19.2 (95% CI, 11.6-not reached) months, respectively. All grade 3/4 treatment-related adverse events (AEs) were less than 10%, except fatigue (14.6%) and skin rash (10.4%). Eighteen patients (35.4%) experienced immune-related AEs without treatment-related death. TMB-H (top 20%; ≥7.1 mut/Mb) only predicted prolonged median PFS but not OS. Up to 28.9% of patients who harbored loss-of-function mutations in chromatin remodeling genes demonstrated significantly longer median PFS and OS than those without alterations. CONCLUSIONS: NGS is a safe and promising regimen in ABTC. Impaired functions of chromatin remodeling genes may be a potential surrogate biomarker with predictive value in the current study