Nivolumab Plus Gemcitabine and S-1 Demonstrates Potential in Advanced Biliary Tract Cancer

According to a phase 2 trial, nivolumab plus modified gemcitabine and S-1 is safe and promising for patients with advanced biliary tract cancer. There may also be potential for impaired function of chromatin remodeling genes as a potential surrogate biomarker with predictive value.

This single-arm, phase 2 trial enrolled 48 patients with advanced or metastatic biliary tract cancer between December 27, 2019, and December 3, 2020. Of the 48 patients, 29 had intrahepatic cholangiocarcinoma, 12 had extrahepatic cholangiocarcinoma, 5 had gallbladder cancer, and 2 had ampulla of Vater cancer. All patients were treated with 240 mg of nivolumab, plus 800 mg/m² gemcitabine on day 1 and daily 80/100/120 mg of S-1 (based on body surface area), on days 1 through 10, in a 2-week cycle. Using targeted next-generation sequencing, the tumor mutation burden and genetic analysis were performed on tumor tissue samples. The primary end point was objective response rate (ORR).

At the data cutoff date of December 31, 2021, there was a median follow-up duration of 17.6 months, with 47 of the 48 patients evaluable. The ORR was 45.9% (95% confidence interval [CI], 31.4% to 60.8%), with 2.1% in complete response, 43.8% in partial response, and 41.7% achieving stable disease.  The median progression-free survival (PFS) was 9.1 months (95% CI, 5.8 to 9.6), and the overall survival (OS) was 19.2 months (95%CI, 11.6 to not reached).

High tumor mutational burden predicted prolonged median PFS, but not OS. There was a 28.9% rate of patients who harbored loss-of-function mutations in chromatin remodeling genes demonstrating significantly longer PFS and OS, than those patients without alterations.

The most common grade 3 treatment-related adverse events were fatigue (14.6%), skin rash (10.4%), and thrombocytopenia (8%). There were no grade 4 treatment-related adverse events reported. While 18 patients (35.4%) experience immune-related adverse events, there were no treatment-related deaths.

The study authors concluded that “nivolumab plus modified [gemcitabine plus S-1] is a well-tolerated regimen with promising outcomes and excellent safety profiles,” and that “the predictive capability of [high tumor mutational burden] and chromatin remodeling gene [loss-of-function] mutations for chemoimmunotherapy in [advanced biliary tract cancer] needs to be validated and explored in a larger cohort.”

Source:

Chiang NJ, Tan KT, Bai LY, et al. Impaired chromatin remodeling predicts better survival to modified gemcitabine and S-1 plus nivolumab in advanced biliary tract cancer: A phase II T1219 study. Clin Cancer Res. Published online August 19, 2022. doi:10.1158/1078-0432.CCR-22-1152