# A Phase II Study of Toripalimab in Combination with Gemcitabine and 5-Fluorouracil as First-Line Therapy for Advanced or Metastatic Biliary Tract Carcinoma

## TL;DR

A new treatment combining toripalimab with chemotherapy showed modest effectiveness and acceptable safety for advanced biliary tract cancer.

## Contribution

This study evaluates toripalimab combined with gemcitabine and 5-FU as a first-line therapy for advanced biliary tract carcinoma.

## Key findings

- The combination therapy achieved an objective response rate of 13% in advanced biliary tract cancer patients.
- No significant improvement was observed in patients with high PD-L1 expression or tumor mutational burden.
- Treatment-related adverse events were common but manageable, with no treatment-related deaths.

## Abstract

Biliary tract carcinoma (BTC) is a rare, aggressive cancer arising from biliary epithelial cells, often diagnosed at advanced stages with a median survival of less than one year. Prior investigations have explored the efficacy of programmed cell death protein 1 (PD-1) inhibitors and gemcitabine-based chemotherapy regimens in advanced BTC. In this phase II study, we evaluated a new regimen for advanced or metastatic BTC using toripalimab combined with gemcitabine and 5-fluorouracil (5-FU). The regimen achieved an objective response rate (ORR) of 13%. Subgroup analyses revealed no significant improvement in outcomes among patients with elevated programmed death-ligand 1 (PD-L1) expression or high tumor mutational burden (TMB). Treatment-related adverse events (TRAEs) occurred in all patients, with grade 3 or higher TRAEs reported in eight patients, including anemia (20%), neutropenia (13.3%), and nausea (6.6%); no treatment-related deaths were observed. Overall, this combination therapy offers a viable alternative for patients with advanced BTC and demonstrates an acceptable safety profile.

Background/Objectives: The anti-PD-L1 antibody has been applied for use in first-line advanced biliary duct cancer patients. However, clinical evidence of toripalimab in combination with biweekly 5-fluorouracil (5-FU) is limited and predictive biomarkers of treatment benefits remain unclear. Methods: This prospective study enrolled patients with unresectable or metastatic BTC who received toripalimab in combination with gemcitabine and biweekly 5-FU. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). Secondary endpoints included overall survival (OS) and safety. Exploratory analyses evaluated associations between programmed cell death-ligand 1 (PD-L1) expression or tumor mutational burden (TMB) and clinical outcomes. Results: A total of 30 patients were enrolled, with a median follow-up duration of 16.0 months. The ORR was 13.0%. The median PFS and OS were 5.3 months (95% CI: 3.59–7.01) and 11.7 months (95% CI: 6.07–17.33), respectively. Subgroup analyses revealed no significant association between PD-L1 status or TMB level and improved PFS. All patients experienced adverse events (AEs), while grade 3–4 AEs occurred in eight patients (26.7%), most commonly anemia (20.0%), leukocytopenia (13.3%), and nausea (6.6%). No grade 5 AEs were observed, and the safety profile was considered manageable. Conclusions: Toripalimab in combination with gemcitabine and 5-fluorouracil showed promising efficacy and was well-tolerated as a first-line therapy in advanced biliary duct cancer patients. Although PD-L1 expression and TMB did not predict treatment benefit, larger studies are needed to validate potential biomarkers and further optimize immunochemotherapy strategies for BTC.