Toripalimab in advanced biliary tract cancer

Wei Li; Yueqi Wang; Yiyi Yu; Qian Li; Yan Wang; Chenlu Zhang; Xiaojing Xu; Xi Guo; Yu Dong; Yuehong Cui; Qing Hao; Lujia Huang; Houbao Liu; Tianshu Liu

doi:10.1016/j.xinn.2022.100255

Toripalimab in advanced biliary tract cancer

Innovation (Camb). 2022 May 10;3(4):100255. doi: 10.1016/j.xinn.2022.100255. eCollection 2022 Jul 12.

Authors

Wei Li¹, Yueqi Wang², Yiyi Yu¹, Qian Li¹, Yan Wang¹, Chenlu Zhang¹, Xiaojing Xu¹, Xi Guo¹, Yu Dong¹, Yuehong Cui¹, Qing Hao³, Lujia Huang³, Houbao Liu², Tianshu Liu^{1

4}

Affiliations

¹ Department of Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
² Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
³ Department of Medicine, Shanghai OrigiMed Co., Ltd., Shanghai 201114, China.
⁴ Center of Evidence-Based Medicine, Fudan University, Shanghai 200032, China.

Abstract

Gemcitabine combined with platinum/fluorouracil drugs is the standard first-line treatment for advanced biliary tract cancers (BTCs). We explored the safety and efficacy of toripalimab plus gemcitabine and S-1 (GS) as the first-line treatment for advanced BTCs. At a one-sided significance level of 0.025, a total of 50 patients could provide 80% power to show the efficacy at targeted progression-free survival (PFS) rate at 6 months of 70% versus 40% for the combined treatment. This single-arm, phase II study enrolled 50 patients with advanced BTCs who previously received no systemic treatment. The regimen was as follows: toripalimab (240 mg, i.v., d1), gemcitabine (1,000 mg/m², i.v., d1 and d8), and S-1 (40-60 mg bid p.o., d1-14, Q21d). The primary endpoint was progression-free survival. The secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety. The associations between response with PD-L1 expression, tumor mutational burden (TMB), and genetic variations were explored. Patients were enrolled from January 2019 to August 2020, with a median follow-up time of 24.0 months (IQR: 4.3-31.0 months). The 6-month PFS rate was 62%. The median PFS was 7.0 months (95% CI: 5.0-8.9 months), and median OS was 15.0 months (95% CI: 11.6-18.4 months). Forty-nine patients completed the evaluation for tumor response. The ORR was 30.6% (95% CI: 17.2%-44.0%), and the disease control rate was 87.8% (95% CI: 78.2%-97.3%). The most common treatment-related adverse events (TRAEs) were leukopenia (98.0%), neutropenia (92%), and anemia (86.0%). Grade III/IV TRAEs included leukopenia (38.0%), neutropenia (32%), skin rash (6%), anemia (2.0%), mucositis (2%), and immune-related colitis (2%). Among them, the grade III/IV immune-related adverse events (irAEs) were skin rash and colitis. In addition, biomarker analysis showed that negative PD-L1 expression and SMARCA4 mutation were significantly associated with worse survival outcomes, while no significant associations were observed for TP53, KRAS, or CDKN 2 A mutation as well as TMB. In conclusion, our data suggest that a regimen of toripalimab plus GS could improve PFS and OS with a good safety profile as a first-line treatment option for advanced BTC and warrants further verification.

Keywords: biliary tract cancers; chemotherapy; immunotherapy; phase II clinical trial; programmed death ligand-1.