Although gemcitabine plus platinum/fluorouracil combinations are the standard first-line treatment for advanced biliary tract cancers (BTCs), overall outcomes are suboptimal. With the goal of improving survival outcomes, a single-arm, phase 2 study explored the safety and efficacy of the addition of anti–PD-1 inhibitor toripalimab to the standard chemotherapy (gemcitabine plus S-1 [tegafur, 5-chloro-2,4-dihydroxypyridine, and oxonic acid]) in the treatment of patients with previously untreated advanced BTC. Results from this study were shared at the 2022 ASCO GI Cancers Symposium.
Eligible patients received toripalimab plus chemotherapy (toripalimab 240 mg intravenously [IV] on day 1; gemcitabine 1000 mg/m2 IV on days 1 and 8; and S-1 40-60 mg orally twice daily on days 1-14 every 21 days). The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), objective response rate (ORR), and safety. An exploratory end point was the association between response with PD-L1 expression, tumor mutational burden (TMB), and genetic variations.
Between January 2019 and August 2020, a total of 50 eligible patients were enrolled in the study. The median age was 62 years; the majority were men (56%) with ECOG performance status of 1 (96%). Of these patients, 20 were diagnosed with intrahepatic cholangiocarcinoma (CCA), 20 with gallbladder cancer, and 10 with extrahepatic CCA. PD-L1 expression combined positive score (CPS) was ≥1 in 32% of patients, <1 in 32% of patients, and unknown in 36% of patients. TMB was high (≥4.5 mut/Mb) in 20 patients and low (<4.5 mut/Mb) in 28 patients.
For the 49 evaluable patients with a median follow-up time of 24 months, the median PFS was 7 months (95% confidence interval [CI], 5.0-8.9 months); median OS was 15 months (95% CI, 11.6-18.4 months). The ORR was 30.6%, including 1 complete response and 14 partial responses; the disease control rate was 87.8% and included 28 patients with stable disease.
The most common all-grade treatment-related adverse events (TRAEs) were leukopenia (98%), neutropenia (92%), and anemia (86%). Grade 3/4 TRAEs included leukopenia (38%), neutropenia (32%), skin rash (6%), anemia (2%), mucositis (2%), and immune-related colitis (2%). In all, 2 patients discontinued toripalimab due to adverse events (immune-related colitis and skin reaction).
Biomarker analysis found that TP53, KRAS, and CDKN2A genes had the highest mutation frequencies. The presence of SMARCA mutations was associated with shorter PFS (4.2 vs 7.9 months; P = .0029) and OS (10 vs 16 months; P = .069) in patients treated with toripalimab plus chemotherapy compared with patients without these mutations.
Exploratory analysis showed that patients with CPS ≥1 had significantly longer PFS compared with CPS <1 (P = .0033); however, median OS was similar in the 2 CPS cohorts (16.1 vs 12.0 months; P = .09). No significant correlation was seen between TMB and PFS.
Based on these results, the researchers concluded that toripalimab combined with gemcitabine plus S-1 had acceptable toxicity and encouraging efficacy in terms of PFS and OS in the first-line treatment of patients with advanced BTC.
Source: OLi W, Wang Y, Yu Y, et al. Toripalimab combined with gemcitabine and S-1 in the first-line treatment of advanced biliary tract cancer. American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2022. Abstract 4081.