Gemcitabine-based chemotherapy plus PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors for initially unresectable intrahepatic cholangiocarcinoma: A multicenter, retrospective cohort study

<title>Abstract</title> <p> <bold>Background</bold> Patients with initially unresectable intrahepatic cholangiocarcinoma (iCCA) have poor prognoses and the current first-line treatments remain unsatisfactory. Our study aimed to evaluate gemcitabine-based chemotherapy plus PD-1/PD-L1 inhibitors and tyrosine kinase inhibitors (TKIs) for iCCA. <bold>Methods</bold> In this multicenter retrospective cohort study, 392 patients were included in the full cohort analysis. For the primary analysis, 88 patients received gemcitabine-based chemotherapy (GEMCIS or GEMOX), and 177 patients received the same chemotherapy backbones combined with PD-1/PD-L1 inhibitors and TKIs. The primary outcome was to evaluate overall survival (OS). The propensity score matching (PSM) method was utilized to reduce potential confounders. <bold>Results</bold> Overall, 392 patients were included from 12 hospitals across China, with data from January 2016 to December 2024. In the full cohort analysis, the combination of GEMCIS/GEMOX with PD‑1/PD‑L1 inhibitors and TKIs significantly prolonged median OS compared to GEMCIS/GEMOX alone (26.7 vs. 15.3 months; hazard ratio [HR] 0.47, 95% CI: 0.35–0.63, <italic>P</italic>  &lt; 0.001). In the primary analysis, the combination strategy was associated with a median OS of 24.8 months and median progression-free survival (PFS) of 11.0 months, with HRs of 0.56 (95% CI: 0.38–0.83, <italic>P</italic>  = 0.004) for OS and 0.46 (95% CI: 0.32–0.66, <italic>P</italic>  &lt; 0.001) for PFS after PSM. Importantly, our treatment strategy increased the rate of conversion surgery to 42% for locally advanced disease, ultimately resulting in significantly improved overall outcomes (HR for OS: 0.17 [95% CI: 0.05–0.61]). <bold>Conclusion</bold> Combining gemcitabine-based chemotherapy with PD-1/PD-L1 inhibitors and TKIs may provide a promising new first-line treatment option for patients with initially unresectable iCCA. </p>