BACKGROUND: Effective first-line treatments for unresectable intrahepatic cholangiocarcinoma (ICC) remain limited. This real-world study aimed to compare the efficacy of immune checkpoint inhibitors (ICIs) plus chemotherapy combined with or without Lenvatinib as first-line treatment in unresectable ICC patients and identify predictors of treatment response and prognosis. METHODS: In this retrospective cohort study, 58 patients with unresectable ICC received either dual therapy (ICIs plus chemotherapy) or triple therapy (ICIs plus chemotherapy and Lenvatinib) as first-line treatment. The endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Survival curve was plotted by the Kaplan-Meier method. A Cox proportional hazards model was performed to investigate risk factors of PFS and OS. RESULTS: No significant differences were observed between triple therapy and dual therapy as first-line treatment for unresectable ICC patients in terms of PFS (median PFS: 10.3 vs. 11.1 months, P >
0.05) and OS (median OS: 14.0 vs. 15.0 months, P >
0.05). The ORR (39.4% vs. 30.4%) and DCR (90.9% vs. 73.9%) were comparable between the triple therapy group and dual therapy group (P >
0.05). In the multivariate analysis, tumor burden score (TBS, ≥ 8) and tumor number (≥ 2) were associated with prolonged PFS (P <
0.05), while TBS was an independent factor for OS (P <
0.05). CONCLUSIONS: Triple therapy did not demonstrate any benefit on both PFS and OS compared to dual therapy as first-line treatment for patients with unresectable ICC. TBS and tumor number may guide treatment stratification.