Efficacy and safety of anlotinib and sintilimab combined with GEMOX in advanced combined hepatocellular-cholangiocarcinoma (cHCC-CCA): A prospective phase II study.

Abstract

e16203 Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer with poor prognosis and no standardized standard-of-care for advanced disease. While immunotherapy-based combinations have improved outcomes in hepatocellular carcinoma and biliary tract cancer separately, evidence for cHCC-CCA remains limited. We hypothesized that a triplet regimen integrating chemotherapy, targeted therapy, and immunotherapy would improve outcomes. We present results from a phase II study evaluating anlotinib and sintilimab combined with gemcitabine and oxaliplatin (GEMOX) in advanced cHCC-CCA. Methods: This prospective, single-arm, phase II study enrolled patients with advanced or metastatic cHCC-CCA who were either treatment-naïve or had progressed on prior systemic therapy. Patients received gemcitabine ($1000\ mg/m^2$ IV, D1, D8) and oxaliplatin ($85\ mg/m^2$ IV, D1) combined with anlotinib (8 mg PO, D1–14) and sintilimab (200 mg IV, D1) every 3 weeks for 6 cycles. This was followed by maintenance with anlotinib and sintilimab until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS). Results: Between December 2023 and November 2025, 12 patients were enrolled. Seven patients (58.3%) had received at least one prior line of systemic therapy. Per RECIST v1.1, the confirmed ORR was 58.3% (7/12) and the disease control rate (DCR) was 91.7% (11/12). The median PFS was 6.3 months (95% CI, 1.5–11.9). Median OS was not reached; the 6-month and 12-month OS rates were 91.7% and 71.3%, respectively. Grade 3/4 treatment-related adverse events included neutropenia, thrombocytopenia, and elevated transaminases, which were manageable with dose adjustments or supportive care. No treatment-related deaths occurred. Conclusions: The combination of GEMOX, anlotinib, and sintilimab demonstrates promising antitumor activity and a manageable safety profile in patients with advanced cHCC-CCA, including those who have progressed on prior therapies. These results support further investigation in larger cohorts. Clinical trial information: NCT06033118 .