A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma

BACKGROUND Advanced cholangiocarcinoma carries a poor prognosis, and no standard treatment exists beyond first‐line gemcitabine/platinum‐based chemotherapy. A single‐arm, phase 2 and biomarker study of cabozantinib, a multikinase inhibitor with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET, was performed for patients with advanced refractory cholangiocarcinoma. METHODS Previously treated patients with unresectable or metastatic cholangiocarcinoma received cabozantinib (60 mg orally and daily on a continuous schedule). The primary endpoint was progression‐free survival (PFS). Tumor MET expression and plasma biomarkers were evaluated. RESULTS The study enrolled 19 patients with cholangiocarcinoma (female, 68%; median age, 67 years; intrahepatic vs extrahepatic, 84% vs 16%). The median PFS was 1.8 months (95% confidence interval, 1.6‐5.4 months), and the median overall survival (OS) was 5.2 months (95% confidence interval, 2.7‐10.5 months). Grade 3/4 adverse events occurred in 89% of the patients and included neutropenia (5%), hyperbilirubinemia (5%), epistaxis (5%), bowel perforation (5%), enterocutaneous fistulas (5%), and hypertension (11%). One patient with 3 + MET expression in the tumor stayed on treatment for 278 days, but the MET expression did not correlate with the outcomes in the overall study population. Plasma vascular endothelial growth factor, placental growth factor, and stromal cell–derived factor 1α increased and soluble VEGFR2 and angiopoietin 2 decreased after treatment (all P values