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

Abstract

Background Advanced cholangiocarcinoma carries a poor prognosis, and no standard treatment exists beyond the first-line gemcitabine/platinum-based chemotherapy. We performed a single arm phase II and biomarker study of cabozantinib, a multikinase inhibitor with potent activity against VEGFR2 and MET, in patients with advanced refractory cholangiocarcinoma. Methods Previously treated patients with unresectable or metastatic cholangiocarcinoma received cabozantinib 60 mg orally daily continuously. 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 67yo; intra- vs extrahepatic, 84% vs 16%). The median PFS was 1.8 months (95%CI; 1.6, 5.4), and the median overall survival was 5.2 months (95%CI; 2.7, 10.5). Grade 3/4 adverse events occurred in 89% of patients, and included neutropenia (5%), hyperbilirubinemia (5%), epistaxis (5%), bowel perforation (5%), enterocutaneous fistula (5%), and hypertension (11%). One patient with 3+ MET expression in the tumor stayed on treatment for 278 days, but MET expression did not correlate with outcomes in the overall study population. Plasma VEGF, PlGF and SDF1α increased and soluble VEGFR2 and Ang2 decreased after treatment (all p<0.01). Plasma TIMP-1 inversely correlated with PFS, and soluble MET (sMET) and IL-6 inversely correlated with OS. Conclusions In unselected patients with cholangiocarcinoma, cabozantinib demonstrated limited activity and significant toxicity. In the first clinical trial to assess the role of MET inhibition in cholangiocarcinoma, one patient with a MET-high tumor had prolonged benefit from treatment. Baseline plasma sMET was associated with OS. Any further development of this drug in cholangiocarcinoma should include dose reduction and a biomarker-driven approach.

Cholangiocarcinoma — evolving concepts and therapeutic strategies

“…A phase I study 119 of the MET inhibitor tivantinib in combination with gemcitabine in patients with solid tumours, including cholangiocarcinoma, demonstrated partial responses and stable disease in 20% and 46% of patients, respectively; one patient with cholangiocarcinoma had a partial response. Cabozantinib, a multikinase inhibitor with activity against MET and VEGFR2, had limited activity (median PFS 1.8 months) and substantial toxicity in unselected patients with cholangiocarcinoma 120 . Moreover, MET expression did not correlate with patient outcomes in this study 120 .…”

“…Cabozantinib, a multikinase inhibitor with activity against MET and VEGFR2, had limited activity (median PFS 1.8 months) and substantial toxicity in unselected patients with cholangiocarcinoma 120 . Moreover, MET expression did not correlate with patient outcomes in this study 120 . The combination of sorafenib, a multikinase inhibitor with activity against VEGFR and RAF family kinases, and the EGFR inhibitor erlotinib had disappointing clinical activity against advanced-stage biliary tract cancer 121 .…”

Novel Biomarkers in Cholangiocarcinoma

“…A phase I study (62) of the MET inhibitor tivantinib in combination with gemcitabine in patients with CCA exhibited partial responses and stable disease in 20% and 46% of patients, respectively (table 1). Cabozantinib, a multikinase inhibitor against MET and VEGFR2, had shown a median PFS of 1.8 months with limited activity and substantial toxicity in unselected CCA patients (63). Moreover, plasma soluble MET, not tissue MET expression, correlated with patient outcome in this study.…”

Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience

“…In this study, the MSI-H rate was 2% in ICC patients; both patients accepted immunotherapy with pembrolizumab, and the therapeutic efficacy was satisfactory. The FDA approved pembrolizumab for the treatment of MSI-H/mismatch repair deficient (dMMR) tumors, which showed a predictive response to immunotherapy with PD-1 checkpoint inhibitors 28 This study was retrospective, which limits its evidence grade. However, we herein integrated the genetic profiles of ICC patients in the Chinese population.…”