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Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.

ABSTRACT: Background:Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts. Patients and methods:Eligible patients had Child-Pugh A liver function and??1 prior systemic anticancer regimen, completed??4 weeks before study entry. The cabozantinib starting dose was 100?mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS). Results:Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with??1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and??1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients. Conclusions:Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions. Trial registration number:NCT00940225.

SUBMITTER: Kelley RK

PROVIDER: S-EPMC5391701 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.

Kelley R K RK Verslype C C Cohn A L AL Yang T-S TS Su W-C WC Burris H H Braiteh F F Vogelzang N N Spira A A Foster P P Lee Y Y Van Cutsem E E

Annals of oncology : official journal of the European Society for Medical Oncology 20170301 3

<h4>Background</h4>Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts.<h4>Patients and methods</h4>Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-w ...[more]

PMID: 28426123

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Project description:IntroductionCabozantinib, an inhibitor of MET, AXL, and VEGF receptors, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced hepatocellular carcinoma (HCC). In this exploratory analysis, outcomes were evaluated according to plasma biomarker levels.MethodsBaseline plasma levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, EPO, ANG2, IGF-1, VEGF-C, and c-KIT for 674/707 randomized patients; and Week 4 levels were evaluated for MET, AXL, VEGFR2, HGF, GAS6, VEGF-A, PlGF, IL-8, and EPO for 614 patients. OS and PFS were analyzed by baseline levels as dichotomized or continuous variables and by on-treatment changes at Week 4 as continuous variables; biomarkers were considered potentially prognostic if p < 0.05 and predictive if p < 0.05 for the interaction between treatment and the biomarker. Multivariable analyses adjusting for clinical covariates were also performed.ResultsIn the placebo group, high levels of MET, HGF, GAS6, IL-8, and ANG2 and low levels of IGF-1 were associated with shorter OS in univariate and multivariable analyses; these associations were also observed for MET, IL-8, and ANG2 in the cabozantinib group. Hazard ratios for OS and PFS favored cabozantinib over the placebo at low and high baseline levels for all biomarkers. No baseline biomarkers were predictive of a treatment benefit. Cabozantinib promoted pharmacodynamic changes in several biomarkers, including increases in VEGF-A, PlGF, AXL, and GAS6 levels and decreases in VEGFR2 and HGF levels; these changes were not associated with OS or PFS.ConclusionCabozantinib improved OS and PFS versus placebo at high and low baseline concentrations for all biomarkers analyzed. Low baseline levels of MET, HGF, GAS6, IL-8, and ANG2 and high levels of IGF-1 were identified as potential favorable prognostic biomarkers for survival in previously treated advanced HCC. Although cabozantinib promoted pharmacodynamic changes in several biomarkers, these changes were not associated with survival.

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Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.

Publications

Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.

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