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.

Keywords: cabozantinib; hepatocellular carcinoma; overall survival; progression-free survival; tumor response; vascular endothelial growth factor receptor.

Figure 1.

(A) Best change from baseline in investigator-assessed measurements of soft-tissue lesions using Response Evaluation Criteria in Solid Tumors (version 1.0) was determined for hepatocellular carcinoma (HCC) patients who had baseline and at least one post-baseline radiographic scan in the first 12 weeks (n = 36). A reduction in the sum of measurable lesions was reported for 78% of assessable patients. Change in measurable disease was independent of prior treatment with sorafenib. (B) Best change from baseline in alpha-fetoprotein (AFP) measurements was determined for HCC patients who had baseline AFP ≥20 ng/ml (n = 26). ^aConfirmed partial response. ^bIncrease >100% from baseline.

Figure 2.

Kaplan–Meier estimates of (A) progression-free survival (PFS) in all patients with HCC by sorafenib pretreatment status. (B) Overall survival (OS) for all patients with HCC.