Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study
R K Kelley1, C Verslype2, A L Cohn3
1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA.
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.
Insights
Cabozantinib demonstrated clinical activity in hepatocellular carcinoma (HCC) patients, showing tumor responses and disease stabilization. Adverse events were manageable with dose adjustments.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Cabozantinib is an oral tyrosine kinase inhibitor targeting MET, AXL, and VEGF receptors.
- Hepatocellular carcinoma (HCC) is a complex malignancy requiring novel therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy and safety of cabozantinib in patients with HCC.
- To assess tumor response and progression-free survival (PFS) in a phase 2 randomized discontinuation trial.
Main Methods:
- 41 HCC patients with Child-Pugh A liver function received 100mg daily cabozantinib for 12 weeks.
- Patients with stable disease (SD) were randomized to continue cabozantinib or receive placebo.
- Primary endpoints were objective response rate (ORR) at week 12 and PFS in the randomized stage.
Main Results:
- Week 12 ORR was 5%, with 66% disease control rate (DCR).
- Median PFS post-randomization was 2.5 months (cabozantinib) vs. 1.4 months (placebo), not statistically significant.
- Median PFS and overall survival from Day 1 were 5.2 and 11.5 months, respectively. Common grade 3/4 AEs included diarrhea and hand-foot syndrome.
Conclusions:
- Cabozantinib exhibits clinical activity in HCC, including objective responses and disease stabilization.
- Alpha-fetoprotein (AFP) reductions were observed in a subset of patients.
- Adverse events were generally manageable through dose reductions.
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