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

Abstract

BackgroundCabozantinib, 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 methodsEligible 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).ResultsAmong 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.ConclusionsCabozantinib 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 numberNCT00940225.

Sorafenib for Advanced Hepatocellular Carcinoma: A Real-Life Experience

“…This approval was based on a double-blind randomized phase III clinical trial showing that REG significantly increased survival in patients with HCC that had tumor progression during treatment with SOR [13]. Nivolumab and cabozantinib as well have demonstrated benefit in this clinical setting in phase II and III studies, respectively [14,15]. As data collected in well controlled clinical trials may not reflect those obtained in clinical practice, it's important to evaluate real life studies.…”

Cabozantinib as a Second-Line Agent in Advanced Hepatocellular Carcinoma

“…1), although the kinase inhibitory activity (IC 50 ) of cabozantinib is different. Cabozantinib was originally identified as a dual inhibitor of VEGFR-2 and c-MET [14, 15], whereas current data suggest that it is a more potent inhibitor of MET, AXL, RET, FLT3, and TIE-2 than regorafenib (Tables 2, 3). VEGF, MET, and AXL are involved in tumor proliferation and angiogenesis, and MET and AXL are involved in the acquisition of resistance to antiangiogenic drugs [14-18].…”

“…Progression-free survival (PFS) was 4.2 months in sorafenib-naïve patients and 5.5 months in sorafenib-pretreated patients, and overall survival (OS) was 11.5 months [15] (Table 4). The overall response rate (ORR) was 5%, the disease control rate was 81%, and PFS was 5.2 months (Table 4).…”

Aktuelle News vom ASCO-GI 2018

“…Nach positiven Ergebnissen aus einer Phase-II-Studie [3] wurde Cabozantinib, ein dualer MET/VEGFR2-Inhibitor, aktuell in der eine zumindest vergleichbare und tendenziell sogar bessere Wirksamkeit, bei insgesamt erreichter höherer Dosisintensität. Im Gesamtüberleben ergab sich ein tendenzieller, aber nicht signifikanter Vorteil (9 vs. 5,9 Monate; HR = 0,65; p = 0,09).…”