Cabozantinib in patients with advanced and progressing hepatocellular carcinoma
Journal
New England Journal of Medicine
Journal Volume
379
Journal Issue
1
Pages
54-63
Date Issued
2018
Author(s)
Abou-Alfa G.K.
Meyer T.
El-Khoueiry A.B.
Rimassa L.
Ryoo B.-Y.
Cicin I.
Merle P.
Chen Y.
Park J.-W.
Blanc J.-F.
Bolondi L.
Kl?mpen H.-J.
Chan S.L.
Zagonel V.
Pressiani T.
Ryu M.-H.
Venook A.P.
Hessel C.
Borgman-Hagey A.E.
Schwab G.
Kelley R.K.
Abstract
BACKGROUND Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. METHODS A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression-free survival and the objective response rate. RESULTS At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar-plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). CONCLUSIONS Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426). Copyright ? 2018 Massachusetts Medical Society.
SDGs
Other Subjects
cabozantinib; placebo; sorafenib; anilide; antineoplastic agent; cabozantinib; protein tyrosine kinase; pyridine derivative; adult; advanced cancer; aged; Article; cancer growth; controlled study; decreased appetite; diarrhea; double blind procedure; drug efficacy; drug response; drug safety; fatigue; female; hand foot syndrome; human; hypertension; hypertransaminasemia; liver cell carcinoma; major clinical study; male; nausea; overall survival; phase 3 clinical trial; priority journal; progression free survival; randomized controlled trial; very elderly; antagonists and inhibitors; clinical trial; disease free survival; Kaplan Meier method; liver cell carcinoma; liver tumor; middle aged; multicenter study; Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Hepatocellular; Disease-Free Survival; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Pyridines; Receptor Protein-Tyrosine Kinases
Publisher
Massachussetts Medical Society
Type
journal article