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 .).