Clinical Pearls & Morning Reports
Despite several advances, outcomes in the majority of patients with hepatocellular carcinoma remain poor, and additional treatment options are needed. Abou-Alfa et al. conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate cabozantinib in previously treated patients with advanced hepatocellular carcinoma. Read the latest NEJM Original Article here.
Q: What is the mechanism of action of cabozantinib?
A: 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.
Q: Why might cabozantinib be effective in patients with hepatocellular carcinoma and prior exposure to sorafenib?
A: MET expression has been shown to increase in tumors after sorafenib exposure in patients with hepatocellular carcinoma, which underscores a possible role for MET in the development of sorafenib resistance. By inhibiting MET and AXL in addition to VEGF receptors, cabozantinib targets multiple oncogenic and angiogenic pathways, which may provide additional efficacy and help overcome resistance to agents that target VEGF receptors.
A: The trial by Abou-Alfa et al. showed that cabozantinib treatment significantly prolonged survival in patients with previously treated advanced hepatocellular carcinoma. The median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo, with a hazard ratio for death of 0.76. Corresponding to this survival benefit, a longer duration of progression-free survival was also observed: the median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo, with a hazard ratio for disease progression or death of 0.44. The most common grade 3 or 4 adverse events in the cabozantinib group were palmar–plantar erythrodysesthesia (17%, vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%).
A: Eligible patients were 18 years of age or older, had received a pathological diagnosis of hepatocellular carcinoma that was not amenable to curative treatment, and had Child–Pugh class A liver function. The patient population included in the trial represents a small percentage of patients with hepatocellular carcinoma. Because the survival of patients who have hepatocellular carcinoma with Child–Pugh liver disease of class B or worse is determined by liver failure, and it may be impossible to discern any effect of treatment on the cancer, it is justified to exclude these patients from pivotal clinical trials. Thus, as with all other agents approved for treatment of hepatocellular carcinoma, additional studies are required to confirm the safety and efficacy of cabozantinib in patients with more compromised liver function or poorer performance status.