Hepatocellular carcinoma is the second most common cause of cancer-related death and occurs most often in patients with cirrhosis. Vascular endothelial growth factor (VEGF) plays an important role in tumor growth and angiogenesis, and is overexpressed in patients with hepatocellular carcinoma. The treatment options for this patient population are limited; sorafenib is the only drug that has shown improved median overall survival (OS). However, sorafenib is associated with significant toxicities. Previous studies with ramucirumab, a VEGF inhibitor, demonstrated antitumor activity in patients with hepatocellular carcinoma and in those with renal-cell carcinoma after sorafenib therapy. A REACH study assessed the safety and efficacy of ramucirumab in patients with advanced hepatocellular carcinoma after first-line therapy with sorafenib (Zhu AX, et al. Lancet Oncol. 2015;16:859-870).
REACH was a randomized, double-blind, multicenter, phase 3 clinical trial of 565 patients with hepatocellular carcinoma who had received sorafenib and were randomized in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo every 2 weeks. The primary end point was OS; the secondary end points included the median progression-free survival (PFS), time to tumor progression, and objective response.
Treatment with ramucirumab did not significantly improve OS compared with placebo; the median OS was 9.2 months with ramucirumab versus 7.6 months with placebo. Nevertheless, Zhu and colleagues reported improvements in the secondary end points. The median PFS was 2.8 months with ramucirumab compared with 2.1 months with placebo; the median time to tumor progression was 3.5 months with ramucirumab versus 2.6 months with placebo, and an objective response was reported in 7% of patients receiving ramucirumab compared with < 1% of patients receiving placebo. The safety profile of ramucirumab was consistent with previous studies.
Although REACH did not meet its primary end point of OS, the study yielded a particularly noteworthy finding. A subgroup analysis showed that ramucirumab was especially effective at improving OS in patients with a baseline α-fetoprotein concentration of ≥400 ng/mL, where the median OS was 7.8 months with ramucirumab versus 4.2 months in the placebo group. Elevated α-fetoprotein concentration is associated with poor prognosis in hepatocellular carcinoma, and the conferred benefit with ramucirumab in patients with an elevated α-fetoprotein concentration bolsters support for targeting angiogenesis in advanced hepatocellular cancer.
In addition, Zhu and colleagues postulated that elevated α-fetoprotein concentrations may help to identify patients who would benefit most from ramucirumab therapy; further studies are needed to confirm this hypothesis.