No Significant Overall Survival Benefit With Second-Line Ramucirumab After Sorafenib in Advanced Hepatocellular Carcinoma


Key Points

  • Ramucirumab did not significantly increase overall survival among all study patients with advanced hepatocellular carcinoma.
  • Ramucirumab was associated with an overall survival benefit in patients with high αlpha-fetoprotein levels.

In the phase III REACH trial reported in The Lancet Oncology, Zhu et al found that the anti-VEGFR2 monoclonal antibody ramucirumab (Cyramza) did not significantly improve overall survival vs placebo in patients with advanced hepatocellular carcinoma who had received first-line treatment with the multi-tyrosine kinase inhibitor sorafenib (Nexavar). An overall survival benefit was observed among patients with high baseline αlpha-fetoprotein levels.

Study Details

In the double-blind trial, 565 patients from 27 countries were randomly assigned between November 2010 and April 2013 to receive ramucirumab 8 mg/kg intravenously (n = 283) or placebo (n = 282) every 2 weeks plus best supportive care until disease progression or unacceptable toxicity. Patients had to have Barcelona Clinic Liver Cancer stage C disease or stage B disease refractory or not amenable to locoregional therapy, Child-Pugh A disease, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Randomization was stratified by geographic region and cause of liver disease. The primary endpoint was overall survival in the intent-to-treat population.

The ramucirumab and placebo groups were generally balanced for age (median 64 and 62 years, 47% and 43% ≥ 65 years), sex (83% and 86% male), ethnicity (49% white in both, 46% and 48% Asian), region (North America and South America for 11% and 12%, Europe for 44% in both, and East Asia for 45% in both), ECOG performance status (0 for 56% and 54%), cause of disease (hepatitis B virus in 35% and 36%, hepatitis C virus in 27% in both, other in 37% in both), αlpha-fetoprotein level (< 400 ng/mL in 57% and 53%, ≥ 400 ng/mL in 42% and 46%), and other systemic therapy in addition to sorafenib (14% and 10%). Sorafenib was discontinued due to progressive disease in 87% and 85% and due to toxicity in 13% and 15%.

Overall Survival

Median follow-up was 8.3 months in the ramucirumab group and 7.0 months in the placebo group. Median overall survival was 9.2 months (95% confidence interval [CI] = 8.0–10.6 months) in the ramucirumab group vs 7.6 months (95% CI = 6.0–9.3 months) in the placebo group (hazard ratio [HR] = 0.87, P = .14). Hazard ratios favored ramucirumab in most prespecified subgroups. Among patients with αlpha-fetoprotein ≥ 400 ng/mL, median overall survival was 7.8 months vs 4.2 months (HR = 0.67, P = .006); among those with levels < 400 ng/mL, median overall survival was 10.1 vs 11.8 months (HR = 1.09, P = 0.51).

Median progression-free survival was 2.8 vs 2.1 months (HR = 0.63, P < .0001), with hazard ratios favoring ramucirumab in all prespecified subgroups. Objective response was observed in 7% vs < 1% of patients (P < .0001). Proportions of patients receiving systemic postdiscontinuation therapy were similar in the two groups, with chemotherapy being the most common.

Adverse Events

The most common grade ≥ 3 adverse events were hypertension (12% vs 4%), malignant neoplasm progression (6% vs 4%), ascites (5% vs 4%), asthenia (5% vs 2%), increased aspartate transaminase levels (5% vs 8%), thrombocytopenia (5% vs < 1%), and increased blood bilirubin (2% vs 5%).

The investigators concluded: “Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable.”

Andrew X. Zhu, MD, of Massachusetts General Hospital Cancer Center, is the corresponding author of The Lancet Oncology article.

The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit

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