No Survival Benefit With Everolimus After Failure of Sorafenib in Advanced Hepatocellular Carcinoma


Key Points

  • Everolimus did not improve overall survival or progression-free survival.
  • There was evidence of benefit of everolimus in patients with HBV etiology and harm in those with etiology other than HBV or HCV.

The multikinase inhibitor sorafenib (Nexavar) is the only effective systemic treatment available in advanced hepatocellular carcinoma. In the phase III EVOLVE-1 trial reported in JAMA, Zhu et al found no survival benefit from treatment with the mTOR inhibitor everolimus (Afinitor) after sorafenib failure in patients with advanced hepatocellular carcinoma. There was some evidence of benefit among patients with hepatitis B virus (HBV) etiology.

Study Details

This double-blind trial included 546 patients from 17 countries with Barcelona Clinic Liver Cancer stage B or C HCC and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were randomly assigned 2:1 between May 2010 and March 2012 to receive everolimus 7.5 mg/d (n = 362) or placebo (n = 184). Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion. The primary endpoint was overall survival.

The everolimus and placebo groups were balanced for age (median, 67 and 64 years), sex (84% and 87% male), geographic region (Asia for 16% and 17%), race (53% and 60% white, 38% and 32% Asian), Eastern Cooperative Oncology Group performance status (0 in 59% and 57%, 1 in 36% and 40%), reason for sorafenib discontinuation (progression in 81% and 80%, intolerance in 18% and 20%), macroscopic vascular invasion (33% in both), extrahepatic disease (74% and 73%), metastatic sites (visceral in 54% and 56%, lung in 43% and 40%), Barcelona Clinic Liver Cancer stage (B in 14% and C in 86% in both), lesion type (target and nontarget in 76% and 71%), etiology (HBV in 25% and 28%, hepatitis C virus [HCV] in 26% and 23%), Child-Pugh score (A in 98% and 99%), and any prior antineoplastic therapy (82% and 81%; radiotherapy in 14% and 15%, surgery in 39% in both, local therapy in 77% and 75%).

Overall Survival Outcomes

Median follow-up was 24.6 months. There was no significant difference in overall survival between the everolimus and placebo groups; death occurred in 83.7% vs 82.1% (hazard ratio [HR] = 1.05, P = .68), and median overall survival was 7.6 vs 7.3 months. Subgroup analysis showed similar outcomes in subgroups, except for an apparent benefit of everolimus in patients with HBV etiology (HR = 0.64, 95% confidence interval [CI] = 0.45–0.93). Further, patients with etiology other than HBV or HCV appeared to have shorter overall survival with everolimus (HR = 1.35, 95% CI = 1.01–1.80).

Median time to disease progression was 3.0 vs 2.6 months (HR = 0.93, 95% CI = 0.75–1.15). The disease control rate was 56.1% vs 45.1% (P = .01), with partial response in 2.2% vs 1.6% of patients.  

After study treatment discontinuation, 38.1% of everolimus patients and 41.3% of placebo recipients received antineoplastic therapy, most commonly chemotherapy (19.6% and 18.5%).

Adverse Events

The most common grade 3 or 4 adverse events in the everolimus group were anemia (7.8% vs 3.3% in placebo group), asthenia (7.8% vs 5.5%), decreased appetite (6.1% vs 0.5%), and HBV reactivation (6.1% vs 4.4%). No patients experienced HCV flare. Overall, HBV reactivation occurred in 8.0% of everolimus patients and 5.5% of placebo patients; all cases were asymptomatic, but treatment was discontinued in three everolimus patients.

The investigators concluded, “Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib.”

They emphasized, “[C]linical and biologic heterogeneity likely affects the performance of targeted therapies in [hepatocellular carcinoma]. In the absence of well-characterized and validated predictive biomarkers, targeted agents will likely continue to have a high risk of failure if phase 3 trials are conducted in unselected populations. Relevant biomarkers that may predict clinical outcome in patients receiving everolimus are being assessed in the EVOLVE-1 population. Future studies of targeted agents for [hepatocellular carcinoma] should aim to enrich patient populations based on molecular classification and predictive biomarkers.”

Andrew X. Zhu, MD, PhD, of Massachusetts General Hospital Cancer Center, is the corresponding author for the JAMA article.

This study was sponsored by Novartis Pharmaceuticals. For full disclosures of the study authors, visit

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