• Andrew X Zhu, Masatoshi Kudo, Eric Assenat, Stéphane Cattan, Yoon-Koo Kang, Ho Yeong Lim, Ronnie T P Poon, Jean-Frederic Blanc, Arndt Vogel, Chao-Long Chen, Etienne Dorval, Markus Peck-Radosavljevic, Armando Santoro, Bruno Daniele, Junji Furuse, Annette Jappe, Kevin Perraud, Oezlem Anak, Dalila B Sellami, and Li-Tzong Chen.
• Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston.
• JAMA. 2014 Jul 2;312(1):57-67.

ImportanceAside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma.ObjectiveTo assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed.Design, Setting, And ParticipantsEVOLVE-1 was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent).InterventionsEverolimus, 7.5 mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group.Main Outcomes And MeasuresThe primary end point was overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease).ResultsNo significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95% CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8% vs 3.3%, respectively), asthenia (7.8% vs 5.5%, respectively), and decreased appetite (6.1% vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy.Conclusions And RelevanceEverolimus 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.Trial Registrationclinicaltrials.gov Identifier: NCT01035229.

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