Andrew X Zhu1, Masatoshi Kudo2, Eric Assenat3, Stéphane Cattan4, Yoon-Koo Kang5, Ho Yeong Lim6, Ronnie T P Poon7, Jean-Frederic Blanc8, Arndt Vogel9, Chao-Long Chen10, Etienne Dorval11, Markus Peck-Radosavljevic12, Armando Santoro13, Bruno Daniele14, Junji Furuse15, Annette Jappe16, Kevin Perraud16, Oezlem Anak16, Dalila B Sellami17, Li-Tzong Chen18. 1. Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston. 2. Kinki University School of Medicine, Osaka, Japan. 3. ICM Val d'Aurelle, Montpellier, France. 4. University Nord De France, Lille, France. 5. Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 6. Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 7. University of Hong Kong, Queen Mary Hospital, Hong Kong, China. 8. Hôpital Saint André, Bordeaux, France. 9. Medical School Hannover, Hannover, Germany. 10. Kaohsiung Chang Gung Memorial Hospital, Taiwan. 11. CHRU de Tours, Tours, France. 12. Medical University of Vienna, Vienna, Austria. 13. Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy. 14. G Rummo Hospital, Benevento, Italy. 15. Kyorin University School of Medicine, Tokyo, Japan. 16. Novartis Pharma, Basel, Switzerland. 17. Novartis Pharmaceuticals, East Hanover, New Jersey. 18. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan19National Cheng Kung University Hospital, Tainan, Taiwan20Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Abstract
IMPORTANCE: Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE: To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS: EVOLVE-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). INTERVENTIONS:Everolimus, 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 theplacebo group. MAIN OUTCOMES AND MEASURES: The 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). RESULTS: No 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 RELEVANCE: Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receivingsorafenib or who were intolerant of sorafenib. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01035229.
RCT Entities:
IMPORTANCE: Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE: To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS: EVOLVE-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). INTERVENTIONS:Everolimus, 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 MEASURES: The 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). RESULTS: No 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 RELEVANCE: 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. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01035229.
Authors: Raymond Wu; Ramachandran Murali; Yasuaki Kabe; Samuel W French; Yi-Ming Chiang; Siyu Liu; Linda Sher; Clay C Wang; Stan Louie; Hidekazu Tsukamoto Journal: Hepatology Date: 2018-10-09 Impact factor: 17.425