Everolimus failed to improve overall survival among patients with advanced hepatocellular carcinoma in a large international phase III clinical trial, according to a report published online July 1 in JAMA.
Everolimus – which targets the mTOR pathway that is a key regulator of cellular growth, proliferation, angiogenesis, and survival – had shown promise in numerous preclinical, phase I, and phase II studies. So the Everolimus for Liver Cancer Evaluation (EVOLVE-1) trial was designed to compare the drug’s efficacy and safety against that of a matching placebo in patients whose HCC was refractory to, or who were intolerant of, sorafenib, said Dr. Andrew X. Zhu of Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, and his associates.
Sorafenib is the only systemic therapy shown to improve survival in advanced HCC, but its benefits are "transient and modest," and it produces significant adverse events, according to the researchers. In this study, sorafenib was discontinued because of disease progression in 81% of patients and because of intolerance in 19%, they noted.
In EVOLVE-1, 546 patients were enrolled during a 2-year period at 111 medical centers in 17 countries, randomly assigned in a double-blind fashion to receive either 7.5 mg oral everolimus (362 subjects) or placebo (184 subjects) daily, and followed for a median of 2.5 years (range, 14.8-36.6 months). The trial was sponsored by Novartis, maker of everolimus.
HCC was associated with hepatitis B virus in 26.2% of the patients, hepatitis C virus in 25.1%, and alcohol abuse in 20.0%. There were 303 deaths (83.7%) in the active-treatment group and 151 (82.1%) in the placebo group.
At 5 months, the primary endpoint of estimated overall survival was not significantly different between patients taking everolimus (67.0%) and those taking placebo (65.6%); the rates also were not significantly different at 7 months (53.4% and 51.4%, respectively). Median overall survival time was 7.6 months for everolimus and 7.3 months with placebo, also a nonsignificant difference, Dr. Zhu and his associates said (JAMA 2014 July 1 [doi:10.1001/jama.2014.7189]).
These findings were consistent across all but one subgroup of patients. Secondary endpoints, including time to disease progression, rate of complete response (0% in both groups), and time to deterioration in quality of life, also were not significantly different between the two study groups.
Serious adverse events, including adverse events leading to treatment discontinuation, were more common with everolimus than with placebo. These included asthenia, anemia, decreased appetite, resurgence of HBV, ascites, and thrombocytopenia.
Thus, "despite the strong scientific rationale and preclinical data," everolimus failed to improve outcomes in advanced HCC, the investigators said.
However, "given the immunosuppressive and antitumor effects of mTOR inhibitors, the potential benefits of this class of agents in the adjuvant setting are being assessed in a phase-III trial of sirolimus for patients with HCC after liver transplantation," they added.