“Despite the strong scientific rationale and preclinical data, everolimus [Afinitor] plus best supportive care failed to improve survival over placebo plus best supportive care” among patients with advanced hepatocellular cancer that progressed during or after receiving sorafenib (Nexavar), or who were intolerant to sorafenib, Andrew X. Zhu, MD, PhD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, and colleagues reported.
The results of the phase III Everolimus for Liver Cancer Evaluation (EVOLVE-1) study were published in the Journal of the American Medical Association.
While sorafenib has been shown to significantly improve overall survival in advanced hepatocellular cancer, its benefits are mostly transient and modest, and disease progression eventually occurs. The EVOLVE-1 study compared everolimus at 7.5 mg/d to matching placebo, both in combination with best supportive care, in 546 adults with hepatocellular cancer, Barcelona Clinic Liver Cancer stage B or C, and Child-Pugh A liver function.
According to the 2:1 randomization scheme, 362 patients were randomly assigned to everolimus and 184 to placebo. Patients continued on trial until disease progression or intolerable toxicity.
“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 researchers reported.
“Adverse events of any grade, regardless of relationship with study drug, were experienced by 99.2% of everolimus and 94.0% of placebo recipients,” according to the study report. Grade 3/4 adverse events occurred more frequently with everolimus, 70.9% vs 52.2% with placebo. The most common grade 3/4 adverse events with everolimus vs placebo were anemia (7.8% vs 3.3%), asthenia (7.8% vs 5.5%), and decreased appetite (6.1% vs 0.5%).
“No patients experienced hepatitis C viral flare,” the investigators stated. “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.” The authors noted that the adverse events profile “observed for everolimus was mostly consistent with the known safety profile of everolimus in other cancers.”
In preclinical models, inhibition of the mammalian target of rapamycin (mTOR) with everolimus and other rapamycin analogs prevented tumor progression and improved survival, and mTOR activation was associated with hepatocellular cancer recurrence, the researchers reported. In addition, everolimus demonstrated manageable safety and clinical activity in early-phase clinical trials.
The EVOLVE-1 results extend the list of failed phase III studies in advanced hepatocellular cancer, “highlighting the challenge of developing effective therapies for this cancer,” the authors noted.
Nevertheless, EVOLVE-1 and the other failed phase III studies “have provided several important lessons,” they continued. “First, it is difficult to assess efficacy signals from [phase II] trials,” the authors continued. “Second, surrogate end points such as time to progression, progression-free survival, and response rate inconsistently predict overall survival in [phase III] trials. Third, clinical and biologic heterogeneity likely affects the performance of targeted therapies in [hepatocellular cancer].”
Patients in the EVOLVE-1 are being assessed for relevant biomarkers that may predict clinical outcomes among patients receiving everolimus. “Future studies of targeted agents for [hepatocellular cancer] should aim to enrich patient populations based on molecular classification and predictive biomarkers,” the authors concluded. ■
Zhu AX, et al: JAMA 312:57-67, 2014.