Study: Everolimus Does Not Improve Survival in Liver Cancer Patients
Failed phase III trials offer important lessons
Despite strong preclinical data, everolimus (Afinitor, Novartis) failed to improve overall survival (OS) in patients with advanced liver cancer compared with placebo, according to a study published in the July 2 issue of JAMA.
Patients with advanced hepatocellular carcinoma (HCC) have a median OS of less than l year, largely because of the absence of effective therapies. Sorafenib is the only systemic therapy shown to significantly improve overall survival in patients with advanced HCC; however, its benefits are mostly modest and transient, and the disease eventually progresses. In preclinical models, everolimus prevented tumor progression and improved survival, according to background information in the article.
In a phase III study (EVOLVE-1), researchers at Massachusetts General Hospital Cancer Center, Harvard Medical School, randomly assigned 546 adults with advanced HCC whose disease progressed during or after sorafenib or who were intolerant of sorafenib to receive everolimus 7.5 mg/day (n = 362) or placebo (n = 184), both given in combination with best supportive care and continued until disease progression or intolerable toxicity occurred.
The investigators found no significant difference in OS between the two groups. A total of 303 deaths (83.7%) occurred in the everolimus group compared with 151 deaths (82.1%) in the placebo group. Median OS was 7.6 months with everolimus and 7.3 months with placebo. The disease control rate (i.e., the percentage of patients with a best overall response of complete or partial response or stable disease) was 56.1% with everolimus and 45.1% with placebo.
Based on laboratory results, hepatitis B viral reactivation was experienced by 29 patients in the everolimus group compared with 10 patients in the placebo group; all cases were asymptomatic, but three everolimus recipients discontinued therapy.
The researchers note that EVOLVE-l and the other failed phase III trials have provided several important lessons, including that it is difficult to assess efficacy signals from phase II studies; that surrogate endpoints, such as time to progression, progression-free survival, and the response rate, inconsistently predict OS in phase III trials; and that clinical and biologic heterogeneity likely affects the performance of targeted therapies in HCC.
“In the absence of well-characterized and validated predictive biomarkers, targeted agents will likely continue to have a high risk of failure if phase III trials are conducted in unselected populations,” the authors conclude.