1. Compared to placebo, treatment with everolimus did not improve survival in patients with advanced hepatocellular carcinoma (HCC) who had previously failed sorafenib treatment.
2. Compared to placebo, everolimus treatment did not delay time to disease progression but did improve the disease control rate.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Advanced hepatocellular carcinoma (HCC) portends a poor prognosis due to the dearth of current available therapies. Sorafenib is the only treatment proven to improve survival in HCC. However, it demonstrates moderate efficacy and has been associated with numerous adverse events. Everolimus is a new medication that is under investigation for the treatment of HCC that acts by inhibiting the mTOR pathway.
This phase 3 clinical trial measured the survival of patients with advanced HCC after disease progression with sorafenib or intolerance to sorafenib treatment who were subsequently treated with either everolimus or placebo. There was no survival benefit or delay in time to disease progression detected with everolimus treatment compared to placebo. While the disease control rate was improved in the everolimus group compared to that of the placebo group, no complete responses to therapy were observed.
The relationship between individual molecular characteristics or biomarkers and response to various targeted therapies for HCC remains unknown. Thus, it is possible that select patient populations may benefit from this treatment. Nevertheless, this study does not demonstrate a survival benefit with everolimus treatment in advanced HCC at this time.
In-Depth [randomized controlled trial]: This study was a randomized controlled double-blind phase 3 study in which patients with advanced HCC and treatment failure or intolerance to sorafenib were randomized to treatment with everolimus (n=362) or placebo (n=184). Patients received 7.5 mg daily of everolimus or placebo with best supportive care for a median follow-up of 24.6 months. Median survival was 7.6 months (95%CI, 6.7-8.7) for the everolimus group and 7.3 months (95%CI, 6.3-8.7) for the placebo group, heralding no difference in the risk of death between the two groups (HR 1.05, 95%CI 0.86-1.27, p=.68). However, patients with Hepatitis B virus as the etiology of HCC had improved survival with everolimus (HR 0.64, 95%CI 0.45-0.93) compared to other etiologies. There was no improvement in time to progression between the two groups (HR 0.93, 95%CI 0.75-1.15). The disease control rate was 56.1% with everolimus compared to 45.1% with placebo but the significance of this finding must be interpreted in the context of the other results.
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