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BACKGROUND:
Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S+E has additive effects compared with single-agent S.
PATIENTS AND METHODS:
Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary endpoint was progression-free survival at 12 weeks (PFS12). Secondary endpoints included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DS), safety and quality of life (QoL) assessments.
RESULTS:
106 pts were randomized: 46 patients received S and 60 patients received S+E. Ninety-three patients were evaluable for the primary endpoint and 105 patients for the safety analysis. The PFS12 rate was 70% (95% CI: 54-83) and 68% (95% CI: 53-81) in patients randomized to S and S+E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S+E arm. Median PFS (6.6 vs. 5.7 months), TTP (7.6 vs. 6.3 months), DS (6.7 vs. 6.7 months), and OS (10 vs. 12 months) were similar in the S and S+E arms, respectively. Grade 3/4 adverse events occurred in 72% and 88% of patients in arm S and arm S+E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S+E.

CONCLUSIONS:
No evidence was found that E+S improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted.