Phase I study of everolimus in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC)

Abstract

BACKGROUND: The PI3K/Akt/mTOR pathway, a key regulator of cellular proliferation and angiogenesis, has emerged as a contributor to hepatocarcinogenesis. Everolimus, an mTOR inhibitor, exhibits antineoplastic activity in preclinical and experimental models of HCC. Sorafenib, a multi-tyrosine kinase (including Raf) inhibitor, is the only targeted therapy demonstrating a survival benefit and approved for first-line treatment in patients with unresectable HCC. Enhanced efficacy may be achieved through dual inhibition of key signaling pathways involved in hepatocarcinogenesis. We evaluated the maximum tolerated dose (MTD) and pharmacokinetics of everolimus in combination with 400 mg bid of sorafenib in patients with advanced HCC. METHODS: In this phase I study (NCT00828594) patients ≥18 years of age with measurable, previously untreated, BCLC Stage B or C HCC and ECOG score of 0-1, Child-Pugh’s A (5-6 points) received escalating doses of everolimus starting at 2.5 mg qd + sorafenib 400 mg bid for 28 days. Primary endpoint was MTD. RESULTS: Thirty patients with advanced HCC were enrolled (everolimus 2.5 mg qd, n=16; everolimus 5 mg qd, n=14). Most patients were Asian (73%) and HBsAg positive (63%), with BCLC Stage C HCC (93%). Dose escalation above 5 mg qd was not achieved. Dose-limiting toxicity was grade 3 AST elevation (n=1) in the 2.5 mg group and grade 3/4 thrombocytopenia (n= 5) and hyperbilirubinemia (n=1) in the 5.0 mg group. Drug-related AE rates leading to dose reductions (42.9% vs 0%) and interruptions (71.4% vs 37.5%) were more common in the 5 mg cohort than the 2.5 mg group. Everolimus pharmacokinetics in this population were dose proportional and comparable to that previously reported for monotherapy in non-HCC patients. Disease stabilization occurred in 10 (62.5%) patients and 5 (35.7%) in the 2.5 mg and 5.0 mg groups, respectively. Median time to progression was 3.5 and 3.6 months in the 2.5 mg and 5.0 mg groups, respectively. CONCLUSIONS: The MTD of everolimus in combination with sorafenib 400 mg bid was 2.5 mg qd in this population. The inability to achieve what is deemed a biologically effective dose of everolimus in combination with sorafenib will preclude progression to phase II in this study.