Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with <i>RAS</i>-Mutated Hepatocellular Carcinoma

Abstract

<b>Purpose:</b> Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with <i>RAS</i>-mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with <i>RAS</i>-mutant unresectable or metastatic HCC.<b>Patients and Methods:</b> Eligible patients with <i>RAS</i> mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS).<b>Results:</b> Of 1,318 patients screened, 59 (4.4%) had a <i>RAS</i> mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in <i>TERT</i> (63.0%), <i>TP53</i> (48.1%), and β-catenin (<i>CTNNB1</i>; 37.0%).<b>Conclusions:</b> Prospective testing for <i>RAS</i> family mutations using ctDNA was a feasible, noninvasive approach for large-scale mutational testing in patients with HCC. A median OS of 12.7 months with refametinib plus sorafenib in this small population of <i>RAS</i>-mutant patients may indicate a synergistic effect between sorafenib and refametinib-this preliminary finding should be further explored. <i>Clin Cancer Res; 24(19); 4650-61. ©2018 AACR</i>.