Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular Carcinoma

Ho Yeong Lim, Philippe Merle, Karl Heinz Weiss, Thomas Yau, Paul Ross, Vincenzo Mazzaferro, Jean Fredèric Blanc, Yuk Ting Ma, Chia Jui Yen, Judit Kocsis, Su Pin Choo, Wattana Sukeepaisarnjaroen, Rene Gerolami, Jean François Dufour, Edward J. Gane, Baek Yeol Ryoo, Markus Peck-Radosavljevic, Thong Dao, Winnie Yeo, Wisut LamlertthonSatawat Thongsawat, Michael Teufel, Katrin Roth, Diego Reis, Barrett H. Childs, Heiko Krissel, Josep M. Llovet

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52 Scopus citations


Purpose: Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with RAS-mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with RAS-mutant unresectable or metastatic HCC. Patients and Methods: Eligible patients with RAS 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). Results: Of 1,318 patients screened, 59 (4.4%) had a RAS 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 TERT (63.0%), TP53 (48.1%), and b-catenin (CTNNB1; 37.0%). Conclusions: Prospective testing for RAS 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 RAS-mutant patients may indicate a synergistic effect between sorafenib and refametinib-this preliminary finding should be further explored.

Original languageEnglish
Pages (from-to)4650-4661
Number of pages12
JournalClinical Cancer Research
Issue number19
StatePublished - 1 Oct 2018


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