Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Clinical Cancer Research Année : 2018

Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma

Thomas Yau

Résumé

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 (OCR) 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 NCS. The most frequently detected mutations were in TERT (63.0%), TP53 (48.1%), and beta-catenin (CTNNBI; 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. (C) 2018 AACR.

Dates et versions

hal-01910322 , version 1 (31-10-2018)

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Ho Yeong Lim, Philippe Merle, Karl Heinz Weiss, Thomas Yau, Paul Ross, et al.. Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma. Clinical Cancer Research, 2018, 24 (19), pp.4650-4661. ⟨10.1158/1078-0432.CCR-17-3588⟩. ⟨hal-01910322⟩
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