Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-mutated Hepatocellular Carcinoma
Mené sur 32 patients atteints d'un carcinome hépatocellulaire présentant une mutation RAS, cet essai de phase II compare l'efficacité, du point de vue du taux de réponse objective, du taux de contrôle de la maladie, de la survie globale et de la survie sans progression, et la toxicité du réfamétinib, un inhibiteur de MEK utilisé en monothérapie, et un traitement combinant réfamétinib et sorafénib
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. 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 1318 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 β-catenin (CTNNB1; 37.0%). Conclusions: Prospective testing for RAS family mutations using ctDNA was a feasible, non-invasive approach for large-scale mutational testing in HCC patients. 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.