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

Abstract

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

Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response

“…36 Our study has also highlighted a synergistic effect of sorafenib in combination with MEK1/2 inhibitors with higher sensitivity in the CL1 and CL2 subgroups of LCCL, in lines with recent studies in HCC preclinical models and in HCC patients. 37,38 Our screening also identified potential new attractive drugs already approved in the clinics in specific molecular contexts. Our results showed responses in LCCL harboring inactivating mutations in TSC1 or TSC2 treated by an mTOR inhibitor, suggesting that the 7% of HCC demonstrating the same alterations could benefit from rapamycin or alternative inhibitors, in line with previous reports (Figure 7).…”

Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma

“…TERT, TP53, and CTNNB1 mutation could be detected in peripheral blood of HCC patients with RAS mutations confirmed by Beaming technology before. The frequencies of detected mutations of ctDNA corresponded with the somatic mutations in the hepatocellular carcinoma were 44% (RAS), 63.0% (TERT), 48.1% (TP53), and 37.0% (CTNNB1) respectively [32]. In Chinese cohorts with high HBV infection frequency, TP53 had the highest mutation rate (60.0%).…”

The interplay of circulating tumor DNA and chromatin modification, therapeutic resistance, and metastasis

“…For instance, some researchers utilized a ctDNA-based NGS analysis of blood samples in 179 patients and identified three subgroups according to their genetic mutations, which favored predictions of drug resistance [177]. Similar practices have also been adopted in prostate carcinoma [178], colorectal cancer [86], and hepatocellular carcinoma [179] among others. Of note, ct-DNA-based NGS analyses have also been conducted in a much larger cohort of 670 patients with more diverse tumors, with encouraging results [180].…”