TY - JOUR
T1 - Phase II studies with Refametinib or Refametinib plus Sorafenib in patients with RAS-mutated Hepatocellular Carcinoma
AU - Lim, Ho Yeong
AU - Merle, Philippe
AU - Weiss, Karl-Heinz
AU - Yau, Thomas CC
AU - Ross, Paul
AU - Blanc, Jean-Frederic
AU - Mazzaferro, Vincenzo
AU - Ma, Yuk
AU - Yen, Chia-Jui
AU - Kocsis, Judit
AU - Choo, Su Pin
AU - Sukeepaisarnjaroen, Wattana
AU - Gérolami, René
AU - Dufour, Jean-François
AU - Gane, Edward J
AU - Ryoo, Baek-Yeol
AU - Peck-Radosavljevic, Markus
AU - Dao, Thong
AU - Yeo, Winnie
AU - Lamlertthon, Wisut
AU - Thongsawat, Satawat
AU - Teufel, Michael
AU - Roth, Katrin
AU - Reis, Diego
AU - Childs, Barrett H
AU - Krissel, Heiko
AU - Llovet, Josep M
PY - 2018/6/27
Y1 - 2018/6/27
N2 - 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.
AB - 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.
U2 - 10.1158/1078-0432.CCR-17-3588
DO - 10.1158/1078-0432.CCR-17-3588
M3 - Article
SN - 1078-0432
JO - Clinical Cancer Research
JF - Clinical Cancer Research
ER -