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
AU - Ross, Paul
AU - Mazzaferro, Vincenzo
AU - Blanc, Jean-Frédéric
AU - Ma, Yuk Ting
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
N1 - ©2018 American Association for Cancer Research.
PY - 2018/10/1
Y1 - 2018/10/1
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.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 β-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. Clin Cancer Res; 24(19); 4650-61. ©2018 AACR.
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.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 β-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. Clin Cancer Res; 24(19); 4650-61. ©2018 AACR.
U2 - 10.1158/1078-0432.CCR-17-3588
DO - 10.1158/1078-0432.CCR-17-3588
M3 - Article
C2 - 29950351
VL - 24
SP - 4650
EP - 4661
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 19
ER -