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| Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Jun 27. pii: 1078-0432.CCR-17-3588. doi: 10.1158/1078-0432.CCR-17-3588 |
| Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with -Mutated Hepatocellular Carcinoma. |
| Lim HY1, Merle P2, Weiss KH3, Yau T4, Ross P5, Mazzaferro V6, Blanc JF7, Ma YT8, Yen CJ9, Kocsis J10, Choo SP11, Sukeepaisarnjaroen W12, Gérolami R13, Dufour JF14, Gane EJ15, Ryoo BY16, Peck-Radosavljevic M17, Dao T18, Yeo W19, Lamlertthon W20, Thongsawat S21, Teufel M22, Roth K23, Reis D24, Childs BH25, Krissel H26, Llovet JM27 |
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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. |
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©2018 American Association for Cancer Research. |
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Publikations ID: 29950351 Quelle: öffnen |
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