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

Lim, Ho Yeong, Merle, Philippe, Weiss, Karl Heinz, Yau, Thomas, Ross, Paul, Mazzaferro, Vincenzo, Blanc, Jean-Frédéric, Ma, Yuk Ting, Yen, Chia Jui, Kocsis, Judit, Choo, Su Pin, Sukeepaisarnjaroen, Wattana, Gérolami, René, Dufour, Jean-François, Gane, Edward J, Ryoo, Baek-Yeol, Peck-Radosavljevic, Markus, Dao, Thong, Yeo, Winnie, Lamlertthon, Wisut, Thongsawat, Satawat, Teufel, Michael, Roth, Katrin, Reis, Diego, Childs, Barrett H, Krissel, Heiko and Llovet, Josep M (2018) Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with -Mutated Hepatocellular Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 24 (19). pp. 4650-4661. ISSN 1078-0432.

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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. .

Item Type: Article
Subjects: QZ Pathology. Oncology
WH Haemic and lymphatic systems. Haematology
WI Digestive system. Gastroenterology
WK Endocrine system. Endocrinology
Divisions: Planned IP Care > Oncology and Clinical Haematology
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Depositing User: Jamie Edgar
Date Deposited: 20 Dec 2019 15:16
Last Modified: 20 Dec 2019 15:16

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