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Clin Cancer Res. 2018 Oct 1;24(19):4650-4661. doi: 10.1158/1078-0432.CCR-17-3588. Epub 2018 Jun 27.

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

Author information

1
Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University, Seoul, Korea. hoylim@skku.edu josep.llovet@mssm.edu melody.tam@mssm.edu.
2
Service of Hepato-Gastroenterology, Hepatology Unit, Croix-Rousse Hospital, Lyon, France.
3
Section of Transplant Hepatology, Liver Cancer Center Heidelberg, Heidelberg, Germany.
4
Department of Medicine, Queen Mary Hospital, Hong Kong.
5
Cancer Centre, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom.
6
Gastrointestinal Surgery and Liver Transplant Unit, The Fondazione IRCCS Istituto Nazionale Tumori (National Cancer Institute) and University of Milan, Milan, Italy.
7
Service of Hepato-Gastroenterology and Digestive Oncology, Hôpital Haut-Lévêque, Bordeaux, France.
8
Department of Medical Oncology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.
9
Division of Hematology and Oncology, National Cheng Kung University Hospital, Tainan, Taiwan.
10
Oncology Department, Debrecen University Clinical Center, Debrecen, Hungary.
11
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
12
Department of Medicine, Srinagarind Hospital, Khon Kaen, Thailand.
13
Service of Hepato-Gastroenterology, Aix-Marseille University, Marseille, France.
14
Department of Hepatology, University Clinic for Visceral Surgery and Medicine, University Hospital of Bern, Bern, Switzerland.
15
New Zealand Liver & Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
16
Department of Oncology, Asan Medical Center, Seoul, Korea.
17
Department of Gastroenterology and Hepatology, Endocrinology, Rheumatology and Nephrology, Medical University of Vienna, Vienna, Austria.
18
Service of Hepato-Gastroenterology and Nutrition, Caen University Hospital, Caen, France.
19
Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong.
20
Chulabhorn Hospital, Bangkok, Thailand.
21
Department of Internal Medicine, Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand.
22
Bayer HealthCare Pharmaceuticals, Inc., Whippany, New Jersey.
23
Bayer AG, Berlin, Germany.
24
Medical and Data Management, Bayer S.A., São Paulo, Brazil.
25
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York. hoylim@skku.edu josep.llovet@mssm.edu melody.tam@mssm.edu.
26
Liver Cancer Translational Research Laboratory, Barcelona Clinic Liver Cancer Group (BCLC), IDIBAPS-Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain.
27
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.

Abstract

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.

PMID:
29950351
DOI:
10.1158/1078-0432.CCR-17-3588
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