Phase II Studies with Refametinib or Refametinib plus Sorafenib in Patients with RAS-Mutated Hepatocellular Carcinoma
Ho Yeong Lim
(1)
,
Philippe Merle
(2)
,
Karl Heinz Weiss
(3)
,
Thomas Yau
(4)
,
Paul Ross
(5)
,
Vincenzo Mazzaferro
(6)
,
Jean-Frederic Blanc
(7, 8)
,
Yuk Ting Ma
(9)
,
Chia Jui Yen
(10)
,
Judit Kocsis
(11)
,
Su Pin Choo
(12)
,
Wattana Sukeepaisarnjaroen
(13)
,
Rene Gerolami
(14, 15)
,
Jean-Francois Dufour
(16)
,
Edward J. Gane
(17)
,
Baek-Yeol Ryoo
(18)
,
Markus Peck-Radosavljevic
(19)
,
Thong Dao
(20, 21)
,
Winnie Yeo
(4)
,
Wisut Lamlertthon
(22)
,
Satawat Thongsawat
(23)
,
Michael Teufel
(24)
,
Katrin Roth
(25)
,
Diego Reis
(25)
,
Barrett H. Childs
(24)
,
Heiko Krissel
(25)
,
Josep M. Llovet
(26)
1
SKKU -
Sungkyunkwan University [Suwon]
2 Service d'Hépatologie [Hôpital de la Croix-Rousse - HCL]
3 Heidelberg University Hospital [Heidelberg]
4 HKU - The University of Hong Kong
5 NHS Foundation Trust [London]
6 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico
7 Physiopathologie du cancer du foie
8 Hôpital Haut-Lévêque [CHU Bordeaux]
9 University of Birmingham [Birmingham]
10 NCKU - National Cheng Kung University
11 University of Debrecen Egyetem [Debrecen]
12 NCCS - National Cancer Centre Singapore
13 KKU - Khon Kaen University [Thailand]
14 APHM - Assistance Publique - Hôpitaux de Marseille
15 MEPHI - Microbes évolution phylogénie et infections
16 UNIBE - Universität Bern / University of Bern
17 University of Auckland [Auckland]
18 Asan Medical Center [Seoul]
19 Medizinische Universität Wien = Medical University of Vienna
20 Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen]
21 COMETE - Mobilités : Vieillissement, Pathologie, Santé
22 Chulabhon Hospital
23 CMU - Chiang Mai University
24 Bayer HealthCare Pharmaceuticals Inc [Whippany]
25 Bayer Pharma AG [Berlin]
26 Clinical and experimental neuroimmunology [IDIBAPS]
2 Service d'Hépatologie [Hôpital de la Croix-Rousse - HCL]
3 Heidelberg University Hospital [Heidelberg]
4 HKU - The University of Hong Kong
5 NHS Foundation Trust [London]
6 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico
7 Physiopathologie du cancer du foie
8 Hôpital Haut-Lévêque [CHU Bordeaux]
9 University of Birmingham [Birmingham]
10 NCKU - National Cheng Kung University
11 University of Debrecen Egyetem [Debrecen]
12 NCCS - National Cancer Centre Singapore
13 KKU - Khon Kaen University [Thailand]
14 APHM - Assistance Publique - Hôpitaux de Marseille
15 MEPHI - Microbes évolution phylogénie et infections
16 UNIBE - Universität Bern / University of Bern
17 University of Auckland [Auckland]
18 Asan Medical Center [Seoul]
19 Medizinische Universität Wien = Medical University of Vienna
20 Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen]
21 COMETE - Mobilités : Vieillissement, Pathologie, Santé
22 Chulabhon Hospital
23 CMU - Chiang Mai University
24 Bayer HealthCare Pharmaceuticals Inc [Whippany]
25 Bayer Pharma AG [Berlin]
26 Clinical and experimental neuroimmunology [IDIBAPS]
Résumé
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 (OCR) 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 NCS. The most frequently detected mutations were in TERT (63.0%), TP53 (48.1%), and beta-catenin (CTNNBI; 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. (C) 2018 AACR.