Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular Carcinoma

Ho Yeong Lim, Philippe Merle, Karl Heinz Weiss, Thomas Yau, Paul Ross, Vincenzo Mazzaferro, Jean Fredèric Blanc, Yuk Ting Ma, Chia Jui Yen, Judit Kocsis, Su Pin Choo, Wattana Sukeepaisarnjaroen, Rene Gerolami, Jean François Dufour, Edward J. Gane, Baek Yeol Ryoo, Markus Peck-Radosavljevic, Thong Dao, Winnie Yeo, Wisut LamlertthonSatawat Thongsawat, Michael Teufel, Katrin Roth, Diego Reis, Barrett H. Childs, Heiko Krissel, Josep M. Llovet

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 b-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.

Original languageEnglish
Pages (from-to)4650-4661
Number of pages12
JournalClinical Cancer Research
Volume24
Issue number19
DOIs
Publication statusPublished - 2018 Oct 1

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Hepatocellular Carcinoma
Mutation
DNA
Magnetics
Disease-Free Survival
Survival
N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
sorafenib
Circulating Neoplastic Cells
Catenins
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Exanthema
Emulsions
Fatigue
Biomarkers
Hypertension
Technology
Population

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lim, Ho Yeong ; Merle, Philippe ; Weiss, Karl Heinz ; Yau, Thomas ; Ross, Paul ; Mazzaferro, Vincenzo ; Blanc, Jean Fredèric ; Ma, Yuk Ting ; Yen, Chia Jui ; Kocsis, Judit ; Choo, Su Pin ; Sukeepaisarnjaroen, Wattana ; Gerolami, Rene ; 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 ; Llovet, Josep M. / Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular Carcinoma. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 19. pp. 4650-4661.
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title = "Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular Carcinoma",
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 b-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.",
author = "Lim, {Ho Yeong} and Philippe Merle and Weiss, {Karl Heinz} and Thomas Yau and Paul Ross and Vincenzo Mazzaferro and Blanc, {Jean Fred{\`e}ric} and Ma, {Yuk Ting} and Yen, {Chia Jui} and Judit Kocsis and Choo, {Su Pin} and Wattana Sukeepaisarnjaroen and Rene Gerolami and Dufour, {Jean Fran{\cc}ois} and Gane, {Edward J.} and Ryoo, {Baek Yeol} and Markus Peck-Radosavljevic and Thong Dao and Winnie Yeo and Wisut Lamlertthon and Satawat Thongsawat and Michael Teufel and Katrin Roth and Diego Reis and Childs, {Barrett H.} and Heiko Krissel and Llovet, {Josep M.}",
year = "2018",
month = "10",
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doi = "10.1158/1078-0432.CCR-17-3588",
language = "English",
volume = "24",
pages = "4650--4661",
journal = "Clinical Cancer Research",
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Lim, HY, Merle, P, Weiss, KH, Yau, T, Ross, P, Mazzaferro, V, Blanc, JF, Ma, YT, Yen, CJ, Kocsis, J, Choo, SP, Sukeepaisarnjaroen, W, Gerolami, R, Dufour, JF, Gane, EJ, Ryoo, BY, Peck-Radosavljevic, M, Dao, T, Yeo, W, Lamlertthon, W, Thongsawat, S, Teufel, M, Roth, K, Reis, D, Childs, BH, Krissel, H & Llovet, JM 2018, 'Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular Carcinoma', Clinical Cancer Research, vol. 24, no. 19, pp. 4650-4661. https://doi.org/10.1158/1078-0432.CCR-17-3588

Phase II studies with refametinib or refametinib plus sorafenib in patients with RAS-mutated hepatocellular Carcinoma. / Lim, Ho Yeong; Merle, Philippe; Weiss, Karl Heinz; Yau, Thomas; Ross, Paul; Mazzaferro, Vincenzo; Blanc, Jean Fredèric; Ma, Yuk Ting; Yen, Chia Jui; Kocsis, Judit; Choo, Su Pin; Sukeepaisarnjaroen, Wattana; Gerolami, Rene; 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; Llovet, Josep M.

In: Clinical Cancer Research, Vol. 24, No. 19, 01.10.2018, p. 4650-4661.

Research output: Contribution to journalArticle

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 Fredèric

AU - Ma, Yuk Ting

AU - Yen, Chia Jui

AU - Kocsis, Judit

AU - Choo, Su Pin

AU - Sukeepaisarnjaroen, Wattana

AU - Gerolami, Rene

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.

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 b-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.

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 b-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.

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U2 - 10.1158/1078-0432.CCR-17-3588

DO - 10.1158/1078-0432.CCR-17-3588

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JF - Clinical Cancer Research

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