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Clin Cancer Res. 2014 Aug 15;20(16):4251-61. doi: 10.1158/1078-0432.CCR-14-0341. Epub 2014 Jun 19.

Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations.

Author information

1
Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
2
Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Phase I unit, CIC- CPCET, Marseille, France.
3
Department of Medical Oncology, Hospital del Mar and Cancer Research Program, IMIM, Barcelona, Spain.
4
Institute Curie, Paris, France.
5
The Netherlands Cancer Institute, Amsterdam, the Netherlands.
6
Hôpital La Pitié-Salpêtrière, IUC/UPMC, Paris, France.
7
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.
8
START Madrid, Hospital Universitario Madrid Sanchinarro, Madrid, Spain.
9
Hospital Virgen del Rocio, Seville, Spain.
10
Royal Marsden NHS Foundation Trust, London, United Kingdom.
11
University of Cambridge, Department of Oncology, Cambridge, United Kingdom.
12
Pharma Research and Early Development, Oncology, Roche Penzberg, Germany.
13
Nuclear Medicine Department, Hôtel-Dieu University Hospital, Nantes, France.
14
Pharma Research and Early Development, Oncology, Roche, Switzerland.
15
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Ruhrlandklinik, University Duisburg-Essen, Essen, Germany. wilfried.eberhardt@uni-duisburg-essen.de.
16
Clinical Investigation Center 1423, Quinze-Vingts Hospital, Paris 6 University, Paris, France.
17
SITEP, Gustave Roussy Cancer Center, University Paris-Sud, Villejuif, Paris, France.

Abstract

PURPOSE:

This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor.

EXPERIMENTAL DESIGN:

We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added.

RESULTS:

Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications.

CONCLUSIONS:

Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251-61. ©2014 AACR.

PMID:
24947927
DOI:
10.1158/1078-0432.CCR-14-0341
[Indexed for MEDLINE]
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