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Cited by 71Melanoma and MAPK PathwaysProtein Tyrosine PhosphatasesProtein Kinase Regulation and GTPase Signaling

The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.

Phase I Expansion and Pharmacodynamic Study of the Oral MEK Inhibitor RO4987655 (CH4987655) in Selected Patients with Advanced Cancer with RAS–RAF Mutations

Zimmer, Lisa, Barlesi, Fabrice, Martinez-Garcia, Maria, Dieras, Veronique, Schellens, Jan H.M., Spano, Jean-Philippe, Middleton, Mark R., Calvo, Emiliano, Paz-Ares, Luiz, Larkin, James, Pacey, Simon, Venturi, Miro, Kraeber-Bodéré, Françoise, Tessier, Jean J.L., Eberhardt, Wilfried Ernst Erich, Paques, Michel, Guarin, Ernesto, Meresse, Valerie, Soria, Jean-Charles·2014·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-14-0341

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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.

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Crossref · 10.1158/1078-0432.ccr-14-0341

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Authors
Zimmer, L., Barlesi, F., Martinez-Garcia, M., Dieras, V., Schellens, J. H. M., Spano, J.-P., Middleton, M. R., Calvo, E., Paz-Ares, L., Larkin, J., Pacey, S., Venturi, M., Kraeber-Bodéré, F., Tessier, J. J. L., Eberhardt, W. E. E., Paques, M., Guarin, E., Meresse, V., & Soria, J.-C.
Affiliations
  • University of Duisburg-Essen (DE)
  • 2Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Phase I unit, CIC- CPCET, Marseille, France.
  • 3Department of Medical Oncology, Hospital del Mar and Cancer Research Program, IMIM, Barcelona, Spain.
  • Institut Curie (FR)
  • The Netherlands Cancer Institute (NL)
  • Pitié-Salpêtrière Hospital (FR)
  • Churchill Hospital (GB)
  • 8START Madrid, Hospital Universitario Madrid Sanchinarro, Madrid, Spain.
  • Hospital Universitario Virgen del Rocío (ES)
  • Royal Marsden NHS Foundation Trust (GB)
  • University of Cambridge (GB)
  • Roche Pharma AG (Germany) (DE)
  • 13Nuclear Medicine Department, Hôtel-Dieu University Hospital, Nantes, France.
  • F. Hoffmann-La Roche AG (CH)
  • Ruhrlandklinik (DE)
  • 16Clinical Investigation Center 1423, Quinze-Vingts Hospital, Paris 6 University, Paris, France.
  • 14Pharma Research and Early Development, Oncology, Roche, Switzerland.
  • Institut Gustave Roussy (FR)
Corresponding author
Eberhardt, Wilfried Ernst Erich
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2014-08-13
Volume
20
Issue
16
Pages
4251-4261
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-14-0341
OpenAlex
W2054913636
Cited by
71
References
50
Citations by year
2026: 4 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 10 · 2020: 4 · 2019: 6 · 2018: 1 · 2017: 7 · 2016: 6 · 2015: 16 · 2014: 4
FWCI
4.51
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
MEK inhibitors, RAS/RAF mutations, BRAF-mutant melanoma, KRAS-mutant non-small cell lung cancer, KRAS-mutant colorectal cancer, ERK1/2 phosphorylation, Ki-67, PIK3CA, anticancer activity, drug safety, acneiform dermatitis, FDG uptake
MeSH terms
Administration, Oral, Adult, Aged, Aged, 80 and over, Benzamides, DNA Mutational Analysis, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Neoplasms, Oxazines, Prognosis, Proto-Oncogene Proteins, Tissue Distribution, Proto-Oncogene Proteins p21(ras), Patient Selection, ras Proteins, Phosphatidylinositol 3-Kinases, MAP Kinase Kinase Kinases, Proto-Oncogene Proteins B-raf, Young Adult, Class I Phosphatidylinositol 3-Kinases

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