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Cancer Discov. 2018 Apr;8(4):428-443. doi: 10.1158/2159-8290.CD-17-1226. Epub 2018 Feb 5.

Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer.

Author information

1
Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts. rbcorcoran@partners.org.
2
Hôpital Saint-Antoine, and Sorbonne Universités, Paris, France.
3
University of California, San Francisco, California.
4
The Netherlands Cancer Institute, Amsterdam, the Netherlands.
5
National Cancer Center Hospital East, Chiba, Japan.
6
Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
7
Institute Gustave Roussy, Villejuif, France.
8
University of North Carolina, Chapel Hill, North Carolina.
9
Niguarda Cancer Center, Grande Osopedale Metropolitano Niguarda and Department of Oncology and Hemato-Oncollogy, Università degli Studi di Milano, Milan, Italy.
10
University of Birmingham and University Hospital, Birmingham, United Kingdom.
11
Aichi Cancer Center Hospital, Nagoya, Japan.
12
Pinnacle Oncology Hematology, Scottsdale, Arizona.
13
Vall d'Hebron University Hospital, Barcelona, Spain.
14
Memorial Sloan Kettering Cancer Center, New York, New York.
15
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
16
St-Luc University Hospital, Brussels, Belgium.
17
Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
18
Amgen Inc., Thousand Oaks, California.
19
Novartis Pharma AG, Basel, Switzerland.
20
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
21
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
22
University Hospitals Leuven and KU Leuven, Leuven, Belgium.

Abstract

Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428-43. ©2018 AACR.See related commentary by Janku, p. 389See related article by Hazar-Rethinam et al., p. 417This article is highlighted in the In This Issue feature, p. 371.

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PMID:
29431699
PMCID:
PMC5882509
DOI:
10.1158/2159-8290.CD-17-1226
[Indexed for MEDLINE]
Free PMC Article

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