Combined BRAF, EGFR, and MEK inhibition in patients with BRAF(V600E)-mutant colorectal cancer Journal Article


Authors: Corcoran, R. B.; André, T.; Atreya, C. E.; Schellens, J. H. M.; Yoshino, T.; Bendell, J. C.; Hollebecque, A.; McRee, A. J.; Siena, S.; Middleton, G.; Muro, K.; Gordon, M. S.; Tabernero, J.; Yaeger, R.; O’Dwyer, P. J.; Humblet, Y.; De Vos, F.; Jung, A. S.; Brase, J. C.; Jaeger, S.; Bettinger, S.; Mookerjee, B.; Rangwala, F.; Van Cutsem, E.
Article Title: Combined BRAF, EGFR, and MEK inhibition in patients with BRAF(V600E)-mutant colorectal cancer
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. ©2018 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 8
Issue: 4
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2018-04-01
Start Page: 428
End Page: 443
Language: English
DOI: 10.1158/2159-8290.cd-17-1226
PROVIDER: scopus
PMCID: PMC5882509
PUBMED: 29431699
DOI/URL:
Notes: Article -- Export Date: 2 July 2018 -- Source: Scopus
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  1. Rona Denit Yaeger
    162 Yaeger