Research article combined BRAF, EGFR, and MEK inhibition in patients with BRAF V600E -mutant colorectal cancer

Ryan B Corcoran, Thierry Andre, Chloe E Atreya, Jan H M Schellens, Takayuki Yoshino, Johanna C Bendell, Antoine Hollebecque, Autumn J McRee, Salvatore Siena, Gary Middleton, Kei Muro, Michael S Gordon, Josep Tabernero, Rona Yaeger, Peter J O'Dwyer, Yves Humblet, Filip De Vos, A Scott Jung, Jan C Brase, Savina JaegerSeverine Bettinger, Bijoyesh Mookerjee, Fatima Rangwala, Eric Van Cutsem

Research output: Contribution to journalArticleAcademicpeer-review


Although BRAF inhibitor monotherapy yields response rates >50% in BRAF V600 - 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.

Original languageEnglish
Pages (from-to)428-443
Number of pages16
JournalCancer Discovery
Issue number4
Early online date5 Feb 2018
Publication statusPublished - Apr 2018


  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Colorectal Neoplasms/drug therapy
  • Drug Resistance, Neoplasm
  • ErbB Receptors/antagonists & inhibitors
  • Female
  • Humans
  • Imidazoles/therapeutic use
  • MAP Kinase Signaling System
  • Male
  • Mitogen-Activated Protein Kinase Kinases/drug effects
  • Oximes/therapeutic use
  • Panitumumab/therapeutic use
  • Protein Kinase Inhibitors/therapeutic use
  • Proto-Oncogene Proteins B-raf/antagonists & inhibitors
  • Pyridones/therapeutic use
  • Pyrimidinones/therapeutic use


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