Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer

J Clin Oncol. 2015 Dec 1;33(34):4023-31. doi: 10.1200/JCO.2015.63.2471. Epub 2015 Sep 21.


Purpose: To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC).

Patients and methods: A total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples.

Results: Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft-bearing mice and the biopsied lesions from each corresponding patient.

Conclusion: The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.

Trial registration: NCT01072175.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biopsy
  • Cohort Studies
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Female
  • Follow-Up Studies
  • Humans
  • Imidazoles / administration & dosage
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • Male
  • Mice
  • Microsatellite Instability
  • Middle Aged
  • Mutation / genetics*
  • Neoplasm Staging
  • Oximes / administration & dosage
  • PTEN Phosphohydrolase / genetics
  • Prognosis
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Pyridones / administration & dosage
  • Pyrimidinones / administration & dosage
  • Xenograft Model Antitumor Assays


  • Imidazoles
  • Oximes
  • Pyridones
  • Pyrimidinones
  • trametinib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • dabrafenib

Associated data