Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600–Mutant Colorectal Cancer
Open accessAbstract
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.
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Clinical trials with MEK inhibitor were disappointing in CRC patients.
“However, the results of clinical trials with MEK inhibitor (MEKi) were disappointing in CRC patients [13, 14].”
From Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer (2022) · cites this paper as [13]
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“Based on this premises, vertical inhibition of the MAPK pathway at different points has been explored in multiple studies, assessing different combinations of BRAFi with EGFR and/or MEK inhibitors, as well as dual inhibition of the MAPK and PI3K/mTOR pathways [14 – 16].”
- Authors
- Corcoran, R. B., Atreya, C. E., Falchook, G. S., Kwak, E. L., Ryan, D. P., Bendell, J. C., Hamid, O., Messersmith, W. A., Daud, A., Kurzrock, R., Pierobon, M., Sun, P., Cunningham, E., Little, S., Orford, K., Motwani, M., Bai, Y., Patel, K., Venook, A. P., & Kopetz, S.
- Affiliations
- University of California, San Francisco (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2015-12-01
- Volume
- 33
- Issue
- 34
- Pages
- 4023-4031
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC4669588
- OpenAlex
- W1922733886
- Cited by
- 507
- References
- 4
- Citations by year
- 2026: 17 · 2025: 27 · 2024: 33 · 2023: 51 · 2022: 52 · 2021: 46 · 2020: 60 · 2019: 52 · 2018: 49 · 2017: 59 · 2016: 58 · 2015: 3
- FWCI
- 24.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- American Association for Cancer Research
- Damon Runyon Cancer Research Foundation
- Pfizer
- AstraZeneca (CA016672)
- GlaxoSmithKline
- Sanofi
- George Mason University
- Celgene
- Array BioPharma
- Incyte (CA016672)
- National Institutes of Health (UL1TR000371, CA- 016672, K08CA175143)
- Genentech
- EMD Serono
- Onyx Pharmaceuticals
- University of Texas MD Anderson Cancer Center ((CA016672), R01CA184843, UL1 RR024148)
- Takeda Oncology
- National Cancer Institute (P50CA127003, K08CA175143, CA 016672, R01CA184843, CA016672 to, K08CA175153, R01CA172670, K08CA166510, P30CA016672)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK026743)
- National Center for Research Resources (UL1RR024148)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Keywords
- dabrafenib, trametinib, BRAF V600 mutation, metastatic colorectal cancer, BRAF/MEK inhibitor combination, MAPK inhibition, PIK3CA mutation, ERK1/2 phosphorylation, patient-derived xenografts, microsatellite instability
- MeSH terms
- Animals, Antineoplastic Combined Chemotherapy Protocols, Biopsy, Female, Follow-Up Studies, Humans, Imidazoles, Male, Middle Aged, Mutation, Neoplasm Staging, Oximes, Prognosis, Pyridones, Pyrimidinones, Colorectal Neoplasms, Cohort Studies, Xenograft Model Antitumor Assays, MAP Kinase Kinase 1, Proto-Oncogene Proteins B-raf, PTEN Phosphohydrolase, Mice, Microsatellite Instability
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