Activity of Combined BRAF and MEK Inhibition in BRAF V600–Mutant Metastatic Colorectal Cancer
In a phase I/II study reported in the Journal of Clinical Oncology, Corcoran et al found that the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) produced responses in some patients with BRAF V600–mutant metastatic colorectal cancer. MAPK signaling was reduced with treatment but to a smaller degree than that observed in BRAF V600–mutant melanoma treated with dabrafenib alone.
Study Details
In the study, 43 patients received dabrafenib 150 mg twice daily and trametinib 2 mg daily. A subgroup underwent biopsies before and during treatment. Archived tissue was analyzed for microsatellite instability, PTEN status, and 487-gene sequencing.
Responses
Response occurred in five patients (12%), including a complete response in one, with a response duration of > 36 months. The complete response was observed in the only patient who had not received prior systemic therapy. Stable disease was observed in 24 patients (56%), and 16 patients (37%) had ≥ 10% reduction in target lesion size.
All nine evaluable during-treatment biopsies showed reduced levels of phosphorylated ERK vs pretreatment biopsies (average decrease of 47%); however, this decrease was smaller than that observed with dabrafenib alone in patients with BRAF-mutant melanoma (average decrease of 75%). PIK3CA mutations at hotspots in exons 9 and 20 were identified in 5 of 15 evaluable patients; among them were two of the patients with a partial response and the one patient with a complete response, with an additional patient having a reduction in target lesion size. PTEN loss and microsatellite instability were not associated with efficacy.
The investigators concluded: “The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600–mutant [metastatic colorectal cancer]. 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.”
Ryan B. Corcoran, MD, PhD, of Massachusetts General Hospital Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
The study was supported by GlaxoSmithKline and in part by awards for the National Cancer Institute and National Institutes of Health. For full disclosures of the study authors, visit jco.ascopubs.org.
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