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

Abstract

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.

Investigating the poor outcomes ofBRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials

“…This is particularly important as B mutant patients have questionable benefit from antiBepidermal growth factor receptor (antiBEGFR) therapies [6] and Btargeted strategies have yet to make clinical impact in aCRC. [7,8] Importantly previous publications have not performed careful multivariate analysis. This is critical as Bmutant aCRC is associated with clinicopathological features which are themselves negative prognostic factors, [9] including defective mismatch repair (dMMR) status [4,10] , right sided primary tumour location (PTL) [11] and a high incidence of peritoneal metastases.…”

DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?

“…As one example, BRAF V600E -mutant colon cancers have modest responses to BRAF inhibition compared to melanomas harboring the same oncogenic driver mutation (9,10). This discrepancy can be explained by the expression of the EGFR gene in colon cancer, a receptor that is activated upon BRAF inhibition in these cancers (11,12).…”

Combined dabrafenib and trametinib treatment in a case of chemotherapy-refractory extrahepatic BRAF V600E mutant cholangiocarcinoma: dramatic clinical and radiological response with a confusing synchronic new liver lesion

“…Dual inhibition of BRAF and MEK delaying the emergence of resistance and increases survival in patients with metastatic melanoma, as MEK inhibitor (trametinib) suppresses the acquired reactivation of the MAPK pathway (17). Not only the toxic effects were much better tolerated in combination treatment but the incidence of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib arm compared to dabrafenib monotherapy (21,24). Based on the available data, dabrafenib plus trametinib became the first targeted combination therapy approved by the Food and Drug Administration (FDA) in metastatic BRAF V600E mutated melanoma.…”

“…Based on the available data, dabrafenib plus trametinib became the first targeted combination therapy approved by the Food and Drug Administration (FDA) in metastatic BRAF V600E mutated melanoma. A few promising data are reported on the use of BRAF plus MEK inhibitors in non-melanoma cancers harboring BRAF V600E mutations (12,24). A phase 2, multicentric, non-randomised trial of dabrafenib plus trametinib demonstrated significant antitumour activity and manageable safety profile on 57 patients with BRAF V600E mutated non-small cell lung cancer (12).…”

“…A phase 2, multicentric, non-randomised trial of dabrafenib plus trametinib demonstrated significant antitumour activity and manageable safety profile on 57 patients with BRAF V600E mutated non-small cell lung cancer (12). A study on 43 patients with metastatic colorectal cancer with BRAF V600 mutation dabrafenib plus trametinib treatment proved to be active in a subset of patients, however the degree of response was less than in BRAF-mutant melanoma treated with dabrafenib alone (24).…”