BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
The inevitable onset of acquired resistance and disease progression in patients treated with BRAF or MEK inhibitor monotherapy led to significant interest in combining these agents. Pre-clinical rationale for combination therapy was strong, as many mechanisms of acquired resistance involve reactivation of the MAPK pathway, including acquired NRAS mutations,  MEK1 mutations , COT overexpression , BRAF amplification , alternate splicing of BRAF  and loss of CDKN2A (through indirect dysregulation of MAPK signaling) . Growth factor upregulation, alterations in the PI3K-AKT-MTOR pathway and decreased apoptosis, also appear to play a role in acquired resistance which may not respond to combined BRAF/MEK inhibition [29–34] (Fig. 4.3).
Fig. 4.3. Mechanisms of acquired resistance to BRAF inhibitors. Resistance arises reactivation of the MAPK pathway, growth factor upregulation, dysregulation of the PI3K-AKT pathway, and decreased apoptosis
A phase I/II trial evaluating dabrafenib and trametinib was conducted with rapid dose escalation to a recommended phase II dosing . A randomized comparison of combination therapy (dabrafenib 150 mg twice daily and trametinib 1 mg or 2 mg daily) to dabrafenib monotherapy was then performed in 162 patients. Patients on the 150/2 mg dosing arm had improved median PFS of 9.4 months compared to 5.6 months with dabrafenib alone, with 41% of patients remaining progression-free at 12 months (hazard ratio for death or progression of 0.39; p <0.001). Improvements were demonstrated regardless of BRAF mutation (V600E or K) and across metastatic stages (M1a/b and M1c). Objective responses occurred more frequently in the combination therapy arm (76 vs. 54%, 9% vs. 4% CR rate). For responding patients, the median duration of response was also superior (10.5 months vs. 5.6 months). Despite the clear improvement in PFS and response rate, an improvement in OS has not yet been demonstrated. An OS benefit may be observed with continued follow-up.
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