BRAF and MEK Inhibitors in Melanoma

High constitutive activity of MAPK pathway has been shown in a majority of melanomas. To date, BRAF and MEK have been shown to be clinically relevant components of this pathway with proven efficacy of agents targeted to BRAF and MEK.

Vemurafenib was the first BRAF inhibitor approved by the FDA in August 2011 for V600E BRAF mutation positive unresectable or metastatic melanoma at a dose of 960 mg orally twice a day. This was based on results of a phase III randomized study (BRIM 3), which showed a highly significant overall survival (OS) benefit, as well an improvement in progression free survival (PFS) and response rate (RR) when compared to dacarbazine. Additional phase I and phase II (BRIM 2) studies done prior to this had shown promising results providing a rationale for the phase III study.

Dabrafenib, also a BRAF inhibitor, was approved by the FDA in May 2013 at a dose of 150 mg orally twice a day, for use in patients with unresectable or metastatic BRAF V600E mutation positive melanoma. Dabrafenib was evaluated in a phase III randomized trial and was shown to cause a significant improvement in PFS compared to dacarbazine.

In May 2013, MEK inihibitor Trametinib was approved for use in metastatic/unresectable melanoma with BRAF V600E and V600F mutations in patients without prior exposure to BRAF inhibitors. This was based on a randomized phase III study comparing Trametinib with chemotherapy (decarbazine or paclitaxel) for BRAF V600E or V600K mutation positive metastatic melanoma. Trametinib led to a statistically significant improvement in rates of progression-free and overall survival.

Inhibiting MAPK Pathway to Improve Response Duration

Although BRAF inhibitors have shown a significant response rate of 50% or more in patients with BRAF mutation positive melanoma, the duration of response has been limited to 5–7 months with emergence of resistance. Evaluation of potential mechanisms of resistance has been an active field of research and one theory is rapid reactivation of MAPK pathway. Based on this hypothesis, a combination of BRAF inhibitor with a MEK inhibitor has been evaluated in an open label multicenter phase I/II trial. In the phase II arm of this trial, a total of 162 patients with BRAF V600 (E or K) mutation were randomized in a 1:1:1 ratio to receive a combination of Dabrafenib 150 mg oral twice a day with 1 mg of Trametinib (n=54), or Dabrafenib 150 mg oral twice a day with 2 mg of Trametinib orally once a day (n=54) or single agent Dabrafenib 150 mg oral twice a day (n=54). At a median follow-up of 14 months, a significant improvement in PFS (9.4 months in combination arm vs 5.8 months in single agent, p<0.001) was noted in the combination arm utilizing Dabrafenib 150 mg twice a day with Trametinib 2 mg once a day. Additionally, combination therapy led to an improvement in response rates (76% vs 54%) as well as duration of response (10.5 months vs 5.6 months). Major adverse effects noted in the combination arm included pyrexia and chills, fatigue, nausea, vomiting and diarrhea. The incidence of squamous cell carcinomas was higher in the monotherapy group compared to combination therapy group.

Based on the results of this study a combination of Trametinib (2 mg orally once a day) with Dabrafenib (150 mg orally twice a day) was approved by the FDA in January 2014 for metastatic or unresectable melanoma with V600E or V600K mutation in BRAF.

To evaluate other potential mechanisms of inhibiting MAPK pathway, a study at RPCI is evaluating ERK inhibition. Read about this study here.

Another significant pathway postulated to play a role in melanoma is the Vascular Endothelial Growth Factor (VEGF) pathway. Studies have supported activity of a second-generation inhibitor of VEGF receptors, Axitinib in metastatic melanoma.

At RPCI we are conducting a phase II trial sponsored by NCCN evaluating single agent Axitinib in the treatment of patients with advanced melanoma.