Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations

The treatment of metastatic melanoma has been greatly enhanced by pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) pathway. Trametinib mediates blockade of MAPK kinase (MEK), which is downstream of BRAF in the MAPK pathway and has been associated with improved progression-free and overall survival in BRAF V600 melanoma (comprising both V600E and V600K mutations). In spite of this, 50% of patients who are treated with BRAF or MEK inhibitors have disease progression within 6 to 7 months after treatment initiation. This is attributed to continued resistance to therapy with BRAF kinase inhibitors, which are associated with reactivation of the MAPK pathway.

In an attempt to delay resistance to BRAF inhibition and explore the safety of combination therapy with BRAF and MEK inhibitors, the authors conducted a phase 1 and 2 study to investigate the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in patients with metastatic BRAF V600 melanoma.

The study [N Engl J Med. 2012;367(18):1694-1703] was an open-label study designed to assess the safety, pharmacokinetic activity, and clinical activity of combination therapy with dabrafenib plus trametinib. From March 26, 2010, to July 7, 2011, the researchers screened 443 patients at 16 centers for participation in the trial. Patients ≥18 years of age who had histological confirmed metastatic melanoma with either BRAF V600E or BRAF V600K mutations were eligible for inclusion.

Eligible patients had measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (with 0 indicating asymptomatic and 1 indicating ambulatory, but restricted in strenuous activity), and adequate organ function. Patients with treated brain metastases and at least a 3-month history of stable disease were allowed to enroll. The authors included a total of 85 patients in the phase of the study that evaluated the side-effect profile, safety, and pharmacokinetic activity of escalating doses of dabrafenib (75 and 150 mg twice daily) in combination with trametinib (1, 1.5, and 2 mg once daily).

Also, 162 patients were randomly assigned to receive combination therapy with dabrafenib
(150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points for this latter group were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.

There were no dose-limiting toxic effects at the first 3 dose levels: (1) 75 mg of dabrafenib twice daily plus 1 mg of trametinib once daily, (2) 150 mg of dabrafenib twice daily plus 1 mg of trametinib once daily (combination 150/1), and (3) 150 mg of dabrafenib twice daily plus 1.5 mg of trametinib once daily. There was one dose-limiting toxic effect among the 24 patients who were treated at the highest dose level(150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily [combination 150/2]). The incidence of cutaneous squamous-cell carcinoma (including keratoacanthoma) in patients receiving dabrafenib monotherapy was 19%, as compared with 2% for combination 150/1 and 7% for combination 150/2. The most frequent adverse events observed in the combination 150/2 group were pyrexia (all grades, 71%; grade 3, 5%) and chills (all grades, 58%; grade 3, 2%).

Median progression-free survival for patients in the combination 150/2 group was 9.4 months, as compared with 5.8 months with dabrafenib monotherapy (hazard ratio for progression or death, 0.39; 95% confidence interval [CI], 0.25-0.62; P<.001).

At 1 year, 41% of patients in the combination 150/2 group were alive and progression-free, as compared with 9% in the monotherapy group (P<.001). Progression-free survival was consistently improved in all prognostic subgroups of the combination 150/2 group, as compared with monotherapy. Patients with the BRAF V600E mutation and those with the BRAF V600K mutation had significant improvement in progression-free survival. In the combination 150/2 group, there was a 76% rate of complete or partial response compared with 54% in the monotherapy group; median duration of response was 10.5 months in the combination 150/2 group (95% CI, 7.4-14.9) versus 5.6 months in the monotherapy group (95% CI, 4.5-7.4).