Improved Survival in BRAF-Mutated Melanoma With Trametinib
Melanoma is a skin cancer that arises from pigment cells called melanocytes. In the under 40-years population, melanoma is the second-most common cancer with 160,000 newly diagnosed cases and 48,000 related deaths every year. Nearly 50% advanced melanoma patients have mutations in B-RAF (BRAF), an enzyme which modulates tumour cell growth. Two mutations, V600E and V600K constitute 95% of observed BRAF mutations Treatment with vemurafenib and ipilimumab enhance survival in BRAF-mutated melanoma patients.
A clinical trial was sponsored by GlaxoSmithKline to evaluate the efficacy of trametinib on tumour progression and disease stabilization in melanoma patients. Patients with significant heart, lung or eye disease were excluded. The enrolled patients had un-resectable stage IIIC/IV cutaneous melanoma with V600E or V600K BRAF mutations.
Patients were randomly assigned to receive trametinib (2 mg/day) or intravenous chemotherapy (1000mg dacarbazine or 175mg paclitaxel per square meter) every 3 weeks. Progression-free survival was the primary end point, and overall survival, response rate, response duration and safety were secondary end points. Tumour assessments were conducted at weeks 0, 6, 12, 21, and 30 and quarterly thereafter.
The average progression-free survival was 4.8 months and 1.5 months in the trametinib and chemotherapy groups respectively (P<0.001). After 6 months, overall survival was 81% and 67% in the trametinib and chemotherapy groups respectively (P=0.01). The response rates, complete or partial response, were 22% and 8% in the trametinib and chemotherapy groups respectively (P=0.01). Both progression-free and overall survival was significantly longer in the trametinib group than in the chemotherapy group.
Progression-free survival did not substantially improve in patients with V600K mutation or ≥65 years.
Adverse events (AEs) were reported in over 15% patients who received at least one dose of study drug. Frequent AEs in trametinib group were rash, diarrhea, peripheral edema, fatigue, and acne-like eruptions, which were controlled by dose reduction and interruption. Reduced heart function was seen in 7% patients. Ocular events (often grade 1-2) occurred in 9% patients, while two patients had severe grade 3 cardiac-related events that led to termination of study drug treatment. AEs led to dose interruptions and reductions in 35% and 27% trametinib-treated patients respectively.
Chemotherapy-induced AEs included fatigue, nausea, constipation, vomiting, and alopecia with dose interruptions and reductions in 22% and 10% patients respectively. Skin cancers of the squamous-cell carcinoma type, previously reported in 18-26% of vemurafenib-treated patients, were absent in trametinib-treated population.
Thus trametinib, as compared with chemotherapy, improved progression-free and overall survival in metastatic melanoma patients with a BRAF V600E or V600K mutation.
Reference:Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma; Keith Flaherty et al; NEJM 2012