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
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
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
, 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
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.
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%
trametinib-treated patients respectively.
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.
Improved Survival with
MEK Inhibition in BRAF-Mutated Melanoma; Keith Flaherty et al; NEJM 2012