Trametinib Improves Survivability In Mutated Melanoma

Trametinib

According to a study published in The New England Journal Of Medicine, targeted therapy with MEK inhibitors improved survival in patients with BRAF-mutated melanoma. So far studies have shown that only ipilimumab, a monoclonal antibody, and vemurafenib, a BRAF inhibitor, prolonged survival of patients with metastatic melanoma. Recently, another drug, trametinib (MEK inhibitor) was shown to prolong survival in BRAF-mutated melanoma.

Researchers conducted a randomized, controlled, phase 3  clinical trial, in which 1022 patients were included initially from 103 centers worldwide. Following investigations, only 322 were eligible, that is they had BRAF V600E and V600K mutations present. Also, another eligibility criterion was stage melanoma: the study included only patients with stage IIIC and IV melanoma skin. Demographic characteristics of patients included in the study were related to  age, male gender, skin melanoma extension, presence of metastases, lactate dehydrogenase level, etc.. They were divided randomly into two study groups: first group (214 patients) received oral trametinib and the second (108) received intravenous chemotherapy consisting of either dacarbazine or paclitaxel every 3 weeks. Side effects occurred in approximately 15% of patients in each study group.

The adverse effects of patients who received trametinib, include diarrhea, rash, peripheral edema and dermatitis acneiform. In 14 patients in group trametinib were observed adverse cardiac effects (decreased ejection fraction or ventricular dysfunction). 2 patients who received trametinib were excluded from the study due to severe cardiac side effects. The most common adverse reactions in patients who received chemotherapy were the gastrointestinal (nausea, constipation, vomiting), fatigue and alopecia.

Melanoma

Trametinib is an inhibitor of mitogen-activated protein kinase. Trametinib specifically binds MEK1 and MEK2,  which are involved in the MAP kinase pathway , and inhibits cancer cell proliferation. Vemurafenib is a BRAF inhibitor approved by FDA in August 2011 to treat metastatic melanoma. In clinical studies, vemurafenib was associated  to prolong survival of patients with BRAF-mutated metastatic melanoma. It seems that both agents improve survival in patients with metastatic melanoma compared with chemotherapy. However, the results of a previous study shows that vemurafenib is  superior to trametinib.  90% of patients treated with vemurafenib had some tumor regression, while only 74% of patients  treated with trametinib had tumor regression . Also, the objective response rate was 48% for vemurafenib while for trametinib was only 22%. However, there  have been reported treatment-related squamous-cell carcinomas among patients who received vemurafenib. This side effect may be due to the fact that BRAF inhibitor stimulates proliferation of skin lesions. Although both drugs appear to be useful in prolonging survival of metastatic melanoma patients, future studies to include those two will show which is best.