Treatment for advanced and metastatic melanoma has been revolutionized over the last couple of years. On the basis of the results from the BRIM-3 trial, vemurafenib is the only molecularly driven targeted agent to have shown improvement in survival for advanced melanoma harbouring BRAF V600E mutation and is now approved for clinical use by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in this subgroup of patients.
Activating mutations in serine–threonine protein kinase BRAF are identified in approximately 50% of patients with advanced melanoma and the most common ones are V600E and V600K. Activated BRAF phosphorylates and activates MEK proteins (MEK1 and MEK2), which then phosphorylates ERK on specific tyrosine and threonine residues and its activation promotes proliferation and survival of tumour cells in many cancers.
In the phase III METRIC study, Dr Flaherty and colleagues randomized (2:1) 322 patients with stage IIIC or IV cutaneous melanoma harbouring BRAF V600E/K mutations to receive the oral selective MEK1/2 inhibitor trametinib or chemotherapy with dacarbazine or paclitaxel until progressive disease, death or withdrawal form the study. Eligible patients could have received one previous chemotherapy regimen for advanced or metastatic melanoma with the exclusion of BRAF and MEK inhibitors and ipilimumab. Patients with stable brain metastases were allowed entry in the study. Primary endpoint was progression-free survival (PFS) and an independent central review of tumour response was performed. Secondary endpoints were overall survival (OS), overall response rate (ORR), duration of response and safety. Crossover to trametinib was permitted for patients in the chemotherapy arm, at disease progression. About one-third of patients had previously received chemotherapy and immunotherapy. Brain metastases were present in 4% and 2% of patients in the trametinib arm and chemotherapy arm, respectively.
In the intention-to treat analysis, patients receiving trametinib had a longer PFS (4.8 v 1.5 months; HR 0.45; 95% CI, 0.33 to 0.63; p<0.001), with a slightly greater improvement in the independent radiological review (HR 0.42; 95% CI, 0.29 to 0.59; p<0.001). There was a 46% reduction of the risk of death in the trametinib group (HR 0.54, 95% CI, 0.32 to 0.92; P=0.01) even if 47% of patients in the chemotherapy group crossed over to receive trametinib. Notably, median OS had not been reached at the time of the publication but ORR was higher in the experimental arm (22% v 8%, p=0.01).
The most common adverse events in the trametinib group were rash, diarrhoea, peripheral oedema, fatigue, and dermatitis acneiform. Differently by what seen with vemurafenib, there were no cutaneous squamous-cell carcinomas reported. Thirty-five percent and 27% of patients in the trametinib arm had treatment interrupted or received a dose-reduction due to adverse events, respectively.
Bearing in mind the limitations and caveats of indirect comparison of trials, vemurafenib showed a 48% ORR, a 74% reduction of the risk of progression and a 63% reduction of the risk of death in the BRAF mutant population when compared to dacarbazine, in the BRIM-3 trial.
It is very important to pint out that, so far, there is no head to head comparison of trametinib and vemurafenib in this setting and therefore is not possible to comment on the difference on clinical activity.
Unfortunately response to these agents is short-lived and mechanisms of resistance play a crucial role. A potential strategy to maximize efficacy in this population could be the combination of MEK and BRAF inhibition. From early phase studies, this seems to be promising and (interestingly) not associated with increased toxicity.
Phase III clinical trials (NCT01584648 and NCT01597908) are currently recruiting patients to test this hypothesis and hopefully will shed some light on future treatment strategies for this challenging disease.