BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Early phase trials
Trametinib (Mekinist, GSK1120212, GlaxoSmithKline, London) is a newer generation selective MEK1/2 inhibitor which has been widely tested in melanoma. A phase I trial was conducted which included 30 patient with BRAF mutant melanoma not previously treated with a BRAF inhibitor and 39 BRAF wild type patients . The response rate was 40% in the untreated BRAF mutant group with a median PFS of 5.7 months. Notably, 10% of patients in the BRAF wild type group also demonstrated an objective response. Within this BRAF wild type cohort, a patient later found to have BRAFL597V mutant melanoma also experienced a response. Side effects were relatively minor and commonly included acneiform rash (38%), diarrhea (35%), and peripheral edema (31%). No cSCCs were identified, and no episodes of retinal vein occlusion (RVO) occurred (complications of early generation MEK inhibitors) in patients receiving the RP2D of 2 mg daily.
Phase III trial
A phase III trial (METRIC) was then conducted 322 patients with advanced BRAFV600E/K mutant melanoma, randomized in a 2:1 fashion to trametinib or investigator’s choice of cytotoxic chemotherapy (dacarbazine or carboplatin/paclitaxel). Improved overall survival was demonstrated (hazard ratio for death 0.54, p= 0.01), despite 47% of patients on the chemotherapy arm crossing over and receiving trametinib. Other key clinical outcomes favored trametinib including median PFS (4.8 months vs. 1.5 months, p< 0.001), and objective response rate (22 vs. 8%, p = 0.01). Although only 22% of patients met criteria for RECIST partial responses, > 70% experienced at least some disease regression. Toxicity profile was similar to the phase I trial although one case of reversible chorioretinopathy occurred. Cardiotoxicity was seen in 7% who developed decreased ejection fraction and two patients who experienced grade 3 cardiac events requiring drug cessation. Based on the results of this trial, trametinib received FDA approval in May 2013.
Trametinib in BRAF inhibitor-resistance
Since many of the mechanisms of acquired resistance to BRAF inhibitors could be hypothesized to confer sensitivity to MEK inhibition, a phase II trial was conducted to assess the efficacy of trametinib in this setting. A total of 40 patients received trametinib following progression with a BRAF inhibitor (either vemurafenib or dabrafenib). Of the patients truly refractory to BRAF inhibitors, no patients had objective responses with 11 patients (28%) experiencing temporary stable disease. Two patients who had developed BRAF inhibitor toxicity but had not progressed on BRAF inhibitor therapy before receiving trametinib did experience a partial response. Median PFS was 1.8 months in this cohort. A sequential strategy of BRAF inhibitors followed by MEK inhibitors is thus not of clinical benefit.
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