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Efficacy and safety of oral MEK162 in patients with locally advanced and unresectable or metastatic cutaneous melanoma harboring BRAFV600 or NRAS mutations.

Background:    BRAF and NRAS mutations occur in 50-60% and 15-20% of cutaneous melanomas, respectively. MEK162, a selective inhibitor of the kinases MEK1 and MEK2, has shown pre-clinical activity in BRAF and NRAS mutant (mt) melanoma models. This open label, phase II study assessed the antitumor activity of MEK162 in patients (pts) with BRAFV600 and NRAS mt advanced cutaneous melanoma. Methods:      MEK162 was administered orally at a starting dose of 45 mg twice daily. Treatment was until unacceptable toxicity, disease progression (PD) or investigator or patient refusal. Tumor response was assessed by CT imaging every 8 weeks (RECIST 1.0) until PD.

Results:      As of 16 Sept 2011, the full analysis and safety populations comprised 66 pts: 42 BRAF mt and 24 NRAS mt. Median age 58.0 years; 57.6% male; 72.7% WHO performance status 0. All NRAS pts and all but 2 BRAF (1 each stage IIIB and IIIC) pts had stage IV disease, and 87.5% of NRAS pts and 66.7% of BRAF pts had received prior therapy at study entry. Median time from 1st diagnosis to 1st dose of drug was 40.4 months. Median time on study was 10.4 and 8.5 weeks for the BRAF and NRAS arms. Relative dose intensities of 80–<100% were received by 71.4% and 70.8% of pts, respectively.

Among 29 BRAF mt and 13 NRAS mt pts evaluable for efficacy, 1 confirmed and 6 unconfirmed partial responses (PRs) and 9 pts with stable disease (SD) were recorded in the BRAF arm and 2 confirmed PRs, 1 unconfirmed PR and 4 pts with SD recorded in the NRAS arm.

Common treatment–related adverse events (AEs), all grades (Gs) and all pts, were rash (40.9%), diarrhea (33.3%), acneiform dermatitis (27.3%), creatine phosphokinase (CK) elevation (25.8%), fatigue (18.2%) and peripheral edema (21.2%). Central serous retinopathy-like retinal events (G 1/2 only) were reported in 8 (12.1%) pts (6 G1, 2 G2). All retinal events were reversible. G3/4 AEs in >1pt were diarrhea (4.5%) and CK elevation (15.2%). 5 pts discontinued due to toxicity. 34 pts are ongoing with more responses under current review.

Conclusions: MEK162 showed clinical activity and good tolerability in pts with BRAF and NRAS mt advanced melanoma. This is the 1st targeted therapy to show activity in pts with NRAS mt melanoma.