Patients with melanoma have some relevant mutations, the most frequent being the BRAF mutation (40-60% of patients); this biomarker is also fundamental due to the success of the therapeutic target associated with it. Other relevant mutations are found in the NRAS genes (15-25% of cases), KIT, TERT and in the case of uveal melanomas, GNAQ and GNA11.
Previous studies have attempted to administer MEK inhibitor therapy to patients with NRAS mutations, the most representative study being the NEMO trial. This trial randomised patients with stage IV NRAS-mutant melanoma between binimetinib (a MEK inhibitor) or dacarbazine. Median progression-free survival (PFS) was shown to improve by 2.8 months versus 1.7 months; the clinical relevance of such a modest improvement in median PFS has been questioned and, due to other advances with immune checkpoint inhibitors (ICIs), this treatment has not been widely adapted in the clinic.
However, the current study by Schuler et al. presents a phase Ib/II trial of the combination of binimetinib with a CDK4/6 inhibitor, ribociclib, for patients with NRAS-mutated melanoma. In this trial, the response rate was 32.5% and the median PFS was 3.7 months and OS was 11.3 months. These results demonstrate that ribociclib plus binimetinib is well tolerated in patients with NRAS-mutated melanoma and that the benefit of treatment is greatest in patients with concurrent CDKN2A, CDK4 or CCND1 alterations.