Neuroblastoma RAS viral oncogene homolog (NRAS)-mutant melanoma makes up 15%–25% of all melanomas, has a poor prognosis, and has no approved targeted therapies. Enhanced mitogen-activated protein kinase (MAPK) pathway signaling and cell cycle checkpoint dysregulation are characteristic of most NRAS-mutant melanomas. Simultaneous inhibition of MAPK kinase (MEK) and cyclin-dependent kinase 4/6 (CDK4/6) has shown synergistic antitumor activity in several preclinical models of NRAS-mutant melanoma. The regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination to assess in an NRAS-mutant melanoma population for toxicity and efficacy. In this phase Ib/II study, Schuler and colleagues demonstrate that the combination of ribociclib + binimetinib achieved target inhibition and tolerability consistent with the known profile of the two agents. Antitumor activity was observed particularly in NRAS-mutant melanomas with concurrent genetic alterations in cell cycle regulators.
Dual timepoint FET-PET acquisition might improve the definition of glioblastoma location and...
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