What is your approach to the initial treatment of metastatic melanoma patients with NRAS mutations?

The incidence of NRAS mutations in the metastatic setting has been reported in up to 15-20% of patients.  There are currently no FDA approved agents specifically for NRAS mutated patients who progress after immunotherapy.  Some studies have shown these patients may have better responses to first line-immunotherapy.  After progression, studies have been done attempting to target downstream pathways, including MEK inhibiton (Binimetinib has shown response rates in phase 2 trials and studied in a phase 3 trial comparison to dacarbazine showing and improvement in PFS with Binimetinib with good tolerability yet no OS benefit).  Although intriguing, patients ideally should be enrolled in clinical trials and combination strategies with MEK inhibitors and PI3K/atk/mtor inhibitors or CDK4/6 inhibitors may show promise.