Dual MAPK / PI3K pathway inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS mutant and wild type melanoma

Summary

Aberrant MAPK and PI3K pathway signaling may drive the malignant phenotype in NRAS mutant and BRAF^WT NRAS^WT metastatic melanoma.

To target these pathways NRAS mutant and BRAF^WT NRAS^WT patients received oral trametinib at 1.5 mg daily and GSK2141795 at 50 mg daily in a 2-cohort Simon 2-stage design. Participants had adequate end organ function and no more than 2 prior treatment regimens. Imaging assessments were performed at 8-week intervals.

10 NRAS mutant and 10 BRAF^WT NRAS^WT patients were enrolled. No objective responses were noted in either cohort. The median PFS and OS were 2.3 and 4.0 months in the NRAS mutant cohort 2.8 and 3.5 months in the wild-type cohort. Grade 3 and 4 adverse events, primarily rash, were observed in 25% of patients.

We conclude that the combination of trametinib and GSK2141795 does not have significant clinical activity in NRAS mutant or BRAF^WT NRAS^WT melanoma.

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