dual mek/akt inhibition with trametinib and gsk2141795 does not yield clinical benefit in metastatic nras-mutant and wild-type melanoma

Aberrant mapk and pi3k pathway signaling may drive the malignant phenotype in nras-mutant and brafwt nraswt metastatic melanoma. to target these pathways, nras-mutant and brafwt nraswt patients received oral trametinib at 1.5 mg daily and gsk2141795 at 50 mg daily in a two-cohort simon two-stage design. participants had adequate end-organ function and no more than two prior treatment regimens. imaging assessments were performed at 8-week intervals. a total of 10 nras-mutant and 10 brafwt nraswt 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 and 2.8 and 3.5 months in the wild-type cohort. grade 3 and grade 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 brafwt nraswt melanoma.