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Dual MEK/AKT inhibition with trametinib and GSK 2141795 does not yield clinical benefit in metastatic NRAS ‐mutant and wild‐type melanoma
Author(s) -
Algazi Alain P.,
EstevePuig Rosaura,
Nosrati Adi,
Hinds Brian,
HobbsMuthukumar Adele,
Nandoskar Prachi,
OrtizUrda Susana,
Chapman Paul B.,
Daud Adil
Publication year - 2018
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12644
Subject(s) - neuroblastoma ras viral oncogene homolog , trametinib , medicine , cohort , mutant , kras , melanoma , cancer research , rash , oncology , wild type , mapk/erk pathway , mek inhibitor , cancer , biology , signal transduction , gene , genetics , colorectal cancer
Summary Aberrant MAPK and PI 3K 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 GSK 2141795 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 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 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 GSK 2141795 does not have significant clinical activity in NRAS ‐mutant or BRAF WT NRAS WT melanoma.