Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma Journal Article
| Authors: | Algazi, A. P.; Esteve-Puig, R.; Nosrati, A.; Hinds, B.; Hobbs-Muthukumar, A.; Nandoskar, P.; Ortiz-Urda, S.; Chapman, P. B.; Daud, A. |
| Article Title: | Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma |
| Abstract: | 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. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd |
| Keywords: | protein kinase b; adult; cancer survival; clinical article; treatment response; aged; overall survival; constipation; fatigue; diarrhea; hypertension; side effect; anorexia; melanoma; progression free survival; enzyme inhibition; phase 2 clinical trial; mucosa inflammation; nausea; thrombocytopenia; vomiting; dehydration; creatinine; diagnostic imaging; wild type; dyspnea; fever; hyperglycemia; pruritus; rash; alanine aminotransferase; aspartate aminotransferase; dysphagia; hypokalemia; malaise; odynophagia; multicenter study; headache; kaplan meier method; akt; dry skin; alopecia; epistaxis; b raf kinase; mitogen activated protein kinase kinase; mek; tachycardia; blurred vision; dysgeusia; metastatic melanoma; oncogene n ras; indigestion; nras; folliculitis; spotting; trametinib; human; male; female; article; uprosertib; gsk2141795 |
| Journal Title: | Pigment Cell & Melanoma Research |
| Volume: | 31 |
| Issue: | 1 |
| ISSN: | 1755-1471 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2018-01-01 |
| Start Page: | 110 |
| End Page: | 114 |
| Language: | English |
| DOI: | 10.1111/pcmr.12644 |
| PROVIDER: | scopus |
| PUBMED: | 28921907 |
| PMCID: | PMC8049535 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2018 -- Source: Scopus |
