Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma Journal Article

Authors: Catalanotti, F.; Solit, D. B.; Pulitzer, M. P.; Berger, M. F.; Scott, S. N.; Iyriboz, T.; Lacouture, M. E.; Panageas, K. S.; Wolchok, J. D.; Carvajal, R. D.; Schwartz, G. K.; Rosen, N.; Chapman, P. B.
Article Title: Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma
Abstract: Purpose: Test the hypothesis that in BRAF-mutated melanomas, clinical responses to selumetinib, a MEK inhibitor, will be restricted to tumors in which the PI3K/AKT pathway is not activated. Experimental Design: We conducted a phase II trial in patients with melanoma whose tumors harbored a BRAF mutation. Patients were stratified by phosphorylated-AKT (pAKT) expression (high vs. low) and treated with selumetinib 75 mg per os twice daily. Pretreatment tumors were also analyzed for genetic changes in 230 genes of interest using an exon-capture approach. Results: The high pAKT cohort was closed after no responses were seen in the first 10 patients. The incidence of low pAKT melanoma tumors was low (∼25% of melanomas tested) and this cohort was eventually closed because of poor accrual. However, among the five patients with melanoma accrued in the low pAKT cohort, there was one partial response (PR). Two other patients had near PRs before undergoing surgical resection of residual disease (one patient) or discontinuation of treatment due to toxicity (one patient). Among the two nonresponding, low pAKT patients with melanoma, co-mutations in MAP2K1, NF1, and/or EGFR were detected. Conclusions: Tumor regression was seen in three of five patients with BRAF-mutated, low pAKT melanomas; no responses were seen in the high pAKT cohort. These results provide rationale for co-targeting MEK and PI3K/AKT in patients with BRAF mutant melanoma whose tumors express high pAKT. However, the complexity of genetic changes in melanoma indicates that additional genetic information will be needed for optimal selection of patients likely to respond to MEK inhibitors. ©2013 AACR.
Keywords: signal transduction; adult; cancer survival; clinical article; controlled study; human tissue; protein expression; treatment outcome; aged; disease-free survival; middle aged; survival rate; young adult; unclassified drug; gene mutation; overall survival; exon; mutation; fatigue; diarrhea; drug efficacy; drug safety; drug withdrawal; heart left ventricle failure; side effect; edema; melanoma; progression free survival; controlled clinical trial; drug eruption; phase 2 clinical trial; cohort studies; anemia; vomiting; drug administration schedule; cohort analysis; enzyme activation; dyspnea; lymphocytopenia; hypoalbuminemia; disease severity; thorax pain; heart failure; cardiotoxicity; proto-oncogene proteins c-akt; pleura effusion; down regulation; upregulation; liver function test; administration, oral; b raf kinase; lymphopenia; mitogen-activated protein kinase kinases; benzimidazoles; lymphocyte count; proto-oncogene proteins b-raf; exanthema; heart right ventricle failure; valvular heart disease; phosphatidylinositol 3-kinases; selumetinib; arry 1428869
Journal Title: Clinical Cancer Research
Volume: 19
Issue: 8
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2013-04-15
Start Page: 2257
End Page: 2264
Language: English
DOI: 10.1158/1078-0432.ccr-12-3476
PROVIDER: scopus
PUBMED: 23444215
PMCID: PMC3932005
Notes: --- - "Export Date: 3 June 2013" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Mario E Lacouture
    261 Lacouture
  2. Gary Schwartz
    359 Schwartz
  3. Neal Rosen
    363 Rosen
  4. Jedd D Wolchok
    656 Wolchok
  5. David Solit
    431 Solit
  6. Melissa P Pulitzer
    127 Pulitzer
  7. Richard D Carvajal
    133 Carvajal
  8. Paul Chapman
    246 Chapman
  9. Katherine S Panageas
    327 Panageas
  10. Michael Forman Berger
    380 Berger
  11. Sasinya Neka Scott
    66 Scott