The results of Phase 2 trial of selumetinib in BRAF-mutated melanoma
Clin Cancer Res. 2013 Feb 26. [Epub ahead of print]
Phase II trial of MEK inhibitor selumetinib (AZD6244) in patients with BRAFV600E/K-mutated melanoma.
Catalanotti F, Solit DB, Pulitzer MP, Berger M, Scott SN, Iyriboz T, Lacouture ME, Panageas K, Wolchok JD, Carvajal RD, Schwartz GK, Rosen N, Chapman PB.
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center.
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.
We conducted a phase II trial in patients with BRAF-mutated melanoma. Patients were stratified by phosphorylated-AKT (pAKT) expression (high vs. low) and treated with selumetinib 75 mg po bid. Pre-treatment tumors were also analyzed for genetic changes in 230 genes of interest using an exon-capture approach.
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 and this cohort was closed because of poor accrual. However, among the 5 melanoma patients accrued , there was 1 PR. Two other patients had near PRs before undergoing surgical resection of residual disease (1 patient) or discontinuation of treatment due to toxicity (1 patient). Among the 2 non-responding, low pAKT melanoma patients, co-mutations in MAP2K1, NF1, and/or EGFR were detected.
Tumor regression was seen in 3 of 5 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.
AstraZeneca – Selumetinib and AZD8330 – MEK Program
In December 2003, we entered into an out-licensing and collaboration agreement with AstraZeneca to develop our MEK program. Under the agreement, AstraZeneca acquired exclusive worldwide rights to our clinical development candidate, selumetinib (previously known as AZD6244, or ARRY-142886)
There are 38 on-going trials with selumetinib, including trials in NSCLC, thyroid cancer, melanoma, ocular melanoma, hepatocellular cancer, rectal cancer, colorectal cancer, pancreatic cancer and breast cancer.