Abstract 2284: Phase II trial of MEK inhibitor selumetinib (AZD6244) in patients with BRAFV600E/K- or NRAS-mutated melanoma.
Authors: Catalanotti Federica , Solit David B. , Pulitzer Melissa P. , Berger Michael F. , Scott Sasinya N. , Iyriboz Tunc , Lacouture Mario E. , Panageas Katherine S. , Wolchok Jedd D. , Carvajal Richard D. , Schwartz Gary K. , Rosen Neal , Chapman Paul B. 
Published: August 2014

Our pre-clinical in vitro data suggested that all BRAF-mutated cell lines, and some NRAS-mutated melanoma are sensitive to MEK inhibition. BRAFwt/NRASwt were uniformly resistant. Among the sensitive cell lines, those with enhanced activation of the PI3K/AKT pathway did not undergo apoptosis. This is consistent with a recent phase II trial with Selumetinib, an allosteric MEK inhibitor, which showed a 6% response rate in unselected melanoma patients. Retrospectively, 5 of 6 of the responders were found to harbor BRAFV600E mutations. We hypothesized that treatment of BRAF-mutated or NRAS-mutated melanomas with Selumetinib will induce clinical responses only in the subset of tumors in which the PI3K/AKT pathway is not activated. In this phase II trial, melanoma patients with either BRAF or NRAS mutation were stratified based on phospho-AKT (pAKT) expression (high vs. low), as measured by immunohistochemistry staining of pre-treatment tumor specimens. Patients were treated with Selumetinib 75 mg p.o. daily in 28-day cycles. We found that the incidence of high pAKT melanoma tumors was about 4 times higher than low pAKT tumors. None of the 10 patients in the high pAKT cohort responded, although 4 patients showed stable disease for ≥4 months. This cohort was closed to further accrual. In contrast, in the low pAKT group, 1 patient had a true partial response (PR) and 2 others had near PRs. One of these patients had to discontinue treatment due to toxicity; the other had his remaining tumor resected. This cohort was closed due to slow patient accrual. We used an exon capture, next-generation sequencing assay to define the mutational status of 230 cancer associated genes in pre-treatment tumors, derived from patients belonging to both cohorts. The assay detects point mutations, small indels and copy number alterations. Among the two low pAKT patients who were resistant to MEK inhibition, one had a mutation in MAP2K1 that encodes for a K57N mutation in helix A of MEK1. We speculate that this is an activating mutation, since a missense mutation in the amino acid just proximal (Q56P) was previously shown to be highly activating. The other non-responding patient in the low pAKT cohort had an activating mutation in EGFR. Both of these could drive increased activation of the MAPK pathway, thus explaining the resistance to the drug. We conclude that future trials with MEK inhibitors in melanoma should exclude patients with high pAKT tumors. The occurrence of complex genetic changes in melanoma requires studies to better stratify the patients according the prediction of response to MEK inhibitors.

Citation Format: Federica Catalanotti, David B. Solit, Melissa P. Pulitzer, Michael F. Berger, Sasinya N. Scott, Tunc Iyriboz, Mario E. Lacouture, Katherine S. Panageas, Jedd D. Wolchok, Richard D. Carvajal, Gary K. Schwartz, Neal Rosen, Paul B. Chapman. Phase II trial of MEK inhibitor selumetinib (AZD6244) in patients with BRAFV600E/K- or NRAS-mutated melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2284. doi:10.1158/1538-7445.AM2013-2284