Cancer Therapy: Clinical Phase II Study of the Oral MEK Inhibitor Selumetinib in Advanced Acute Myelogenous Leukemia: A University of Chicago Phase II Consortium Trial

Purpose: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown. Experimental Design: Selumetinib is an oral small-molecule inhibitor of MAP–ERK kinase (MEK)-1/2. Forty-seven patientswith relapsed/refractory AMLor 60 years old ormorewith untreatedAMLwere enrolled on aphase II study. Patientswere stratified by FLT3 ITDmutation status. The primary endpointwas response rate (complete, partial, andminor). Leukemia cells were analyzed for extracellular signal—regulated kinase (ERK) and mTOR phosphorylation. Results: Common drug-related toxicities were grade 1–2 diarrhea, fatigue, nausea, vomiting, and skin rash. In theFLT3wild-type cohort, six of 36 (17%)patients had a response [onepartial response, threeminor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRASmutations were detected in 7% and 2%of patients, respectively. The sole patient with KRASmutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P 1⁄4 0.027). Conclusions: Selumetinib is associatedwithmodest single-agent antileukemic activity in advancedAML. However, given its favorable toxicity profile, combinationwith drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials. Clin Cancer Res; 20(2); 1–9. 2013 AACR.