Faculty Collaboration Database

Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res 2014 Jan 15;20(2):490-8

Date

11/02/2013

Pubmed ID

24178622

Pubmed Central ID

PMC4310865

DOI

10.1158/1078-0432.CCR-13-1311

Scopus ID

2-s2.0-84892716958 (requires institutional sign-in at Scopus site)   96 Citations

Abstract

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 patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). 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 the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation 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 = 0.027).

CONCLUSIONS: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with 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.

Author List

Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, Kirschbaum MH, Karrison T, Erba HP, Green M, Poire X, Koval G, Shannon K, Reddy PL, Joseph L, Atallah EL, Dy P, Thomas SP, Smith SE, Doyle LA, Stadler WM, Larson RA, Stock W, Odenike O

Author

Ehab L. Atallah MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Administration, Oral
Adult
Aged
Aged, 80 and over
Antineoplastic Agents
Benzimidazoles
Female
Genes, ras
Humans
Leukemia, Myeloid, Acute
Male
Middle Aged
Mitogen-Activated Protein Kinase Kinases
Mutation
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-kit
Treatment Outcome
fms-Like Tyrosine Kinase 3