Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial.

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.

• Authors: Nitin Jain, Emily Curran, Neil M Iyengar, Ernesto Diaz-Flores, Rangesh Kunnavakkam, Leslie Popplewell, Mark H Kirschbaum, Theodore Karrison, Harry P Erba, Margaret Green, Xavier Poire, Greg Koval, Kevin Shannon, Poluru L Reddy, Loren Joseph, Ehab L Atallah, Philip Dy, Sachdev P Thomas, Scott E Smith, L Austin Doyle, Walter M Stadler, Richard A Larson, Wendy Stock, Olatoyosi Odenike
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 2 Pg. 490-8 (Jan 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 24178622 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)
• Copyright: ©2013 AACR.

Chemical References

• AZD 6244
• Antineoplastic Agents
• Benzimidazoles
• Protein Kinase Inhibitors
• FLT3 protein, human
• Proto-Oncogene Proteins c-kit
• fms-Like Tyrosine Kinase 3
• Mitogen-Activated Protein Kinase Kinases

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• Benzimidazoles (administration & dosage, adverse effects, therapeutic use)
• Female
• Genes, ras
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism, pathology)
• Male
• Middle Aged
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Mutation
• Protein Kinase Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Proto-Oncogene Proteins c-kit (genetics)
• Treatment Outcome
• fms-Like Tyrosine Kinase 3 (genetics)