TY - JOUR
T1 - Phase 2 study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia
T2 - A university of chicago phase 2 consortium trial
AU - Jain, Nitin
AU - Curran, Emily
AU - Iyengar, Neil M.
AU - Diaz-Flores, Ernesto
AU - Kunnavakkam, Rangesh
AU - Popplewell, Leslie
AU - Kirschbaum, Mark H.
AU - Karrison, Theodore
AU - Erba, Harry P.
AU - Green, Margaret
AU - Poire, Xavier
AU - Koval, Greg
AU - Shannon, Kevin
AU - Reddy, Poluru L.
AU - Joseph, Loren
AU - Atallah, Ehab L.
AU - Dy, Philip
AU - Thomas, Sachdev P.
AU - Smith, Scott E.
AU - Doyle, Austin
AU - Stadler, Walter M.
AU - Larson, Richard A.
AU - Stock, Wendy
AU - Odenike, Olatoyosi
PY - 2014/1/15
Y1 - 2014/1/15
N2 - 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/refractoryAMLor 60 years old or more with untreatedAMLwere 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. Clin Cancer Res; 20(2); 490-8.
AB - 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/refractoryAMLor 60 years old or more with untreatedAMLwere 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. Clin Cancer Res; 20(2); 490-8.
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U2 - 10.1158/1078-0432.CCR-13-1311
DO - 10.1158/1078-0432.CCR-13-1311
M3 - Article
C2 - 24178622
AN - SCOPUS:84892716958
SN - 1078-0432
VL - 20
SP - 490
EP - 498
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -