TY - JOUR
T1 - Aurora A Functional Single Nucleotide Polymorphism (SNP) Correlates With Clinical Outcome in Patients With Advanced Solid Tumors Treated With Alisertib, an Investigational Aurora A Kinase Inhibitor
AU - Niu, Huifeng
AU - Shin, Hyunjin
AU - Gao, Feng
AU - Zhang, Jacob
AU - Bahamon, Brittany
AU - Danaee, Hadi
AU - Melichar, Bohuslav
AU - Schilder, Russell J.
AU - Coleman, Robert L.
AU - Falchook, Gerald
AU - Adenis, Antoine
AU - Behbakht, Kian
AU - DeMichele, Angela
AU - Dees, Elizabeth Claire
AU - Perez, Kimberly
AU - Matulonis, Ursula
AU - Sawrycki, Piotr
AU - Huebner, Dirk
AU - Ecsedy, Jeffrey
N1 - Publisher Copyright:
© 2017 The Authors
PY - 2017/11
Y1 - 2017/11
N2 - Background Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. Methods This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n = 62) or paclitaxel alone (n = 60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. Findings TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p < 0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n = 53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n = 32, 38%; HR 0.5; p = 0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n = 47, 39%) had a trend towards improved PFS (7.5 months) vs paclitaxel alone (n = 32, 26%; 3.8 months; HR 0.618; p = 0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1 months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. Interpretation These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted.
AB - Background Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. Methods This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n = 62) or paclitaxel alone (n = 60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. Findings TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p < 0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n = 53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n = 32, 38%; HR 0.5; p = 0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n = 47, 39%) had a trend towards improved PFS (7.5 months) vs paclitaxel alone (n = 32, 26%; 3.8 months; HR 0.618; p = 0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1 months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. Interpretation These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted.
KW - Alisertib
KW - Aurora A kinase inhibitor
KW - Correlative analysis
KW - Predictive biomarker
KW - Prognosis
KW - SNP
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U2 - 10.1016/j.ebiom.2017.10.015
DO - 10.1016/j.ebiom.2017.10.015
M3 - Article
C2 - 29122619
AN - SCOPUS:85033229821
SN - 2352-3964
VL - 25
SP - 50
EP - 57
JO - EBioMedicine
JF - EBioMedicine
ER -