EBioMedicine (Nov 2017)

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

  • Huifeng Niu,
  • Hyunjin Shin,
  • Feng Gao,
  • Jacob Zhang,
  • Brittany Bahamon,
  • Hadi Danaee,
  • Bohuslav Melichar,
  • Russell J. Schilder,
  • Robert L. Coleman,
  • Gerald Falchook,
  • Antoine Adenis,
  • Kian Behbakht,
  • Angela DeMichele,
  • Elizabeth Claire Dees,
  • Kimberly Perez,
  • Ursula Matulonis,
  • Piotr Sawrycki,
  • Dirk Huebner,
  • Jeffrey Ecsedy

DOI
https://doi.org/10.1016/j.ebiom.2017.10.015
Journal volume & issue
Vol. 25, no. C
pp. 50 – 57

Abstract

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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.

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