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

Abstract

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 (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; 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 5.1months), 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.

Keywords: Alisertib; Aurora A kinase inhibitor; Correlative analysis; Predictive biomarker; Prognosis; SNP.

Fig. 1

OS in TCGA patients with solid tumors according to Aurora A SNPs at A) codon 57 (all solid tumors), B) codon 57 (breast, HNSCC, NSCLC, GE, and ovarian cancers), and C) codon 31 (all solid tumors). CI, confidence interval; GE, gastro-oesophageal adenocarcinoma; HNSCC, head and neck squamous-cell carcinoma; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; SNP, single nucleotide polymorphism; TCGA, The Cancer Genome Atlas.

Fig. 2

PFS according to Aurora A SNP at codon 57 in patients treated with alisertib in the NCT01045421 study. p-Value calculated using proportional hazard model and stratified by tumor indication. CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; SNP, single nucleotide polymorphism.

Fig. 3

PFS according to Aurora A SNP at codon 57 in patients treated with alisertib in the NCT01045421 study with A) GE, B) SCLC, C) HNSCC, D) NSCLC, or E) breast cancer. CI, confidence interval; GE, gastro-oesophageal adenocarcinoma; HNSCC, head and neck squamous-cell carcinoma; HR, hazard ratio; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; SNP, single nucleotide polymorphism.

Fig. 4

Percentage tumor size change from baseline in patients treated with alisertib in the NCT01045421 study according to Aurora A SNP at codon 57: A) II vs IV vs VV, B) II or IV vs VV, and C) II vs IV or VV. p-Value calculated by ANOVA, adjusted for tumor indication, SNP, single nucleotide polymorphism.

Fig. 5

Best response (CR + PR; RECIST v1.1) in patients treated with alisertib in the NCT01045421 study according to Aurora A SNP at codon 57. CR, complete response; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease; SNP, single nucleotide polymorphism.

Fig. 6

PFS in patients receiving alisertib plus paclitaxel vs paclitaxel alone in the NCT01091428 study: A) patients with VV alleles at Aurora A codon 57, and B) overall mITT study population. CI, confidence interval; HR, hazard ratio; mITT, modified intent-to-treat; PFS, progression-free survival.