Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer

Tufia C Haddad,Antonino D’Assoro,Matthew P Goetz,Mateusz Opyrchal,Prema Peethambaram,Vera Suman,James N Ingle,Minetta C Liu

doi:10.1007/s10549-017-4616-7

Abstract

PurposeIn estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC).MethodsIn this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant.ResultsTen patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95% CI 5.3–not met), and the 6-month clinical benefit rate was 77.8% (95% CI 40.0–87.2%).ConclusionsIn patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1–3, 8–10, and 15–17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.

Highlights

Approximately 1.2 million women worldwide are diagnosed with estrogen receptor-positive (ER+) breast cancer [1]
Aberrant Aurora A kinase (AURKA) activity is required to induce the expression of SMAD5 and SOX2 [14, 15], two master transcription factors involved in the regulation of epithelial-to-mesenchymal transition (EMT) and stemness reprogramming [16,17,18,19]
One patient entered at the 50 mg dose level was found to be ineligible and replaced as she was on a proton pump inhibitor at the time of registration

Summary

Introduction

Approximately 1.2 million women worldwide are diagnosed with estrogen receptor-positive (ER+) breast cancer [1]. During tumor progression, deregulated activation of Aurora A kinase (AURKA) is functionally linked to epithelial-to-mesenchymal transition (EMT) reprogramming and expansion of a subpopulation of tumor-initiating cells harboring a C D44+/CD24low/− phenotype [10,11,12] These tumor-initiating cells have stem cell-like properties characterized by their capacity to self-renew, resist drug therapies, and promote distant metastases [13]. In luminal ER+ breast cancer models, activation of AURKA is required to induce EMT and clonal expansion of CD44+/CD24low/− cells, driving tumor progression [14]. These cells are further characterized by loss of ERα protein expression and resistance to endocrine therapy [15]. Aberrant AURKA activity is required to induce the expression of SMAD5 and SOX2 [14, 15], two master transcription factors involved in the regulation of EMT and stemness reprogramming [16,17,18,19]

Methods

Results

Conclusion