Abstract PD1-05: Results from the phase Ib/II clinical trial of bazedoxifene and palbociclib in hormone receptor positive metastatic breast cancer
Authors: Jeselsohn R , Guo H , Rees R , Barry WT , Barlett CH , Tung NM , Krop IE , Brown M , Winer EP 
Published: May 2019

Abstract
Background: Despite the efficacy of endocrine treatments (ETs), most patients with ER+ metastatic breast cancer (MBC) will ultimately develop resistance to these treatments. In most cases of endocrine resistance, ER continues to be expressed. About 30% of patients with ER+ MBC acquire an activating ER mutation that confers resistance to aromatase inhibitors. Thus, ER remains an important driver in a substantial number of patients with MBC despite resistance to currently available ETs. Bazedoxifene is a third generation selective ER modulator (SERM) with selective ER degradation (SERD) activity. The structural characteristics of bazedoxifene differ from those of tamoxifen and raloxifene. Pre-clinical studies showed that bazedoxifene has increased ER antagonistic activity compared to tamoxifen and fulvestrant and has synergistic activity in combination with the CDK4/6 inhibitor, palbociclib. We evaluated the safety and efficacy of bazedoxifene in combination with palbociclib in ER+ MBC.
Methods: This was a phase Ib/II study of patients with ER+/HER2- MBC who had progressed on at least one line of ET for metastatic disease or within 12 months of adjuvant ET. Treatment included daily continuous bazedoxifene 40mg and palbociclib 125 mg for 21 days out of a 28-day cycle. Primary endpoint was clinical benefit rate (CBR; CR + PR + SD ≥ 24 weeks). Secondary end points included objective response, progression free survival (PFS) and safety. The study used a Simon optimal two-stage design and included a safety run-in phase with the first six patients. The sample size was chosen to have 90% power and a one-sided Type I error of ≤10% to reject the null (CBR of &lt; 20%). A biopsy from a metastatic site was obtained from 21 patients and serial plasma samples were collected from all patients for correlative studies.
Results: From July, 2015 to July, 2017 36 patients enrolled in the study (34 females, 2 males). More than 80% of the patients received at least 1 prior line of endocrine treatment for metastatic disease. 45% of the patients received ≥ 2 lines of endocrine treatment and 52% received 1-2 lines of chemotherapy prior to the study. More than 80% of the patients had visceral disease. The combination of bazedoxifene and palbociclib was well tolerated. The most commonly observed adverse events (any grade) were fatigue and neutropenia. Grade 4 adverse events were uncommon (2 patients). The CBR was 36% (95% CI 23-49%). The objective response rate was 8% (95% CI 2-22%). Median PFS was 3.6 months (95% CI 2-8.5 months). There were 5 patients with a durable clinical benefit of ≥12 months. Correlative analysis of the pre-treatment tissue samples and serial plasma samples are ongoing.
Conclusions: The combination of bazedoxifene and palbociclib was well tolerated and demonstrated significant clinical activity in heavily pre-treated patients with ER+ MBC. Further studies investigating bazedoxifene in ER+ breast cancer are warranted.
Citation Format: Jeselsohn R, Guo H, Rees R, Barry WT, Barlett CH, Tung NM, Krop IE, Brown M, Winer EP. Results from the phase Ib/II clinical trial of bazedoxifene and palbociclib in hormone receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-05.