Abstract P5-11-02: Dose-escalation study of SAR439859, an oral selective estrogen receptor degrader, in postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer
Authors: Campone Mario , Bardia Aditya , Ulaner Gary A , Chandarlapaty Sarat , Gosselin Alice , Doroumian Séverine , Ming Jeffrey , Celanovic Marina , Linden Hannah M 
Published: March 2020

Abstract
Background: Selective estrogen receptor (ER) degraders (SERDs) result in ER competitive antagonism and degradation and can block signaling in ER-dependent tumors resistant to other endocrine therapies. This study investigates SAR439859, a potent oral SERD, as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor, palbociclib, in ER-positive (+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). We previously presented preliminary results (ASCO 2019). Here we describe safety, pharmacokinetics (PK), ER gene (ESR1)profiling and updated antitumor activity for SAR439859 monotherapy dose escalation.
Methods: Part A of this open-label, Phase 1/2 first-in-human study (NCT03284957; TED14856) assessed SAR439859 dose escalation (3 + 3 design) in postmenopausal women with ER+/HER2- mBC treated for ≥ 6 months with prior endocrine therapy and ≤ 3 chemotherapies in the advanced setting. Dose levels ranged from 20-600 mg once daily (QD). Primary objectives: dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended dose. Secondary objectives: safety, PK, tumor response (RECIST v1.1), pharmacodynamic (PD) inhibition of ER occupancy (18F-fluoroestradiol positron emission tomography[18F-FES PET] scan). Exploratory objective: mutation profiling of ESR1 (circulating tumor DNA was assessed for 12 ESR1 mutations at baseline and end of Cycle 2 using multiplex droplet digital polymerase chain reaction).
Results: As of May 29, 2019, 16 patients were treated. Median age: 59.5 years (range 40-79); ECOG performance status: 0 (62.5%) or 1 (37.5%); median prior anticancer therapies in the advanced setting: 3 (range 1-8). All patients had ≥ 1 treatment-emergent adverse event (TEAE), mostly grade 1-2; most frequent were hot flushes, diarrhea, constipation, nausea (all 37.5%) and decreased appetite (31.3%). Most frequent TEAEs related to treatment were hot flushes (31.3%), diarrhea, nausea (both 25%), decreased appetite, constipation, night sweats, asthenia (all 18.8%), arthralgia and fatigue (both 12.5%); no event was grade ≥ 3. There were no DLTs at any of the five dose levels (maximum administered dose 600 mg QD); MTD was not reached. In 18F-FES PET scans, signal inhibition &gt; 87% occurred with plasma concentrations &gt; 100 ng/mL. PK profile showed rapid SAR439859 absorption (median tmax ~ 3 hours) and an apparent terminal half-life of ~ 8 hours after first administration. After repeated QD administration, there was no or low accumulation and exposure (Cmax/AUC0-24h) increased with doses up to 600 mg. Food intake did not have a major effect on exposure. Best overall response (BOR) was confirmed partial response (PR) in one patient at 150 mg QD (6.3%) and stable disease (SD) in eight patients (50.0%) including seven (43.8%) with long-term SD (≥ 24 weeks). Seven had progressive disease (43.8%). Tumor shrinkage &gt; 10% was seen in eight patients (50.0%), without any dose dependency. ESR1 mutations were detected at baseline in 11 patients (68.8%), with five patients harboring &gt; 1 mutation. Similar BOR was seen regardless of ESR1 mutation status with SD seen in 54.5% (6/11) of patients with ESR1 mutations and SD/PR seen in 60.0% (SD: 2/5; PR: 1/5) of patients with wild-type ESR1.
Conclusions: SAR439859 demonstrated a favorable safety profile and high ER occupancy in pretreated patients with ER+/HER2- mBC. Most patients had ESR1 mutations. Preliminary antitumor activity was encouraging in both ESR1 mutated and wild-type patients. With no DLTs and no MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK. Additional data on PK, PD, antitumor activity and the ESR1 mutational profile, and any correlations, will be presented. Funding: Sanofi.
Citation Format: Mario Campone, Aditya Bardia, Gary A Ulaner, Sarat Chandarlapaty, Alice Gosselin, Séverine Doroumian, Jeffrey Ming, Marina Celanovic, Hannah M Linden. Dose-escalation study of SAR439859, an oral selective estrogen receptor degrader, in postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-02.