Dose-escalation study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).

Aditya Bardia Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA info_outline Aditya Bardia, Hannah M. Linden, Gary A. Ulaner, Sarat Chandarlapaty, Alice Gosselin, Séverine Doroumian, Marina Celanovic, Mario Campone

Authors Aditya Bardia Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA info_outline Aditya Bardia, Hannah M. Linden, Gary A. Ulaner, Sarat Chandarlapaty, Alice Gosselin, Séverine Doroumian, Marina Celanovic, Mario Campone Organizations Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, University of Washington Medical Center, Seattle Cancer Care Alliance, Seattle, WA, Memorial Sloan Kettering Cancer Center, New York, NY, Sanofi, Paris, France, Sanofi, Montpellier, France, Sanofi, Cambridge, MA, Institut de Cancérologie de l'Ouest, René Gauducheau, St Herblain, France Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: 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, +/- palbociclib in ER+/HER2- mBC. Here are preliminary results, as of 28 Nov 2018, for single-agent SAR439859 dose escalation. Methods: Part A of this Phase 1/2 study (NCT03284957; TED14856) assessed SAR439859 dose escalation (dose range: 20–600 mg once daily [QD]; 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. Endpoints: dose-limiting toxicities (DLTs); maximum tolerated dose (MTD); safety; pharmacokinetics (PK); tumor response (RECIST 1.1); pharmacodynamic (PD) inhibition of ER occupancy ( 18 FES-PET scan). Results: Patients (pts; n = 16) had a median age of 59.5 years (range 40–79), ECOG performance status of 0 (62.5%) or 1 (37.5%) and a median of three prior anticancer therapies (range 1–8) in the advanced setting (endocrine therapy n = 16; chemo/targeted therapy n = 13). All pts had ≥ 1 treatment emergent adverse event (mostly grade 1–2); most frequent were asthenia/fatigue (43.8%), hot flushes (37.5%), nausea (37.5%), diarrhea (31.3%), constipation (31.3%), and decreased appetite (31.3%). There were no DLTs at any of the five dose levels (maximum administered dose: 600 mg QD); MTD was not reached. In 18 FES-PET scans, signal inhibition > 87% occurred with plasma concentrations > 100 ng/mL. There was a dose proportional increase of exposure up to 400 mg after repeated QD doses. Average C trough was reached after repeated 400 mg QD allowing 90% of 18 FES-PET signal inhibition. One pt (6.3%) had confirmed partial response (150 mg QD); eight (50%) had stable disease (SD) including three (18.8%) long-term SD (≥ 24 weeks); seven (43.8%) had progressive disease. Conclusions: SAR439859 had a favorable safety profile, high ER occupancy and encouraging antitumor activity (to be confirmed in dose expansion) in pretreated pts with ER+/HER2- mBC. With no DLTs and MTD, 400 mg QD was selected for expansion cohorts based on safety, PD and PK data. Funding: Sanofi. Clinical trial information: NCT03284957