Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1
Authors: Linden Hannah M , Campone Mario , Bardia Aditya , Ulaner Gary A , Gosselin Alice , Doroumian Séverine , Pelekanou Vasiliki , Celanovic Marina , Chandarlapaty Sarat 
Published: February 2021

Abstract
Background SERDs belong to a class of ER-targeted therapies that antagonize and degrade ERs, including in ER-dependent tumors resistant to other endocrine therapies (ET). This study (AMEERA-1; NCT03284957) investigates SAR439859, an oral SERD, as monotherapy and (in ongoing cohorts) in combination with targeted therapies in patients (pts) with ER+/HER2- mBC. Here we report updated safety and antitumor activity with SAR439859 monotherapy, including exploratory analyses by prior therapy and ESR1 status. Methods This open-label, phase 1/2, first-in-human study assessed SAR439859 as monotherapy in Parts A (dose escalation 20-600 mg once daily [QD]) and B (dose expansion with recommended dose at 400 mg QD). Eligible pts were heavily pre-treated, postmenopausal women with ER+/HER2- mBC and measurable disease who received ≥6 months of prior ET in the advanced setting. Prior chemotherapy, mammalian target of rapamycin inhibitors (mTORi) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for advanced disease were allowed. This analysis pooled data from pts receiving SAR439859 ≥150 mg (Part A) and 400 mg (Part B), administered in 28-day cycles. Antitumor activity was assessed by the objective response rate and clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] ≥24 weeks) per RECIST v1.1, determined by investigators. Analyses by prior therapy and baseline ESR1 mutation status were performed. Safety was also evaluated. Results Pts (n = 62; Part A: 13; Part B: 49) had a median age of 63 (range 37-88) years and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral metastases. Pts had a median of 2 (range 1-8) prior lines of therapy in the advanced setting (48.4% had ≥3 prior lines): all had prior ET and 72.6% had prior targeted therapy. SAR439859 monotherapy showed antitumor activity in the response-evaluable population (n = 59) and in subset populations with ≤3 prior lines (n = 33) or without prior mTORi, CDK4/6i, or SERD (n = 14) (Table 1). For pts with ESR1 status (n = 58), CBR with SAR439859 was comparable in ESR1 wild-type (36.7%) and mutant mBC (32.1%), with similar results in subpopulations. Treatment-related adverse events (TRAEs) occurred in 62.9% of pts (all grade 1-2); none resulted in SAR439859 discontinuation. Most frequent TRAEs were hot flush (16.1%); constipation and arthralgia (each 9.7%); decreased appetite, vomiting, diarrhea and nausea (each 8.1%); and fatigue (6.5%). Conclusions Among heavily pre-treated pts, SAR439859 demonstrated antitumor activity, similar to historical single-agent fulvestrant activity in less heavily pre-treated pts with advanced/mBC (2L+ setting; no prior targeted agents) (indirect comparison). In both subsets of pts with fewer prior advanced lines of therapy, SAR439859 showed trends of greater clinical activity versus historical fulvestrant activity. SAR439859 had a favorable safety profile with limited TRAEs. No safety signals of cardiac or ocular toxicities were observed. Ongoing parts of the study are investigating SAR439859 in combination with targeted therapies. Based on the monotherapy results, a randomized phase 2 study is investigating SAR439859 compared with physician’s choice in a 2L+ setting (AMEERA-3; NCT04059484). Funding: Sanofi.
Antitumor activity overall and in subpopulations by prior lines of therapy (Parts A+B)Overall population (A+B)≤3 Prior advanced linesWithout prior targeted therapy(n = 59)a(n = 33)b(n = 14)cBOR, n (%)–CR000–PR5 (8.5)5 (15.2)3 (21.4)–SD24 (40.7)15 (45.5)8 (57.1)–PD30 (50.8)13 (39.4)3 (21.4)ORR, n (%)5 (8.5)5 (15.2)3 (21.4)CBR, n (%)20 (33.9)14 (42.4)9 (64.3)aPooled cohort (A ≥150 mg QD + B);bSubset of pooled cohort with ≤3 prior lines in the metastatic setting, including ≤1 of either prior chemotherapy or CDK4/6i and no prior mTORi; cSubset of pooled cohort with no prior mTORi, CDK4/6i, or fulvestrant.BOR, best overall response; CBR, clinical benefit rate; CR, complete response; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.
Citation Format: Hannah M Linden, Mario Campone, Aditya Bardia, Gary A Ulaner, Alice Gosselin, Séverine Doroumian, Vasiliki Pelekanou, Marina Celanovic, Sarat Chandarlapaty. A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-08.