277MO SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in ER+/ HER2- metastatic breast cancer (mBC): Biomarker analyses from a phase I/II study

Abstract

SAR439859 has antitumor activity in patients (pts) with wild type (WT) and mutated ESR1 mBC. Here we describe tumor molecular features and evidence of on target activity in SAR439859-treated pts. Plasma circulating cell-free DNA (cfDNA) and paired biopsies were collected at baseline (BL), on treatment (OT) and end of treatment (EOT: cfDNA only) from heavily pretreated postmenopausal pts with ER+/HER2- mBC who received SAR439859 monotherapy (Part A: dose range 20–600 mg QD; Part B: 400 mg QD) in a phase I/II study (NCT03284957). In cfDNA at BL and EOT, mutation (mut) analysis was performed on a next generation sequencing panel of 77 genes. ESR1 muts in cfDNA at BL and OT were assessed by droplet digital polymerase chain reaction (ddPCR). In tumor tissue, ER and progesterone receptor (PgR), Ki67 and Bcl-2 expression over time were assessed by immunohistochemistry; changes in ER signaling pathway activation were assessed by gene set variation analysis (RNA sequencing). Response was assessed in pts who received SAR439859 ≥150 mg QD. At BL, in cfDNA from 63 pts, 95% had ≥1 mut, 52% had ≥1 ESR1 mut, 92% had ≥1 non-ESR1 mut and 49% had concurrent ESR1 and other muts. Most prevalent BL non-ESR1 muts were in PIK3CA (44% of pts), EGFR (33%), TP53 (30%) and MET (25%). ESR1 muts most commonly detected at BL and EOT were D538G, Y537S and Y537N. ESR1 muts tended to decrease OT; of 14 pts with ESR1 muts at BL, 2 had WT ESR1 OT. In 8 paired biopsies (7 were highly proliferative luminal B tumors), ER, PgR and Ki67 decreased (median relative change from BL: -58%, -88% and -33%), while Bcl-2 increased (24%). ER activation score decreased in 3/5 paired biopsies tested (median change from BL -0.38). SAR439859 showed clinical benefit (complete response + partial response [PR] + stable disease ≥24 weeks) in 40% (12/30) of WT ESR1 pts and 32% (9/28) of mutated ESR1 pts, per ddPCR. Of the 5 pts with PRs, 4 had WT ESR1 and 1 had 2 ESR1 muts, at BL. Common genomic alterations, including in ESR1 and PIK3CA, were detected in most mBC pts. SAR439859 showed clinical benefit irrespective of ESR1 mut status and resulted in ER degradation and pathway inhibition in heavily pretreated pts.