SAR439859 Achieves On-Target Activity in Metastatic ER+ Breast Cancer

Partner | Cancer Centers | <b>Memorial Sloan Kettering Cancer Center </b>

December 28, 2020 - The investigational selective estrogen receptor degrader SAR439859 elicited clinical, on-target activity in patients with heavily pretreated estrogen receptor–positive, HER2-negative metastatic breast cancer, even in the presence of multiple resistance mechanisms.

The investigational selective estrogen receptor degrader (SERD) SAR439859 elicited clinical, on-target activity in patients with heavily pretreated estrogen receptor (ER)–positive, HER2-negative metastatic breast cancer, even in the presence of multiple resistance mechanisms, according to phase 1/2 results of a biomarker analysis.

Results of the analysis, which was presented during the 2020 ESMO Virtual Congress, showed that the notable on-target activity, was defined as a greater than 50% decrease in ER protein expression, as well as decreases in progesterone receptor (PR) protein expression, Ki-67 protein expression, and ER activation gene score. The on-target activity, however, was most evident in those who had experienced clinical benefit while on SAR439859.

Moreover, SAR439859 led to a clinical benefit rate of 40% in patients with ESR1 wild-type disease; this rate was 32% in patients with ESR1 mutations. Of the 5 patients with partial responses, 4 had an ESR1 mutation and 1 had 2 ESR1 mutations at baseline.

“[To explain] what happened when the drug hit the target, we looked at tumor biopsies,” Sarat Chandarlapaty, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center. “ER protein expression is downregulated consistently, ER signaling is downregulated consistently, and often the proliferation of Ki-67 is downregulated. However, sometimes that's uncoupled, which would be expected in this heavily pretreated patient population. There will be some ER-independent tumors.”

Previously, SAR439859 previously demonstrated in vivo activity against Y537S, a ESR1 resistance mutation, in addition to antitumor activity in heavily pretreated women with ER-positive, HER2-negative disease, including those with ESR1 mutations.

In this first-in-human, open label phase 1/2 study of SAR439859, investigators sought to evaluate the agent's on-target activity, determine the molecular features of this patient population, and identify changes to the molecular landscape at the time of treatment with SAR439859 and at disease progression. Plasma circulating cell-free DNA (cfDNA) and paired biopsies were collected at baseline, on treatment, and end of treatment.

The trial, which comprised a postmenopausal patient population, consisted of 2 parts: a dose-escalation portion that ranged giving 20 mg to 600 mg of SAR439859 to patients, and a dose-expansion portion with the recommended phase 2 dose of 400 mg.

"In particular we had baseline, on-treatment, and off-treatment sampling using both blood and tumor biopsies,” Chandarlapaty added.

The patient population had hormone-refractory disease, many of whom had previously received prior treatment with an aromatase inhibitor (95.4%; n = 62) and fulvestrant (Faslodex; 47.7%; n = 31). In cfDNA of 63 pts, 95% had at least 1 mutation; the mutation scope included at least 1 ESR1 mutation (52%), at least 1 non-ESR1 mutation (92%), and concurrent ESR1 and other mutations (49%). The prevalent non-ESR1 mutations at baseline were in PIK3CA (44%) EGFR (33%), TP53 (30%), and MET (25%). The ESR1 mutations most commonly detected at baseline and end of treatment included D538G, Y537S and Y537N.

Additional findings indicated that SAR439859 achieved clinical response in tumors harboring ESR1 mutations in cfDNA at baseline. Moreover, mutated ESR1 allele frequency decreased following treatment in 93% of patients (n = 13) who had 1 or more ESR1 mutation.

"Many of the patients who had ligand-binding domain mutations had clinical benefit; many also did not. But, certainly, no mutation appeared to be non-targetable or associated with consistent resistance,” Chandarlapaty said.

Numerous baseline genomic aberrations were identified in cfDNA that were not limited to ESR1 mutations. Investigators noted that some aberrations were preclinically associated with ER resistance.

“It's clear that not everyone who had an ESR1 mutation benefitted [from treatment],” Chandarlapaty explained. “One reason for that is the presence of other genomic alterations concurrently in ESR1 mutations. Looking at next-generation sequencing of the population, both in the clinical benefit and the no clinical benefit groups, concurrent alterations such as in the MAP kinase pathway might be important in mediating the lack of activity of a single agent.”

“For the most part, ESR1 mutations are consistently down and often undetectable at the end of the study. In some cases, they do appear to have risen, but no specific mutation is associated with a rise in allele frequency,” Chandarlapaty concluded. “When looking at other alterations, we do see some preservation of PIK3CA mutations consistent with a clonal mutation in the population and some rises in TP53 that can be more associated with the ER-independent tumors.”

Reference

  1. Chandarlapaty S, Bardio A, Lord S, et al. SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), in ER+/ HER2- metastatic breast cancer (mBC): biomarker analyses from a phase I/II study. Ann Oncol. 2020;31(suppl_4):S251. doi:10.1016/j.annonc.2020.08.379