ER degradation for ER+/HER2‒ advanced or metastatic breast cancer: a phase 1 trial

AC699, an oral, novel chimeric estrogen receptor-α (ERα) binds, ubiquitinates, and degrades ERα by engaging cereblon E3 ligase. We report AC699 (100‒600 mg daily), safety/tolerability, and preliminary antitumor efficacy from a first-in-human, phase 1, dose-escalation study in 37 patients with heavily-pretreated, locally-advanced/metastatic ER+/HER2- breast cancer. 78% of patients had treatment-emergent adverse events (TEAEs), most commonly nausea (19%), fatigue (16%), and neutrophil count decreased (16%). All treatment-related AEs (TRAE) were Grade 1/2. No TRAE-associated dose reductions/discontinuations occurred. The maximum tolerated dose was not reached. Among 26 evaluable patients, 4 (15%) achieved confirmed partial response (PR) and the clinical benefit rate (CBR; including stable disease ≥24 weeks) was 23%. Corresponding values in patients with ESR1 mutations were 40% (4/10 patients, all PRs) and 45% (5/11 patients). These results demonstrate promising safety/tolerability, and antitumor activity in patients with ER+/HER2‒ advanced/metastatic breast cancer, with notable PRs in 40% of patients with ESR1 mutations.