Work

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

Year: 2025

Type: article

Abstract: AC699 is a novel, orally bioavailable chimeric estrogen receptor-α (ERα) degrader that induces proteasome-dependent ERα degradation via cereblon E3 ligase recruitment. Here we report findings from a first-in-human, phase 1, dose-escalation study of once-daily AC699 (100–600 mg) in patients with heavily-pretreated, locally-advanced/metastatic ER-positive/HER2-negative breast cancer (ClinicalTrials.gov Identifier: NCT05654532). Primary objectives are to assess dose-limiting toxicities and treatment-emergent adverse events (TEAEs). Secondary objectives are to evaluate pharmacokinetics, objective response rate (ORR), clinical benefit rate (CBR, including stable disease ≥24 weeks), duration of response (DOR), and progression-free survival (PFS). Among 37 treated patients, TEAEs occurred in 78% of patients, most commonly nausea (19%), fatigue (16%), and neutropenia (16%). All treatment-related adverse events were Grade 1/2, with no dose reductions/discontinuations; the maximum tolerated dose was not reached. Of 26 efficacy-evaluable patients, 4 (15%) achieved partial responses and CBR was 23%. In exploratory analysis of patients with ESR1 mutations, ORR and CBR were 40% and 45%, respectively. Median DOR and PFS were 6.5 and 3.6 months overall, and 6.5 and 7.4 months in ESR1-mutant patients. AC699 steady-state exposure increased approximately dose-proportionally between 100–400 mg, plateauing at 600 mg. AC699 demonstrated favorable safety, predictable PK, and encouraging antitumor activity, particularly in ESR1-mutant disease. In patients with hormone receptor positive, human epidermal growth factor receptor 2-negative (HR+/HER-) breast cancer, endocrine therapy is standard of care but resistance often occurs. Here, the authors report a phase I trial investigating the ER degrader, AC699, in patients with locally advanced or metastatic ER+/HER2- breast cancer.

Source: Nature Communications

DOI: 10.1038/s41467-025-67485-y