Related Experiment Video
Updated: Jan 8, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
ER degradation for ER+/HER2- advanced or metastatic breast cancer: a phase 1 trial
Erika Hamilton1, Rachel M Layman2, David Cosgrove3
1Sarah Cannon Research Institute, Nashville, TN, USA. erika.hamilton@scri.com.
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.
Insights
AC699, a novel oral estrogen receptor degrader, shows promising safety and antitumor activity in advanced breast cancer. The drug was particularly effective in patients with ESR1 mutations, warranting further investigation.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Estrogen receptor-α (ERα) is a key driver in ER-positive breast cancer.
- Novel therapeutic strategies targeting ERα degradation are needed for heavily pretreated patients.
- AC699 is an orally bioavailable ERα degrader utilizing cereblon E3 ligase recruitment.
Purpose of the Study:
- To assess the safety and tolerability of AC699 in a phase 1 dose-escalation study.
- To evaluate the pharmacokinetics and preliminary efficacy of AC699.
- To explore the activity of AC699 in patients with ESR1 mutations.
Main Methods:
- First-in-human, phase 1, open-label, dose-escalation study of AC699 (100-600 mg once daily).
- Patients with heavily pretreated, locally-advanced/metastatic ER+/HER2- breast cancer were enrolled.
- Safety (TEAEs, dose-limiting toxicities), PK, ORR, CBR, DOR, and PFS were assessed.
Main Results:
- 78% of 37 patients experienced treatment-emergent adverse events (TEAEs), primarily nausea, fatigue, and neutropenia (all Grade 1/2).
- No dose reductions or discontinuations due to toxicity were observed; maximum tolerated dose was not reached.
- In 26 efficacy-evaluable patients, ORR was 15% and CBR was 23%. In ESR1-mutant patients, ORR was 40% and CBR was 45%.
Conclusions:
- AC699 demonstrated a favorable safety profile and predictable pharmacokinetics in this phase 1 study.
- Encouraging antitumor activity was observed, especially in patients with ESR1 mutations.
- Further investigation of AC699, particularly in the ESR1-mutant population, is warranted.
