Preliminary results from a phase 1 study of AC699, an orally bioavailable chimeric estrogen receptor degrader, in patients with advanced or metastatic breast cancer.
Authors: Patel Manish R. , Layman Rachel M. , Danso Michael A. , Cosgrove David , Zettler Marjorie E. , Pehlivan Katherine C. , Hamilton Erika P. 
Published: June 2024

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Background: Endocrine therapy is a critical component of treatment for over 200,000 patients diagnosed yearly with estrogen receptor positive (ER+)/HER2- breast cancer. Although selective ER degraders (SERDs) have improved progression-free survival in this patient population, as monotherapy they have shown very limited overall response rates (ORR). AC699 is a novel chimeric degrader that binds, ubiquitinates and degrades ERα by bringing it into close proximity with an E3 ligase. This mechanism of action may result in greater specificity and more complete target blockade compared to SERDs. Initial results from the ongoing first-in-human dose escalation study of AC699 (NCT05654532) are presented here. Methods: The study employed a 3+3 design, with the option of adding backfill patients to each cohort cleared and deemed safe. Patients must have had locally advanced or metastatic ER+/HER2- breast cancer and received at least 2 prior lines of endocrine treatment, or at least 1 prior line if combined with a CDK4/6 inhibitor. AC699 was administered orally once daily in 28-day cycles. Tumor responses were assessed every 2 cycles using RECIST v1.1 criteria. The relationship between ESR1 mutational status and anti-tumor activity was investigated as an exploratory analysis. Results: A total of 22 patients had received AC699 in 3 dose cohorts (100, 200 and 300 mg) at the time of data cutoff. The median age was 61 years and the median lines of prior therapy was 5 (range 2-10). Prior treatments included CDK4/6 inhibitor (100%), aromatase inhibitor (91%), fulvestrant (82%), novel oral SERD or covalent antagonist (SERCA) (23%), and ER chimeric degrader (14%). Eighteen patients had measurable disease while 4 had bone lesions only. There were no dose-limiting toxicities, dose reductions or discontinuations for treatment-related AEs, and the maximum tolerated dose was not reached. The most common treatment-emergent AEs were fatigue (23%), dehydration (18%) and nausea (18%). All treatment-related AEs were Grade 1 or 2, including nausea (18%) and hot flushes (14%). Fifteen patients had at least 1 scan before the data cutoff date and of these, 3 were not evaluable for ORR due to having bone lesions only. Among the 12 evaluable patients, 4 (33%) achieved partial response: 3 confirmed and one unconfirmed. The clinical benefit rate (CBR) which also includes patients with stable disease ≥24 weeks was 42% (5/12). In the subgroup of evaluable patients harboring a confirmed ESR1 mutation, the ORR was 67% (4/6), the CBR was 83% (5/6) and the median time on treatment was 168 days (range 56-336), with 4 of 7 patients still receiving AC699. Conclusions: Preliminary data from the ongoing phase 1 trial evaluating AC699 indicate promising safety, tolerability, and anti-tumor activity, at doses up to 300 mg orally once daily. A phase 2 study will begin enrolling in early 2024. Clinical trial information: NCT05654532 .