637P - AC699, a novel chimeric estrogen receptor degrader, in a phase I study in breast cancer

Background

Endocrine therapy is a critical component of treatment for patients with estrogen receptor (ER) positive breast cancer. Selective ER degraders (SERD) such as elacestrant and fulvestrant result in objective response rates (ORR) of approximately 7% and 2% in the EMERALD trial. This improves to 11% and 3% in a subset of patients who have a mutation in the ESR1 gene. AC699 is a novel chimeric degrader that binds, ubiquitinates and degrades ERα by bringing it into proximity with an E3 ligase. Here, we present updated efficacy findings from an ongoing phase 1 study (NCT05654532) and disclose pharmacokinetic (PK) results.

Methods

The study employed a 3+3 design, with the option of enrolling additional patients into each cleared cohort. Patients must have had locally advanced or metastatic ER+/HER2- breast cancer and received at least two prior lines of endocrine treatment or one prior line if combined with a CDK inhibitor. AC699 was administered orally once daily in 28-day cycles. Extensive PK was collected on days 1 and 15 of cycle 1 and tumor responses were assessed every two cycles.

Results

A total of 29 patients had received AC699 at four dose levels (100, 200, 300, 400 mg) at the time of the data cutoff. The median lines of prior therapy were 5 (range 2-10) including 3 (1-8) in the metastatic setting. Prior treatments included a CDK4/6 inhibitor (100%), fulvestrant (82%), novel SERDs (23%), and an ER chimeric degrader (14%). There were no dose-limiting toxicities, dose reductions or discontinuations for treatment-related adverse events (AE). The maximum tolerated dose was not reached. The most common AEs were nausea (21%), dehydration (17%) and fatigue (17%). There were no >Grade 3 treatment-related AEs. The PK profile showed linear, dose-dependent proportionality from 100 to 400 mgs. Among 19 evaluable patients, the ORR was 21% (4/19). In a subgroup of patients harboring a confirmed ESR1 mutation with a variant allele frequency >1%, the ORR was 50% (4/8).

Conclusions

Preliminary data from this ongoing phase 1 trial evaluating AC699 indicate promising safety, tolerability, and anti-tumor activity, with linear PK up to 400 mg orally once daily. Phase 1b and phase 2 studies are planned.

Clinical trial identification

NCT05654532.

Editorial acknowledgement

Legal entity responsible for the study

Accutar Biotechnology, Inc.

Funding

Accutar Biotechnology Inc.

Disclosure

E.P. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, Olema Pharmaceuticals, Stemline Therapeutics, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Tubulis, Verascity Science, Theratechnologies; Financial Interests, Institutional, Other, Consulting: Accutar Biotechnology, Entos, Fosun Pharma, Gilead Sciences, Jazz Pharmaceuticals, Jefferies Llc, Medical Pharma Services, Tempus Labs, Zentalis Pharmaceuticals; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Rgenix, Arqule, Clovis, Millennium, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Molecular Templates, Dana Farber Cancer Inst, Hutchinson MediPharma, MedImmune, SeaGen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFfector Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Atlas MedX, Ellipses Pharma, Incyte, Jacobio, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Relay Therapeutics, Tolmar, Torque Therapeutics; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Eisai, Fochon Pharmaceuticals, Gilead Sciences, Inspirna, Myriad Genetic Laboratories, Silverback Therapeutics, Stemline Therapeutics. R. Layman: Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, Celcuity, Gilead Sciences, BioTheryx; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Institutional, Local PI: Accutar Biotechnology, Eli Lilly, Pfizer, Celcuity; Financial Interests, Personal, Steering Committee Member: Eli Lilly, Celcuity; Financial Interests, Institutional, Research Grant, Supply of drug for clinical trial: Novartis, Puma; Financial Interests, Institutional, Research Grant: Celcuity; Financial Interests, Institutional, Trial Chair: Arvinas. M.A. Danso: Financial Interests, Personal, Advisory Board: Agendia, AstraZeneca, BioTheranostics, Genentech, Gilead Sciences, Lilly, Puma, Sanofi, Seattle Genetics, Stemline Therapeutics, Pfizer. X. Wang, H. Zhang, G. Brown, S.Y. Kim: Financial Interests, Personal, Full or part-time Employment: Accutar. M.R. Patel: Financial Interests, Personal, Advisory Board: Daiichi, Janssen, accutar, Olema, Mitsubishi, Kura, Nurix; Financial Interests, Personal, Advisory Board: ION; Financial Interests, Institutional, Local PI, institution received research funding: Daiichi. All other authors have declared no conflicts of interest.