FDA Grants Fast Track Status to AC699 for ER+/HER2–, ESR1-Mutated Breast Cancer

Jie Fan, PhD

The FDA has awarded fast track designation to the investigation of AC699 as a potential therapeutic option for patients with estrogen receptor (ER)­–positive, HER2-negative, ESR1-mutated, advanced or metastatic breast cancer that progressed on or following 1 more lines of endocrine-based therapy.¹

The orally bioavailable, chimeric ERα degrader is designed to bring an ER ligand to cereblon E3 ligase and elicit subsequent ubiquitination and ER degradation.² It is hypothesized that the agent’s mechanism of action could lead to stronger specificity, allow for the ability to overcome endocrine resistance, and achieve more complete target blockade vs SERDs.

Preclinical data indicated that the agent led to potent and selective protein degradation of ERα wild-type and mutants and had positive pharmacological properties.1 In ER-positive animal cancer models, AC699 also demonstrated antitumor activity. The safety, tolerability, pharmacokinetics, and preliminary antitumor activity of the agent is under exploration in the phase 1 AC699-001 study (NCT05654532)

“Receiving fast track designation for AC699 from the FDA highlights their recognition of the serious and life-threatening nature of this malignancy, the critical unmet medical needs not fully addressed by existing therapies, and the potential of AC699 to fill in the gap,” Jie Fan, PhD, chief executive officer of Accutar Biotechnology, Inc., stated in a news release.¹ “We look forward to working closely with the FDA to optimize and expedite the development program.

The first-in-human, open-label, phase 1 study utilizes a 3+3 design and is recruiting patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer who have previously received at least 2 lines of endocrine regimens in any setting or 1 or more prior lines if paired with a CDK4/6 inhibitor.² Patients are also required to have at least 1 measurable lesion by RECIST 1.1 criteria, acceptable organ or hematologic function at baseline, and a life expectancy of at least 12 weeks following treatment initiation

They could not have symptomatic brain metastases in need for systemic corticosteroids, nor could they have received any cytotoxic chemotherapy, investigational drugs or anticancer drugs for locally advanced or metastatic disease within 2 weeks before the first dose of AC699, radiation therapy within 2 weeks before the first dose of the study drug that did not resolve to acceptable toxicity or previous irradiation to greater than 25% of bone marrow, or major surgery occurring within 21 days before the first study drug dose.

The dose levels of AC699 under exploration in the phase 1 dose-escalation include 100 mg, 200 mg, 300 mg, and 400 mg.2 The primary objective of the study is to examine the safety and tolerability of the agent and secondary objectives include characterizing the pharmacokinetic (PK) profile of single and multiple doses of AC699 and evaluate early antitumor activity.

Preliminary results from the study were shared at the 2024 ASCO Annual Meeting. At a data cutoff date of April 8, 2024, a total of 29 patients received treatment with AC699.

The median patient age was 60 years (range, 41-81). Regarding baseline ECOG performance status, 34% of patients had a status of 0 and 66% had a status of 1. In terms of ESR1 status at baseline, 59% were wild-type, 34% were mutant, and 7% had information pending. Most patients (79%) had measurable disease. Patients were heavily pretreated, with a median of 5 lines of prior regimens (range, 2-10). All patients previously received CDK4/6 inhibitors; 93% of patients previously received SERD, SERCA, or ER chimeric degraders. Ninety-three percent of patients previously received an aromatase inhibitor.

AC699 was found to have a favorable toxicity profile. Treatment-emergent adverse effects (TEAEs) occurred in 79% of patients, and no grade 3 or higher TEAEs occurred. The most common TEAEs to occur in 10% or more of patients included nausea (all grade, 21%; grade ≥3, 0%), dehydration (17%; 7%), fatigue (17%; 3%), hot flush (14%; 0%), abdominal pain (10%; 3%), and decreased neutrophil count (10%; 3%). Related TEAEs included all-grade nausea (14%), hot flush (14%), fatigue (10%), and decreased neutrophil counts (7%).

No dose-limiting toxicities were reported, and AEs did not result in any dose reductions or treatment discontinuations. Notably, no study drug­–related AEs led to dose interruptions. Although 8 patients experienced serious AEs, none of them were determined to be related to AC699.

In all evaluable patients (n = 19), the objective response rate achieved with AC699 was 21%; in those with ESR1-mutated disease (n = 8), this rate was 50%. The clinical benefit rates in all evaluable patients (n = 21) and the ESR1-mutated subgroup (n = 9) were 29% and 56%, respectively.

PK data revealed a dose proportional relationship.

With the fast track designation, Accutar Biotechnology, Inc., the drug developer, is eligible for more frequent meetings and communications with the regulatory agency during the clinical development of AC699, and if relevant criteria are met, potential priority review and accelerated approval.¹

References

1. Accutar Biotechnology receives fast track designation for AC699 in ER+/HER2- breast cancer. News release. Accutar Biotechnology, Inc. August 14, 2024. Accessed August 14, 2024. https://www.businesswire.com/news/home/20240814155176/en
2. Patel MR, Layman RM, Danso MA, et al. Preliminary results from a phase 1 study of AC699, an orally bioavailable chimeric estrogen receptor degrader, in patients with advanced or metastatic breast cancer. J Clin Oncol. 2024;42(suppl 16):3074. doi:10.1200/JCO.2024.42.16_suppl.3074