686P - Phase I study of HRS8807, an oral selective ER covalent antagonist (SERCA), in ER+/HER2- locally advanced (LA) or metastatic (M) breast cancer (BC)

Background

HRS8807 exerts strong antitumor effect in wild-type and mutant ER+ BC cells and mouse xenograft models. Here we report the preliminary results of HRS8807, the second SERCA to enter clinical development, in patients (pts) with ER+/HER2- LA/M BC.

Methods

In this phase 1 study, eligible pts were women of any menopausal status who had received ≥1 line of endocrine therapy and/or ≤2 lines of chemo with radiologically confirmed disease progression from the most recent anticancer regimen. Dose escalation was started at 25 mg with 1 pt and then switched to i3+3 design at doses of 75 to 600 mg. 3 d after a single dose, HRS8807 was given continuously qd in 28-d cycles. Dose-limiting toxicities (DLTs) were observed from the first dose to end of the first cycle (ie, 31 d).

Results

As of Apr 12, 2023, 7 pts were recruited (1 at 25 mg, 3 at 75 mg, and 3 at 150 mg). Median age was 53 yr. All had ECOG PS of 1. 71.4% were PR+. Median time from diagnosis to enrollment was 44.6 mo. For the LA/M disease, 57.1% had ≥2 lines of prior anticancer therapies; 71.4% had prior selective ER modulator degrader (SERD) and 85.7% had prior CDK4/6i. No DLTs were observed. Treatment-related adverse events (TRAEs) were reported in all pts, with the most common being hypertriglyceridemia, increased AST, hyperuricemia, increased ALT, increased blood creatinine, and anemia. No grade ≥3 TRAEs occurred, and no TRAEs led to treatment discontinuation. 3 pts achieved PR (1 at 75 mg and 2 at 150 mg; in which 2 had prior SERD [fulvestrant] and all had prior CDK4/6i in the M setting; treatment duration was 8.4, 8.6+, and 7.0+ mo). Impressively, ORR reached 42.9% (95% CI 9.9-81.6) in overall population, and 66.6% (95% CI 9.4-99.2) at 150 mg and 33.3% (95% CI 0.8-90.6) at 75 mg. The active metabolite SHR180451, a reversible ER inhibitor slightly more potent than HRS8807 in prohibiting BC cell proliferation in vitro, had longer terminal elimination half-life than and comparable systemic exposure to the parent. ¹⁸F-FES PET-CT SUV_max decreased significantly after treatment.

Conclusions

HRS8807 was well-tolerated and showed early signs of robust antitumor activity, favorable PK properties (both parent and active metabolite), and high ER occupancy in pretreated ER+/HER2- LA/M BC.

Clinical trial identification

NCT04993430, Release date: 6 August 2021.

Editorial acknowledgement

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Funding

Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Disclosure

Y. Zhang, J. Wang, W. Xin, X. Zhu: Financial Interests, Personal, Full or part-time Employment: Jiangsu Hengrui Pharmaceuticals Co., Ltd. All other authors have declared no conflicts of interest.