Abstract CT518: First-in-human dose-escalation study of the phosphatidylinositol 3-kinase α-selective inhibitor HS-10352 in advanced breast cancer
Authors: Ouyang Quchang , Wang Ying , Zhang Jian , Wu Qiong , Sun Changan , Wei Hongying , Qian Xiaoling , Hu Xichun 
Published: June 2022

Abstract
Background: PIK3CA mutation is particularly prevalent in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. HS-10352 is a highly potent and selective small molecule inhibitor of phosphoinositide 3-kinase α. Preclinical studies have indicated the favorable safety and antitumor activity of HS-10352 in PIK3CA-mutated tumor models.
Methods: A phase 1, open-label, dose-escalation study was conducted to assess the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity, in patients (pts) with advanced HR+HER2- breast cancer for whom standard therapy was ineffective or unavailable. The rolling six dose-escalation scheme was used to determine the maximum tolerated dose (MTD). Tumor tissues were collected for retrospectively central determination of PIK3CA mutation status.
Results: Eighteen pts were treated with HS-10352 orally once daily (2 mg n=3; 4 mg n=3; 6 mg n=6; 8 mg n=6). All patients were HR+HER2- female breast cancer with visceral metastases after a median number of 3 prior systemic therapies for advanced disease. The median treatment duration was 111.5 days (range: 13~388). Dose limiting toxicities occurred in 2 pts at 8 mg (2 Grade 3 hyperglycemia). The MTD was established as 6 mg. According to the CTCAE 5.0, the most common (≥ 30%) treatment-related adverse events (TRAEs) were hyperglycemia (88.9%, n=16), weight decreased (61.1%, n=11), insulin C-peptide increased and diarrhea (33.3% each, n=6). Grade 3-4 TRAEs were hyperglycemia (8 mg, n=2), weight decreased (6 mg, n=2), fatigue (8 mg, n=1), vision blurred (8 mg, n=1), hyperkalemia (8 mg, n=1) and hypocalcemia (8 mg, n=1). Hyperglycemia was generally manageable with oral anti-hyperglycemic medications (13/16). Treatment-related rash were mild (22.2%, grade 1: n=2; grade 2: n=2). The overall response rate (ORR) and disease control rate (DCR) for all patients (n=18) were 27.8% and 55.6% respectively. For 6 pts with PIK3CA mutation, ORR was 50.0% (confirmed partial response [PR] in 3 pts at 6 mg) and DCR was 100.0% (6 mg, n=4; 8 mg, n=2), and the 9-month progression-free survival (PFS) rate was 66.7% (95% CI: 28.9%~100.0%). Of 4 pts with PIK3CA mutation at potentially recommended phase 2 dose of 6 mg, three pts (75.0%) achieved confirmed PR and 1 patient (25.0%) had stable disease (PFS ≥ 7.4m). Plasma exposure of HS-10352 increased proportionally following single dose. The mean plasma half-life of HS-10352 was 11~15 hours.
Conclusions: HS-10352 showed a manageable safety profile and favorable PK properties. The promising antitumor activity was observed in patients with HR+HER2- advanced breast cancer harboring PIK3CA mutation. Clinical trial information: NCT04631835.
Citation Format: Quchang Ouyang, Ying Wang, Jian Zhang, Qiong Wu, Changan Sun, Hongying Wei, Xiaoling Qian, Xichun Hu. First-in-human dose-escalation study of the phosphatidylinositol 3-kinase α-selective inhibitor HS-10352 in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT518.