背景:大约40%的激素受体(HR)阳性和人表皮生长因子受体2(HER2)阴性的晚期乳腺癌(ABC)患者表现出PIK3CA突变。
目的:本研究旨在评估安全性,耐受性,药代动力学,以及选择性PI3Kα抑制剂HS-10352的初步抗肿瘤活性,在这个患者群体中。
方法:作为1期剂量递增试验进行,HS-10352以2、4、6和8mg的剂量水平每天一次(QD)口服给药。主要终点是剂量限制性毒性(DLT)和最大耐受剂量(MTD)。本研究在ClinicalTrials.gov(NCT04631835)注册。
结果:在2020年8月至2022年3月期间,共招募了18名女性患者。DLT,表现为高血糖,发生在8mgQD组的两名患者中,建立6mgQD的MTD。最常见的治疗相关不良事件是高血糖(88.9%)和体重减轻(61.3%)。在6mgQD组中,4例患者(66.7%)部分缓解(PR),1例(16.7%)病情稳定(SD)。在该剂量组中的四名PIK3CA突变肿瘤患者中,3人(75.0%)有PR,1人(25.0%)有SD。中位无进展生存期未达到(95%置信区间,11.1-NA)。
结论:HR阳性患者在6mgQD时的HS-10352耐受性良好,HER2阴性ABC,并在PIK3CA突变肿瘤患者中显示出初步的抗肿瘤活性。这些发现支持HS-10352的进一步临床开发。
Approximately 40% of patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) exhibit PIK3CA mutations.
This study aims to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of HS-10352, a selective PI3Kα inhibitor, in this patient population.
Conducted as a phase 1 dose-escalation trial, HS-10352 was administered orally once-daily (QD) at dose levels of 2, 4, 6, and 8 mg. The primary endpoints were dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). This study is registered at ClinicalTrials.gov (NCT04631835).
Between August 2020 and March 2022, a total of 18 female patients were enrolled. DLT, manifested as hyperglycemia, occurred in two patients in the 8 mg QD group, establishing an MTD of 6 mg QD. The most common treatment-related adverse events were hyperglycemia (88.9%) and weight loss (61.3%). In the 6 mg QD group, four patients (66.7%) had a partial response (PR), and one (16.7%) had stable disease (SD). Among the four patients with PIK3CA mutated tumors in this dosage group, three (75.0%) had PR and one (25.0%) had SD. The median progression-free survival was not reached (95% confidence interval, 11.1-NA).
HS-10352 at 6 mg QD was well-tolerated in patients with HR-positive, HER2-negative ABC, and showed preliminary antitumor activity in patients with PIK3CA mutated tumors. These findings support the further clinical development of HS-10352.