PO.CT01.01 · 临床试验

HRS-6209（一种高选择性CDK4抑制剂）在晚期实体瘤患者中的1期研究

Phase 1 study of HRS-6209, a highly selective CDK4 inhibitor, in patients with advanced solid tumors

编号 CT117 展板 9 时间 4/20 02:00–05:00 区域 Section 51 主讲 Lin Dong

分会场 Phase 0 and First-in-Human Phase I Clinical Trials

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作者与单位 Authors & Affiliations

Jiong Wu¹, Jian Zhang¹, Ning Lu², Caigang Liu³, Qiang Ding⁴, Huangming Hong⁵, Hui Wang⁶, Yuping Sun⁷, Hong Zhang⁸, Min Yan⁹, Ying Wang¹⁰, Yiqun Du¹, Yanchun Meng¹, Dongfang Li⁶, Huihui Li⁷, Zhengkui Sun⁸, Xiaoyu Zhu¹¹, Xia Zhang¹¹, Xiaonan Sheng¹¹, Qiushi Xie¹¹, Mengzhu Yu¹¹

¹Fudan University Shanghai Cancer Center, Shanghai, China,²Tianjin Medical University Cancer Institute & Hospital, Tianjin, China,³Shengjing Hospital of China Medical University, Shenyang, China,⁴Jiangsu Provincial People's Hospital (The First Affiliated Hospital of Nanjing Medical University), Nanjing, China,⁵Sichuan Cancer Hospital, Chengdu, China,⁶Hunan Cancer Hospital, Changsha, China,⁷Affiliated Cancer Hospital of Shandong First Medical University, Jinan, China,⁸Jiangxi Provincial Cancer Hospital, Nanchang, China,⁹The Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China,¹⁰Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China,¹¹Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China

摘要 Abstract

中文摘要

背景：这项首次人体、开放标签、多中心、剂量递增和剂量扩展的1期研究评估了高选择性CDK4抑制剂HRS-6209在晚期实体瘤患者（pts）中的安全性、药代动力学（PK）和初步疗效。方法：既往标准治疗后进展或缺乏可用治疗选择的晚期实体瘤患者符合入选条件，接受HRS-6209单药治疗，共5个剂量队列（100 mg QD、50 mg BID、75 mg BID、100 mg BID和200 mg BID）。主要目标是评估HRS-6209的安全性/耐受性并确定推荐2期剂量。结果：截至2025年11月15日，共入组56例患者，包括48例（85.7%）HR+/HER2−乳腺癌患者。在HR+/HER2−乳腺癌患者中，转移阶段既往内分泌治疗和化疗的中位线数分别为1.5和1.0；分别有32例（66.7%）、39例（81.3%）和29例（60.4%）既往接受过CDK4/6抑制剂、芳香化酶抑制剂和氟维司群治疗。未观察到剂量限制性毒性，未达到最大耐受剂量。55例（98.2%）患者发生TRAE。22例患者（39.3%）报告≥3级TRAE，最常见的为中性粒细胞计数下降（18例[32.1%]）、WBC计数下降（8例[14.3%]）和贫血（3例[5.4%]）。无患者因TRAE停止治疗，无治疗相关死亡。在HR+/HER2−乳腺癌中，ORR为6.3%（3/48；50、75和100 mg BID各1例）；在50、75和100 mg BID时，CBR分别为26.7%、56.3%和53.8%，中位PFS分别为1.8、7.4和9.1个月（表1）。PK暴露在50-200 mg BID范围内大致呈剂量比例关系，中位Tmax为2-4 h，平均t1/2为8.94-9.96 h，Cmax蓄积比为1.27-1.61，AUC0-12蓄积比为1.45-1.70。结论：HRS-6209耐受性良好，在晚期实体瘤患者中表现出良好的安全性和PK特征，并在既往经治的HR+/HER2-乳腺癌患者中展现出有前景的抗肿瘤活性。表1. HR+/HER2-乳腺癌患者的关键基线特征和疗效 50 mg BID（n=15） 75 mg BID（n=16） 100 mg BID（n=13）全部（n=48）转移阶段既往内分泌治疗线数（中位）2.0 1.0 2.0 1.5 转移阶段既往化疗线数（中位）1.0 0 1.0 1.0 确认的ORR，%（n/N；95% CI）6.7（1/15；0.2-32.0）6.3（1/16；0.2-30.2）7.7（1/13；0.2-36.0）6.3（3/48；1.3-17.2）临床获益率*，%（n/N；95% CI）26.7（4/15；7.8-55.1）56.3（9/16；29.9-80.3）53.8（7/13；25.1-80.8）43.8（21/48；29.5-58.8）中位PFS，月（95% CI）1.8（1.7，4.2）7.4（1.9，NA）9.1（1.9，14.5）5.5（3.7，7.7） * 定义为完全缓解或部分缓解，或持续≥24周的疾病稳定。

查看英文原文 English abstract

Background: This first-in-human, open-label, multicenter, dose-escalation and dose-expansion phase 1 study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of HRS-6209, a highly selective CDK4 inhibitor, in patients (pts) with advanced solid tumors. Methods: Pts with advanced solid tumors who progressed on standard therapies or lacked available options were eligible and received HRS-6209 monotherapy at 5 dose cohorts (100 mg QD, 50 mg BID, 75 mg BID, 100 mg BID and 200 mg BID). The primary objectives were to assess the safety/tolerability of HRS-6209 and determine the recommended phase 2 dose. Results: As of November 15, 2025, 56 pts were enrolled, including 48 (85.7%) with HR+/HER2− breast cancer. In HR+/HER2− breast cancer pts, the median prior lines of endocrine therapy and chemotherapy in the metastatic setting were 1.5 and 1.0, respectively; 32 (66.7%), 39 (81.3%), and 29 (60.4%) had received prior CDK4/6 inhibitor, aromatase inhibitor, and fulvestrant, respectively. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. TRAEs occurred in 55 (98.2%) pts. Grade ≥3 TRAEs were reported in 22 pts (39.3%), with the most common being decreased neutrophil count (18 [32.1%]), decreased WBC count (8 [14.3%]), and anemia (3 [5.4%]). No pts discontinued treatment due to TRAEs, and there were no treatment-related deaths. In HR+/HER2− breast cancer, ORR was 6.3% (3/48; 1 pt each at 50, 75, and 100 mg BID); CBR was 26.7%, 56.3%, and 53.8%, and median PFS was 1.8, 7.4, and 9.1 months at 50, 75, and 100 mg BID, respectively (Table 1). PK exposure was approximately dose proportional across 50-200 mg BID, with median T max 2-4 h, mean t 1/2 8.94-9.96 h, and accumulation ratios of 1.27-1.61 for C max and 1.45-1.70 for AUC 0-12 . Conclusions: HRS-6209 was well-tolerated, exhibiting favorable safety and PK profiles in patients with advanced solid tumors, and demonstrated promising anti-tumor activity in pretreated patients with HR+/HER2- breast cancer. Table 1. Key baseline characteristics and efficacy in patients with HR+/HER2- breast cancer 50 mg BID (n=15) 75 mg BID (n=16) 100 mg BID (n=13) All (n=48) Prior lines of endocrine therapy in metastatic setting (median) 2.0 1.0 2.0 1.5 Prior lines of chemotherapy in metastatic setting (median) 1.0 0 1.0 1.0 Confirmed ORR, % (n/N; 95% CI) 6.7 (1/15; 0.2-32.0) 6.3 (1/16; 0.2-30.2) 7.7 (1/13; 0.2-36.0) 6.3 (3/48; 1.3-17.2) Clinical benefit rate*, % (n/N; 95% CI) 26.7 (4/15; 7.8-55.1) 56.3 (9/16; 29.9-80.3) 53.8 (7/13; 25.1-80.8) 43.8 (21/48; 29.5-58.8) Median PFS, mo (95% CI) 1.8 (1.7, 4.2) 7.4 (1.9, NA) 9.1 (1.9, 14.5) 5.5 (3.7, 7.7) * Defined as complete or partial response, or stable disease lasting ≥24 weeks.

利益披露 Disclosure

J. Wu, None.. J. Zhang, None.. N. Lu, None.. C. Liu, None.. Q. Ding, None.. H. Hong, None.. H. Wang, None.. Y. Sun, None.. H. Zhang, None.. M. Yan, None.. Y. Wang, None.. Y. Du, None.. Y. Meng, None.. D. Li, None.. H. Li, None.. Z. Sun, None. X. Zhu, Jiangsu Hengrui Pharmaceuticals Co., Ltd. Employment. X. Zhang, Jiangsu Hengrui Pharmaceuticals Co., Ltd. Employment. X. Sheng, Jiangsu Hengrui Pharmaceuticals Co., Ltd. Employment. Q. Xie, Jiangsu Hengrui Pharmaceuticals Co., Ltd. Employment. M. Yu, Jiangsu Hengrui Pharmaceuticals Co., Ltd. Employment.

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