Phase I Clinical Trial Center, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Breast Cancer Res. 2023 Jul 6;25(1):81. doi: 10.1186/s13058-023-01679-4.
Patients with HER2-positive metastatic breast cancer (MBC) are at high risk of developing central nervous system (CNS) metastases. A potent and selective HER2 inhibitor with good blood-brain barrier (BBB) penetration is highly desirable.
The design and structure-activity relationship of DZD1516 was described. The potency and selectivity of DZD1516 were determined by enzymatic and cellular assays. The antitumor activity of DZD1516 monotherapy or in combination with HER2 antibody-drug conjugate was assessed in CNS and subcutaneous xenograft mouse models. A phase 1 first-in-human study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of DZD1516 in patients with HER2+ MBC who relapsed from standard of care.
DZD1516 showed good selectivity against HER2 over wild-type EGFR in vitro and potent antitumor activity in vivo. Twenty-three patients were enrolled and received DZD1516 monotherapy treatment across six dose levels (25-300 mg, twice daily). Dose-limiting toxicities were reported at 300 mg, and thus 250 mg was defined as the maximum tolerated dose. The most common adverse events included headache, vomiting, and hemoglobin decreased. No diarrhea or skin rash was observed at ≤ 250 mg. The mean K was 2.1 for DZD1516 and 0.76 for its active metabolite DZ2678. With median seven lines of prior systemic therapy, the best antitumor efficacy in intracranial, extracranial and overall lesions was stable disease.
DZD1516 provides positive proof of concept for an optimal HER2 inhibitor with high BBB penetration and HER2 selectivity. Further clinical evaluation of DZD1516 is warranted, with the RP2D being 250 mg BID.
gov identifier NCT04509596. Registered on August 12, 2020; Chinadrugtrial: CTR20202424 Registered on December 18, 2020.
HER2 阳性转移性乳腺癌（MBC）患者存在发生中枢神经系统（CNS）转移的高风险。具有良好血脑屏障（BBB）穿透能力的强效和选择性 HER2 抑制剂是非常需要的。
描述了 DZD1516 的设计和结构-活性关系。通过酶和细胞测定来确定 DZD1516 的效力和选择性。在 CNS 和皮下异种移植小鼠模型中评估 DZD1516 单药治疗或与 HER2 抗体药物偶联物联合治疗的抗肿瘤活性。一项 I 期首次人体研究评估了在接受标准治疗后复发的 HER2+MBC 患者中，DZD1516 的安全性、耐受性、药代动力学和初步抗肿瘤活性。
DZD1516 在体外对野生型 EGFR 具有良好的选择性，对 HER2 具有强大的抗肿瘤活性。23 名患者入组并接受了六个剂量水平（25-300mg，每日两次）的 DZD1516 单药治疗。在 300mg 时报告了剂量限制毒性，因此将 250mg 定义为最大耐受剂量。最常见的不良反应包括头痛、呕吐和血红蛋白降低。在≤250mg 时未观察到腹泻或皮疹。DZD1516 的平均 K 为 2.1，其活性代谢物 DZ2678 的 K 为 0.76。中位接受过 7 线系统治疗，颅内、颅外和总体病变的最佳抗肿瘤疗效为疾病稳定。
DZD1516 为具有高 BBB 穿透性和 HER2 选择性的最佳 HER2 抑制剂提供了积极的概念验证。需要进一步评估 DZD1516 的临床疗效，推荐的 2 期剂量为 250mg，每日两次。
gov 标识符 NCT04509596。于 2020 年 8 月 12 日注册；中国临床试验：CTR20202424，于 2020 年 12 月 18 日注册。
