Disitamab vedotin, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpression and HER2-low advanced breast cancer: a phase I/Ib study

IF 20.1 1区医学 Q1 ONCOLOGY Cancer Communications Pub Date : 2024-06-28 DOI:10.1002/cac2.12577

Jiayu Wang, Yunjiang Liu, Qingyuan Zhang, Wei Li, Jifeng Feng, Xiaojia Wang, Jianmin Fang, Yiqun Han, Binghe Xu

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Abstract

Background

Disitamab vedotin (DV; RC48-ADC) is an antibody-drug conjugate comprising a human epidermal growth factor receptor 2 (HER2)-directed antibody, linker and monomethyl auristatin E. Preclinical studies have shown that DV demonstrated potent antitumor activity in preclinical models of breast, gastric, and ovarian cancers with different levels of HER2 expression. In this pooled analysis, we report the safety and efficacy of DV in patients with HER2-overexpression and HER2-low advanced breast cancer (ABC).

Methods

In the phase I dose-escalation study (C001 CANCER), HER2-overexpression ABC patients received DV at doses of 0.5-2.5 mg/kg once every two weeks (Q2W) until unacceptable toxicity or progressive disease. The dose range, safety, and pharmacokinetics (PK) were determined. The phase Ib dose-range and expansion study (C003 CANCER) enrolled two cohorts: HER2-overexpression ABC patients receiving DV at doses of 1.5-2.5 mg/kg Q2W, with the recommended phase 2 dose (RP2D) determined, and HER2-low ABC patients receiving DV at doses of 2.0 mg/kg Q2W to explore the efficacy and safety of DV in HER2-low ABC.

Results

Twenty-four patients with HER2-overexpression ABC in C001 CANCER, 46 patients with HER2-overexpression ABC and 66 patients with HER2-low ABC in C003 CANCER were enrolled. At 2.0 mg/kg RP2D Q2W, the confirmed objective response rates were 42.9% (9/21; 95% confidence interval [CI]: 21.8%-66.0%) and 33.3% (22/66; 95% CI: 22.2%-46.0%), with median progression-free survival (PFS) of 5.7 months (95% CI: 5.3-8.4 months) and 5.1 months (95% CI: 4.1-6.6 months) for HER2-overexpression and HER2-low ABC, respectively. Common (≥5%) grade 3 or higher treatment-emergent adverse events included neutrophil count decreased (17.6%), gamma-glutamyl transferase increased (13.2%), asthenia (11.0%), white blood cell count decreased (9.6%), peripheral neuropathy such as hypoesthesia (5.9%) and neurotoxicity (0.7%), and pain (5.9%).

Conclusion

DV demonstrated promising efficacy in HER2-overexpression and HER2-low ABC, with a favorable safety profile at 2.0 mg/kg Q2W.

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HER2 表达和 HER2 低表达晚期乳腺癌患者的 HER2 定向抗体-药物共轭物 Disitamab vedotin：一项 I/Ib 期研究。

背景介绍迪西他单抗维多汀（Disitamab vedotin，DV；RC48-ADC）是一种抗体-药物共轭物，由人类表皮生长因子受体2（HER2）定向抗体、连接体和单甲基金丝桃素E组成。临床前研究表明，DV在不同HER2表达水平的乳腺癌、胃癌和卵巢癌临床前模型中表现出了强大的抗肿瘤活性。在这项汇总分析中，我们报告了DV对HER2-表达和HER2-低表达晚期乳腺癌（ABC）患者的安全性和疗效：在I期剂量递增研究（C001 CANCER）中，HER2-表达ABC患者接受DV治疗，剂量为0.5-2.5 mg/kg，每两周一次（Q2W），直至出现不可接受的毒性或疾病进展。该研究确定了剂量范围、安全性和药代动力学（PK）。Ib 期剂量范围和扩展研究（C003 CANCER）招募了两个组群：HER2-表达ABC患者接受剂量为1.5-2.5 mg/kg Q2W的DV治疗，并确定了2期推荐剂量（RP2D）；HER2-低表达ABC患者接受剂量为2.0 mg/kg Q2W的DV治疗，以探索DV在HER2-低表达ABC中的疗效和安全性：24名C001癌症中HER2-表达ABC患者、46名C003癌症中HER2-表达ABC患者和66名HER2-低表达ABC患者入组。在2.0 mg/kg RP2D Q2W剂量下，HER2-表达和HER2-低表达ABC患者的确诊客观反应率分别为42.9%（9/21；95%置信区间[CI]：21.8%-66.0%）和33.3%（22/66；95% CI：22.2%-46.0%），中位无进展生存期（PFS）分别为5.7个月（95% CI：5.3-8.4个月）和5.1个月（95% CI：4.1-6.6个月）。常见的（≥5%）3级或3级以上治疗突发不良事件包括中性粒细胞计数减少（17.6%）、γ-谷氨酰转移酶升高（13.2%）、气喘（11.0%）、白细胞计数减少（9.6%）、周围神经病变如感觉减退（5.9%）和神经毒性（0.7%）以及疼痛（5.9%）：结论：DV对HER2-表达和HER2-低表达的ABC具有良好的疗效，在2.0 mg/kg Q2W剂量下具有良好的安全性。

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来源期刊

Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research

CiteScore

25.50

自引率

4.30%

发文量

153

审稿时长

4 weeks

期刊介绍： Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.