Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC).
Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC).
复制标题
patritumab deruxtecan（一种针对 HER3 的抗体药物偶联物 (ADC)）在表达 HER3 的转移性乳腺癌 (MBC) 患者中进行的 1/2 期研究结果。
DOI：
10.1200/jco.2022.40.16_suppl.1002
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发表时间：
2022
影响因子：
45.3
通讯作者：
K. Yonemori
中科院分区：
文献类型：
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作者：
I. Krop;N. Masuda;T. Mukohara;S. Takahashi;T. Nakayama;K. Inoue;H. Iwata;T. Toyama;Yutaka Yamamoto;D. Hansra;M. Takahashi;A. Osaki;K. Koyama;Tatsuya Inoue;Takatoshi Yonekura;Joseph Mostillo;S. Ohwada;Yoshimi Tanaka;D. Sternberg;K. Yonemori
1002 背景：Paritumab deruxtecan (HER3-DXd) 是一种新型研究性 ADC，由人抗 HER3 单克隆抗体通过稳定的基于四肽的可裂解接头共价结合至拓扑异构酶 I 抑制剂有效负载组成。在此，我们报告了这项正在进行的 HER3-DXd 研究（U31402-A-J101；NCT02980341；JapicCTI-163401）在既往接受过 MBC 治疗的患者中的最新安全性和有效性数据。方法：U31402-A-J101 是一项针对 HER3 表达 MBC 患者 (N = 182) 进行 HER3-DXd 的 1/2 期、多中心、开放标签、首次人体研究。该研究将患者纳入剂量递增（3.2-8.0 mg/kg IV Q3W）和跨分子亚型的剂量探索部分（n = 66；包括 HER2+ MBC，n = 14），然后对以下亚型进行剂量扩展：HER3 高（4.8 mg/kg [n = 33] 或 6.4 mg/kg [n = 31]）、HER3 低（6.4 mg/kg） [n = 21]) HR+/HER2− MBC 或 HER3 高 TNBC (6.4 mg/kg [n = 31])。 HER3-高和-低被定义为≥75%和25%-<75%膜阳性。主要目标是评估安全性和有效性；次要目标包括确定疗效和 HER3 表达之间的关系。结果：在数据截止时（2021 年 8 月 16 日），中位研究持续时间为 31.9 个月（范围为 15-56 个月）。中位年龄为 57 岁（范围 30-83 岁）； 132 名 (72.5%) 和 50 名 (27.5%) 患者的 ECOG PS 为 0 或 1。患者之前接受过局部晚期/转移性疾病治疗的中位数为 5 线（范围为 1-13）。 HER3-DXd 的中位治疗持续时间为 5.9 个月（范围，0.7-30.6）。在剂量递增/发现和扩展的汇总评估中，表中显示了 HR+/HER2− MBC、TNBC 和 HER2+ MBC 患者的疗效。总体而言，130 名患者 (71.4%) 的 TEAE ≥3 级；最常见的（≥15%）是中性粒细胞计数减少（39.6%）、血小板计数减少（30.8%）、贫血（18.7%）和白细胞计数减少（18.1%）。根据中央裁决，12 名患者 (6.6%) 经历了与治疗相关的间质性肺疾病，其中包括 1 起 5 级事件。结论：对这一经过大量预处理的人群进行的汇总分析表明，对于 HR+/HER2− 和 HER2+ MBC 以及 TNBC 患者具有良好的疗效。长期随访的安全性与之前的报告一致，并显示出足够的安全性和耐受性。针对 MBC 肿瘤类型的研究正在进行中，重点是与疗效相关的生物标志物。临床试验信息：NCT02980341。 [表：见正文]
1002 Background: Patritumab deruxtecan (HER3-DXd) is a novel, investigational ADC composed of a human anti-HER3 monoclonal antibody covalently bound to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Here we report updated safety and efficacy data from this ongoing study (U31402-A-J101; NCT02980341; JapicCTI-163401) of HER3-DXd in pts with previously treated MBC. Methods: U31402-A-J101 is a phase 1/2, multicenter, open-label, first-in-human study of HER3-DXd in pts with HER3-expressing MBC (N = 182). The study enrolled pts in dose-escalation (3.2-8.0 mg/kg IV Q3W) and dose-finding portions across molecular subtypes (n = 66; including HER2+ MBC, n = 14) followed by dose expansion in the following subtypes: HER3 high (4.8 mg/kg [n = 33] or 6.4 mg/kg [n = 31]), HER3 low (6.4 mg/kg [n = 21]) HR+/HER2− MBC or HER3-high TNBC (6.4 mg/kg [n = 31]). HER3-high and -low were defined as ≥75% and 25% ‒ < 75% membrane positivity. The primary objective was to assess safety and efficacy; secondary objectives included determining the relationship between efficacy and HER3 expression. Results: At data cutoff (16 Aug 2021), median study duration was 31.9 mo (range, 15-56). Median age was 57 y (range, 30-83); 132 (72.5%) and 50 (27.5%) pts had an ECOG PS of 0 or 1. Pts had a median of 5 (range, 1-13) prior lines of therapy for locally advanced/metastatic disease. Median treatment duration with HER3-DXd was 5.9 mo (range, 0.7-30.6). In a pooled evaluation of dose escalation/finding and expansion, efficacy is shown in pts with HR+/HER2− MBC, TNBC, and HER2+ MBC in the Table. Overall, 130 pts (71.4%) had grade ≥3 TEAEs; the most common (≥15%) were decreased neutrophil count (39.6%), decreased platelet count (30.8%), anemia (18.7%), and decreased white blood cell count (18.1%). 12 pts (6.6%) experienced treatment-related interstitial lung disease according to central adjudication, including 1 grade 5 event. Conclusions: A pooled analysis in this heavily pretreated population showed promising efficacy in pts with HR+/HER2− and HER2+ MBC as well as TNBC. The safety profile with longer follow-up is consistent with previous reports and showed adequate safety and tolerability. Studies are ongoing in MBC tumor types, with a focus on biomarkers associated with efficacy. Clinical trial information: NCT02980341. [Table: see text]