A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229)
A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229)
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DOI：
10.1634/theoncologist.2019-0321
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发表时间：
2019-08-16
期刊：
影响因子：
5.8
通讯作者：
Seymour, Lesley
中科院分区：
文献类型：
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作者：
Chia, Stephen;Bedard, Phillipe L.;Seymour, Lesley
免疫检查点抑制剂在广泛的癌症中具有活性，包括程序性死亡配体1（PD-L1）阳性、三阴性、转移性乳腺癌（MBC）。抗体依赖性细胞介导的细胞毒性是曲妥珠单抗的作用机制。我们在既往接受过化疗和抗HER 2抗体治疗的HER 2阳性MBC中进行了一项durvalumab和曲妥珠单抗的Ib期试验，以评估安全性、疗效和相关终点。患者和方法根据标准3 + 3设计招募HER 2阳性MBC患者。剂量水平1为durvalumab（第1天静脉注射1，125 mg）和曲妥珠单抗（第1天静脉注射8 mg/kg，然后第1天静脉注射6 mg/kg），每3周1次。在推荐的II期剂量（RP 2D）下的扩展队列在基线和第1周期后进行肿瘤活检。主要终点是确定RP 2D。结果2016年4月至12月共纳入15例患者，其中14例可评价疗效。中位年龄为54岁（范围40-86岁）;大多数患者患有内脏疾病（87%）和至少3种既往（辅助和/或转移性）化疗（73%），包括曲妥珠单抗（93%）、帕妥珠单抗（60%）和曲妥珠单抗-美坦新偶联物（93%）治疗MBC。在第1周期中，在剂量水平1（n = 6）或剂量扩展（n = 9）下未观察到剂量限制性毒性。1例患者发生≥ 3级免疫相关不良事件（4级糖尿病）。根据RECIST未观察到缓解，14例患者中有4例（29%）在第6周（中位持续时间为2.7个月）时显示疾病稳定为最佳缓解。所有患者均有
Background Immune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD-L1)-positive, triple-negative, metastatic breast cancer (MBC). Antibody-dependent cell-mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2-positive MBC previously treated with chemotherapy and anti-HER2 antibodies to assess safety, efficacy, and correlative endpoints. Patients and Methods Patients with HER2-positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D. Results Fifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40-86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab-emtansine (93%) for MBC. No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade >= 3 immune-related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had