#大药编#趋化因子受体拮抗剂治疗转移性乳腺癌一期临床研究
C-X-C趋化因子受体4(CXCR4)基质细胞衍生因子-1α(SDF-1α)轴具有调节和运输免疫细胞和肿瘤微环境的功能。CXCR4拮抗剂在临床前实验已被证实可以增强动物模型中不同抗癌治疗的活性。最新发表在《柳叶刀 肿瘤》上的一期临床研究评估了CXCR4拮抗剂balixafortide的安全性、耐受性、药代动力学和前期第一阶段的活性,并与经治疗后复发转移性乳腺癌患者的艾瑞布林(eribulin)化疗相结合。

在 2014年1月28日至2016年10月4日期间,共有56名患者参与这项临床试验。没有剂量限制的毒性,并没有达到最大耐受剂量。21天为一周期,最大剂量为第2天和第9天eribulin 1·4 mg/m2, 第1- 3天和8-10天balixafortide 5·5 mg/kg。54例进行抗肿瘤疗效评价的患者有16(30%)名观察到客观反应(所有部分缓解)(95% CI 18-44)。任何等级的最常见的治疗紧急事件是疲劳(44[79%]的56例),中性粒细胞减少(32[57%]),与输血相关的反应(27[48%]),脱发(26[46%]),便秘(26[46%])和恶心(25[45%])。56例患者中有21例(38%)发生严重不良反应,其中5例(9%)有发热性中性粒细胞减少(9%),中性粒细胞计数减少2例(4%),便秘2例(4%),2例(4%)患者有肺炎,3例(5%)患者发生尿路感染。在接受研究治疗的56例患者中,有2名(4%)死亡;一个是脓毒性休克,另一个是肺炎。


Balixafortide辅助eribulin治疗的安全性和耐受性似乎与eribulin或balixafortide单药治疗相似,并且在HER2阴性转移性乳腺癌患者中,这一组合的初步疗效似乎很有希望。结果表明,balixafortide辅助eribulin有望为转移性乳腺癌患者提供新的治疗方案,并将在随机试验中进一步研究。

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Background

The C-X-C chemokine receptor type 4 (CXCR4)–stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer.


Findings

Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m2 on days 2 and 9, and balixafortide 5·5 mg/kg on days 1–3 and 8–10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18–44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia.


Interpretation

The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials.

Reference: Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial


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