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编者按：趋化因子受体CXCR4为趋化因子CXCL12（又称基质细胞衍生因子-1，SDF-1）特异受体。CXCL12及其受体CXCR4受到多种因素调控并表达，在乳腺癌发生发展的多个过程中，可以调节免疫细胞的功能和运输以及肿瘤微环境，临床前模型已经显示CXCR4拮抗剂可以增强不同抗癌疗法的活性，多项研究证实CXCL12及CXCR4不仅有助于判断乳腺癌患者的预后，而且CXCR4靶向治疗更为乳腺癌患者提供了新的联合治疗方案和更为理想的疗效。 2018年4月26日，英国《柳叶刀》肿瘤学分册在线发表西班牙、美国、瑞士、德国的单组剂量递增1期研究报告，评定了瑞士新药CXCR4拮抗剂巴利萨弗肽联合化疗药艾日布林对于难治型复发转移性HER2阴性乳腺癌患者的安全性、耐受性、药物代谢动力学、初步1期活性。 该单组剂量递增1期研究于2014年1月28日～2016年10月4日从西班牙和美国11家单位入组年龄≥18岁、组织学证实为HER2阴性转移性乳腺癌、肿瘤细胞表达CXCR4、东部肿瘤协作组（ECOG）体力状态评分0或1、曾经接受1～3种转移性乳腺癌化疗方案以及至少1种内分泌治疗（如果激素受体阳性，除非被认为不适合内分泌治疗）女性患者56例。按照标准的3＋3剂量递增设计，如果未见联合用药剂量限制毒性反应，随后按照确定的最大耐受剂量或最大剂量进行队列扩大。第一队列研究接受每轮21天艾日布林＋巴利萨弗肽治疗发生治疗相关致死不良事件后，研究方案修订将研究设计改为两个部分。第1部分入组患者接受每轮28天初始治疗，某些队列接受剂量递减的艾日布林＋巴利萨弗肽，评定联合用药的安全性和药物代谢动力学。第1部分评估未确认任何剂量限制毒性反应或艾日布林与巴利沙坦相互作用，因此第2部开始入组患者接受每轮21天的艾日布林（按最初计划剂量第2、9天1.4 mg/m²）和巴利萨弗肽（第1～3天和第8～10天起始剂量2mg/kg，递增0.5或1mg/kg）。两种药物均以静脉注射给药。所有患者接受治疗直至疾病进展或毒性反应无法耐受。主要终点为剂量限制毒性反应和不良事件，并且确定最大耐受剂量或推荐2期剂量以及药物代谢动力学指标。对于所有接受至少一次研究治疗的患者进行安全性分析，对于所有接受至少一轮完整研究治疗的患者进行抗肿瘤活性分析。该研究在美国政府临床研究注册网站的编号为NCT01837095，入组已经结束。 结果，无剂量限制毒性反应被确认，最大耐受剂量未达到。确定最大剂量为每轮21天的第2天和第9天艾日布林1.4mg/m²、第1～3天和第8～10天巴利萨弗肽5.5mg/kg。 可评价抗肿瘤活性患者54例，其中客观缓解（均为部分缓解）16例（30%，95%置信区间：18～44）。 可评价安全性患者56例，最常见的治疗相关任何级别不良事件包括疲劳44例（79%）、中性粒细胞减少32例（57%）、注射相关反应27例（48%）、脱发26例（46%）、便秘26例（46%）和恶心25例（45%）；严重不良事件21例（38%），其中发热性中性粒细胞减少5例（9%）、中性粒细胞计数减少2例（4%）、便秘2例（4%）、尿路感染3例（5%）。死亡2例（4%），分别死于感染性休克、肺炎。 因此，对于HER2阴性转移性乳腺癌患者，巴利萨弗肽＋艾日布林的安全性和耐受性与艾日布林或巴利萨弗肽单药治疗相似，并且该联合方案的初步活性令人鼓舞。该研究结果表明，巴利萨弗肽＋艾日布林可能为难治型转移性乳腺癌患者提供新的治疗选择，有必要开展下一步随机对照研究。 Lancet Oncol. 2018 Apr 26. [Epub ahead of print] Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial. Sonia Pernas, Miguel Martin, Peter A Kaufman, Marta Gil-Martin, Patricia Gomez Pardo, Sara Lopez-Tarruella, Luis Manso, Eva Ciruelos, Jose Alejandro Perez-Fidalgo, Cristina Hernando, Foluso O Ademuyiwa, Katherine Weilbaecher, Ingrid Mayer, Timothy J Pluard, Maria Martinez Garcia, Linda Vahdat, Jose Perez-Garcia, Achim Wach, Debra Barker, Samson Fung, Barbara Romagnoli, Javier Cortes. Institut Català d'Oncologia L'Hospitalet-Barcelona, Spain; Instituto de Investigación Sanitaria Gregorio Maranón, Centro de Investigación Biomédica en Red Cáncer, Universidad Complutense, Madrid, Spain; Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital Clínico Universitario de Valencia, INCLIVA, Centro de Investigación Biomédica en Red Cáncer, Valencia, Spain; Washington University, St Louis, MO, USA; Vanderbilt University School of Medicine, Nashville, TN, USA; St Luke's Cancer Institute, Kansas City, MO, USA; Servei d'Oncologia Medica, Hospital del Mar, Barcelona, Spain; Weill Cornell Medicine, New York, NY, USA; Baselga Institute of Oncology, Hospital Quiron, Barcelona, Spain; Polyphor, Allschwil, Switzerland; Fung Consulting Healthcare and Life Sciences, Munich, Germany; Breast Cancer Unit and Gynaecological Tumours, Ramon y Cajal University Hospital, Madrid, Spain; Vall d'Hebron Institute of Oncology, Barcelona, Spain; Baselga Oncology Institute, Quiron Group, Madrid and Barcelona, Spain. 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. METHODS: This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1.4 mg/m² on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0.5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. 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. FUNDING: Polyphor. DOI: 10.1016/S1470-2045(18)30147-5
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