Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases
Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases
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DOI：
10.1200/jco.2015.63.0343
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发表时间：
2016-03-20
影响因子：
45.3
通讯作者：
Lin, Nancy U.
中科院分区：
文献类型：
--
作者：
Freedman, Rachel A.;Gelman, Rebecca S.;Lin, Nancy U.
目的：转移性、人表皮生长因子受体2（HER 2）阳性的中枢神经系统乳腺癌的循证治疗是有限的。来那替尼是erbB 1、HER 2和erbB 4的不可逆抑制剂，在HER 2阳性乳腺癌中具有良好的活性;然而，其在CNS中的活性尚不清楚。我们在一项多中心、II期开放标签试验中评估了来那替尼治疗HER 2阳性乳腺癌脑转移患者的疗效。（最长尺寸>= 1 cm），在接受一种或多种CNS导向治疗（如全脑放疗、立体定向放射外科手术、和/或手术切除。患者接受来那替尼240 mg口服，每日一次，每两个周期评估一次肿瘤。主要终点是复合CNS客观缓解率（ORR），需要满足以下所有条件：靶CNS病变体积总和减少>= 50%，非靶病变无进展，新发病变，皮质类固醇增加，神经系统体征/症状进展，或非CNS进展-成功的阈值是40个应答者中的5个。结果40例患者在2012年2月至2013年6月期间入组; 78%的患者既往接受过全脑放疗。3名女性获得部分缓解（CNS客观缓解率，8%; 95% CI，2%-22%）。接受的中位周期数为2个（范围1 - 7个周期），中位无进展生存期为1.9个月。5名妇女接受了6个或更多周期。最常见的≥ 3级事件是腹泻（21%的预先指定洛哌丁胺预防性治疗患者和28%的未进行预防性治疗患者发生腹泻）。研究中的患者经历了随着时间的推移生活质量下降。结论虽然来那替尼的活性较低，没有达到我们的成功阈值，12.5%的患者接受了6个或更多周期。在CNS疾病患者中进行的来那替尼联合化疗的研究正在进行中。
Purpose Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial.Patients and Methods Eligible patients were those with HER2-positive brain metastases (>= 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: >= 50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression-the threshold for success was five of 40 responders.Results Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade >= 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time.Conclusion Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.