TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases
TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases
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DOI：
10.1200/jco.18.01511
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发表时间：
2019-05-01
影响因子：
45.3
通讯作者：
Lin, Nancy U.
中科院分区：
文献类型：
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作者：
Freedman, Rachel A.;Gelman, Rebecca S.;Lin, Nancy U.
转移至中枢神经系统的人表皮生长因子受体2（HER 2）阳性乳腺癌的循证治疗有限。我们先前报告了来那替尼单药治疗对HER 2阳性乳腺癌脑转移的适度活性。患者和方法患有可测量的、进行性的、HER 2阳性脑转移瘤的患者（92%在接受CNS手术和/或放疗后）接受来那替尼240 mg口服，每日一次，加卡培他滨750 mg/m2，每日两次，共14天，然后停药7天。入组了拉帕替尼初治（队列3A）和拉帕替尼治疗（队列3B）患者。如果35例患者中有9例或更多（队列3A）或25例患者中有3例或更多（队列3B）有CNS客观缓解率（ORR），则认为该药物组合有希望。主要终点是复合中枢神经系统的ORR在每个队列分别，需要减少50%或更多的目标中枢神经系统病变体积的总和没有进展的非靶病变，新的病变，类固醇，进行性神经系统体征或症状，或non-CNS progression.Results 49例患者入组队列3A（n = 37）和3B（n = 12;队列关闭缓慢的积累）。在队列3A中，复合CNS ORR = 49%（95% CI，32%至66%），队列3B中的CNS ORR = 33%（95% CI，10%至65%）。队列3A和3B的中位无进展生存期分别为5.5和3.1个月;中位生存期为13.3和15.1个月。腹泻是最常见的3级毒性（队列3A和3B中为29%）。结论来那替尼联合卡培他滨对难治性HER 2阳性乳腺癌脑转移有效，增加了额外的证据表明，化疗可增强脑中HER 2靶向治疗的疗效。为了获得最佳耐受性，需要努力减少腹泻。(C)2019年美国临床肿瘤学会
PURPOSE Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer to the CNS are limited. We previously reported modest activity of neratinib monotherapy for HER2-positive breast cancer brain metastases. Here we report the results from additional study cohorts.PATIENTS AND METHODS Patients with measurable, progressive, HER2-positive brain metastases (92% after receiving CNS surgery and/or radiotherapy) received neratinib 240 mg orally once per day plus capecitabine 750 mg/m(2) twice per day for 14 days, then 7 days off. Lapatinib-naive (cohort 3A) and lapatinib-treated (cohort 3B) patients were enrolled. If nine or more of 35 (cohort 3A) or three or more of 25 (cohort 3B) had CNS objective response rates (ORR), the drug combination would be deemed promising. The primary end point was composite CNS ORR in each cohort separately, requiring a reduction of 50% or more in the sum of target CNS lesion volumes without progression of nontarget lesions, new lesions, escalating steroids, progressive neurologic signs or symptoms, or non-CNS progression.RESULTS Forty-nine patients enrolled in cohorts 3A (n = 37) and 3B (n = 12; cohort closed for slow accrual). In cohort 3A, the composite CNS ORR = 49% (95% CI, 32% to 66%), and the CNS ORR in cohort 3B = 33% (95% CI, 10% to 65%). Median progression-free survival was 5.5 and 3.1 months in cohorts 3A and 3B, respectively; median survival was 13.3 and 15.1 months. Diarrhea was the most common grade 3 toxicity (29% in cohorts 3A and 3B).CONCLUSION Neratinib plus capecitabine is active against refractory, HER2-positive breast cancer brain metastases, adding additional evidence that the efficacy of HER2-directed therapy in the brain is enhanced by chemotherapy. For optimal tolerance, efforts to minimize diarrhea are warranted. (C) 2019 by American Society of Clinical Oncology