曲妥珠单抗、曲妥珠单抗和卡培他滨治疗人表皮生长因子受体 2 阳性转移性乳腺癌。
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.
机构信息
From M.D. Anderson Cancer Center, Houston (R.K.M., G.H.); Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (S. Loi); the Royal Marsden NHS Foundation Trust, London (A.O.), and Edinburgh Cancer Research Centre, Edinburgh (D.C.) - both in the United Kingdom; Winship Cancer Institute, Atlanta (E.P.); Sarah Cannon Research Institute/Tennessee Oncology-Nashville (E.H.) and Vanderbilt University Medical Center (V.A.), Nashville; University of California, Los Angeles, Medical Center-Jonsson Comprehensive Cancer Center, Los Angeles (S.A.H., D.S.), and Stanford Comprehensive Cancer Institute, Palo Alto (M.P.) - both in California; Dana-Farber Cancer Institute, Boston (N.U.L., I.K., E.P.W.); University of Colorado Cancer Center, Aurora (V.B.); Duke Cancer Institute, Durham (C.A.), and University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (L.A.C.) - both in North Carolina; University Health Network, Princess Margaret Cancer Centre, Toronto (P.L.B.), and British Columbia Cancer, Vancouver (K.G.) - both in Canada; Hospital Universitario Vall D'Hebron, Barcelona (M.O.); Sygehus Lillebaelt-Vejle Sygehus, Vejle, Denmark (E.J.); Centre Léon Bérard, Lyon, France (T.B.); Rambam Health Care Campus, Haifa, Israel (S.S.S.); Universitaetsklinikum Hamburg-Eppendorf, Hamburg (V.M.), and German Breast Group, Neu-Isenburg (S. Loibl) - both in Germany; Hospital Cuf Descobertas R. Mário Botas, Lisbon, Portugal (S.B.); Cliniques Universitaires Saint-Luc, Brussels (F.P.D.); Third Medical Department, Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials, and Cancer Cluster Salzburg, Salzburg, Austria (R.G.); Istituto Europeo di Oncologia, IRCCS, University of Milan, Milan (G.C.); and Seattle Genetics, Bothell, WA (M.C.P.-W., L.W., W.F.).
出版信息
N Engl J Med. 2020 Feb 13;382(7):597-609. doi: 10.1056/NEJMoa1914609. Epub 2019 Dec 11.
BACKGROUND
Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.
METHODS
We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.
RESULTS
Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.
CONCLUSIONS
In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).
背景
接受过多种曲妥珠单抗靶向药物治疗后疾病进展的人表皮生长因子受体 2（HER2）阳性转移性乳腺癌患者，其治疗选择有限。Tucatinib 是一种研究性的、口服的、高度选择性的 HER2 酪氨酸激酶抑制剂。
方法
我们将先前接受过曲妥珠单抗、帕妥珠单抗和曲妥珠单抗恩坦辛治疗、有或没有脑转移的 HER2 阳性转移性乳腺癌患者随机分配接受 tucatinib 或安慰剂联合曲妥珠单抗和卡培他滨治疗。主要终点是前 480 名接受随机分组的患者的无进展生存期。次要终点（在总共 612 名患者中评估）包括总生存期、有脑转移患者的无进展生存期、确认的客观缓解率和安全性。
结果
tucatinib 联合组的 1 年无进展生存率为 33.1%，安慰剂联合组为 12.3%（疾病进展或死亡的风险比，0.54；95%置信区间 [CI]，0.42 至 0.71；P<0.001），无进展生存期的中位数分别为 7.8 个月和 5.6 个月。tucatinib 联合组的 2 年总生存率为 44.9%，安慰剂联合组为 26.6%（死亡风险比，0.66；95%CI，0.50 至 0.88；P=0.005），总生存期的中位数分别为 21.9 个月和 17.4 个月。在有脑转移的患者中，tucatinib 联合组的 1 年无进展生存率为 24.9%，安慰剂联合组为 0%（风险比，0.48；95%CI，0.34 至 0.69；P<0.001），无进展生存期的中位数分别为 7.6 个月和 5.4 个月。tucatinib 组常见的不良反应包括腹泻、掌跖红斑感觉迟钝综合征、恶心、疲劳和呕吐。腹泻和氨基转移酶升高 3 级或更高级别的发生率在 tucatinib 联合组高于安慰剂联合组。
结论
在曲妥珠单抗治疗后疾病进展的 HER2 阳性转移性乳腺癌患者中，包括有脑转移的患者，与安慰剂联合曲妥珠单抗和卡培他滨相比，联合使用 tucatinib 可改善无进展生存期和总生存期；腹泻和氨基转移酶升高的风险更高。（由西雅图遗传学公司资助；HER2CLIMB ClinicalTrials.gov 编号，NCT02614794。）
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