Tucatinib+曲妥珠單抗+卡培他濱治療HER2陽性轉移性乳腺癌延長生存期
作者：
小柯機器人發布時間：2019/12/17 16:37:53
美國達納法伯癌症研究所Eric P. Winer聯合德克薩斯大學安德森腫瘤中心Rashmi K. Murthy團隊的一項最新研究，探討了Tucatinib+曲妥珠單抗+卡培他濱治療HER2陽性轉移性乳腺癌的療效。2019年12月11日，國際知名學術期刊《新英格蘭醫學雜誌》發表了這一成果。
人表皮生長因子受體2（HER2）陽性轉移性的乳腺癌患者經多個HER2靶向藥物治療後病情進展，其選擇極其有限。Tucatinib是一種研究性、口服、高選擇性的HER2酪氨酸激酶抑制劑。
研究組招募了480名HER2陽性的轉移性乳腺癌患者，此前他們均接受過曲妥珠單抗、帕妥珠單抗和曲妥珠單抗-美坦新治療，伴或不伴腦轉移。將其隨機分組，分別接受Tucatinib或安慰劑聯合曲妥珠單抗+卡培他濱進行治療。
Tucatinib聯合組和安慰劑聯合組治療1年的無進展生存率分別為33.1%和12.3%，差異顯著，中位無進展生存期分別為7.8個月和5.6個月。Tucatinib聯合組和安慰劑聯合組治療2年的總生存率分別為44.9%和26.6%，差異顯著，中位總生存期分別為21.9個月和17.4個月。
在腦轉移患者中，Tucatinib聯合組1年無進展生存率為24.9%，安慰劑聯合組為0%，差異顯著，中位無進展生存期分別為7.6個月和5.4個月。Tucatinib組常見的不良反應包括腹瀉、掌蹠感覺障礙症候群、噁心、疲勞和嘔吐。Tucatinib聯合組中3級及以上腹瀉和轉氨酶升高的發生率顯著高於安慰劑聯合組。
總之，在HER2陽性轉移性乳腺癌包括腦轉移的重度患者中，與安慰劑相比，曲妥珠單抗+卡培他濱+Tucatinib顯著提高了無進展生存率和總生存率，但亦增加了腹瀉和轉氨酶升高的風險。
附：英文原文
Title: Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer
Author: Rashmi K. Murthy, M.D.,, Sherene Loi, M.D.,, Alicia Okines, M.D.,, Elisavet Paplomata, M.D.,, Erika Hamilton, M.D.,, Sara A. Hurvitz, M.D.,, Nancy U. Lin, M.D.,, Virginia Borges, M.D.,, Vandana Abramson, M.D.,, Carey Anders, M.D.,, Philippe L. Bedard, M.D.,, Mafalda Oliveira, M.D.,, Erik Jakobsen, M.D.,, Thomas Bachelot, M.D.,, Shlomit S. Shachar, M.D.,, Volkmar Müller, M.D.,, Sofia Braga, M.D.,, Francois P. Duhoux, M.D.,, Richard Greil, M.D.,, David Cameron, M.D.,, Lisa A. Carey, M.D.,, Giuseppe Curigliano, M.D., Ph.D.,, Karen Gelmon, M.D.,, Gabriel Hortobagyi, M.D.,, Ian Krop, M.D., Ph.D.,, Sibylle Loibl, M.D.,, Mark Pegram, M.D.,, Dennis Slamon, M.D.,, M. Corinna Palanca-Wessels, M.D., Ph.D.,, Luke Walker, M.D.,, Wentao Feng, Ph.D.,, and Eric P. Winer, M.D.
Issue&Volume: December 11, 2019
Abstract:
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.
DOI: 10.1056/NEJMoa1914609
Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1914609