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對于多種HER2靶向藥物治療失敗的HER2陽性晚期乳腺癌患者，治療選擇所剩無幾。妥卡替尼是一種新型、口服、高選擇性HER2酪氨酸激酶抑制劑。 2019年12月11日，國際四大醫(yī)學期刊之首、美國麻省醫(yī)學會《新英格蘭醫(yī)學雜志》和全球乳腺癌學術(shù)會議之首、美國圣安東尼奧乳腺癌論壇同時發(fā)表美國德克薩斯大學MD安德森癌癥中心、溫什普癌癥研究所、薩拉坎農(nóng)研究所、田納西腫瘤醫(yī)院、范德堡大學、洛杉磯加利福尼亞大學、斯坦福大學、哈佛大學達納法伯癌癥研究所、科羅拉多大學、杜克大學、北卡羅來納大學萊恩伯格綜合癌癥中心、西雅圖基因科技、澳大利亞墨爾本大學彼得麥卡倫癌癥中心、英國倫敦大學皇家馬斯登醫(yī)院、愛丁堡大學、加拿大多倫多大學瑪格麗特公主癌癥中心、不列顛哥倫比亞癌癥中心、西班牙巴塞羅納大學、丹麥瓦埃勒醫(yī)院、法國里昂貝拉德中心、以色列蘭巴姆醫(yī)院、德國乳腺癌研究協(xié)作組、漢堡大學、葡萄牙里斯本醫(yī)院、比利時魯汶大學、奧地利帕拉塞爾蘇斯醫(yī)科大學、薩爾茨堡癌癥研究所、意大利米蘭大學、歐洲腫瘤研究院的HER2CLIMB研究報告，探討了妥卡替尼＋曲妥珠單抗＋卡培他濱治療HER2陽性晚期乳腺癌的效果。
該國際多中心雙盲隨機對照而期臨床研究于2016年2月23日～2019年5月3日從15個國家155家醫(yī)院入組HER2陽性乳腺癌既往曲妥珠單抗、帕妥珠單抗、T-DM1治療后仍然發(fā)生遠處轉(zhuǎn)移（包括腦轉(zhuǎn)移）患者612例，，按2∶1的比例隨機分入兩組：其中410例接受妥卡替尼＋曲妥珠單抗＋卡培他濱，其余202例接受安慰劑＋曲妥珠單抗＋卡培他濱。主要研究終點為首批480例隨機入組患者的無進展生存。次要研究終點為全部612例患者的總生存、291例腦轉(zhuǎn)移患者的無進展生存、客觀緩解率和安全性。 結(jié)果，中位隨訪14.1個月期間，妥卡替尼聯(lián)合組與安慰劑聯(lián)合組相比：
對于腦轉(zhuǎn)移患者，妥卡替尼聯(lián)合組與安慰劑聯(lián)合組相比：
妥卡替尼組發(fā)生率最高的不良事件包括腹瀉、手足綜合征、惡心、疲勞、嘔吐。妥卡替尼聯(lián)合組與安慰劑聯(lián)合組相比，腹瀉、轉(zhuǎn)氨酶升高≥3級的發(fā)生率較高。 因此，該研究結(jié)果表明，對于多種HER2靶向藥物治療失敗的HER2陽性乳腺癌轉(zhuǎn)移（包括腦轉(zhuǎn)移）患者，曲妥珠單抗＋卡培他濱＋妥卡替尼與曲妥珠單抗＋卡培他濱＋安慰劑相比，無進展生存和總生存結(jié)果顯著較好；妥卡替尼的腹瀉和轉(zhuǎn)氨酶水平升高風險較高。  該研究通訊作者：Eric P. Winer N Engl J Med. 2019 Dec 11. [Epub ahead of print] Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. Rashmi K. Murthy, Sherene Loi, Alicia Okines, Elisavet Paplomata, Erika Hamilton, Sara A. Hurvitz, Nancy U. Lin, Virginia Borges, Vandana Abramson, Carey Anders, Philippe L. Bedard, Mafalda Oliveira, Erik Jakobsen, Thomas Bachelot, Shlomit S. Shachar, Volkmar Müller, Sofia Braga, Francois P. Duhoux, Richard Greil, David Cameron, Lisa A. Carey, Giuseppe Curigliano, Karen Gelmon, Gabriel Hortobagyi, Ian Krop, Sibylle Loibl, Mark Pegram, Dennis Slamon, M. Corinna Palanca-Wessels, Luke Walker, Wentao Feng, Eric P. Winer. M.D. Anderson Cancer Center, Houston; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Royal Marsden NHS Foundation Trust, London; Edinburgh Cancer Research Centre, Edinburgh, United Kingdom; Winship Cancer Institute, Atlanta; Sarah Cannon Research Institute/Tennessee Oncology-Nashville, Vanderbilt University Medical Center, Nashville; University of California, Los Angeles, Medical Center-Jonsson Comprehensive Cancer Center, Los Angeles; Stanford Comprehensive Cancer Institute, Palo Alto, California; Dana-Farber Cancer Institute, Boston; University of Colorado Cancer Center, Aurora; Duke Cancer Institute, Durham; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina; University Health Network, Princess Margaret Cancer Centre, Toronto; British Columbia Cancer, Vancouver, Canada; Hospital Universitario Vall D'Hebron, Barcelona; Sygehus Lillebaelt-Vejle Sygehus, Vejle, Denmark; Centre Léon Bérard, Lyon, France; Rambam Health Care Campus, Haifa, Israel; Universitaetsklinikum Hamburg-Eppendorf, Hamburg; German Breast Group, Neu-Isenburg, Germany; Hospital Cuf Descobertas R. Mário Botas, Lisbon, Portugal; Cliniques Universitaires Saint-Luc, Brussels; Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute-Center for Clinical Cancer and Immunology Trials, Cancer Cluster Salzburg, Salzburg, Austria; Istituto Europeo di Oncologia, IRCCS, University of Milan, Milan; Seattle Genetics, Bothell, WA. 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 DOI: 10.1056/NEJMoa1914609
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