难治型晚期乳腺癌的妥卡替尼联合疗效
对于多种HER2靶向药物治疗失败的HER2阳性晚期乳腺癌患者，治疗选择所剩无几。妥卡替尼是一种新型、口服、高选择性HER2酪氨酸激酶抑制剂。
2019年12月11日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》和全球乳腺癌学术会议之首、美国圣安东尼奥乳腺癌论坛同时发表美国德克萨斯大学MD安德森癌症中心、温什普癌症研究所、萨拉坎农研究所、田纳西肿瘤医院、范德堡大学、洛杉矶加利福尼亚大学、斯坦福大学、哈佛大学达纳法伯癌症研究所、科罗拉多大学、杜克大学、北卡罗来纳大学莱恩伯格综合癌症中心、西雅图基因科技、澳大利亚墨尔本大学彼得麦卡伦癌症中心、英国伦敦大学皇家马斯登医院、爱丁堡大学、加拿大多伦多大学玛格丽特公主癌症中心、不列颠哥伦比亚癌症中心、西班牙巴塞罗纳大学、丹麦瓦埃勒医院、法国里昂贝拉德中心、以色列兰巴姆医院、德国乳腺癌研究协作组、汉堡大学、葡萄牙里斯本医院、比利时鲁汶大学、奥地利帕拉塞尔苏斯医科大学、萨尔茨堡癌症研究所、意大利米兰大学、欧洲肿瘤研究院的HER2CLIMB研究报告，探讨了妥卡替尼＋曲妥珠单抗＋卡培他滨治疗HER2阳性晚期乳腺癌的效果。
HER2CLIMB: A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer: Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib vs Placebo in Combination With Capecitabine and Trastuzumab in Patients With Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma (NCT02614794)
2019 SABCS GS1-01: Tucatinib vs placebo, both combined with capecitabine and trastuzumab, for patients with pretreated HER2-positive metastatic breast cancer with and without brain metastases (HER2CLIMB)
该国际多中心双盲随机对照而期临床研究于2016年2月23日～2019年5月3日从15个国家155家医院入组HER2阳性乳腺癌既往曲妥珠单抗、帕妥珠单抗、T-DM1治疗后仍然发生远处转移（包括脑转移）患者612例，，按2∶1的比例随机分入两组：其中410例接受妥卡替尼＋曲妥珠单抗＋卡培他滨，其余202例接受安慰剂＋曲妥珠单抗＋卡培他滨。主要研究终点为首批480例随机入组患者的无进展生存。次要研究终点为全部612例患者的总生存、291例脑转移患者的无进展生存、客观缓解率和安全性。
结果，中位随访14.1个月期间，妥卡替尼联合组与安慰剂联合组相比：
1年无进展生存率：33.1%比12.3%（疾病进展或死亡风险比：0.54，95%置信区间：0.42～0.71，P<0.001）
中位无进展生存：7.8比5.6个月
2年总生存率：44.9%比26.6%（死亡风险比：0.66，95%置信区间：0.50～0.88，P=0.005）
中位总生存：21.9比17.4个月
对于脑转移患者，妥卡替尼联合组与安慰剂联合组相比：
1年无进展生存率：24.9%比1%（风险比：0.48，95%置信区间：0.34～0.69，P<0.001）
中位无进展生存：7.6比5.4个月
妥卡替尼组发生率最高的不良事件包括腹泻、手足综合征、恶心、疲劳、呕吐。妥卡替尼联合组与安慰剂联合组相比，腹泻、转氨酶升高≥3级的发生率较高。
因此，该研究结果表明，对于多种HER2靶向药物治疗失败的HER2阳性乳腺癌转移（包括脑转移）患者，曲妥珠单抗＋卡培他滨＋妥卡替尼与曲妥珠单抗＋卡培他滨＋安慰剂相比，无进展生存和总生存结果显著较好；妥卡替尼的腹泻和转氨酶水平升高风险较高。
该研究通讯作者：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