奈拉替尼（来那替尼）治疗早期乳腺癌的适应性随机研究

　　2016年7月7日，美国麻省（马萨诸塞州）医学会官方期刊《新英格兰医学杂志》发表了加利福尼亚大学旧金山分校、戴维斯分校、圣迭戈分校、量子飞越医疗协作组织、巴克老年研究所、南加利福尼亚大学、乔治城大学隆巴迪综合癌症中心、明尼苏达大学、梅奥医院、德克萨斯大学西南医学中心、M.D.安德森癌症中心、贝瑞咨询、双子集团、宾夕法尼亚大学、俄勒冈健康科学大学、西雅图瑞典医学中心、芝加哥大学、洛约拉大学、伊诺瓦·费法克斯医院、丹佛大学、亚利桑那大学、堪萨斯大学、埃默里大学的两项《影像和分子分析预测治疗效果系列研究调查》（I-SPY 2 TRIAL）研究报告之一：奈拉替尼（来那替尼）治疗早期乳腺癌的适应性随机研究。

　　结果发现，对于HER2阳性、激素受体阴性乳腺癌患者，115例新辅助化疗＋奈拉替尼（来那替尼）组的平均估算病理学完全缓解率为85%（95%贝叶斯概率区间：37%～73%），高于78例新辅助化疗对照组的33%（95%贝叶斯概率区间：11%～54%），Ⅲ期检验成功的最终预测概率为79%。

　　因此，对于HER2阳性、激素受体阴性乳腺癌患者，标准化疗＋奈拉替尼（来那替尼）与标准化疗＋曲妥珠单抗相比，病理学完全缓解率很有可能更高。

N Engl J Med. 2016 Jul 7;375(1):11-22.

Adaptive Randomization of Neratinib in Early Breast Cancer.

John W. Park, Minetta C. Liu, Douglas Yee, Christina Yau, Laura J. van't Veer, W. Fraser Symmans, Melissa Paoloni, Jane Perlmutter, Nola M. Hylton, Michael Hogarth, Angela DeMichele, Meredith B. Buxton, A. Jo Chien, Anne M. Wallace, Judy C. Boughey, Tufia C. Haddad, Stephen Y. Chui, Kathleen A. Kemmer, Henry G. Kaplan, Claudine Isaacs, Rita Nanda, Debasish Tripathy, Kathy S. Albain, Kirsten K. Edmiston, Anthony D. Elias, Donald W. Northfelt, Lajos Pusztai, Stacy L. Moulder, Julie E. Lang, Rebecca K. Viscusi, David M. Euhus, Barbara B. Haley, Qamar J. Khan, William C. Wood, Michelle Melisko, Richard Schwab, Teresa Helsten, Julia Lyandres, Sarah E. Davis, Gillian L. Hirst, Ashish Sanil, Laura J. Esserman, Donald A. Berry; I-SPY 2 Investigators.

University of California, San Francisco; QuantumLeap Healthcare Collaborative, San Francisco; Buck Institute for Research and Aging, Novato; University of California, Davis, Davis; University of California, San Diego, San Diego ; University of Southern California, Los Angeles, California; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; University of Minnesota, Minneapolis; Mayo Clinic, Rochester, Minnesota; M.D. Anderson Cancer Center, Houston, University of Texas Southwestern Medical Center, Dallas; Berry Consultants, Austin, Texas; Gemini Group, Ann Arbor, MI; University of Pennsylvania, Philadelphia; Oregon Health and Sciences University, Portland; Swedish Medical Center, Seattle; University of Chicago; Loyola University, Chicago; Inova Fairfax Hospital, Falls Church, VA; University of Denver, Denver; Mayo Clinic, Scottsdale; University of Arizona, Tucson, Arizona; University of Kansas, Lawrence; Emory University, Atlanta.

BACKGROUND: The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery).

METHODS: We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature.

RESULTS: Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%.

CONCLUSIONS: Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer.

Funded by QuantumLeap Healthcare Collaborative and others

I-SPY 2 TRIAL ClinicalTrials.gov number: NCT01042379

DOI: 10.1056/NEJMoa1513750