卡铂＋维利帕布（维利帕尼）治疗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、芝加哥大学、洛约拉大学、宾夕法尼亚大学、双子集团、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、明尼苏达大学、梅奥医院、西雅图瑞典医学中心、乔治城大学隆巴迪综合癌症中心、堪萨斯大学、亚利桑那大学、俄勒冈健康科学大学、丹佛大学、伊诺瓦·费法克斯医院、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）研究报告之二：卡铂＋维利帕布（维利帕尼）治疗三阴性乳腺癌的适应性随机研究。

　　结果发现，对于三阴性乳腺癌，卡铂＋维利帕布（维利帕尼）Ⅲ期试验成功取得88%的预测概率。共有72例患者随机接受标准疗法＋卡铂＋维利帕布（维利帕尼），44例患者接收接受对照标准疗法。当化疗结束时，在三阴性乳腺癌人群中，卡铂＋维利帕布（维利帕尼）组的估算病理学完全缓解率为51%（95%贝叶斯概率区间：36%～66%），对照组为26%（95%贝叶斯概率区间：9%～43%）。卡铂＋维利帕布（维利帕尼）组与对照组相比，毒性较大。

　　因此，标准疗法＋卡铂＋维利帕布（维利帕尼）与单用标准疗法相比，尤其对于三阴性乳腺癌的病理学完全缓解率较高。

N Engl J Med. 2016 Jul 7;375(1):23-34.

Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.

Hope S. Rugo, Olufunmilayo I. Olopade, Angela DeMichele, Christina Yau, Laura J. van't Veer, Meredith B. Buxton, Michael Hogarth, Nola M. Hylton, Melissa Paoloni, Jane Perlmutter, W. Fraser Symmans, Douglas Yee, A. Jo Chien, Anne M. Wallace, Henry G. Kaplan, Judy C. Boughey, Tufia C. Haddad, Kathy S. Albain, Minetta C. Liu, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Rebecca K. Viscusi, Lajos Pusztai, Stacy L. Moulder, Stephen Y. Chui, Kathleen A. Kemmer, Anthony D. Elias, Kirsten K. Edmiston, David M. Euhus, Barbara B. Haley, Rita Nanda, Donald W. Northfelt, Debasish Tripathy, William C. Wood, Cheryl Ewing, Richard Schwab, Julia Lyandres, Sarah E. Davis, Gillian L. Hirst, Ashish Sanil, Donald A. Berry, Laura J. Esserman; 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; University of Chicago; Loyola University, Chicago; University of Pennsylvania, Philadelphia; Gemini Group, Ann Arbor, MI; University of Texas M.D. Anderson Cancer Center, Houston; UT Southwestern Medical Center, Dallas; Berry Consultants, Austin, Texas; University of Minnesota, Minneapolis; Mayo Clinic, Rochester, Minnesota; Swedish Medical Center, Seattle; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; University of Kansas, Lawrence; University of Arizona, Tucson; Mayo Clinic, Scottsdale, Arizona; Oregon Health and Sciences University, Portland; University of Denver, Denver; Inova Fairfax Hospital, Falls Church, VA; Emory University, Atlanta.

BACKGROUND: The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin.

METHODS: In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well.

RESULTS: With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control.

CONCLUSIONS: The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer.

Funded by the QuantumLeap Healthcare Collaborative and others

I-SPY 2 TRIAL ClinicalTrials.gov number: NCT01042379

DOI: 10.1056/NEJMoa1513749