王者之蝶：晚期乳腺癌内分泌疗法失败后的新希望
细胞周期的失调是肿瘤生长和转移的典型标志之一，周期蛋白依赖型激酶（CDK）对乳腺癌细胞增殖有重要作用，而CDK抑制剂可阻止肿瘤细胞进入细胞周期的循环，抑制肿瘤细胞的增殖或者诱导肿瘤细胞的凋亡。早期的广谱CDK抑制剂对CDK选择性差，导致治疗效果不理想，且毒性反应大。选择性CDK4/6抑制剂是靶向针对CDK4/6的口服药，选择性高，能有效抑制激素受体阳性的乳腺癌细胞，且与抗雌激素药物有协同作用。
2017年6月3日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表美国斯坦福大学、凯泽永久医疗集团、达特茅斯学院希区柯克医学中心、日本京都大学、埼玉癌症中心、大阪国立医院、比利时鲁汶大学医院、韩国首尔延世大学癌症中心、法国贝桑松大学让·米诺兹中心医院、法国礼来、德国图宾根大学女子医院、美国礼来、西班牙礼来、西班牙巴伦西亚大学阿纳尔·维拉诺瓦医院的国际双盲Ⅲ期研究（MONARCH2）报告全文，对氟维司群±阿本昔布（选择性CDK4/6抑制剂）用于激素受体阳性和HER2阴性晚期乳腺癌的有效性和安全性。
MONARCH：帝王斑蝶或君主斑蝶，又称黑脉金斑蝶或大桦斑蝶，可能是世界上知名度最高的蝴蝶。原因有二：一是因为帝王蝴蝶非常漂亮，被称为世界上最好看的蝴蝶；二是因为帝王蝴蝶是唯一一种迁徙性蝴蝶，每年冬天来临的时候，帝王蝴蝶就从加拿大和美国北部起飞，成千上万地聚集在一起，飞行上千公里躲避北美的严寒，长途迁徙到温暖的墨西哥过冬，然后再返回加拿大，这种习性在昆虫里是独一无二的。1874年，由哈佛大学塞缪尔·斯卡德取名，因为它们是最大的蝴蝶之一，并统管众多，以纪念荷兰国父、荷兰共和国第一任执政、奥兰治亲王威廉一世。
MONARCH1 (NCT02102490): A Study Of Abemaciclib (LY2835219) In Participants With Previously Treated Breast Cancer That Has Spread.
MONARCH2 (NCT02107703): A Study of Abemaciclib (LY2835219) Combined With Fulvestrant in Women With Hormone Receptor Positive HER2 Negative Breast Cancer.
MONARCH3 (NCT02246621): A Study of Nonsteroidal Aromatase Inhibitors Plus Abemaciclib (LY2835219) in Postmenopausal Women With Breast Cancer.
MONARCH+ (NCT02763566): A Study of Abemaciclib (LY2835219) in Participants With Breast Cancer.
该国际多中心双盲Ⅲ期研究于2014年8月～2015年12月入组669例接受新辅助或辅助内分泌疗法时、辅助内分泌疗法结束后≤12个月、接受晚期转移病变一线内分泌疗法时发生进展的激素受体阳性和HER2阴性晚期乳腺癌女性，按2∶1随机分配接受阿本昔布或安慰剂（150mg每天2次）和氟维司群（500mg，按说明书）。主要终点为调查者评定的无进展生存，关键次要终点包括总生存、客观缓解率、缓解持续时间、临床获益率、生活质量和安全性。
结果发现，阿本昔布＋氟维司群（446例）与安慰剂＋氟维司群（223例）相比：
中位无进展生存显著延长7.1个月（16.4比9.3个月）
疾病进展或死亡风险降低44.7%（风险比：0.553，95%置信区间：0.449～0.681，P＜0.001）
病变可测量患者的客观缓解率显著增加（48.1%比21.3%，95%置信区间：42.6%～53.6%、15.1%～27.6%）
最常见的不良事件为腹泻（86.4%比24.7%）、中性粒细胞减少（46.0%比4.0%）、恶心（45.1%比22.9%）、疲劳（39.9%比26.9%）
因此，对于接受内分泌疗法时发生进展的激素受体阳性和HER2阴性晚期乳腺癌女性，阿本昔布150mg每天2次＋氟维司群有效，显著改善无进展生存和客观缓解率，安全性可接受。
对此，密歇根大学癌症中心、约翰霍普金斯大学金梅尔综合癌症中心发表同期评论：CDK4/6抑制剂治疗乳腺癌的突飞猛进与囊中羞涩。
相关阅读
J Clin Oncol. 2017 Jun 3. [Epub ahead of print]
MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy.
George W. Sledge, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Kenichi Inoue, Xavier Pivot, Olga Burdaeva, Meena Okera, Norikazu Masuda, Peter A. Kaufman, Han Koh, Eva-Maria Grischke, Martin Frenzel, Yong Lin, Susana Barriga, Ian C. Smith, Nawel Bourayou, Antonio Llombart-Cussac.
Stanford University, Stanford; Kaiser Permanente Medical Group, Bellflower, CA; Kyoto University; Saitama Cancer Center, Saitama; Osaka National Hospital, Osaka, Japan; Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg, Leuven, Belgium; Yonsei Cancer Center, Seoul, Korea; CHU de Besancon Hopital Jean Minjoz, Besancon Cedex; Eli Lilly, Paris, France; Arkhangelsk Regional Clinical Oncology Dispensary, Arkhangelsk, Russian Federation; Adelaide Cancer Centre, Adelaide, Australia; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Universitatsklinikum Tübingen Frauenklinik, Tübingen, Germany; Eli Lilly, Indianapolis, IN; Eli Lilly, Madrid; Hospital Arnau Vilanova, Valencia, Spain.
PURPOSE: MONARCH 2 (ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC).
PATIENTS AND METHODS: MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤ 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Patients were randomly assigned 2:1 to receive abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label). The primary end point was investigator-assessed progression-free survival (PFS), and key secondary end points included overall survival, objective response rate (ORR), duration of response, clinical benefit rate, quality of life, and safety.
RESULTS: Between August 2014 and December 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 27.6%) in the control arm. The most common adverse events in the abemaciclib versus placebo arms were diarrhea (86.4% v 24.7%), neutropenia (46.0% v 4.0%), nausea (45.1% v 22.9%), and fatigue (39.9% v 26.9%).
CONCLUSIONS: Abemaciclib at 150 mg twice daily plus fulvestrant was effective, significantly improving PFS and ORR and demonstrating a tolerable safety profile in women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who progressed while receiving ET.
DOI: 10.1200/JCO.2017.73.7585
J Clin Oncol. 2017 Jun 3. [Epub ahead of print]
Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Breast Cancer: More Breakthroughs and an Embarrassment of Riches.
Jennifer J. Griggs, Antonio C. Wolff.
University of Michigan Cancer Center, Ann Arbor, MI; The Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD.
DOI: 10.1200/JCO.2017.73.9375