英国《柳叶刀》在线发表中国学者参与的《猎鹰》研究全文
2016年11月28日，英国《柳叶刀》在线发表英国诺丁汉大学皇家德比医院、乌克兰第聂伯罗彼得罗夫斯克国立医学院、俄罗斯圣彼得堡列宁格勒地区肿瘤中心、俄罗斯鄂木斯克临床肿瘤中心、加拿大蒙特利尔犹太总医院、俄罗斯圣彼得堡市立临床肿瘤中心、利乌克兰沃夫州立地区肿瘤诊疗中心、墨西哥蒙特雷科技大学、秘鲁利马大学、西班牙圣女罗西奥大学医院、复旦大学附属肿瘤医院（邵志敏）、日本大阪大学院医学研究院、英国阿斯利康、美国阿斯利康、美国贝勒医学院莱斯特与苏·史密斯乳腺中心的国际随机双盲Ⅲ期研究报告《氟维司群500mg与阿那曲唑1mg用于激素受体阳性晚期乳腺癌》，研究代号：猎鹰（FALCON）。
芳香酶抑制剂是绝经后激素受体阳性局部晚期或转移性乳腺癌的治疗标准方案，该研究调查了氟维司群（选择性雌激素受体抗拮药，可以高亲和力地结合、阻断并降解雌激素受体，既是雌激素受体的拮抗药也是下调药，但不会干扰自身雌激素水平）与阿那曲唑（芳香酶抑制剂）相比，是否可以改善既往未经内分泌治疗患者的无进展生存。
该Ⅲ期随机双盲研究入组了20个国家113个学术医院和社区中心组织学证实雌激素受体阳性和（或）孕酮受体阳性符合条件的局部晚期或转移性乳腺癌患者。符合条件的患者既往未经内分泌治疗、WHO体力状态0～2、至少一个可测量或不可测量的病变。使用计算机生成的随机化方案，将患者随机（1∶1）分入氟维司群组（500mg，肌内注射，第0、14、28天，然后每28天）或阿那曲唑（每天口服1mg）。主要终点为无进展生存，根据实体肿瘤疗效评价标准（RECIST）1.1版确定需要通过手术或放疗进行干预的疾病恶化或任何原因引起的死亡，在意向治疗人群中进行评定。对所有接受至少一次剂量随机治疗（包括安慰剂）的患者评定安全结局。该研究已在美国政府临床研究网站（ClinicalTrials.gov）注册，编号：NCT01602380。
结果，该研究于2012年10月17日～2014年7月11日共入选524例患者。其中462例患者进行了随机化，氟维司群组、阿那曲唑组分别为230例、232例。氟维司群组与阿那曲唑组相比，中位无进展生存分别为16.6、13.8（95%置信区间：13.83～20.99、11.99～16.59）个月，显著改善20.3%（风险比：0.797，95%置信区间：0.637～0.999，P=0.0486）。氟维司群组、阿那曲唑组最常见的不良事件为关节疼痛（38例[17%]∶24例[10%]）和发热潮红（26例[11%]∶24例[10%]），由于不良事件而中断治疗的患者分别占7%（16/228）和5%（11/232）。
因此，作者认为对于既往未经内分泌治疗的激素受体阳性局部晚期或转移性乳腺癌患者，氟维司群与第三代芳香酶抑制剂（一线治疗标准方案）相比具有优效性，是首选的治疗方案。
在将该研究结果应用于临床实践前，需要注意两个问题：第一，猎鹰研究仅入组了既往未经内分泌治疗的乳腺癌，但是临床有很多晚期患者在发病初期已经接受了内分泌治疗。其次，由于晚期乳腺癌治疗的不断进步，美国已批准CDK4/6抑制剂帕泊昔布上市并可与芳香酶抑制剂联合使用，而猎鹰研究设计是单药方案。未来还需要开展相关研究帮助确定晚期乳腺癌的最佳用药方案。
对此，美国西北大学范伯格医学院罗伯特·鲁里综合癌症中心肿瘤内科学家发表同期述评：关注转移性乳腺癌的内分泌敏感性。
此前，英国《自然·综述·临床肿瘤学》编辑部还发表述评：蒙娜利莎（MONALEESA-2）与猎鹰（FALCON）的无进展生存获益。
相关阅读
Lancet. 2016 Nov 28. [Epub ahead of print]
Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial.
John F R Robertson, Igor M Bondarenko, Ekaterina Trishkina, Mikhail Dvorkin, Lawrence Panasci, Alexey Manikhas, Yaroslav Shparyk, Servando Cardona-Huerta, Kwok-Leung Cheung, Manuel Jesus Philco-Salas, Manuel Ruiz-Borrego, Zhimin Shao, Shinzaburo Noguchi, Jacqui Rowbottom, Mary Stuart, Lynda M Grinsted, Mehdi Fazal, Matthew J Ellis.
University of Nottingham, Royal Derby Hospital Centre, Derby, UK; Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine; Leningrad Regional Oncology Dispensary, St Petersburg, Russia; Clinical Oncology Dispensary, Omsk, Russia; Jewish General Hospital, Montreal, Canada; City Clinical Oncology Dispensary, St Petersburg, Russia; Lviv State Oncology Regional Treatment and Diagnostic Centre, Lviv, Ukraine; Tecnológico de Monterrey, Monterrey, Mexico; Instituto Oncológico de Lima, Lima, Peru; Hospital Universitario Virgen del Rocío, Seville, Spain; Fudan University Shanghai Cancer Center, Shanghai, China; Osaka University Graduate School of Medicine, Osaka, Japan; AstraZeneca, Alderley Park, Macclesfield, UK; AstraZeneca, Cambridge, UK; AstraZeneca, Gaithersburg, MD, USA; Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA.
Background: Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy.
Methods: In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0-2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1.1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380.
Findings: Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0.797, 95% CI 0.637-0.999, p=0.0486). Median progression-free survival was 16.6 months (95% CI 13.83-20.99) in the fulvestrant group versus 13.8 months (11.99-16.59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events.
Interpretation: Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients.
Funding: AstraZeneca.
DOI: 10.1016/S0140-6736(16)32389-3
Lancet. 2016 Nov 28. [Epub ahead of print]
Metastatic breast cancer: focus on endocrine sensitivity.
Massimo Cristofanilli.
Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
DOI: 10.1016/S0140-6736(16)32418-7
Nat Rev Clin Oncol. 2016;13(12):717.
Breast cancer: MONALEESA-2 and FALCON - PFS advantage.
Romero D.
PMID: 27805629
DOI: 10.1038/nrclinonc.2016.174