三阳性晚期乳腺癌全靶向无化疗新方案
对于至少二线治疗方案已经失败的HER2阳性晚期乳腺癌患者，目前缺乏有效的治疗选择。细胞周期蛋白依赖性激酶CDK4/6靶向抑制剂哌柏西利、瑞博西利、阿贝西利已被批准联合内分泌药物用于治疗激素受体阳性HER2阴性晚期乳腺癌，不过CDK4/6抑制剂的作用机制并不局限于HER2阴性乳腺癌。其中，美国礼来的阿贝西利首先被尝试用于治疗HER2阳性乳腺癌。
2020年4月27日，英国《柳叶刀》肿瘤学分册在线发表美国礼来、哈佛大学达纳法伯癌症研究院、纽约纪念医院斯隆凯特林癌症中心、英国曼彻斯特学术健康科学中心、曼彻斯特大学、伦敦皇家马斯登医院、英国礼来研究中心、意大利圣拉斐尔医院、加拿大渥太华医院、渥太华大学、法国巴黎文理研究大学居里研究院、巴黎萨克雷大学古斯塔夫鲁西研究院、韩国首尔大学医院、蔚山大学首尔峨山医院、澳大利亚西澳乳腺癌研究中心、科廷大学、彼得麦卡伦癌症中心、墨尔本大学的monarcHER研究报告，对阿贝西利＋曲妥珠单抗±氟维司群或标准化疗＋曲妥珠单抗治疗三阳性晚期乳腺癌女性的疗效进行了比较。
monarcHER: A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of Abemaciclib (LY2835219) Plus Trastuzumab With or Without Fulvestrant to Standard-of-Care Chemotherapy of Physician's Choice Plus Trastuzumab in Women With HR , HER2 Locally Advanced or Metastatic Breast Cancer (NCT02675231)
该国际多中心三组非盲随机对照二期临床研究于2016年5月31日～2018年2月28日从全球14个国家或地区的75家医院、诊所和医疗中心入组激素受体阳性、HER2阳性晚期乳腺癌无法切除、局部转移、复发或远处转移、美国东部肿瘤协作组ECOG体力状态评分0或1、此前至少两种晚期HER2靶向治疗失败的年龄≥18岁女性237例，按1∶1∶1的比例随机分为3组：
A组79例：阿贝西利＋曲妥珠单抗＋氟维司群
B组79例：阿贝西利＋曲妥珠单抗
C组79例：标准化疗＋曲妥珠单抗
阿贝西利用法：每21天的第1～21天每12小时口服150毫克；曲妥珠单抗用法：每21天每公斤体重静脉注射6毫克（首次8毫克）。氟维司群用法：第1、15、29天肌肉注射500毫克，随后每4周一次；标准化疗用法：具体方案由医师决定、根据药品说明书用药。按此前晚期乳腺癌、可测量病变和不可测量病变的全身治疗方案数量对随机分组进行分层。主要终点为研究者评定的意向治疗患者无进展生存，首先比较A组与C组，预设双侧α<0.2为显著，若结果显著，则比较B组与C组。对实际治疗患者进行安全性评定。该研究目前仍在进行长期生存随访。
结果，经过19.0个月的中位随访（四分位：14.7～25.1），该研究达到其主要终点。
A组与C组相比：
中位无进展生存显著延长2.6个月（8.3比5.7，95%置信区间：5.9～12.6、5.4～7.0）
进展或死亡风险显著减少33%（风险比：0.67，95%置信区间：0.45～1.00，P=0.051）
B组与C组相比：
中位无进展生存相似（5.7比5.7，95%置信区间：4.2～7.2）
进展或死亡风险相似（风险比：0.94，95%置信区间：0.64～1.38，P=0.77）
发生率最高的3～4级治疗所致不良事件为中性粒细胞减少：
A组：27%
B组：22%
C组：26%
发生率最高的严重不良事件：
A组：发热4%、腹泻3%、尿路感染3%、急性肾损伤3%
B组，腹泻3%、肺炎3%
C组：中性粒细胞减少6%、胸腔积液3%
治疗所致死亡2例：
B组：1例，死于肺纤维化
C组：1例，死于发热伴中性粒细胞减少
因此，该研究结果表明，对于激素受体阳性HER2阳性晚期乳腺癌患者，阿贝西利＋曲妥珠单抗＋氟维司群与标准化疗＋曲妥珠单抗相比，无进展生存显著较长、进展或死亡风险显著减少，安全性可耐受，该全靶向无化疗方案可能成为激素受体阳性HER2阳性晚期乳腺癌患者的替代治疗选择，故有必要进一步开展三期临床研究进行验证。
对此，英国萨顿皇家马斯登医院发表同期评论：HER2阳性乳腺癌的CDK4/6抑制意义。
相关链接
Lancet Oncol. 2020 Apr 27. [Epub ahead of print]
Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial.
Sara M Tolaney, Andrew M Wardley, Stefania Zambelli, John F Hilton, Tiffany A Troso-Sandoval, Francesco Ricci, Seock-Ah Im, Sung-Bae Kim, Stephen RD Johnston, Arlene Chan, Shom Goel, Kristen Catron, Sonya C Chapman, Gregory L Price, Zhengyu Yang, M Corona Gainford, Fabrice André.
Dana-Farber Cancer Institute, Boston, MA, USA; Manchester Academic Health Science Centre, Manchester, UK; University of Manchester, Manchester, UK; Ospedale San Raffaele, IRCCS, Milano, Italy; The Ottawa Hospital and University of Ottawa, Ottawa, Canada; Memorial Sloan Kettering Cancer Center, New York, NY, USA; Institut Curie, PSL Research University, Paris, France; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Royal Marsden Hospital, London, UK; Breast Cancer Research Centre-WA, Nedlands, WA, Australia; Curtin University, Nedlands, WA, Australia; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia; Eli Lilly, Indianapolis, IN, USA; Eli Lilly, Windlesham, UK; Gustave Roussy, Université Paris Saclay, Villejuif, France.
BACKGROUND: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer.
METHODS: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up.
FINDINGS: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19.0 months (IQR 14.7-25.1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0.2 in median progression-free survival between group A (8.3 months, 95% CI 5.9-12.6) and group C (5.7 months, 5.4-7.0; HR 0.67 [95% CI 0.45-1.00]; p=0.051). No difference was observed between median progression-free survival in group B (5.7 months, 95% CI 4.2-7.2) and group C (HR 0.94 [0.64-1.38]; p=0.77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C.
INTERPRETATION: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer.
FUNDING: Eli Lilly and Company
DOI: 10.1016/S1470-2045(20)30112-1
Lancet Oncol. 2020 Apr 27. [Epub ahead of print]
CDK4/6 inhibition in HER2-positive breast cancer.
Nicolò Matteo Luca Battisti, Alistair Ring.
The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.
The cyclin-dependent kinase 4 (CDK4) and 6 (CDK6) inhibitors have revolutionised the management of advanced hormone receptor-positive, HER2-negative breast cancer. Palbociclib, ribociclib, and have been approved in combination with endocrine therapy on the basis of consistent improvements in progression-free survival, and emerging improvements in overall survival, in treatment-naive and pretreated advanced breast cancer.
DOI: 10.1016/S1470-2045(20)30164-9