晚期乳腺癌的依维莫司一线治疗-SIBCS

编者按：依维莫司（诺华）为哺乳动物雷帕霉素靶蛋白（mTOR）口服抑制剂，与雌激素抑制剂联合龙科忆 ，可能预防或延缓晚期乳腺癌患者对一线内分泌治疗的耐药。根据3期研究（BOLERO-2）结果，与雌激素芳香酶灭活剂依西美坦（辉瑞）相比，依维莫司＋依西美坦，对于雌激素芳香酶抑制剂来曲唑（诺华）或阿那曲唑（阿斯利康）一线治疗失败的晚期激素受体阳性且HER2阴性乳腺癌绝经后女性，中位无进展生存延长4.6个月、进展风险减少55%。根据亚组分析结果，对于早期乳腺癌术后辅助治疗失败的晚期患者，依维莫司＋依西美坦一线治疗的中位无进展生存延长7.4个月、进展风险减少61%；根据集中复核叶峻雄 ，中位无进展生存延长11.0个月、复发风险减少68%。那么，对于此类患者，依维莫司＋来曲唑一线治疗能否提供临床获益？
2018年3月22日，《美国医学会杂志》肿瘤学分册在线发表美国诺华、新墨西哥大学、阿拉巴马大学伯明翰分校、芝加哥西北大学、法国诺华、里昂贝拉尔中心、贝桑松大学、波尔多癌症研究中心、土耳其伊斯坦布尔大学、巴西癌症控制研究所、圣保罗大学、阿雷格里港医院、日本名古屋市立大学、韩国延世大学、泰国玛希敦大学诗里拉吉医院、葡萄牙尚帕利莫基金会临床中心的研究报告，对依维莫司＋来曲唑一线治疗雌激素受体阳性且HER2阴性晚期乳腺癌绝经后女性进行了尝试。
该多中心非盲单组2期临床研究（BOLERO-4）于2013年3月7日～2014年12月17日从245例患者筛选出符合条件女性202例冠珠卫浴官网 ，中位年龄64.0岁（四分位距58.0～70.0岁）念念勿忘 ，其中转移性乳腺癌194例（96.0%）、局部晚期乳腺癌8例（4.0%）。接受每天依维莫司10mg＋来曲唑2.5mg一线治疗，初始疾病进展时由研究者酌情改予每天依维莫司10mg＋依西美坦25mg二线治疗。主要终点为研究者根据实体肿瘤疗效评价标准（RECIST）1.0版评定一线治疗的无进展生存，并对实际接受治疗患者评定药物安全性极品官运。截至2016年12月17日，中位随访已达29.5个月。
结果发现：
依维莫司＋来曲唑一线治疗202例患者中位无进展生存22.0个月（95%置信区间：18.1～25.1个月），由于死亡病例尚未达到一半，故尚未获得中位总生存时间；24个月的总生存率约为78.7%（95%置信区间：72.1%～83.9%）。
依维莫司＋依西美坦二线治疗50例患者中位无进展生存3.7个月（95%置信区间：1.9～7.4个月）
不良事件类型与既往研究相同滴血深宅 ，未见新的安全问题。
最常见的所有级别不良事件：
一线治疗：口腔炎139例（68.8%）
二线治疗：口腔炎10例（20.0%）、体重减轻10例（20.0%）
最常见的3～4级不良事件：
一线治疗：贫血21例（10.4%）
二线治疗：高血压5例（10.0%）
研究期间死亡50例（24.8%），其中死于乳腺癌40例。汪则翰
因此，该2期研究结果为依维莫司＋来曲唑一线治疗雌激素受体阳性且HER2阴性晚期乳腺癌绝经后女性提供了初步依据，为进一步开展3期研究奠定了基础。
补充阅读
真实世界回顾研究：依维莫司对中国转移性乳腺癌患者的有效性和安全性
依维莫司＋曲妥珠单抗＋紫杉醇用于亚洲晚期乳腺癌患者的亚组分析
柳叶刀肿瘤学：地塞米松漱口水可以预防乳腺癌女性的依维莫司相关口腔炎
HER2过表达转移性乳腺癌分子学变化与依维莫司疗效：BOLERO-1和BOLERO-3联合探索性生物标志物分析
柳叶刀肿瘤学：依维莫司＋曲妥珠单抗＋紫杉醇一线治疗HER2阳性晚期乳腺癌患者
JAMA Oncol. 2018 Mar 22. [Epub ahead of print]
Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial.
Melanie Royce; Thomas Bachelot; Cristian Villanueva; Mustafa Ozgüroglu; Sergio J. Azevedo; Felipe Melo Cruz; Marc Debled; Roberto Hegg; Tatsuya Toyama; Carla Falkson; Joon Jeong; Vichien Srimuninnimit; William J. Gradishar; Christina Arce; Antonia Ridolfi; Chinjune Lin; Fatima Cardoso.
University of New Mexico Comprehensive Cancer Center, Albuquerque; Centre Léon Bérard, Lyon, France; Centre Hospitalier Régional Universitaire de Besancon, Besancon, France; Istanbul University, Istanbul, Turkey; Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Instituto Brasileiro de Controle do Cancer, Sao Paulo, Brazil; Institut Bergonié, Bordeaux, France; Universidade de Sao Paulo, Sao Paulo, Brazil; Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; University of Alabama Comprehensive Cancer Center, Birmingham; Yonsei University Health System, Seoul, Republic of Korea; Siriraj Hospital, Mahidol University, Bangkok, Thailand; Feinberg School of Medicine刘钟永 , Northwestern University, Chicago, Illinois; Novartis Oncology, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; Novartis Pharma S.A.S., Rueil-Malmaison, France; Champalimaud Clinical Centre, Champalimaud Foundation, Lisbon, Portugal.
This clinical trial evaluates the use of everolimus combined with endocrine therapy in women with estrogen receptor-positive王富曲 , human epidermal growth receptor 2-negative advanced breast cancer.
QUESTION: Does first-line everolimus plus endocrine therapy provide a clinical benefit for patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer?
FINDINGS: In this phase 2, single-arm study, 202 patients treated with everolimus plus letrozole in the first-line setting achieved a median progression-free survival of 22.0 months; median overall survival was not reached. For 50 patients whose cancer progressed and who received continued treatment with everolimus plus exemestane, median progression-free survival was 3.7 months.
MEANING: These results suggest a rationale for providing first-line everolimus plus letrozole therapy to patients with estrogen receptor-positive advanced breast cancer.
IMPORTANCE: Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer.
OBJECTIVE: To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: In the multicenter, open-label朱俞硕, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17官路青云 , 2016).
INTERVENTIONS: Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole李思澄 , 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression.
MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment.
RESULTS: A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range海豚人 , 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer).
CONCLUSIONS AND RELEVANCE: The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01698918
DOI: 10.1001/jamaoncol.2018.0060