晚期乳腺癌的依維莫司一線治療

最新 03-27

編者按：依維莫司（諾華）為哺乳動物雷帕黴素靶蛋白（mTOR）口服抑製劑，與雌激素抑製劑聯合，可能預防或延緩晚期乳腺癌患者對一線內分泌治療的耐葯。根據3期研究（BOLERO-2）結果，與雌激素芳香酶滅活劑依西美坦（輝瑞）相比，依維莫司＋依西美坦，對於雌激素芳香酶抑製劑來曲唑（諾華）或阿那曲唑（阿斯利康）一線治療失敗的晚期激素受體陽性且HER2陰性乳腺癌絕經後女性，中位無進展生存延長4.6個月、進展風險減少55%。根據亞組分析結果，對於早期乳腺癌術後輔助治療失敗的晚期患者，依維莫司＋依西美坦一線治療的中位無進展生存延長7.4個月、進展風險減少61%；根據集中複核，中位無進展生存延長11.0個月、複發風險減少68%。那麼，對於此類患者，依維莫司＋來曲唑一線治療能否提供臨床獲益？

2018年3月22日，《美國醫學會雜誌》腫瘤學分冊在線發表美國諾華、新墨西哥大學、阿拉巴馬大學伯明翰分校、芝加哥西北大學、法國諾華、里昂貝拉爾中心、貝桑松大學、波爾多癌症研究中心、土耳其伊斯坦布爾大學、巴西癌症控制研究所、聖保羅大學、阿雷格里港醫院、日本名古屋市立大學、韓國延世大學、泰國瑪希敦大學詩里拉吉醫院、葡萄牙尚帕利莫基金會臨床中心的研究報告，對依維莫司＋來曲唑一線治療雌激素受體陽性且HER2陰性晚期乳腺癌絕經後女性進行了嘗試。

該多中心非盲單組2期臨床研究（BOLERO-4）於2013年3月7日～2014年12月17日從245例患者篩選出符合條件女性202例，中位年齡64.0歲（四分位距58.0～70.0歲），其中轉移性乳腺癌194例（96.0%）、局部晚期乳腺癌8例（4.0%）。接受每天依維莫司10mg＋來曲唑2.5mg一線治療，初始疾病進展時由研究者酌情改予每天依維莫司10mg＋依西美坦25mg二線治療。主要終點為研究者根據實體腫瘤療效評價標準（RECIST）1.0版評定一線治療的無進展生存，並對實際接受治療患者評定藥物安全性。截至2016年12月17日，中位隨訪已達29.5個月。

結果發現：

依維莫司＋來曲唑一線治療202例患者中位無進展生存22.0個月（95%置信區間：18.1～25.1個月），由於死亡病例尚未達到一半，故尚未獲得中位總生存時間；24個月的總生存率約為78.7%（95%置信區間：72.1%～83.9%）。

依維莫司＋依西美坦二線治療50例患者中位無進展生存3.7個月（95%置信區間：1.9～7.4個月）

不良事件類型與既往研究相同，未見新的安全問題。

最常見的所有級別不良事件：

一線治療：口腔炎139例（68.8%）

二線治療：口腔炎10例（20.0%）、體重減輕10例（20.0%）

最常見的3～4級不良事件：

一線治療：貧血21例（10.4%）

二線治療：高血壓5例（10.0%）

研究期間死亡50例（24.8%），其中死於乳腺癌40例。

因此，該2期研究結果為依維莫司＋來曲唑一線治療雌激素受體陽性且HER2陰性晚期乳腺癌絕經後女性提供了初步依據，為進一步開展3期研究奠定了基礎。

補充閱讀

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, 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, 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, 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, 2016).

INTERVENTIONS: Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 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, 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.

DOI: 10.1001/jamaoncol.2018.0060