晚期乳腺癌：依维莫司＋依西美坦

依维莫司＋依西美坦对晚期乳腺癌

绝经后德国女性的有效性和安全性

　　对于激素受体（HR）阳性、人类表皮生长因子受体2（HER2）阴性的晚期乳腺癌，目前的治疗指南支持一线治疗进展后继续进行内分泌治疗，包括依维莫司＋依西美坦的联合疗法。根据BOLERO-2研究结果，非甾体芳香酶抑制剂进展后，依维莫司＋依西美坦与依西美坦单药相比，HR阳性、HER2阴性晚期乳腺癌绝经后女性的中位无进展生存时间延长一倍（7.8比3.2个月）、复发或死亡风险减少55%（风险比：0.45，95%置信区间：0.38～0.54，P<0.0001），中位随访18个月的总缓解率为12.6%比1.7%（95%置信区间：9.8～15.9%、0.5～4.2%）。

　　2018年10月30日，国际抗癌联盟《国际癌症杂志》清样发表德国法兰克福血液学与肿瘤学中心、慕尼黑门诊患者癌症治疗中心、拉文斯堡肿瘤医院、波恩妇科中心、海德堡大学医院、国家肿瘤疾病中心、基尔大学医院、黑森东部医疗中心、埃尔朗根纽伦堡大学、柏林大学医学院、法兰克福西北医院、乌尔姆大学医院、纽伦堡诺华、蒂宾根大学医院的IIIB期4EVER研究报告，评估了依维莫司＋依西美坦对HR阳性、HER2阴性晚期乳腺癌绝经后女性的有效性、安全性和生活质量。由于该研究对非甾体芳香酶抑制剂、既往晚期病变化疗或既往依西美坦治疗后的进展时间无限制，与既往主要研究相比，评估的患者人群范围更大，故更能反映真实世界的临床实践。

　　该非盲单组IIIB期4EVER研究于2012年6月～2013年11月从82个德国中心入组HR阳性HER2阴性晚期乳腺癌非甾体芳香酶抑制剂治疗期间或之后发生进展的绝经后女性患者299例，评估了依维莫司＋依西美坦对其中281例患者的临床有效性和299例患者的安全性。主要终点为治疗前24周内的总缓解率（完全缓解＋部分缓解的患者百分比）。次要终点包括无进展生存、总生存、安全性和健康相关生活质量。

　　结果，总缓解率为8.9%（95%置信区间：5.8～12.9%），中位无进展生存时间为5.6个月（95%置信区间：5.4～6.0个月），均低于BOLERO-2研究，可能由于晚期患者较多、既往治疗较多。最常见的3/4级不良事件为口腔炎、一般身体健康恶化、呼吸困难、贫血，发生率分别为8.4%、6.7%、4.7%、4.3%。

　　因此，该研究结果表明，这些数据证实了依维莫司＋依西美坦对HR阳性、HER2阴性晚期乳腺癌绝经后女性的临床获益和已知安全性。

Int J Cancer. 2018 Oct 30. [Epub ahead of print]

Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial.

Tesch H, Stoetzer O, Decker T, Kurbacher CM, Marmé F, Schneeweiss A, Mundhenke C, Distelrath A, Fasching PA, Lux MP, Lüftner D, Peyman H, Janni W, Muth M, Kreuzeder J, Quiering C, Taran FA.

Center for Hematology and Oncology Bethanien, Frankfurt am Main, Germany; Outpatient Cancer Care Center, Munich, Germany; Oncology Ravensburg, Ravensburg, Germany; Gynaecological Centre Bonn-Friedensplatz, Bonn, Germany; University Hospital Heidelberg, Heidelberg, Germany; National Center for Tumor Diseases, Heidelberg, Germany; University Hospital Kiel, Kiel, Germany; Medical Healthcare Centre East Hessen GmbH, Fulda, Germany; Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Charité Campus Benjamin Franklin, Berlin, Germany; Hospital North West, Frankfurt, Germany; University Hospital Ulm, Ulm, Germany; Novartis Pharma GmbH, Nuremberg, Germany; University Hospital Tübingen, Tübingen, Germany.

What's new? Current treatment guidelines for HR+, HER2- advanced breast cancer support continued endocrine therapy after progression on first-line treatment, including the use of everolimus and exemestane combined. Here, the authors report on the phase IIIB 4EVER trial, which evaluated the efficacy, safety and quality of life effects of everolimus plus exemestane in postmenopausal women with pretreated, HR+, HER2- advanced breast cancer. The patient population was broader than that evaluated in previous major trials, and thus more reflective of real-world practice. Overall, the results confirm the clinical benefits and known safety profile of everolimus plus exemestane in this patient population.

In BOLERO-2, adding everolimus to exemestane resulted in a twofold increase in median progression-free survival (PFS) vs exemestane in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (aBC) after progression on a non-steroidal aromatase inhibitor (NSAI). Here, we report on the open-label, single-arm, phase IIIB 4EVER trial (NCT01626222). This trial evaluated the clinical effectiveness of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC who had progressed on or after an NSAI, but with no restrictions on the time of progression after NSAI, prior chemotherapy for advanced disease or previous exemestane. The primary endpoint was overall response rate (ORR; i.e. the percentage of patients with a best overall response of complete or partial response per RECIST 1.1) within the first 24 weeks of treatment. Secondary endpoints included PFS, overall survival, safety and health-related quality of life. Between June 2012 and November 2013, 299 patients were enrolled at 82 German centers: 281 patients were evaluable for efficacy and 299 for safety. The ORR was 8.9% (95% confidence interval [CI]: 5.8-12.9%). Median PFS was 5.6 months (95% CI: 5.4-6.0 months). The most frequent grade 3/4 adverse events were stomatitis (8.4%), general physical health deterioration (6.7%), dyspnea (4.7%) and anemia (4.3%). The ORR in 4EVER was lower than in BOLERO-2, likely due to inclusion of patients with more advanced disease and extensive pretreatment. These data confirm the clinical benefits and known safety profile of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC.

KEYWORDS: HER2-negative; advanced breast cancer; estrogen receptor-positive; everolimus; exemestane

PMID: 29992557

DOI: 10.1002/ijc.31738

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