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编者按：依维莫司为哺乳动物雷帕霉素靶蛋白抑制剂，可以靶向治疗抗雌激素疗法耐药的雌激素受体阳性乳腺癌。对于雌激素非甾体芳香酶抑制剂治疗失败后的绝经后激素受体阳性晚期乳腺癌，根据BOLERO-2研究结果，依维莫司＋依西美坦（不可逆型甾体类芳香酶灭活剂）与单用依西美坦相比，可以显著改善无进展生存，故被批准用于晚期乳腺癌的二线治疗；根据RIBBON-1研究结果，单用卡培他滨也可显著改善无进展生存。那么，依维莫司＋依西美坦与单用依维莫司或卡培他滨相比，效果如何？ 2018年6月3日，《美国医学会杂志》肿瘤学分册在线发表比利时列日大学医院、澳大利亚皇家墨尔本医院、瑞士诺华、法国诺华、美国诺华、洛杉矶加利福尼亚大学琼森综合癌症中心、莎拉·坎农研究所、田纳西肿瘤医院、雷尼尔肿瘤医院、俄罗斯癌症研究中心、丹麦哥本哈根大学医院、南丹麦大学、土耳其伊斯坦布尔大学医学院、匈牙利乌若基教学医院的II期随机对照临床研究（BOLERO-6）报告，对依维莫司＋依西美坦与单用依维莫司或卡培他滨二线治疗雌激素受体阳性、HER2阴性晚期乳腺癌进行了比较。
该非盲随机对照II期临床研究（BOLERO-6）于2013年3月4日～2014年11月24日从18个国家83个医疗中心入组非甾体芳香酶抑制剂治疗失败后的绝经后激素受体阳性晚期乳腺癌女性309例（年龄范围32～88岁，中位61岁），随机分配接受3种治疗方案：104例依维莫司每天10mg＋依西美坦每天25mg、103例单用依维莫司每天10mg、102例单用卡培他滨每天2次1250mg/m2。主要结局衡量指标为依维莫司＋依西美坦与单用依维莫司（主要目标）或单用卡培他滨（关键次要目标）相比的无进展生存风险比，安全性为次要目标。该研究方案未计划正式统计学比较。 结果，从随机分组至分析截止日期（2017年6月1日）中位随访37.6个月，依维莫司＋依西美坦的疾病进展或死亡风险：
由于各治疗组患者入组时的特征不均衡，故通过分层多因素比例风险回归模型对风险比可能存在的信息偏倚进行校正：
单用卡培他滨的3～4级不良事件发生率较高：
依维莫司＋依西美坦的严重不良事件发生率较高：
因此，根据该研究结果表明，依维莫司＋依西美坦与单用依维莫司相比，可以提供无进展生存获益，并且支持继续用于对此类患者。单用卡培他滨与依维莫司＋依西美坦相比，由于各治疗组患者入组时的特征不均衡，可能存在的信息偏倚，故对于两者无进展生存差异应该谨慎解读。 相关阅读 JAMA Oncol. 2018 Jun 3. [Epub ahead of print] Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial. Guy Jerusalem, Richard H. de Boer, Sara Hurvitz, Denise A. Yardley, Elena Kovalenko, Bent Ejlertsen, Sibel Blau, Mustafa Ozgüroglu, László Landherr, Marianne Ewertz, Tetiana Taran, Jenna Fan, Florence Noel-Baron, Anne-Laure Louveau, Howard Burris. CHU Sart Tilman Liege and Liege University, Liege, Belgium; Royal Melbourne Hospital, Victoria, Australia; Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Sarah Cannon Research Institute, Nashville, Tennessee; Tennessee Oncology, PLLC, Nashville, Tennessee; Russian Cancer Research Center, Moscow, Russia; Copenhagen University Hospital, Copenhagen, Denmark; Rainier Hematology-Oncology, Northwest Medical Specialties, Tacoma, Washington; Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey; Uzsoki Teaching Hospital, Budapest, Hungary; University of Southern Denmark, Odense, Denmark; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey; Novartis Pharma AG, Basel, Switzerland; Novartis Pharma SAS, Paris, France. IMPORTANCE: Everolimus plus exemestane and capecitabine are approved second-line therapies for advanced breast cancer. OBJECTIVE: A postapproval commitment to health authorities to estimate the clinical benefit of everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. DESIGN: Open-label, randomized, phase 2 trial of treatment effects in postmenopausal women with advanced breast cancer that had progressed during treatment with nonsteroidal aromatase inhibitors. INTERVENTIONS: Patients were randomized to 3 treatment regimens: (1) everolimus (10 mg/d) plus exemestane (25 mg/d); (2) everolimus alone (10 mg/d); and (3) capecitabine alone (1250 mg/m2 twice daily). MAIN OUTCOMES AND MEASURES: Estimated hazard ratios (HRs) of progression-free survival (PFS) for everolimus plus exemestane vs everolimus alone (primary objective) or capecitabine alone (key secondary objective). Safety was a secondary objective. No formal statistical comparisons were planned. RESULTS: A total of 309 postmenopausal women were enrolled, median age, 61 years (range, 32-88 years). Of these, 104 received everolimus plus exemestane; 103, everolimus alone; and 102, capecitabine alone. Median follow-up from randomization to the analysis cutoff (June 1, 2017) was 37.6 months. Estimated HR of PFS was 0.74 (90% CI, 0.57-0.97) for the primary objective of everolimus plus exemestane vs everolimus alone and 1.26 (90% CI, 0.96-1.66) for everolimus plus exemestane vs capecitabine alone. Between treatment arms, potential informative censoring was noted, and a stratified multivariate Cox regression model was used to account for imbalances in baseline characteristics; a consistent HR was observed for everolimus plus exemestane vs everolimus (0.73; 90% CI, 0.56-0.97), but the HR was closer to 1 for everolimus plus exemestane vs capecitabine (1.15; 90% CI, 0.86-1.52). Grade 3 to 4 adverse events were more frequent with capecitabine (74%; n=75) vs everolimus plus exemestane (70%; n=73) or everolimus alone (59%; n=61). Serious adverse events were more frequent with everolimus plus exemestane (36%; n=37) vs everolimus alone (29%; n=30) or capecitabine (29%; n=30). CONCLUSIONS AND RELEVANCE: These findings suggest that everolimus plus exemestane combination therapy offers a PFS benefit vs everolimus alone, and they support continued use of this therapy in this setting. A numerical PFS difference with capecitabine vs everolimus plus exemestane should be interpreted cautiously owing to imbalances among baseline characteristics and potential informative censoring. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01783444 DOI: 10.1001/jamaoncol.2018.2262 |
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