Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial
Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial
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Denosumab辅助治疗早期乳腺癌(D-CARE)：一项国际性、多中心、随机、对照的3期试验
DOI：
10.1016/s1470-2045(19)30687-4
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发表时间：
2020-01-01
期刊：
影响因子：
51.1
通讯作者：
Chan, Arlene
中科院分区：
文献类型：
--
作者：
Coleman, Robert;Finkelstein, Dianne M.;Chan, Arlene
Denosumab是一种全人源单克隆抗体，可结合并抑制RANKL受体激活剂（TNFSF 11），可能影响乳腺癌生物学，如临床前证据所示。我们的目的是评估地舒单抗与标准辅助治疗或新辅助全身治疗和局部治疗相结合是否会提高乳腺癌女性的无骨转移生存率。方法在这项国际、双盲、随机、安慰剂对照、3期研究（D-CARE）中，从39个国家的389个中心招募了患者。我们招募了组织学证实为II期或III期乳腺癌且东部肿瘤协作组体力状态为0或1的女性（年龄≥ 18岁）。在资格确认时，每个研究中心的研究者通过电话联系交互式语音应答系统，根据固定分层排列区组随机化列表（区组大小4）集中随机分配患者（1：1），接受地舒单抗（120 mg）或匹配安慰剂皮下注射，每3-4周一次，从新辅助或辅助化疗开始，持续约6个月，然后每12周一次，共持续5年。分层因素包括乳腺癌治疗、淋巴结状态、激素受体和HER 2状态、年龄和地理区域。主要终点是无骨转移生存期的复合终点。该试验注册于ClinicalTrials.gov，NCT 01077154。结果在2010年6月2日至2012年8月24日期间，4509名女性被随机分配接受地舒单抗（n=2256）或安慰剂（n=2253），并纳入意向治疗分析。当所有患者都有机会完成5年随访时，进行了研究的主要分析，分析数据截止日期为2017年8月31日。两组间无骨转移生存期的主要终点无显著差异（两组均未达到中位数;风险比0.97，95% CI 0.82-1.14; p=0.70）。在至少接受一剂试验用药品的患者中报告的最常见的3级或更严重的治疗后出现的不良事件（地舒单抗组2241例患者vs安慰剂组2218例患者），中性粒细胞减少（340 [15%] vs 328 [15%]）、发热性中性粒细胞减少症（112 [5%] vs 142 [6%]）和白细胞减少症（62 [3%] vs 61 [3%]）。在2241例接受地舒单抗治疗的患者中，122例（5%）发生了明确判定的颌骨骨坏死，
Background Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer.Method In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged >= 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154.Findings Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0.97, 95% CI 0.82-1.14; p=0.70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (