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Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial.
The Lancet Oncology ( IF 51.1 ) Pub Date : 2019-12-02 , DOI: 10.1016/s1470-2045(19)30687-4
Robert Coleman 1 , Dianne M Finkelstein 2 , Carlos Barrios 3 , Miguel Martin 4 , Hiroji Iwata 5 , Roberto Hegg 6 , John Glaspy 7 , Alvaro Montaño Periañez 8 , Katia Tonkin 9 , Ines Deleu 10 , Joohyuk Sohn 11 , John Crown 12 , Suzette Delaloge 13 , Tian Dai 14 , Ying Zhou 14 , Danielle Jandial 14 , Arlene Chan 15
Affiliation  

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 (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness. INTERPRETATION Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer. FUNDING Amgen.

中文翻译:

早期乳腺癌的辅助地诺单抗(D-CARE):一项国际,多中心,随机,对照的3期临床试验。

背景技术如临床前证据所示,地诺单抗是一种完全人单克隆抗体,可结合并抑制RANKL的受体激活剂(TNFSF11),并可能影响乳腺癌生物学。我们旨在评估地诺单抗联合护理标准的辅助治疗或新辅助的全身治疗以及局部治疗是否可以增加乳腺癌女性的无骨转移生存率。方法在这项国际性,双盲,随机,安慰剂对照的3期研究(D-CARE)中,从39个国家/地区的389个中心招募了患者。我们招募了经组织学证实为II或III期乳腺癌,且东部合作肿瘤小组的工作状态为0或1的妇女(年龄≥18岁)。每个站点的研究人员都致电交互式语音应答系统,根据固定的分层排列的区块随机分组表(区块大小4)在中央随机分配患者(1:1),以每3-4次皮下注射地诺单抗(120 mg)或匹配的安慰剂从新辅助或辅助化学治疗开始,大约需要6个月,然后每12周一次,总共需要5年。分层因素包括乳腺癌治疗,淋巴结状态,激素受体和HER2状态,年龄和地理区域。主要终点是无骨转移生存的复合终点。该试验已在ClinicalTrials.gov(NCT01077154)上进行了注册。调查结果在2010年6月2日至2012年8月24日之间,4509名妇女被随机分配接受denosumab(n = 2256)或安慰剂(n = 2253),并纳入意向性治疗分析。当所有患者都有机会完成5年随访且分析数据截止日期为2017年8月31日时,便进行了研究的初步分析。两组之间无骨转移生存的主要终点没有显着差异(两组均未达到中位数;危险比0·97,95%CI 0·82-1·14; p = 0·70)。至少接受一剂研究产品的患者(2241例地诺单抗患者与2218例安慰剂患者)报告的最常见的3级或更严重的治疗紧急不良事件是中性粒细胞减少症(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%])。接受地诺单抗治疗的2241名患者中有122名(5%)发生了颌骨正定性坏死,而接受安慰剂治疗的2218名患者中有4名(<1%)发生了颌骨坏死。紧急治疗引起的低血钙症发生率分别为152(7%)和82(4%)。安慰剂组有2例与治疗相关的死亡,原因是急性髓细胞性白血病和意识水平下降。解释尽管临床前证据表明RANKL抑制可能会延迟早期乳腺癌患者的骨转移或疾病复发,但在这项研究中,denosumab并未改善高危早期乳腺癌妇女的疾病相关预后。资助安进。安慰剂组中有2例与治疗相关的死亡,原因是急性髓细胞性白血病和意识水平下降。解释尽管临床前证据表明RANKL抑制可能会延迟早期乳腺癌患者的骨转移或疾病复发,但在这项研究中,denosumab并未改善高危早期乳腺癌妇女的疾病相关预后。资助安进。安慰剂组中有2例与治疗相关的死亡,原因是急性髓细胞性白血病和意识水平下降。解释尽管临床前证据表明RANKL抑制可能会延迟早期乳腺癌患者的骨转移或疾病复发,但在这项研究中,denosumab并未改善高危早期乳腺癌妇女的疾病相关预后。资助安进。
更新日期:2020-01-04
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