6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial
6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial
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DOI：
10.1016/s0140-6736(19)30650-6
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发表时间：
2019-06-29
期刊：
影响因子：
168.9
通讯作者：
Dunn, Janet A.
中科院分区：
文献类型：
--
作者：
Earl, Helena M.;Hiller, Louise;Dunn, Janet A.
背景 辅助曲妥珠单抗可显着改善 HER2 阳性早期乳腺癌患者的预后。标准治疗持续时间为 12 个月，但更短的治疗时间可以提供类似的疗效，同时降低毒性和成本。我们的目的是调查在无病生存方面，6 个月曲妥珠单抗辅助治疗是否不劣于标准 12 个月治疗。 方法 本研究是一项开放标签、随机 3 期非劣效性试验。患者是从英国 152 个中心招募的。我们通过计算机最小化过程 (1:1) 将年龄 18 岁或以上且有明确化疗指征的 HER2 阳性早期乳腺癌患者随机分配，接受每 3 周静脉注射（负荷剂量 8 mg/kg，随后维持剂量 6 mg/kg）或皮下注射（600 mg）的 6 个月或 12 个月曲妥珠单抗联合给药 与化疗（同时或序贯）。主要终点是无病生存率，通过意向治疗进行分析，4 年无病生存率的非劣效界值为 3%。对所有接受曲妥珠单抗治疗的患者进行安全性分析。该试验已在 EudraCT（编号 2006-007018-39）、ISRCTN（编号 52968807）和 ClinicalTrials.gov（编号 NCT00712140）注册。结果 2007 年 10 月 4 日至 2015 年 7 月 31 日期间，2045 名患者被分配接受为期 12 个月的曲妥珠单抗治疗，2044 名患者被分配接受为期 12 个月的曲妥珠单抗治疗。 6个月的治疗（一名患者被排除，因为他们 双重随机）。两个治疗组的中位随访时间均为 5.4 年（IQR 3.6-6.7），在此期间，6 个月组 2043 名患者中有 265 名患者（13%）发生无病生存事件，12 个月组 2045 名患者中有 247 名患者（12%）发生无病生存事件。 6 个月组的 4 年无病生存率为 89.4% (95% CI 87.9-90.7)，12 个月组为 89.8% (88.3-91.1)（风险比 1.07 [90% CI 0.93-1.24]，非劣效性 p= 0.011），显示治疗6个月。 6个月的曲妥珠单抗治疗导致较少的患者报告严重不良事件（1939名患者中的373名[19%] vs 1894名患者中的459名[24%]，p = 0.0002）或因心脏毒性而提前停止（1939名患者中的61名[3%] vs 1894名患者中的146名[8%]，p<0.0001）。表明 6 个月 对于 HER2 阳性早期乳腺癌患者，曲妥珠单抗治疗不劣于 12 个月治疗，且心脏毒性较小，严重不良事件也较少。这些结果支持考虑缩短与试验中复发风险相似的女性的曲妥珠单抗疗程。版权所有 (C) 2019 作者。由爱思唯尔有限公司出版
Background Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival.Methods This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140).Findings Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5.4 years (IQR 3.6-6.7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89.4% (95% CI 87.9-90.7) in the 6-month group and 89.8% (88.3-91.1) in the 12-month group (hazard ratio 1.07 [90% CI 0.93-1.24], non-inferiority p= 0.011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p= 0.0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p< 0.0001).Interpretation We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.