An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0–1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with , . Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1–32·9) with trastuzumab deruxtecan and 26·5 months (14·5–31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4–37·9) with trastuzumab deruxtecan and 6·8 months (5·6–8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26–0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months–not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months–not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64 [95% CI 0·47–0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group. Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. Daiichi Sankyo and AstraZeneca.

中文翻译：

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曲妥珠单抗 deruxtecan 与曲妥珠单抗 emtansine 治疗 HER2 阳性转移性乳腺癌患者：DESTINY-Breast03（一项随机、开放标签、3 期试验）的最新结果

DESTINY-Breast03 试验的无进展生存期中期分析显示，与曲妥珠单抗 emtansine 相比，曲妥珠单抗 deruxtecan 可以改善 HER2 阳性转移性乳腺癌患者的无进展生存期。DESTINY-Breast03 的目的是比较曲妥珠单抗 deruxtecan 与曲妥珠单抗 emtansine 的疗效和安全性。这项开放标签、随机、多中心 3 期试验在北美、亚洲、欧洲、澳大利亚和南美的 169 个研究中心进行。符合条件的患者年龄为 18 岁或以上，患有 HER2 阳性的不可切除或转移性乳腺癌，之前接受过曲妥珠单抗和紫杉烷治疗，东部肿瘤合作组表现状态为 0-1，并且每个实体瘤疗效评估标准至少有一个可测量的病变1.1 版。患者被随机分配（1:1）接受曲妥珠单抗 deruxtecan 5·4 mg/kg 或曲妥珠单抗 emtansine 3·6 mg/kg，均每 3 周静脉输注一次。随机分组根据激素受体状态、既往帕妥珠单抗治疗情况和内脏疾病史进行分层，并通过基于网络的交互式系统进行管理。在每个层中，使用平衡区组随机化，区组大小为四。患者和研究人员并未对所接受的治疗感到隐瞒。主要终点是通过盲法独立中央审查得出的无进展生存期。关键的次要终点是总生存期，这个预先指定的第二次总生存期中期分析报告了更新的总生存期、疗效和安全性结果。使用完整的分析集进行功效分析。安全性分析包括所有随机分配的至少接受一剂研究治疗的患者。这项研究已在 注册。2018年7月20日至2020年6月23日期间，对699名患者进行了资格筛查，其中524名患者入组并随机分配接受曲妥珠单抗deruxtecan (n=261)或曲妥珠单抗emtansine (n=263)治疗。曲妥珠单抗 deruxtecan 的研究随访中位持续时间为 28·4 个月 (IQR 22·1–32·9)，曲妥珠单抗 emtansine 的中位随访时间为 26·5 个月 (14·5–31·3)。根据盲法独立中央审查，曲妥珠单抗德鲁替康的中位无进展生存期为 28·8 个月 (95% CI 22·4–37·9)，曲妥珠单抗 emtansine 的中位无进展生存期为 6·8 个月 (5·6–8·2)（风险比） [HR] 0·33 [95% CI 0·26–0·43]；标称 p<0·0001）。曲妥珠单抗 deruxtecan 组未达到中位总生存期（95% CI 40·5 个月 - 不可估计），其中 72 例 (28%) 总生存期事件为 97 例（34·0 个月 - 不可估计）曲妥珠单抗 emtansine 组中 (37%) 总生存事件（HR 0·64 [95% CI 0·47–0·87]；p=0·0037）。接受曲妥珠单抗 deruxtecan 治疗的患者与接受曲妥珠单抗 emtansine 治疗的患者中，3 级或更严重的治疗相关不良事件的数量相似（145 例 [56%] 患者 vs 135 例 [52%] 患者）。接受曲妥珠单抗 deruxtecan 治疗的 39 名患者 (15%) 和接受曲妥珠单抗 emtansine 治疗的 8 名患者 (3%) 发生经裁定的药物相关间质性肺疾病或肺炎，两组均未发生 4 级或 5 级事件。与曲妥珠单抗 emtansine 相比，曲妥珠单抗 deruxtecan 在 HER2 阳性转移性乳腺癌患者中显示出总生存期显着改善，并且报告的中位无进展生存期最长，这再次证实了曲妥珠单抗 deruxtecan 作为二线治疗的标准。曲妥珠单抗 deruxtecan 的安全性可控，且治疗持续时间较长。第一三共和阿斯利康。