In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population. This randomised, open-label, multicentre, phase 3 trial was conducted at 227 sites (hospitals, university hospitals, clinics, community centres, and private oncology centres) in North America, Europe, Asia, Australia, Brazil, Israel, and Türkiye. Eligible patients were aged 18 years or older, had unresectable or HER2-positive metastatic breast cancer, previously received trastuzumab emtansine, disease progression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate renal and hepatic function. Patients were randomly assigned (2:1) to receive trastuzumab deruxtecan (intravenously at 5·4 mg/kg once every 3 weeks) or treatment of physician's choice using block randomisation. Treatment of physician's choice was either capecitabine (1250 mg/m; orally twice per day on days 1–14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m) plus lapatinib (1250 mg orally once per day on days 1–21), with a 21-day schedule. The primary endpoint was progression-free survival based on blinded independent central review in the full analysis set. This study is registered with , . Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). 608 (100%) patients were included in the full analysis set. The median age was 54·2 years (IQR 45·5–63·4) in the trastuzumab deruxtecan group and 54·7 years (48·0–63·0) in the treatment of physician's choice group. 384 (63%) patients were White, 603 (99%) were female, and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2–28·4) in the trastuzumab deruxtecan group and 18·6 months (8·8–26·0) in the treatment of physician's choice group. Median progression-free survival by blinded independent central review was 17·8 months (95% CI 14·3–20·8) in the trastuzumab deruxtecan group versus 6·9 months (5·5–8·4) in the treatment of physician's choice group (HR 0·36 [0·28–0·45]; p<0·0001). The most common treatment-emergent adverse events were nausea (293 [73%] of 404 with trastuzumab deruxtecan 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] 25 [13%]), alopecia (150 [37%] eight [4%]), fatigue (147 [36%] 52 [27%]), diarrhoea (109 [27%] 105 [54%]), and palmar–plantar erythrodysaesthesia (seven [2%] 100 [51%]). Grade 3 or higher treatment-emergent adverse events occurred in 213 (53%) patients receiving trastuzumab deruxtecan versus 86 (44%) receiving treatment of physician's choice; whereas drug-related interstitial lung disease occurred in 42 (10%; including two grade 5 death events) versus one (<1%). DESTINY-Breast02 shows the favourable benefit–risk profile of trastuzumab deruxtecan in patients with HER2 positive metastatic breast cancer, as previously reported in DESTINY-Breast01, and is the first randomised study to show that one antibody-drug conjugate can overcome resistance to a previous one. Daiichi Sankyo and AstraZeneca.

中文翻译：

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曲妥珠单抗 deruxtecan 与医生选择的治疗 HER2 阳性转移性乳腺癌患者的比较 (DESTINY-Breast02)：一项随机、开放标签、多中心、3 期试验


在单组 2 期 DESTINY-Breast01 试验中，曲妥珠单抗 deruxtecan 在对曲妥珠单抗 emtansine 难治或耐药的 HER2 阳性转移性乳腺癌患者中显示出强大的活性；缺乏有效治疗的人群。在 DESTINY-Breast02 中，我们旨在比较曲妥珠单抗 deruxtecan 与医生选择的治疗对该患者群体的疗效和安全性。这项随机、开放标签、多中心、3 期试验在北美、欧洲、亚洲、澳大利亚、巴西、以色列和土耳其的 227 个地点（医院、大学医院、诊所、社区中心和私人肿瘤中心）进行。符合条件的患者年龄为 18 岁或以上，患有不可切除或 HER2 阳性转移性乳腺癌，既往接受过曲妥珠单抗 emtansine，疾病进展，东部肿瘤合作组表现状态为 0 或 1，并且肾功能和肝功能良好。患者被随机分配 (2:1) 接受曲妥珠单抗 deruxtecan（每 3 周静脉注射 5·4 mg/kg 一次）或采用分组随机化的医生选择治疗。医生选择的治疗方案是卡培他滨（1250 mg/m2；第 1-14 天每天口服两次）加曲妥珠单抗（第 1 天静脉注射 8 mg/kg，然后每天一次 6 mg/kg）或卡培他滨（1000 mg/m2） ）加拉帕替尼（1250 mg，第 1-21 天，每天口服一次），疗程为 21 天。主要终点是基于完整分析集中盲法独立中央审查的无进展生存期。这项研究已在 注册。 2018年9月6日至2020年12月31日期间，608名患者被随机分配接受曲妥珠单抗deruxtecan（n = 406；两名未接受治疗）或医生选择的治疗（n = 202；七名未接受治疗）。 完整分析集中包含 608 名 (100%) 患者。曲妥珠单抗 deruxtecan 组的中位年龄为 54·2 岁 (IQR 45·5–63·4)，而医生选择治疗组的中位年龄为 54·7 岁 (48·0–63·0)。 384 名患者 (63%) 为白人，603 名患者 (99%) 为女性，5 名患者 (<1%) 为男性。曲妥珠单抗deruxtecan组的中位随访时间为21·5个月（IQR 15·2–28·4），医生选择治疗组的中位随访时间为18·6个月（8·8–26·0）。根据盲法独立中央审查，曲妥珠单抗 deruxtecan 组的中位无进展生存期为 17·8 个月（95% CI 14·3–​​20·8），而曲妥珠单抗 deruxtecan 组的中位无进展生存期为 6·9 个月（5·5–8·4）。医生选择组（HR 0·36 [0·28–0·45]；p<0·0001）。最常见的治疗中出现的不良事件是恶心（使用曲妥珠单抗德鲁替康治疗的 404 例患者中有 293 例 [73%]，接受医生选择的治疗的 195 例患者中有 73 例 [37%]）、呕吐（152 例 [38%] 25 例 [13%]）、脱发(150 [37%] 八 [4%])、疲劳 (147 [36%] 52 [27%])、腹泻 (109 [27%] 105 [54%]) 和掌跖红肿感觉障碍 (7 [2 %] 100 [51%]）。接受曲妥珠单抗 deruxtecan 治疗的患者中有 213 名 (53%) 发生了 3 级或以上治疗引起的不良事件，而接受医生选择治疗的患者中有 86 名 (44%) 发生了这种情况；而与药物相关的间质性肺疾病发生率分别为 42 例（10%；包括两例 5 级死亡事件）和 1 例（<1%）。 DESTINY-Breast02 显示了曲妥珠单抗 deruxtecan 在 HER2 阳性转移性乳腺癌患者中的有利获益-风险概况，如 DESTINY-Breast01 中先前报道的那样，并且是第一项随机研究，表明一种抗体-药物缀合物可以克服先前的耐药性一。第一三共和阿斯利康。