Institut Gustave Roussy, Université Paris Saclay, Villejuif, France.
Samsung Medical Center, Seoul, South Korea.
Lancet. 2023 May 27;401(10390):1773-1785. doi: 10.1016/S0140-6736(23)00725-0. Epub 2023 Apr 20.
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 ClinicalTrials.gov, NCT03523585.
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 vs 73 [37%] of 195 with treatment of physician's choice), vomiting (152 [38%] vs 25 [13%]), alopecia (150 [37%] vs eight [4%]), fatigue (147 [36%] vs 52 [27%]), diarrhoea (109 [27%] vs 105 [54%]), and palmar-plantar erythrodysaesthesia (seven [2%] vs 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.
在单臂、2 期 DESTINY-Breast01 试验中，曲妥珠单抗-德鲁替康在曲妥珠单抗恩美曲妥珠单抗耐药或难治的 HER2 阳性转移性乳腺癌患者中显示出强大的活性；这是一个有效治疗方法稀缺的人群。在 DESTINY-Breast02 中，我们旨在比较曲妥珠单抗-德鲁替康与该患者人群中医生选择的治疗方法的疗效和安全性。
这是一项在北美、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）进行的随机、开放标签、多中心、3 期试验。符合条件的患者年龄在 18 岁或以上，患有不可切除或 HER2 阳性转移性乳腺癌，先前接受过曲妥珠单抗恩美曲妥珠单抗治疗，疾病进展，东部合作肿瘤学组体力状态 0 或 1，以及足够的肾功能和肝功能。患者按 2:1 的比例随机分配（2:1）接受曲妥珠单抗-德鲁替康（静脉滴注，5.4mg/kg，每 3 周一次）或医生选择的治疗。医生选择的治疗方法为卡培他滨（1250mg/m2；每天口服两次，第 1-14 天）联合曲妥珠单抗（第 1 天静脉注射 8mg/kg，然后每天 6mg/kg）或卡培他滨（1000mg/m2）联合拉帕替尼（每天口服 1250mg），每 21 天一个疗程。主要终点是盲法独立中心评估的无进展生存期，该分析集在全分析集。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT03523585。
2018 年 9 月 6 日至 2020 年 12 月 31 日期间，608 例患者被随机分配接受曲妥珠单抗-德鲁替康（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）。608（100%）例患者被纳入全分析集。曲妥珠单抗-德鲁替康组的中位年龄为 54.2 岁（四分位距 45.5-63.4），医生选择治疗组的中位年龄为 54.7 岁（48.0-63.0）。384（63%）例患者为白人，603（99%）例为女性，5 例（<1%）为男性。曲妥珠单抗-德鲁替康组的中位随访时间为 21.5 个月（四分位距 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）。盲法独立中心评估的中位无进展生存期为 17.8 个月（95%CI 14.3-20.8），而医生选择治疗组为 6.9 个月（5.5-8.4）（HR 0.36[0.28-0.45]；p<0.0001）。最常见的治疗相关不良事件是恶心（曲妥珠单抗-德鲁替康组 293[73%]例与医生选择治疗组 73[37%]例）、呕吐（152[38%]例与 25[13%]例）、脱发（150[37%]例与 8[4%]例）、疲劳（147[36%]例与 52[27%]例）、腹泻（109[27%]例与 105[54%]例）和掌跖感觉丧失性红斑（七[2%]例与 100[51%]例）。接受曲妥珠单抗-德鲁替康治疗的患者中有 213 例（53%）发生 3 级或更高级别的治疗相关不良事件，而接受医生选择治疗的患者中有 86 例（44%）（HR 0.36[0.28-0.45]；p<0.0001）。而药物相关间质性肺病发生在 42 例（10%；包括 2 例 5 级死亡事件），而 1 例（<1%）。
DESTINY-Breast02 显示了曲妥珠单抗-德鲁替康在 HER2 阳性转移性乳腺癌患者中的有利风险状况，与之前的 DESTINY-Breast01 报告一致，并且是第一个显示一种抗体药物偶联物可以克服对先前药物的耐药性的随机研究。
第一三共株式会社和阿斯利康公司。
