从9年前开始，对于HER2阳性晚期乳腺癌，曲妥珠单抗＋紫杉类治疗失败后，恩美曲妥珠单抗被指南推荐为二线治疗首选药物。直至2021年，德喜曲妥珠单抗与恩美曲妥珠单抗的头对头随机对照研究DESTINY-Breast03改写了指南。2022年3月，全球四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》正式发表DESTINY-Breast03研究第一次中期分析报告全文，德喜曲妥珠单抗与恩美曲妥珠单抗相比，12个月进展或死亡风险减少72%、死亡风险减少45%，显著改变了HER2阳性晚期乳腺癌患者的命运。
DESTINY-Breast03 (NCT03529110): DS-8201a Versus T-DM1 for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane
2022年12月7日，全球四大医学期刊之一英国《柳叶刀》正刊和美国第45届圣安东尼奥乳腺癌大会同时发表美国、巴西、中国、韩国、法国、澳大利亚、英国、日本、比利时、加拿大、意大利、西班牙等国学者联合发表的DESTINY-Breast03研究第二次中期分析报告全文，对德喜曲妥珠单抗与恩美曲妥珠单抗二线治疗HER2阳性晚期乳腺癌的有效性和安全性进行了再次比较。
该国际多中心非盲随机对照三期临床试验于2018年7月20日～2020年6月23日从北美、亚洲、欧洲、澳大利亚和南美169个研究中心入组年龄≥18岁、HER2阳性乳腺癌不可切除或转移、经过曲妥珠单抗和紫杉类治疗、美国东部肿瘤协作组体力状态评分0～1、根据实体瘤疗效评价标准1.1版至少有1个可测量病灶患者524例，按1∶1随机分入两组，其中261例接受德曲妥珠单抗5.4mg/kg，其余263例接受恩美曲妥珠单抗3.6mg/kg，均为每3周通过静脉输注给药。根据激素受体状态、既往帕妥珠单抗治疗和内脏疾病史对随机分组进行分层，并通过网络交互系统进行处理。患者和研究者对接受治疗非盲。主要终点为盲法独立集中复核的无进展生存。关键次要终点为总生存。本文为预设第二次总生存中期分析报告，对总生存、疗效和安全性结果进行更新。对全部意向治疗患者进行有效性分析，对全部实际治疗患者进行安全性分析。
结果，对于524例意向治疗患者，德曲妥珠单抗与恩美曲妥珠单抗相比：
中位随访：28.4比26.5个月（四分位：22.1～32.9、14.5～31.3）
中位无进展生存：28.8比6.8个月（95%置信区间：22.4～37.9、5.6～8.2）
进展或死亡风险：减少67%（风险比：0.33，95%置信区间：0.26～0.43，估算P<0.0001）
中位总生存：未达中位（95%置信区间：至少40.5个月、至少34.0个月）
总死亡风险：减少36%（风险比：0.64，95%置信区间：0.47～0.87，P=0.0037）
对于518例实际治疗患者，德曲妥珠单抗与恩美曲妥珠单抗相比：
≥3级治疗相关不良事件发生率：56%比52%
药物相关间质性肺病或肺炎发生率：15%比3%
两组均未发生4或5级事件。
因此，该研究结果表明，对于HER2阳性晚期乳腺癌，德曲妥珠单抗与恩美曲妥珠单抗相比，患者总生存显著改善，中位无进展生存延长超过四倍，进展或死亡风险减少超过三分之二，再次确认德曲妥珠单抗二线治疗标准地位。随着治疗持续时间延长，德曲妥珠单抗可控的安全性得到证实。
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Lancet. 2022 Dec 7;39810314):1867. IF: 202.731
Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.
Sara A Hurvitz, Roberto Hegg, Wei-Pang Chung, Seock-Ah Im, William Jacot, Vinod Ganju, Joanne Wing Yan Chiu, Binghe Xu, Erika Hamilton, Srinivasan Madhusudan, Hiroji Iwata, Sevilay Altintas, Jan-Willem Henning, Giuseppe Curigliano, José Manuel Perez-Garcia, Sung-Bae Kim, Vanessa Petry, Chiun-Sheng Huang, Wei Li, Jean-Sebastien Frenel, Silvia Antolin, Winnie Yeo, Giampaolo Bianchini, Sherene Loi, Junji Tsurutani, Anton Egorov, Yali Liu, Jillian Cathcart, Shahid Ashfaque, Javier Cortés.
David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; Medica Scientia Innovation Research, Ridgewood, NJ, USA; Daiichi Sankyo, Basking Ridge, NJ, USA; Clinica de Pesquisas e Centro de Estudos em Oncologia Ginecologica e Mamaria Ltda, Sao Paolo, Brazil; ICESP—Instituto do Cancer do Estado de Sao Paulo Octavio Frias de Oliveria, Sao Paulo, Brazil; National Cheng Kung University Hospital, Tainan, Taiwan, China; National Cheng Kung University, Tainan, Taiwan, China; National Taiwan University Hospital, Taipei, Taiwan, China; University of Hong Kong, Queen Mary Hospital, Hong Kong, China; Chinese University of Hong Kong, Ma Liu Shui, Hong Kong, China; Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; The First Hospital of Jilin University, Changchun, China; Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University, Seoul, Korea; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; Institut du Cancer de Montpellier, Montpellier University, Montpellier, France; Institut de Cancerologie de l'Ouest, Site Rene Gauducheau, Saint-Herblain, France; Peninsula and South Eastern Haematology and Oncology Group, Frankston, VIC, Australia; Peter MacCallum Cancer, Melbourne, VIC, Australia; University of Nottingham, Nottingham University Hospital, Nottingham, UK; Aichi Cancer Center Hospital, Aichi, Japan; Showa University Hospital, Tokyo, Japan; Antwerp University Hospital, Edegem, Belgium; Tom Baker Cancer Centre, Calgary, AB, Canada; European Institute of Oncology, IRCCS, Milan, Italy; University of Milano, Milan, Italy; IRCCS Ospedale San Raffaele, Milan, Italy; International Breast Cancer Center, Pangaea Oncology, Quironsalud Group, Barcelona, Spain; Medica Scientia Innovation Research, Barcelona, Spain; Complejo Hospitalario Universitario A Coruna, La Coruna, Spain; Universidad Europea de Madrid, Madrid, Spain.
BACKGROUND: 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.
METHODS: 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 ClinicalTrials.gov, NCT03529110.
FINDINGS: 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.
INTERPRETATION: 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.
FUNDING: Daiichi Sankyo and AstraZeneca.
DOI: 10.1016/S0140-6736(22)02420-5
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