大约60%的HER2阴性晚期乳腺癌虽然HER2基因原位杂交阴性，但是HER2蛋白免疫组化评分为1+或2+，传统的HER2靶向药物对此类HER2低表达乳腺癌无效，如果激素受体阴性，目前主要依靠化疗。随着新一代抗体缀合（旧译偶联）药物德喜曲妥珠单抗（又称DS-8201或T-DXd）的问世，能否改变HER2低表达晚期乳腺癌患者的命运？
2022年6月5日，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》和美国临床肿瘤学会（ASCO）第58届年会同时发表美国纽约纪念医院斯隆凯特林癌症中心、德克萨斯大学MD安德森癌症中心、克利夫兰医学中心、旧金山加利福尼亚大学海伦迪勒家族综合癌症中心、第一三共、法国蒙彼利埃大学、巴黎大学居里研究院、日本神奈川癌症中心、九州癌症中心、昭和大学医院、东海大学医学院、韩国延世大学癌症中心、成均馆大学三星首尔医院、首尔大学医院、蔚山大学首尔峨山医院、庆北大学漆谷医院、高阳国家癌症中心、西班牙巴塞罗那大学医院、加泰罗尼亚肿瘤研究所、以色列拉宾医疗中心、特拉维夫大学、希腊雅典亚历山大综合医院、比利时布鲁塞尔自由大学朱尔斯博代研究院、英国伦敦大学玛丽王后学院、爱丁堡大学癌症中心、德国慕尼黑大学医院综合癌症中心、中国医学科学院肿瘤医院徐兵河、浙江省肿瘤医院王晓稼、吉林大学第一医院李薇、中山大学孙逸仙纪念医院刘强、四川大学华西医院罗婷、辽宁省肿瘤医院孙涛等学者的DESTINY-Breast04研究报告，对HER2低表达晚期乳腺癌化疗失败患者接受德喜曲妥珠单抗或医师选择化疗方案的有效性和安全性进行了比较，这也是德喜曲妥珠单抗的DESTINY系列研究第5次登上《新英格兰医学杂志》。
DESTINY-Breast04 (NCT03734029): Trastuzumab Deruxtecan (DS-8201a) Versus Investigator's Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed (A Phase 3, Multicenter, Randomized, Open-label, Active Controlled Trial of DS-8201a, an Anti-HER2-antibody Drug Conjugate (ADC), Versus Treatment of Physician's Choice for HER2-low, Unresectable and/or Metastatic Breast Cancer Subjects)
该国际多中心非盲随机对照三期临床研究于2018年12月27日～2021年12月31日入组HER2低表达晚期乳腺癌化疗失败患者557例，按2∶1的比例随机分为两组：德喜曲妥珠单抗组373例、医师选择化疗方案组184例，其中激素受体阳性494例（88.7%，德喜曲妥珠单抗组331例、医师选择化疗方案组163例）、激素受体阴性63例（11.3%）。主要终点为激素受体阳性患者的无进展生存。关键次要终点为全部患者的无进展生存、激素受体阳性患者和全部患者的总生存。
结果，中位随访18.4个月（95%置信区间：17.7～18.9）。
德喜曲妥珠单抗组与医师选择化疗方案组相比：
激素受体阳性患者
中位无进展生存：10.1个月比5.4个月
进展或死亡风险：减少49%（风险比：0.51，P<0.001）
中位总生存：23.9个月比17.5个月
总死亡风险：减少36%（风险比，0.64，P=0.003）
全部患者
中位无进展生存：9.9个月比5.1个月
进展或死亡风险：减少50%（风险比，0.50，P<0.001）
中位总生存：23.4个月比16.8个月
总死亡风险：减少36%（风险比，0.64，P=0.001）
≥3级不良事件发生率：52.6%比67.4%
药物相关间质性肺病或肺炎发生率：12.1%比0.6%
5级事件发生率：0.8%比0
亚组分析表明，无论是否用过CDK4/6抑制剂、免疫组化1+或2+、一或二线化疗失败、年龄、种族、地区、体力状态评分、是否内脏转移，德喜曲妥珠单抗组的无进展生存都优于医师选择化疗方案组。
即使对于HER2低表达的激素受体阴性（传统被归入三阴性）患者，德喜曲妥珠单抗组的无进展生存和总生存也显著优于医师选择化疗方案组。
因此，该研究结果表明，对于HER2低表达晚期乳腺癌患者，德喜曲妥珠单抗与医师选择化疗方案相比，无进展生存和总生存都显著延长。
相关链接
N Engl J Med. 2022 Jun 5. Online ahead of print.
Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.
Shanu Modi, William Jacot, Toshinari Yamashita, Joohyuk Sohn, Maria Vidal, Eriko Tokunaga, Junji Tsurutani, Naoto T. Ueno, Aleix Prat, Yee Soo Chae, Keun Seok Lee, Naoki Niikura, Yeon Hee Park, Binghe Xu, Xiaojia Wang, Miguel Gil-Gil, Wei Li, Jean-Yves Pierga, Seock-Ah Im, Halle C.F. Moore, Hope S. Rugo, Rinat Yerushalmi, Flora Zagouri, Andrea Gombos, Sung-Bae Kim, Qiang Liu, Ting Luo, Cristina Saura, Peter Schmid, Tao Sun, Dhiraj Gambhire, Lotus Yung, Yibin Wang, Jasmeet Singh, Patrik Vitazka, Gerold Meinhardt, Nadia Harbeck, David A. Cameron.
Memorial Sloan Kettering Cancer Center, New York; Institut du Cancer de Montpellier, Université Montpellier, INSERM Unité 1194, Montpellier; Institut Curie, Université Paris Cité, Paris, France; Kanagawa Cancer Center, Yokohama; Kyushu Cancer Center, National Hospital Organization, Fukuoka; Showa University Hospital, Tokyo; Tokai University School of Medicine, Isehara-shi, Japan; Yonsei Cancer Center, Yonsei University Health System; Samsung Medical Center, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Kyungpook National University Chilgok Hospital, Daegu; National Cancer Center, Goyang-si, Korea; Hospital Clínic de Barcelona, Translational Genomics and Targeted Therapies in Solid Tumors, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Institute of Oncology-Quirón Salud, Institut Catala d'Oncologia l'Hospitalet-Hospital Duran i Reynals, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; University of Texas M.D. Anderson Cancer Center, Houston; Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; Zhejiang Cancer Hospital, Hangzhou; First Hospital of Jilin University, Changchun; Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou; West China Hospital, Sichuan University, Chengdu; Liaoning Cancer Hospital and Institute, Shenyang, China; Cleveland Clinic Foundation, Cleveland; University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco; Rabin Medical Center, Petah Tikva, Tel Aviv University, Tel Aviv, Israel; Alexandra Regional General Hospital, Athens; Institut Jules Bordet, Brussels; Queen Mary University of London, London; Edinburgh Cancer Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom; Daiichi Sankyo, Basking Ridge, NJ; Comprehensive Cancer Center Munich, Ludwig Maximilian University Hospital, Munich, Germany.
More than half of breast cancers express low levels of HER2. In a phase 3 trial, the antibody-drug conjugate trastuzumab deruxtecan resulted in longer progression-free and overall survival than the physician's choice of chemotherapy among patients with HER2-low breast cancer.
BACKGROUND: Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers.
METHODS: We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients.
RESULTS: Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P=0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P=0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events.
CONCLUSIONS: In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy.
Funded by Daiichi Sankyo and AstraZeneca
DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029
2021版CBCS指南与规范完整版
2021版CBCS指南与规范精编版
2021版CBCS指南与规范小程序
联系客服
