Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.
Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.
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DOI：
10.1056/nejmoa2203690
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发表时间：
2022-07-07
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在没有人表皮生长因子受体2（HER 2）扩增、过表达或两者兼有的乳腺癌中，大部分表达低水平的HER 2，这可能是可靶向的。目前可用的HER 2导向疗法在患有这些“HER 2低”癌症的患者中无效。我们进行了一项3期试验，涉及既往接受过1或2线化疗的HER 2低转移性乳腺癌患者。(Low HER 2表达定义为免疫组织化学[IHC]分析评分为1+或原位杂交结果为阴性且IHC评分为2+。）患者以2：1的比例随机分配接受曲妥珠单抗deruxtecan或医生选择的化疗。主要终点是激素受体阳性队列的无进展生存期。关键的次要终点包括激素受体阳性队列和所有患者的无进展生存期。在接受随机分组的557例患者中，494例（88.7%）患有激素受体阳性疾病，63例（11.3%）患有激素受体阴性疾病。在激素受体阳性队列中，曲妥珠单抗组的中位无进展生存期为10.1个月，医生选择组为5.4个月（疾病进展或死亡的风险比为0.51; P<0.001），总生存期分别为23.9个月和17.5个月（死亡的风险比为0.64; P=0.003）。在所有患者中，曲妥珠单抗组和医生选择组的中位无进展生存期分别为9.9个月和5.1个月（风险比，0.50; P<0.001），总生存期分别为23.4个月和16.8个月（死亡风险比，0.64; P=0.001）。52.6%接受曲妥珠单抗deruxtecan治疗的患者和67.4%接受医生选择的化疗的患者发生了3级或以上的不良事件。12.1%接受曲妥珠单抗deruxtecan治疗的患者发生裁定的药物相关间质性肺病/肺炎; 0.8%发生5级事件。在这项涉及HER 2低转移性乳腺癌患者的试验中，曲妥珠单抗deruxtecan导致的无进展生存期和总生存期显著长于医生选择的化疗。（由Daiichi Sankyo和AstraZeneca资助; DESTINY-Breast 04 ClinicalTrials.gov，NCT 03734029）。
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. 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 included progression-free survival in the hormone receptor–positive cohort and among all patients. 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, 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/pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. 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, NCT03734029).