美国纪念斯隆·凯特林癌症中心Shanu Modi团队研究而了曲妥珠单抗-Deruxtecan治疗低HER2晚期乳腺癌的疗效。相关论文于2022年6月5日发表在《新英格兰医学杂志》上。

在没有人表皮生长因子受体2（HER2）扩增、过度表达或两者兼有的乳腺癌中，很大一部分表达低水平的可靶向HER2。目前可用的HER2导向疗法对这些“HER2低”癌症患者无效。

研究组进行了一项3期临床试验，招募低HER2转移性乳腺癌患者，他们之前接受过一到两种化疗。HER2低表达定义为免疫组织化学（IHC）分析得分为1+，或IHC得分为2+但原位杂交结果为阴性。将患者按2:1的比例随机分组，分别接受曲妥珠单抗-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率。次要关键终点是所有患者的无进展生存率以及激素受体阳性队列和所有患者的总生存率。

557名接受随机分组的患者中，494名（88.7%）患有激素受体阳性疾病，63名（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-Deruxtecan组的中位无进展生存期为10.1个月，医生选择化疗组为5.4个月（疾病进展或死亡的危险比为0.51），总生存期分别为23.9个月和17.5个月（死亡危险比为0.64），组间差异均显著。

在所有患者中，曲妥珠单抗-Deruxtecan组的中位无进展生存期为9.9个月，医生选择化疗组为5.1个月（疾病进展或死亡的危险比为0.50），总生存期分别为23.4个月和16.8个月（死亡危险比为0.64），组间差异均显著。在接受曲妥珠单抗-Deruxtecan治疗的患者中，有52.6%发生3级及以上不良事件，而在接受医生选择化疗的患者中有67.4%。在接受曲妥珠单抗-Deruxtecan治疗的患者中，12.1%发生药物相关的间质性肺病或肺炎；0.8%发生5级事件。

研究结果表明，对于低HER2转移性乳腺癌患者，与医生选择的化疗相比，曲妥珠单抗-Deruxtecan治疗的无进展生存期和总生存期显著延长。

附：英文原文

Title: Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer | NEJM

Author: Shanu Modi, M.D.,, William Jacot, M.D., Ph.D.,, Toshinari Yamashita, M.D., Ph.D.,, Joohyuk Sohn, M.D.,, Maria Vidal, M.D., Ph.D.,, Eriko Tokunaga, M.D., Ph.D.,, Junji Tsurutani, M.D., Ph.D.,, Naoto T. Ueno, M.D., Ph.D.,, Aleix Prat, M.D., Ph.D.,, Yee Soo Chae, M.D., Ph.D.,, Keun Seok Lee, M.D., Ph.D.,, Naoki Niikura, M.D., Ph.D.,, Yeon Hee Park, M.D., Ph.D.,, Binghe Xu, M.D., Ph.D.,, Xiaojia Wang, M.D., Ph.D.,, Miguel Gil-Gil, M.D., Ph.D.,, Wei Li, M.D., Ph.D.,, Jean-Yves Pierga, M.D., Ph.D.,, Seock-Ah Im, M.D., Ph.D.,, Halle C.F. Moore, M.D.,, Hope S. Rugo, M.D.,, Rinat Yerushalmi, M.D.,, Flora Zagouri, M.D., Ph.D.,, Andrea Gombos, M.D.,, Sung-Bae Kim, M.D., Ph.D.,, Qiang Liu, M.D., Ph.D.,, Ting Luo, M.D.,, Cristina Saura, M.D., Ph.D.,, Peter Schmid, M.D., Ph.D.,, Tao Sun, M.D.,, Dhiraj Gambhire, M.D., M.P.H.,, Lotus Yung, Pharm.D.,, Yibin Wang, Ph.D.,, Jasmeet Singh, M.D., M.P.H.A.,, Patrik Vitazka, M.D., Ph.D.,, Gerold Meinhardt, M.D.,, Nadia Harbeck, M.D., Ph.D.,, and David A. Cameron, M.D.

Issue&Volume: 2022-06-05

Abstract:

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.

DOI: 10.1056/NEJMoa2203690

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2203690