Dilawari Asma, Zhang Hui, Shah Mirat, Gao Xin, Fiero Mallorie, Bhatnagar Vishal, Pierce William, Mixter Bronwyn, Pazdur Richard, Amiri-Kordestani Laleh
Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, MD.
Center for Devices and Radiological Health (CDRH), U.S. Food and Drug Administration, Silver Spring, MD.
J Clin Oncol. 2025 Sep 10;43(26):2942-2951. doi: 10.1200/JCO-25-00812. Epub 2025 Aug 5.
The US Food and Drug Administration (FDA) approved trastuzumab deruxtecan (T-DXd, DS-8201a) for patients with unresectable or metastatic breast cancer (MBC) who have tumor progression on previous endocrine therapy (ET) and have hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]-) or HER2-ultralow (IHC 0 with membrane staining) tumors.
Approval was based on DESTINY-Breast06, a randomized, open-label, multicenter trial of 866 patients with HR-positive breast cancer, including 713 patients with HER2-low and 153 with HER2-ultralow tumors. Patients were required to have progressed on previous ET and must not have received chemotherapy in the metastatic setting. Random assignment was 1:1 to T-DXd or investigator's choice of chemotherapy (paclitaxel, nab-paclitaxel, or capecitabine). Previous CDK4/6 inhibitor treatment, previous taxane use in the (neo)adjuvant setting, and HER2 status (IHC2+/ISH- 1+ IHC 0 with membrane staining) were stratification factors.
There was a statistically significant improvement in progression-free survival (PFS) by blinded independent central review (BICR) in the HER2-low population of 13.2 months (95% CI, 11.4 to 15.2) in the T-DXd arm and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy arm (hazard ratio [HR], 0.62 [95% CI, 0.52 to 0.75], < .0001). The trial also met its key secondary end point, PFS by BICR in the overall population, with a HR of 0.64 (95% CI, 0.54 to 0.76, < .0001).
T-DXd is a new treatment option for patients with hormone receptor-positive, unresectable or MBC with HER2-low or HER2-ultralow tumors who have experienced progression on ET. This is the first indication specifying the category of HER2-ultralow expression in breast cancer, and an assay to select patients for this category was approved contemporaneously.
美国食品药品监督管理局（FDA）批准了曲妥珠单抗德瓦鲁单抗（T-DXd，DS-8201a）用于既往内分泌治疗（ET）后出现肿瘤进展、激素受体阳性、人表皮生长因子受体2（HER2）低表达（免疫组化[IHC]1+或IHC 2+/原位杂交[ISH]-）或HER2极低表达（IHC 0伴膜染色）的不可切除或转移性乳腺癌（MBC）患者。
批准基于DESTINY-Breast06，这是一项随机、开放标签、多中心试验，纳入866例HR阳性乳腺癌患者，其中713例为HER2低表达患者，153例为HER2极低表达患者。患者需既往ET治疗后病情进展，且在转移阶段未接受过化疗。随机分组比例为1:1，分别接受T-DXd或研究者选择的化疗（紫杉醇、白蛋白结合型紫杉醇或卡培他滨）。既往CDK4/6抑制剂治疗、既往（新）辅助治疗中使用紫杉烷以及HER2状态（IHC2+/ISH-、1+、IHC 0伴膜染色）为分层因素。
经盲法独立中央审查（BICR），T-DXd组HER2低表达人群的无进展生存期（PFS）有统计学显著改善，为13.2个月（95%CI，11.4至15.2），化疗组为8.1个月（95%CI，7.0至9.0）（风险比[HR]，0.62[95%CI，0.52至0.75]，P<0.0001）。该试验还达到了其关键次要终点，即总体人群经BICR评估的PFS，HR为0.64（95%CI，0.54至0.76，P<0.0001）。
T-DXd是既往ET治疗后病情进展的激素受体阳性、不可切除或MBC伴HER2低表达或HER2极低表达肿瘤患者的一种新治疗选择。这是乳腺癌中首次明确HER2极低表达类别的适应证，同时批准了一种用于选择该类患者的检测方法。
