Ouyang Quchang, Rodon Jordi, Liang Yan, Wu Xinhong, Li Qun, Song Lihua, Yan Min, Tong Zhongsheng, Liu YunPeng, Wainberg Zev A, Wang Ying, Geng Cuizhi, Ulahannan Susanna V, Yu Guohua, Sharma Manish R, Wang Xiang, Wang Judy S, Spira Alexander, Zhao Weihong, Sanborn Rachel E, Cheng Ying, Wang Xian, Liu Gesha, Li Yaling, Ge Junyou, Chartash Elliot, Akala Omobolaji O, Yin Yongmei
Hunan Cancer Hospital, Changsha, China.
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
J Hematol Oncol. 2025 Jun 6;18(1):61. doi: 10.1186/s13045-025-01705-2.
BACKGROUND: Sacituzumab tirumotecan (sac-TMT) is an antibody-drug conjugate composed of an anti-TROP2 monoclonal antibody coupled to a cytotoxic belotecan-derived topoisomerase I inhibitor (KL610023) via a novel linker. We report results from the phase 1 dose-escalation cohorts in advanced solid tumors and phase 2 expansion cohorts for metastatic triple-negative breast cancer (TNBC) from the first-in-human MK-2870-001 (KL264-01) study (NCT04152499). METHODS: Patients had unresectable locally advanced/metastatic solid tumors refractory to standard therapies. In the phase 1 dose-escalation cohorts, patients had unresectable locally advanced/metastatic solid tumors refractory to standard therapies. Sac-TMT was administered by intravenous administration every 2 weeks at 2 to 12 mg/kg. In phase 2, patients with TNBC and HR+/HER2- breast cancer received sac-TMT per recommended doses for expansion (RDEs) identified in phase 1. Primary objectives were determining maximum tolerated dose (MTD) of sac-TMT and establishing RDEs (phase 1) and determining ORR per RECIST v1.1 by investigator assessment (phase 2). Adverse events were assessed per NCI-CTCAE version 5.0. RESULTS: Thirty patients were enrolled in phase 1 and received sac-TMT 2 mg/kg (n = 4), 4 mg/kg (n = 7), 5 mg/kg (n = 7), 5.5 mg/kg (n = 5), and 6 mg/kg (n = 7). Five patients had dose-limiting toxicities: grade 3 stomatitis at 4, 5.5, and 6 mg/kg; grade 3 rash at 5 mg/kg; and grade 3 urticaria at 6 mg/kg. MTD was 5.5 mg/kg and RDEs were 4 and 5 mg/kg. In the phase 2 dose expansion, ORR (95% CI) was 34.8% (16.4%, 57.3%) in the 4-mg/kg group (n = 23) and 38.9% (23.1%, 56.5%) in the 5-mg/kg group (n = 36) for TNBC. ORR (95% CI) was 31.7% (18.1%, 48.1%) for HR+/HER2- breast cancer (n = 41). CONCLUSIONS: Sac-TMT demonstrated manageable safety profile in patients with unresectable locally advanced/metastatic solid tumors and promising antitumor activity in metastatic TNBC and HR+/HER2 - breast cancer. Sac-TMT is being investigated in phase 3 studies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04152499.
背景：赛托珠单抗戈沙妥珠单抗（sac-TMT）是一种抗体药物偶联物，由一种抗TROP2单克隆抗体通过一种新型连接子与一种细胞毒性的贝洛替康衍生的拓扑异构酶I抑制剂（KL610023）偶联而成。我们报告了首次人体MK-2870-001（KL264-01）研究（NCT04152499）中晚期实体瘤1期剂量递增队列以及转移性三阴性乳腺癌（TNBC）2期扩展队列的结果。 方法：患者患有无法切除的局部晚期/转移性实体瘤，对标准疗法难治。在1期剂量递增队列中，患者患有无法切除的局部晚期/转移性实体瘤，对标准疗法难治。赛托珠单抗戈沙妥珠单抗每2周静脉给药一次，剂量为2至12mg/kg。在2期，TNBC和HR+/HER2-乳腺癌患者接受在1期确定的推荐扩展剂量（RDE）的赛托珠单抗戈沙妥珠单抗。主要目标是确定赛托珠单抗戈沙妥珠单抗的最大耐受剂量（MTD）并确定RDE（1期），以及通过研究者评估确定根据RECIST v1.1的客观缓解率（ORR）（2期）。根据美国国立癌症研究所不良事件通用术语标准第5.0版评估不良事件。 结果：30名患者入组1期并接受了2mg/kg（n = 4）、4mg/kg（n = 7）、5mg/kg（n = 7）、5.5mg/kg（n = 5）和6mg/kg（n = 7）的赛托珠单抗戈沙妥珠单抗。5名患者出现剂量限制性毒性：4、5.5和6mg/kg时出现3级口腔炎；5mg/kg时出现3级皮疹；6mg/kg时出现3级荨麻疹。MTD为5.5mg/kg，RDE为4和5mg/kg。在2期剂量扩展中，TNBC的4mg/kg组（n = 23）的ORR（95%CI）为34.8%（16.4%，57.3%），5mg/kg组（n = 36）为38.9%（23.1%，56.5%）。HR+/HER2-乳腺癌（n = 41）的ORR（95%CI）为31.7%（18.1%，48.1%）。 结论：赛托珠单抗戈沙妥珠单抗在无法切除的局部晚期/转移性实体瘤患者中显示出可控的安全性，在转移性TNBC和HR+/HER2-乳腺癌中具有有前景的抗肿瘤活性。赛托珠单抗戈沙妥珠单抗正在进行3期研究。 试验注册：ClinicalTrials.gov，NCT04152499。
Breast Cancer Res Treat. 2021-11
N Engl J Med. 2021-4-22
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