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Background <p>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&#xa0;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).</p> Methods <p>Patients had unresectable locally advanced/metastatic solid tumors refractory to standard therapies. In the&#xa0;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&#xa0;weeks at 2 to 12&#xa0;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.</p> Results <p>Thirty patients were enrolled in phase 1 and received sac-TMT 2&#xa0;mg/kg (<i>n</i> = 4), 4&#xa0;mg/kg (<i>n</i> = 7), 5&#xa0;mg/kg (<i>n</i> = 7), 5.5&#xa0;mg/kg (<i>n</i> = 5), and 6&#xa0;mg/kg (<i>n</i> = 7). Five patients had dose-limiting toxicities: grade 3 stomatitis at 4, 5.5, and 6&#xa0;mg/kg; grade 3 rash at 5&#xa0;mg/kg; and grade 3 urticaria at 6&#xa0;mg/kg. MTD was 5.5&#xa0;mg/kg and RDEs were 4 and 5&#xa0;mg/kg. In the&#xa0;phase 2 dose expansion, ORR (95% CI) was 34.8% (16.4%, 57.3%) in the 4-mg/kg group (<i>n</i> = 23) and 38.9% (23.1%, 56.5%) in the&#xa0;5-mg/kg group (<i>n</i> = 36) for TNBC. ORR (95% CI) was 31.7% (18.1%, 48.1%) for HR+/HER2− breast cancer (<i>n</i> = 41).</p> Conclusions <p>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.</p> Trial registration <p>ClinicalTrials.gov, NCT04152499.</p>

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Results of a phase 1/2 study of sacituzumab tirumotecan in patients with unresectable locally advanced or metastatic solid tumors refractory to standard therapies

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  • 发表日期：

    2025年6月6日

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  • Quchang Ouyang,
  • Jordi Rodon,
  • Yan Liang,
  • Xinhong Wu,
  • Qun Li,
  • Lihua Song,
  • Min Yan,
  • Zhongsheng Tong,
  • YunPeng Liu,
  • Zev A. Wainberg,
  • Ying Wang,
  • Cuizhi Geng,
  • Susanna V. Ulahannan,
  • Guohua Yu,
  • Manish R. Sharma,
  • Xiang Wang,
  • Judy S. Wang,
  • Alexander Spira,
  • Weihong Zhao,
  • Rachel E. Sanborn,
  • Ying Cheng,
  • Xian Wang,
  • Gesha Liu,
  • Yaling Li,
  • Junyou Ge,
  • Elliot Chartash,
  • Omobolaji O. Akala,
  • Yongmei Yin

摘要

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.