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<p>Trophoblast cell-surface antigen 2 (TROP2)-directed antibody–drug conjugate (ADC) is a promising anticancer agent that has shown remarkable efficacy in several malignancies. However, in lung cancer, two phase 3 trials on TROP2-ADCs in unselected patients with advanced non-small-cell lung cancer (NSCLC) have both failed. Sacituzumab tirumotecan (sac-TMT) is a novel TROP2-directed ADC. Here we report the efficacy and safety of sac-TMT in previously treated, advanced NSCLC with or without activating <i>EGFR</i> mutations from the phase 1/2 KL264-01 and phase 2 SKB264-II-08 studies. Primary endpoint was objective response rate (ORR). KL264-01 enrolled <i>EGFR</i>-wild-type and <i>EGFR</i>-mutant NSCLC (<i>n</i> = 43). Confirmed ORR was 40% (17 of 43; 95% confidence interval (CI), 25–56). Median progression-free survival (PFS) was 6.2 months (95% CI, 5.3–11.3). Post-hoc subgroup analyses found better outcomes in the <i>EGFR</i>-mutant subset (22 of 43, 51%) with a confirmed ORR of 55% (12 of 22) and median PFS of 11.1 months. These findings were independently supported by results from SKB264-II-08, where sac-TMT led to confirmed ORR of 34% (22 of 64; 95% CI, 23–47) and median PFS of 9.3 months (95% CI, 7.6–11.4) in 64 patients with <i>EGFR</i>-mutant NSCLC. For a total of 107 patients receiving sac-TMT, the most common treatment-related adverse events were hematologic toxicities. Diarrhea (4%) and interstitial lung disease (1%) were uncommon. Exploration of potential mechanisms revealed that the presence of <i>EGFR</i> mutation substantially increased the internalization and activity of sac-TMT in vitro. Overall, sac-TMT showed encouraging single-agent activity and manageable tolerability in previously treated, advanced NSCLC with EGFR mutations. Randomized phase 3 trials in treatment-naive and previously treated patients with EGFR-mutant NSCLC are ongoing. ClinicalTrials.gov Identifiers: <a href="https://clinicaltrials.gov/study/NCT04152499?term=NCT04152499&amp;rank=1">NCT04152499</a>, <a href="https://clinicaltrials.gov/study/NCT05631262?term=NCT05631262&amp;rank=1">NCT05631262</a>.</p>

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Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials

  • 期刊论文

  • 发表日期：

    2025年4月10日

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  • Shen Zhao,
  • Ying Cheng,
  • Qiming Wang,
  • Xingya Li,
  • Jun Liao,
  • Jordi Rodon,
  • Xiangjiao Meng,
  • Yongzhong Luo,
  • Zhendong Chen,
  • Wei Wang,
  • Tienan Yi,
  • Yongsheng Li,
  • Yongmei Yin,
  • Huiting Xu,
  • Guohua Yu,
  • Yanjun Mi,
  • Yun Fan,
  • Zev A. Wainberg,
  • Xiang Wang,
  • Cuiyun Su,
  • Qitao Yu,
  • Shuzhen Lai,
  • Longhua Sun,
  • Wu Zhuang,
  • Xian Wang,
  • Jiacheng Yang,
  • Yaling Li,
  • Junyou Ge,
  • Jin Li,
  • Li Zhang,
  • Wenfeng Fang

摘要

Trophoblast cell-surface antigen 2 (TROP2)-directed antibody–drug conjugate (ADC) is a promising anticancer agent that has shown remarkable efficacy in several malignancies. However, in lung cancer, two phase 3 trials on TROP2-ADCs in unselected patients with advanced non-small-cell lung cancer (NSCLC) have both failed. Sacituzumab tirumotecan (sac-TMT) is a novel TROP2-directed ADC. Here we report the efficacy and safety of sac-TMT in previously treated, advanced NSCLC with or without activating EGFR mutations from the phase 1/2 KL264-01 and phase 2 SKB264-II-08 studies. Primary endpoint was objective response rate (ORR). KL264-01 enrolled EGFR-wild-type and EGFR-mutant NSCLC (n = 43). Confirmed ORR was 40% (17 of 43; 95% confidence interval (CI), 25–56). Median progression-free survival (PFS) was 6.2 months (95% CI, 5.3–11.3). Post-hoc subgroup analyses found better outcomes in the EGFR-mutant subset (22 of 43, 51%) with a confirmed ORR of 55% (12 of 22) and median PFS of 11.1 months. These findings were independently supported by results from SKB264-II-08, where sac-TMT led to confirmed ORR of 34% (22 of 64; 95% CI, 23–47) and median PFS of 9.3 months (95% CI, 7.6–11.4) in 64 patients with EGFR-mutant NSCLC. For a total of 107 patients receiving sac-TMT, the most common treatment-related adverse events were hematologic toxicities. Diarrhea (4%) and interstitial lung disease (1%) were uncommon. Exploration of potential mechanisms revealed that the presence of EGFR mutation substantially increased the internalization and activity of sac-TMT in vitro. Overall, sac-TMT showed encouraging single-agent activity and manageable tolerability in previously treated, advanced NSCLC with EGFR mutations. Randomized phase 3 trials in treatment-naive and previously treated patients with EGFR-mutant NSCLC are ongoing. ClinicalTrials.gov Identifiers: NCT04152499, NCT05631262.