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<p>Antibody–drug conjugates (ADCs) have emerged as a transformative modality in the treatment of solid tumors. YL201, a novel B7H3-targeting ADC, leverages a tumor microenvironment activable linker-payload platform, coupled with a novel topoisomerase 1 inhibitor via a protease-cleavable linker. Here we report the findings from a large-scale, global, multicenter, phase 1 trial evaluating the safety, pharmacokinetics and preliminary efficacy of YL201 in patients with advanced solid tumors refractory to standard therapies. The trial included a dose-escalation part (phase 1) and a dose-expansion part (phase 1b). A total of 312 patients were enrolled across multiple tumor types, including extensive-stage small cell lung cancer (ES-SCLC), nasopharyngeal carcinoma (NPC), non-small cell lung cancer, esophageal squamous cell carcinoma and other solid tumors. The maximum tolerated dose was determined to be 2.8 mg kg<sup>−1</sup>, and the recommended expansion dose was selected as 2.0 mg kg<sup>−1</sup> and 2.4 mg kg<sup>−1</sup> every 3 weeks. The most common grade 3 or higher treatment-related adverse events included neutropenia (31.7%), leukopenia (29.5%) and anemia (25.0%). Only 4 cases of interstitial lung disease (1.3%) and 1 case of infusion reactions (0.3%) were observed. Encouraging anti-tumor activity was observed, particularly in patients with ES-SCLC (objective response rate (ORR), 63.9%), NPC (ORR, 48.6%), lung adenocarcinoma (ORR, 28.6%) and lymphoepithelioma-like carcinoma (ORR, 54.2%). No significant correlation between B7H3 membrane expression and the ORR was found. YL201 demonstrated an acceptable safety profile and a promising efficacy in heavily pretreated patients with advanced solid tumors, particularly in those with ES-SCLC, NPC or lymphoepithelioma-like carcinoma. Phase 3 clinical trials for patients with SCLC and NPC have already been initiated. ClinicalTrials.gov identifiers: <a href="https://clinicaltrials.gov/study/NCT05434234">NCT05434234</a> and <a href="https://clinicaltrials.gov/study/NCT06057922">NCT06057922</a>.</p>

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A B7H3-targeting antibody–drug conjugate in advanced solid tumors: a phase 1/1b trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月13日

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  • Yuxiang Ma,
  • Yunpeng Yang,
  • Yan Huang,
  • Wenfeng Fang,
  • Jinhui Xue,
  • Xiangjiao Meng,
  • Yun Fan,
  • Siqing Fu,
  • Lin Wu,
  • Yulong Zheng,
  • Jian Liu,
  • Zhihua Liu,
  • Wu Zhuang,
  • Seth Rosen,
  • Song Qu,
  • Bihui Li,
  • Mingjun Li,
  • Yanqiu Zhao,
  • Shujun Yang,
  • Yinghua Ji,
  • David Sommerhalder,
  • Suxia Luo,
  • Kunyu Yang,
  • Jingao Li,
  • Dongqing Lv,
  • Peng Zhang,
  • Yuanyuan Zhao,
  • Shaodong Hong,
  • Yang Zhang,
  • Shen Zhao,
  • Steve Chin,
  • Xian Zhang,
  • Wei Lian,
  • Jiaqiang Cai,
  • Tongtong Xue,
  • Li Zhang,
  • Hongyun Zhao

摘要

Antibody–drug conjugates (ADCs) have emerged as a transformative modality in the treatment of solid tumors. YL201, a novel B7H3-targeting ADC, leverages a tumor microenvironment activable linker-payload platform, coupled with a novel topoisomerase 1 inhibitor via a protease-cleavable linker. Here we report the findings from a large-scale, global, multicenter, phase 1 trial evaluating the safety, pharmacokinetics and preliminary efficacy of YL201 in patients with advanced solid tumors refractory to standard therapies. The trial included a dose-escalation part (phase 1) and a dose-expansion part (phase 1b). A total of 312 patients were enrolled across multiple tumor types, including extensive-stage small cell lung cancer (ES-SCLC), nasopharyngeal carcinoma (NPC), non-small cell lung cancer, esophageal squamous cell carcinoma and other solid tumors. The maximum tolerated dose was determined to be 2.8 mg kg−1, and the recommended expansion dose was selected as 2.0 mg kg−1 and 2.4 mg kg−1 every 3 weeks. The most common grade 3 or higher treatment-related adverse events included neutropenia (31.7%), leukopenia (29.5%) and anemia (25.0%). Only 4 cases of interstitial lung disease (1.3%) and 1 case of infusion reactions (0.3%) were observed. Encouraging anti-tumor activity was observed, particularly in patients with ES-SCLC (objective response rate (ORR), 63.9%), NPC (ORR, 48.6%), lung adenocarcinoma (ORR, 28.6%) and lymphoepithelioma-like carcinoma (ORR, 54.2%). No significant correlation between B7H3 membrane expression and the ORR was found. YL201 demonstrated an acceptable safety profile and a promising efficacy in heavily pretreated patients with advanced solid tumors, particularly in those with ES-SCLC, NPC or lymphoepithelioma-like carcinoma. Phase 3 clinical trials for patients with SCLC and NPC have already been initiated. ClinicalTrials.gov identifiers: NCT05434234 and NCT06057922.