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

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: NCT05434234 and NCT06057922 .

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Publication Details

Journal
Nature Medicine
Published
2025-03-13
DOI
https://doi.org/10.1038/s41591-025-03600-2
Citations
48
Primary Topic
Radiopharmaceutical Chemistry and Applications
Type
article
Field-Weighted Citation Impact
65.29

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article

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

Hongyun Zhao, Xiangjiao Meng, Yuanyuan Zhao, Yunpeng Yang et al.
48 citations
Nature Medicine
Radiopharmaceutical Chemistry and Applications
65.29
article

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

Hongyun Zhao, Xiangjiao Meng, Yuanyuan Zhao, Yunpeng Yang, Yanqiu Zhao, Seth Rosen, Siqing Fu, Wen‐Feng Fang, Bihui Li, Dongqing Lv, David Sommerhalder, Xianzhong Zhang, Tongtong Xue, Lin Wu, Kunyu Yang, Shen Zhao, Peng Zhang, Jianjun Liu, Zhihua Liu, Li Zhang, Jinhui Xue, Mingjun Li, Zhuang Wu, Yun Fan, Yan Huang, Yuxiang Ma, Yulong Zheng, Yinghua Ji, Jingao Li, Suxia Luo, S Q Qu, Jiaqiang Cai, Wei Lian, Shaodong Hong, Shujun Yang, Steve Chin, Yang Zhang
article en
48 citations

Abstract

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: NCT05434234 and NCT06057922 .

Nature MedicineVol. 31(6)
The University of Texas MD Anderson Cancer Center (US), Sun Yat-sen University (CN), Guangxi Medical University (CN), Guilin Medical University (CN), Wenzhou Medical University (CN), Texas Oncology (US), Jiangxi Provincial Cancer Hospital (CN), Zhejiang Cancer Hospital (CN), Shandong Tumor Hospital (CN), First Affiliated Hospital of Xinxiang Medical University (CN), Hunan Cancer Hospital (CN), Sichuan Cancer Hospital (CN), Suzhou Research Institute (CN), Wuhan Union Hospital (CN), Henan Cancer Hospital (CN), Hematology Oncology Associates (US), Sun Yat-sen University Cancer Center (CN), Fujian Provincial Cancer Hospital (CN), First Affiliated Hospital of Zhengzhou University (CN), Zhejiang Taizhou Hospital (CN), Shandong First Medical University (CN), First Affiliated Hospital Zhejiang University (CN), Zhejiang University (CN), Henan Medical University (CN)
National Natural Science Foundation of China
Openalex Percentile: Top 0%
Radiopharmaceutical Chemistry and Applications
65.29
DOIOpen Access PDFOpenAlex
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