In a phase 1/1b trial, Ma et al. evaluated YL201, a B7H3-targeting antibody–drug conjugate (ADC), in 312 heavily pretreated patients with advanced solid tumors. YL201 releases its conjugated topoisomerase 1 inhibitor after cleavage in both the TME and the intracellular lysosome. The objective response rate was 40.8%, and the disease control rate was 83.6%, with a median PFS of 5.9 months and a median response duration of 6.3 months. Grade 3 or higher AEs occurred in 54.5% of patients, as seen for other B7H3 ADCs. YL201 activity was not dependent on B7H3 expression levels or soluble B7H3 concentrations. Phase 3 trials of YL201 are underway.
Contributed by Ute Burkhardt
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(-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 .
Author Info: (1) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Dia
Author Info: (1) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (2) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (3) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (4) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (5) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (6) Department of Chest Radiotherapy IV, Shandong Cancer Hospital and Institute, Jinan, China. (7) Department of Chest Medicine, Zhejiang Cancer Hospital, Hangzhou, China. (8) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Internal Thoracic, Hunan Cancer Hospital, Changsha, China. (10) Department of Medical Oncology/Clinical Pharmacy Research Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (11) Department of Medical Oncology/Clinical Pharmacy Research Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (12) Department of Thoracic Tumor Radiotherapy I, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. (13) Department of Thoracic Oncology, Fujian Cancer Hospital, Fuzhou, China. (14) Hematology Oncology Associates of the Treasure Coast, Port Saint Lucie, FL, USA. (15) Department of Radiotherapy, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, China. (16) Department of Medical Oncology, The Second Affiliated Hospital of Guilin Medical University, Guilin, China. (17) Department of Oncology II, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. (18) Department of Respiratory Medicine I, Henan Cancer Hospital, Zhengzhou, China. (19) Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China. (20) Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China. (21) NEXT Oncology, San Antonio, TX, USA. (22) Phase I Clinical Trial Center, Henan Cancer Hospital, Zhengzhou, China. (23) Department of Head and Neck Oncology, Union Hospital Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (24) Department of Head and Neck Radiotherapy II, Jiangxi Cancer Hospital (Jiangxi Second People's Hospital), Nanchang, China. (25) Department of Respiratory Medicine, Taizhou Hospital of Zhejiang Province, Taizhou, China. (26) Department of Radiotherapy, Sichuan Cancer Hospital, Chengdu, China. (27) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (28) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (29) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (30) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. (31) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. (32) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. (33) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. (34) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. (35) MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China. tony@medilinkthera.com. (36) Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. zhangli@sysucc.org.cn. (37) Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China. zhaohy@sysucc.org.cn.
