J Zhang, R Liu, S Wang, Z Feng, H Yang, S Gao, X Li, X Yao, J Chen, Z Gong, Y Li, X Li, S Wang, C Hu, J Liu, M Zhang, F Yuan, B Shi, H Lou, P Zhao, F Qiu, H Guo, B Hu, D Xu, H Huang, X Zhang, M Feng, X Wang, G Li, D Liu, X Chen, P Wang
{"title":"9MW2821，新一代Nectin-4靶向抗体-药物偶联物，用于晚期实体瘤患者：一项首次人体、开放标签、多中心、期Ⅰ/Ⅱ研究","authors":"J Zhang, R Liu, S Wang, Z Feng, H Yang, S Gao, X Li, X Yao, J Chen, Z Gong, Y Li, X Li, S Wang, C Hu, J Liu, M Zhang, F Yuan, B Shi, H Lou, P Zhao, F Qiu, H Guo, B Hu, D Xu, H Huang, X Zhang, M Feng, X Wang, G Li, D Liu, X Chen, P Wang","doi":"10.1016/j.annonc.2025.04.009","DOIUrl":null,"url":null,"abstract":"<p><strong>Backgroud: </strong>A first-in-human study was performed to assess the safety and preliminary antitumor activity of 9MW2821, a next-generation monoclonal antibody-drug conjugate (ADC) that delivers monomethylauristatin E (MMAE) to cells expressing Nectin-4, in patients with advanced solid tumors.</p><p><strong>Patients and methods: </strong>This is a first-in-human, open label, multicenter study included dose escalation, dose expansion and cohort expansion periods. Patients with advanced solid tumors who failed ≥1 line of systemic therapy were recruited to receive 9MW2821 by intravenous (IV) infusion at doses of 0.33-1.5mg/kg on days 1,8 and 15 of each 28-day cycle. Primary objective were assessment of safety and preliminary efficacy. (NCT05216965, CTR20220106) RESULTS: Between June 11, 2022, and Apr 3, 2024, 274 patients were enrolled, including 51 with urothelial cancer, 62 with cervical cancer, 49 with esophageal cancer, 20 with triple negative breast cancer and 92 with other solid tumors. In dose escalation phase, one dose limiting toxicity was observed in 1.5mg/kg group, which was grade 4 neutropenia lasted more than 5 days. Maximum tolerated dose of 9MW2821 was not reached. However, the recommended phase Ⅱ dose was identified as 1.25mg/kg based on balance of safety and efficacy. The most common ≥Grade 3 treatment related adverse events were neutrophil count decreased, white blood cell (WBC) count decreased, anemia, gamma-glutamyl transferase (GGT) increased rash and peripheral sensory neuropathy in 1.25mg/kg group. Among 226 patients evaluable for efficacy, objective response rates were 54.1%, 32.1%, 14.0% and 50% in urothelial cancer, cervical cancer, esophageal cancer and triple negative breast cancer, respectively.</p><p><strong>Conclusion: </strong>The results suggest that 9MW2821 was tolerable and clinically significant in efficacy in various types of solid tumors besides urothelial cancer. Several pivotal trials are currently in progress. (NCT06196736, NCT06592326, NCT06692166).</p>","PeriodicalId":8000,"journal":{"name":"Annals of Oncology","volume":" ","pages":""},"PeriodicalIF":56.7000,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"9MW2821, a next-generation Nectin-4 targeting antibody-drug conjugate, in patients with advanced solid tumors: a first-in-human, open label, multicenter, phase Ⅰ/Ⅱ study.\",\"authors\":\"J Zhang, R Liu, S Wang, Z Feng, H Yang, S Gao, X Li, X Yao, J Chen, Z Gong, Y Li, X Li, S Wang, C Hu, J Liu, M Zhang, F Yuan, B Shi, H Lou, P Zhao, F Qiu, H Guo, B Hu, D Xu, H Huang, X Zhang, M Feng, X Wang, G Li, D Liu, X Chen, P Wang\",\"doi\":\"10.1016/j.annonc.2025.04.009\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Backgroud: </strong>A first-in-human study was performed to assess the safety and preliminary antitumor activity of 9MW2821, a next-generation monoclonal antibody-drug conjugate (ADC) that delivers monomethylauristatin E (MMAE) to cells expressing Nectin-4, in patients with advanced solid tumors.</p><p><strong>Patients and methods: </strong>This is a first-in-human, open label, multicenter study included dose escalation, dose expansion and cohort expansion periods. Patients with advanced solid tumors who failed ≥1 line of systemic therapy were recruited to receive 9MW2821 by intravenous (IV) infusion at doses of 0.33-1.5mg/kg on days 1,8 and 15 of each 28-day cycle. Primary objective were assessment of safety and preliminary efficacy. (NCT05216965, CTR20220106) RESULTS: Between June 11, 2022, and Apr 3, 2024, 274 patients were enrolled, including 51 with urothelial cancer, 62 with cervical cancer, 49 with esophageal cancer, 20 with triple negative breast cancer and 92 with other solid tumors. In dose escalation phase, one dose limiting toxicity was observed in 1.5mg/kg group, which was grade 4 neutropenia lasted more than 5 days. Maximum tolerated dose of 9MW2821 was not reached. However, the recommended phase Ⅱ dose was identified as 1.25mg/kg based on balance of safety and efficacy. The most common ≥Grade 3 treatment related adverse events were neutrophil count decreased, white blood cell (WBC) count decreased, anemia, gamma-glutamyl transferase (GGT) increased rash and peripheral sensory neuropathy in 1.25mg/kg group. Among 226 patients evaluable for efficacy, objective response rates were 54.1%, 32.1%, 14.0% and 50% in urothelial cancer, cervical cancer, esophageal cancer and triple negative breast cancer, respectively.</p><p><strong>Conclusion: </strong>The results suggest that 9MW2821 was tolerable and clinically significant in efficacy in various types of solid tumors besides urothelial cancer. Several pivotal trials are currently in progress. (NCT06196736, NCT06592326, NCT06692166).</p>\",\"PeriodicalId\":8000,\"journal\":{\"name\":\"Annals of Oncology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":56.7000,\"publicationDate\":\"2025-04-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.annonc.2025.04.009\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.annonc.2025.04.009","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景：一项首次进行的人体研究评估了9MW2821的安全性和初步抗肿瘤活性，9MW2821是一种新一代单克隆抗体-药物偶联物（ADC），可向表达Nectin-4的细胞递送单甲基月lauristatin E (MMAE)，用于晚期实体瘤患者。患者和方法：这是一项首次人体试验，开放标签，多中心研究，包括剂量递增，剂量扩展和队列扩展期。招募≥1线全身治疗失败的晚期实体瘤患者，在每28天周期的第1、8和15天静脉滴注剂量为0.33-1.5mg/kg的9MW2821。主要目的是评估安全性和初步疗效。结果：在2022年6月11日至2024年4月3日期间，纳入274例患者，其中尿路上皮癌51例，宫颈癌62例，食管癌49例，三阴性乳腺癌20例，其他实体瘤92例。剂量递增期，1.5mg/kg组出现1次剂量限制性毒性，出现4级中性粒细胞减少，持续5 d以上。未达到9MW2821的最大耐受剂量。然而，基于安全性和有效性的平衡，建议的阶段Ⅱ剂量被确定为1.25mg/kg。1.25mg/kg组最常见的≥3级治疗相关不良事件为中性粒细胞计数减少、白细胞（WBC）计数减少、贫血、γ -谷氨酰转移酶（GGT）升高、皮疹和周围感觉神经病变。在226例可评价疗效的患者中，尿路上皮癌、宫颈癌、食管癌和三阴性乳腺癌的客观有效率分别为54.1%、32.1%、14.0%和50%。结论：9MW2821对除尿路上皮癌外的各类实体瘤均有耐受性，临床疗效显著。几项关键试验目前正在进行中。（nct06196736, nct06592326, nct06692166）。
9MW2821, a next-generation Nectin-4 targeting antibody-drug conjugate, in patients with advanced solid tumors: a first-in-human, open label, multicenter, phase Ⅰ/Ⅱ study.
Backgroud: A first-in-human study was performed to assess the safety and preliminary antitumor activity of 9MW2821, a next-generation monoclonal antibody-drug conjugate (ADC) that delivers monomethylauristatin E (MMAE) to cells expressing Nectin-4, in patients with advanced solid tumors.
Patients and methods: This is a first-in-human, open label, multicenter study included dose escalation, dose expansion and cohort expansion periods. Patients with advanced solid tumors who failed ≥1 line of systemic therapy were recruited to receive 9MW2821 by intravenous (IV) infusion at doses of 0.33-1.5mg/kg on days 1,8 and 15 of each 28-day cycle. Primary objective were assessment of safety and preliminary efficacy. (NCT05216965, CTR20220106) RESULTS: Between June 11, 2022, and Apr 3, 2024, 274 patients were enrolled, including 51 with urothelial cancer, 62 with cervical cancer, 49 with esophageal cancer, 20 with triple negative breast cancer and 92 with other solid tumors. In dose escalation phase, one dose limiting toxicity was observed in 1.5mg/kg group, which was grade 4 neutropenia lasted more than 5 days. Maximum tolerated dose of 9MW2821 was not reached. However, the recommended phase Ⅱ dose was identified as 1.25mg/kg based on balance of safety and efficacy. The most common ≥Grade 3 treatment related adverse events were neutrophil count decreased, white blood cell (WBC) count decreased, anemia, gamma-glutamyl transferase (GGT) increased rash and peripheral sensory neuropathy in 1.25mg/kg group. Among 226 patients evaluable for efficacy, objective response rates were 54.1%, 32.1%, 14.0% and 50% in urothelial cancer, cervical cancer, esophageal cancer and triple negative breast cancer, respectively.
Conclusion: The results suggest that 9MW2821 was tolerable and clinically significant in efficacy in various types of solid tumors besides urothelial cancer. Several pivotal trials are currently in progress. (NCT06196736, NCT06592326, NCT06692166).
期刊介绍：
Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine.
The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings.
Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.
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