Lee Jii Bum, Shim Joo Sung, Cho Byoung Chul
Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Nat Rev Clin Oncol. 2025 Jul 18. doi: 10.1038/s41571-025-01051-9.
Alterations in the proto-oncogene MET are associated with tumour development, invasion and metastasis across various solid cancers. Therapeutically actionable MET alterations include MET exon 14 skipping (METex14) mutations, MET amplification and/or MET overexpression and MET fusions, which vary in incidence by tumour type. In contrast to rare de novo MET alterations, acquired MET amplification and/or MET overexpression is a relatively common phenomenon that is associated with distinct clinical implications and responses to treatment. METex14 is a distinct oncogenic driver mutation in non-small-cell lung cancer (NSCLC). To date, the MET tyrosine-kinase inhibitors (TKIs) capmatinib, tepotinib and savolitinib have been approved for the treatment of advanced-stage METex14-mutant NSCLC. However, the treatment paradigms for MET-altered solid tumours are rapidly evolving to include diverse MET-targeted agents. Emerging data support the role of MET TKIs, anti-MET antibodies and MET-directed antibody-drug conjugates (ADCs) as monotherapy or in combination with other therapies for NSCLC or other tumour types with MET amplification and/or overexpression. Indeed, in May 2025, the MET-directed ADC telisotuzumab vedotin was approved by the FDA for patients with previously treated advanced-stage nonsquamous NSCLC overexpressing MET (≥50% of tumour cells with 3+ staining on immunohistochemistry). Understanding the unique MET-related adverse events will be crucial when incorporating these agents into daily clinical practice. In this Review, we highlight the rationale for targeting MET alterations across various solid tumour types and provide a summary of the clinical efficacy and toxicity profiles of the approved and emerging MET-targeted TKIs, monoclonal or bispecific antibodies and ADCs.
原癌基因MET的改变与多种实体癌的肿瘤发生、侵袭和转移相关。具有治疗意义的MET改变包括MET第14外显子跳跃（METex14）突变、MET扩增和/或MET过表达以及MET融合，其发生率因肿瘤类型而异。与罕见的原发性MET改变不同，获得性MET扩增和/或MET过表达是一种相对常见的现象，具有独特的临床意义和治疗反应。METex14是非小细胞肺癌（NSCLC）中一种独特的致癌驱动突变。迄今为止，MET酪氨酸激酶抑制剂（TKIs）卡马替尼、替泊替尼和赛沃替尼已被批准用于治疗晚期METex14突变的NSCLC。然而，MET改变的实体瘤的治疗模式正在迅速发展，包括多种MET靶向药物。新出现的数据支持MET TKIs、抗MET抗体和MET导向的抗体药物偶联物（ADCs）作为单一疗法或与其他疗法联合用于治疗NSCLC或其他具有MET扩增和/或过表达的肿瘤类型。事实上，2025年5月，MET导向的ADC替雷利珠单抗维朵汀被美国食品药品监督管理局（FDA）批准用于先前接受过治疗的、MET过表达（免疫组化染色3+且≥50%肿瘤细胞）的晚期非鳞状NSCLC患者。在将这些药物纳入日常临床实践时，了解与MET相关的独特不良事件至关重要。在本综述中，我们强调了针对各种实体瘤类型中MET改变的基本原理，并总结了已批准和新出现的MET靶向TKIs、单克隆或双特异性抗体以及ADCs的临床疗效和毒性特征。
