{"title":"<i>EGFR</i> Exon 20 insertions in NSCLC: from biology to amivantamab, optimal treatment strategy and emerging therapeutics.","authors":"Naoki Furuya","doi":"10.1080/14796694.2025.2550927","DOIUrl":null,"url":null,"abstract":"<p><p><i>EGFR</i> exon 20 insertion (Ex20ins) mutations are the third most frequent <i>EGFR</i> mutations, which accounts for around 4-12% of <i>EGFR</i> mutations in advanced NSCLC. It is well known that conventional EGFR-TKI monotherapy is less effective for patients with <i>EGFR</i> Ex20ins. Amivantamab is the first in class drug for established standard therapy of advanced stage NSCLC harboring Ex20ins mutations. Amivantamab has the following four unique mechanisms of action for Ex20ins mutated NSCLC; 1) dual-blocking receptor and inhibition of signaling pathway of <i>EGFR</i> and <i>cMET</i>, 2) antibody-dependent cellular cytotoxicity (ADCC) by NK cells, 3) antibody-dependent cellular trogocytosis (ADCT) by macrophages, 4) lysosomal receptor internalization and subsequent degradation. Amivantamab, in combination with carboplatin plus permetexed, was established in the PAPILLON study. However, it is unclear regarding the efficacy and CNS penetration of amivantamab for patients with Ex20ins mutations involving CNS/brain metastases. For patients with A763_Y764insFQEA mutation involving serious brain metastases, conventional EGFR-TKI might be an important treatment option. There are four phase III studies ongoing investigating new EGFR-TKI monotherapies or combination therapy with cytotoxic chemotherapy for <i>EGFR</i> Ex20ins mutations in the first-line setting. This review comprehensively summarized the biology and clinical characteristics of Ex20ins mutations and provide cutting-edge information and future perspectives.</p>","PeriodicalId":12672,"journal":{"name":"Future oncology","volume":" ","pages":"2995-3004"},"PeriodicalIF":2.6000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490370/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Future oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/14796694.2025.2550927","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/22 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
EGFR exon 20 insertion (Ex20ins) mutations are the third most frequent EGFR mutations, which accounts for around 4-12% of EGFR mutations in advanced NSCLC. It is well known that conventional EGFR-TKI monotherapy is less effective for patients with EGFR Ex20ins. Amivantamab is the first in class drug for established standard therapy of advanced stage NSCLC harboring Ex20ins mutations. Amivantamab has the following four unique mechanisms of action for Ex20ins mutated NSCLC; 1) dual-blocking receptor and inhibition of signaling pathway of EGFR and cMET, 2) antibody-dependent cellular cytotoxicity (ADCC) by NK cells, 3) antibody-dependent cellular trogocytosis (ADCT) by macrophages, 4) lysosomal receptor internalization and subsequent degradation. Amivantamab, in combination with carboplatin plus permetexed, was established in the PAPILLON study. However, it is unclear regarding the efficacy and CNS penetration of amivantamab for patients with Ex20ins mutations involving CNS/brain metastases. For patients with A763_Y764insFQEA mutation involving serious brain metastases, conventional EGFR-TKI might be an important treatment option. There are four phase III studies ongoing investigating new EGFR-TKI monotherapies or combination therapy with cytotoxic chemotherapy for EGFR Ex20ins mutations in the first-line setting. This review comprehensively summarized the biology and clinical characteristics of Ex20ins mutations and provide cutting-edge information and future perspectives.
期刊介绍:
Future Oncology (ISSN 1479-6694) provides a forum for a new era of cancer care. The journal focuses on the most important advances and highlights their relevance in the clinical setting. Furthermore, Future Oncology delivers essential information in concise, at-a-glance article formats - vital in delivering information to an increasingly time-constrained community.
The journal takes a forward-looking stance toward the scientific and clinical issues, together with the economic and policy issues that confront us in this new era of cancer care. The journal includes literature awareness such as the latest developments in radiotherapy and immunotherapy, concise commentary and analysis, and full review articles all of which provide key findings, translational to the clinical setting.