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Early use of poorly selective multikinase RET inhibitors produced limited responses and meaningful toxicity. Highly selective RET inhibitors, selpercatinib and pralsetinib, received accelerated approval for advanced RET fusion–positive NSCLC and show strong efficacy in treatment-naive and previously treated patients. This review covers RET-rearranged NSCLC biology, clinical features, the evolution of therapies, mechanisms of resistance, and new agents aimed at overcoming resistance.",{"@graph":69,"@context":115},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/treatment-of-nonsmall-cell-lung-cancer-with-ret-rearrangements-review-article/371370/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/treatment-of-nonsmall-cell-lung-cancer-with-ret-rearrangements-review-article/371370.png","ImageObject",300,407,{"name":92,"@type":93},"Genevieve","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",16,{"@type":107,"mainEntity":108},"FAQPage",[109],{"name":110,"@type":111,"acceptedAnswer":112},"What challenges remain even with selective RET inhibitors?","Question",{"text":113,"@type":114},"Drug resistance eventually emerges, and the review discusses current resistance mechanisms and strategies, including development of new-generation agents to overcome resistance.","Answer","https://schema.org",{"og:url":83,"og:type":117,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":119,"canonical":83},"index,follow",{"doc_id":121,"site_id":62},371370,1790217347,{"code":4,"msg":5,"data":124},{"doc_id":121,"user_id":125,"nickname":92,"user_avatar":126,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":127,"file_id":128,"file_url":129,"file_type":130,"file_size":131,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":132,"language":133,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":134,"faqs":135,"seo_title":136,"seo_description":67,"update_tm":137,"read_time":138},1374391974585,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","DOI: 10. 1002/cncr.35779  \nREVIEW ARTICLE  \nTreatment of non–small cell lung cancer with RET rearrangements  \nHui Jing Hoe MBBS, FRACP1  | Benjamin J. Solomon MBBS, PhD, FRACP1,2  \n1Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia  \n2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia  \nCorrespondence  \nBenjamin J. Solomon, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia.  \nEmail: [ben.solomon@petermac.org](ben.solomon@petermac.org)  \nAbstract  \nAberrant activation of the RET oncogene by mutations or gene fusions drives various malignancies, including 1%–2% of all non–small cell lung cancers (NSCLCs) that harbor RET gene fusions. Initial attempts to target RET fusion–positive NSCLC with poorly selective multikinase RET inhibitors were associated with significant toxicities and limited efficacy. Two highly potent and selective RET small-molecule inhibitors, selpercatinib and pralsetinib, were granted accelerated approval for advanced RET fusion–positive NSCLC by the US Food and Drug Administration, and have been shown to be highly effective both in treatment-naive and previously treated patients with NSCLC. Selpercatinib has shown superiority over chemotherapy in a phase 3 study (LIBRETTO-431) in previously untreated patients with RET fusion–positive NSCLC, which established its place as the standard of care in this patient population. This review discusses the biology and clinical characteristics of RET-rearranged NSCLC and summarizes the evolution of treatment strategies, current understanding of mechanisms of resistance, and development of newgeneration agents to overcome resistance.  \nKEYWORDS  \nlung cancer, non–small cell lung cancer (NSCLC), pralsetinib, RET, RET fusion, RET NSCLC, RET rearrangements, selpercatinib  \nINTRODUCTION  \nLung cancer is the leading cause of cancer-related mortality globally by accounting for 1.8 million deaths worldwide.1 Non–small cell lung cancer (NSCLC) accounts for 85% of all lung cancers, with adenocarcinoma being the most common histological subtype. Molecular characterization of NSCLC has identified targetable oncogenic alterations in more than half of all lung adenocarcinomas.2,3  \nInternational guidelines recommend mandatory biomarker testing inpatients with newly diagnosed NSCLC to guide treatment selection with drugs directed at molecular targets approved for routine use as well as broader testing that may be used to support early drug access or clinical trials.4–6  \nThe rearranged during transfection (RET) gene may be aberrantly activated by mutations or gene fusions in approximately 2% of all cancers.7 Although RET-activating mutations most frequently occur  \n\n| The findings and conclusions in this supplement are those of the authors and do not necessarily reflect the official position of the American Cancer Society, John Wiley & Sons, Inc., or the opinions of the journal editors. |\n| --- |\n| This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.\u003Cbr>© 2025 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. |\n\nCancer. 2025;e35779.  \n[https://doi.org/10.1002/cncr.35779](https://doi.org/10.1002/cncr.35779)  \nwi[leyonlinelibrary.com/journal/cncr](leyonlinelibrary.com/journal/cncr)  \n1 of 11  \nin medullary thyroid carcinoma (MTC),8 RET gene fusions are found in 5%–10% of papillary thyroid carcinoma (PTC) cases and 1%–2% of all NSCLCs. 9,10  \nEarly clinical trials using poorly selective multikinase inhibitors (MKIs) in RET-rearranged NSCLC yielded disappointing results, with low response rates (16%–32%) and a modest median progressionfree survival (mPFS) of 2.2–7.3 months coupled with substantial ","cbCaiaD9x3GEd6rO","https://ap.wps.com/l/cbCaiaD9x3GEd6rO","pdf",582410,11,"English","# Introduction\n## Biology and clinical characteristics\n## Biology of RET\n## RET as an oncogene","[{\"question\":\"What challenges remain even with selective RET inhibitors?\",\"answer\":\"Drug resistance eventually emerges, and the review discusses current resistance mechanisms and strategies, including development of new-generation agents to overcome resistance.\"}]","Treatment of non–small cell lung cancer with RET rearrangements - Review Article | PDF",1790191919,28]