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The discussion highlights a progression-free survival benefit with acceptable toxicity, while emphasizing limitations such as restricted population characteristics, uncertainty of extrapolation to Western patients, absence of mature overall survival data, and lack of molecular biomarker insight. Additional concerns address PD-L1 cut-off selection and subgroup behaviors, including reduced benefit in central nervous system metastases and VEGF-related adverse events.",{"@graph":69,"@context":122},[70,84,105],{"@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/ivonescimab-promise-or-reality-for-advanced-non-small-cell-lung-cancer-editorial-commentary/448125/",{"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/ivonescimab-promise-or-reality-for-advanced-non-small-cell-lung-cancer-editorial-commentary/448125.png","ImageObject",300,407,{"name":92,"@type":93},"Liam","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is ivonescimab, and how does it differ from pembrolizumab in the HARMONi-2 trial?","Question",{"text":112,"@type":113},"Ivonescimab is a bispecific antibody targeting PD-1 and VEGF-A receptor pathways. The commentary contrasts its dual action and reported PFS advantage against pembrolizumab, an anti–PD-1 therapy.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What efficacy benefit does the commentary focus on from HARMONi-2?",{"text":117,"@type":113},"The commentary highlights a progression-free survival benefit for ivonescimab, reported as 11.1 vs 5.8 months with a hazard ratio of 0.51 in the overall sample. It also notes consistency across several subgroups by histology and PD-L1 category.",{"name":119,"@type":110,"acceptedAnswer":120},"Why does the commentary caution against adopting the results as standard clinical practice?",{"text":121,"@type":113},"Concerns include all-enrolled patients being Asian, limited extrapolation to Western populations and certain tumor types, lack of mature overall survival data and deeper statistical analysis, and missing information on molecular biomarkers that could influence response. It also questions the PD-L1 cut-off strategy and the lack of benefit for patients with central nervous system metastases.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},448125,1790812312,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":24,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144,"preview_page_count":4},8796095461564,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Editorial Commentary  \nIvonescimab: promise or reality for advanced non-small cell lung cancer?  \nAlejandro Olivares-Hernández1,2, Pedro Gonzalez Santa-Catalina1,2^, Emilio Fonseca-Sánchez1,2,3, Edel del Barco-Morillo1,2,3  \n1Department of Medical Oncology, Salamanca University Hospital, Salamanca, Spain; 2Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain; 3Faculty of Medicine, University of Salamanca (USAL), Salamanca, Spain  \nCorrespondence to: Pedro Gonzalez Santa-Catalina, MD. Department of Medical Oncology, Salamanca University Hospital, Paseo de la Transición Española s/n, 37007, Salamanca, Castilla y León, Spain; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain. [Email: pgonzalezsanta@saludcastillayleon.es](Email: pgonzalezsanta@saludcastillayleon.es).  \nComment on: Xiong A, Wang L, Chen J, et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet 2025;405:839-49 . Erratum in: Lancet 2025;406:2062 .  \nKeywords: Non-small cell lung cancer (NSCLC); immune checkpoint inhibitor (ICI); ivonescimab; bispecific antibody  \nSubmitted Oct 08, 2025. Accepted for publication Nov 19, 2025. Published online Dec 24, 2025.  \ndoi: 10.21037/tlcr-2025-aw-1146  \nView this article at: [https://dx.doi.org/10.21037/tlcr-2025-aw-1146](https://dx.doi.org/10.21037/tlcr-2025-aw-1146)  \nThe published results of the HARMONi-2 trial once again demonstrate the interesting role that bispecific antibodies can play in the treatment of non-small cell lung cancer (NSCLC) . Ivonescimab, an antibody against programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF)-A receptors, has shown favorable results compared to pembrolizumab in the treatment of patients with advanced NSCLC and programmed deathligand 1 (PD-L1)-positive tumors (1) . The HARMONi-2 trial presents both strengths and limitations and therefore warrants a critical evaluation. Although the results are positive, their extrapolation to the entire population with advanced NSCLC is uncertain and opens an important path that is currently unclear.  \nHARMONi-2 is a phase 3 study that randomized 398 patients to receive first-line ivonescimab versus pembrolizumab in patients with advanced PD-L1-positive NSCLC. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. The rationale for dual action on PD-1 and VEGF offers the advantages of greater tumor permeability by cytotoxic T lymphocytes and a lower presence of immune regulatory  \ncells such as regulatory T cells or myeloid-derived suppressor cells, in addition to the already known effects of antiangiogenic agents (2,3) . The results of the trial, with immature overall survival (OS) data, showed a PFS benefit for the ivonescimab group compared to pembrolizumabin the overall sample [11.1 vs. 5.8 months; hazard ratio (HR), 0.51; P\u003C0.0001] . This benefit was consistent across subgroups by histology, PD-L1 ( ≥ 50% or 1–49%) or presence of liver metastases. In contrast, no benefit was seen in patients with central nervous system metastases. The toxicity profile was acceptable, with a grade ≥3 adverse event rate of 22% for ivonescimab, with 10% of grade ≥3 adverse events being VEGF-related.  \nWithout a doubt, the study is a very clear promise of a possible therapy that offers advantages over the anti-PD(L)1 drugs used to date. Obviously, there are some points in the trial that must be analyzed with caution. The selection of the population, the control therapy used, the toxicity of antiangiogenic drugs, and the lack of OS data with a more in-depth statistical analysis mean that further studies are needed before this therapy can become standard in clinical practice. Firstly, all the patients selected are Asian, with  \n^ ORCID: 0009-0009-3716-036X.  \n© AME Publishing Company. Transl Lung Cancer Res 2025;14(12):5203-5207 | [https://dx.doi.org/10.21037/tlcr-2025","cbCair1vhYVkzC8v","https://ap.wps.com/l/cbCair1vhYVkzC8v","pdf",185279,"English","# Editorial Commentary\n## Study design and efficacy signals\n## Safety profile and subgroup observations\n## Key limitations and extrapolation concerns\n## PD-L1 cut-off selection and endpoint issues","[{\"question\":\"What is ivonescimab, and how does it differ from pembrolizumab in the HARMONi-2 trial?\",\"answer\":\"Ivonescimab is a bispecific antibody targeting PD-1 and VEGF-A receptor pathways. The commentary contrasts its dual action and reported PFS advantage against pembrolizumab, an anti–PD-1 therapy.\"},{\"question\":\"What efficacy benefit does the commentary focus on from HARMONi-2?\",\"answer\":\"The commentary highlights a progression-free survival benefit for ivonescimab, reported as 11.1 vs 5.8 months with a hazard ratio of 0.51 in the overall sample. It also notes consistency across several subgroups by histology and PD-L1 category.\"},{\"question\":\"Why does the commentary caution against adopting the results as standard clinical practice?\",\"answer\":\"Concerns include all-enrolled patients being Asian, limited extrapolation to Western populations and certain tumor types, lack of mature overall survival data and deeper statistical analysis, and missing information on molecular biomarkers that could influence response. It also questions the PD-L1 cut-off strategy and the lack of benefit for patients with central nervous system metastases.\"}]","Ivonescimab: promise or reality for advanced non-small cell lung cancer? - Editorial Commentary | PDF",1790725600,13]