Efficacy and safety of immune checkpoint inhibitors versus chemotherapy in advanced non-small cell lung cancer: A systematic review of randomized controlled trials

Efficacy and safety of immune checkpoint inhibitors versus chemotherapy in advanced non-small cell lung cancer: A systematic review of randomized controlled trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Efficacy and safety of immune checkpoint inhibitors versus chemotherapy in advanced non-small cell lung cancer: A systematic review of randomized controlled trials Moontasir Ahmed, Shadman Newaz, Jannatara Tina, M. F. Rabbi, Avijit Debnath, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9240131/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for advanced non-small cell lung cancer (NSCLC). This systematic review synthesizes the evidence from randomized controlled trials (RCTs) to evaluate the efficacy and safety of ICI-based therapies compared to chemotherapy. Methods We systematically searched PubMed for RCTs published between January 2015 and January 2026 that compared ICI monotherapy or combinations to chemotherapy in patients with advanced NSCLC. Data on overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were extracted. The risk of bias was assessed using the Cochrane Risk of Bias tool. Results 96 RCTs were included. ICI-based regimens demonstrated a consistent and significant improvement in OS (Hazard Ratio [HR] range: ~0.40–0.79) and PFS (HR range: ~0.37–0.70) compared to chemotherapy. Benefit was observed across lines of therapy, from first-line metastatic to perioperative settings. High PD-L1 expression and tumor mutational burden (TMB) were key predictive biomarkers for greater efficacy. While ICIs were associated with a distinct profile of immune-related AEs, they generally showed a favorable safety profile compared to chemotherapy, with lower rates of severe hematological and gastrointestinal toxicities. Conclusion ICI-based therapies represent a superior standard of care for advanced NSCLC, offering significant and durable survival benefits over chemotherapy. Treatment decisions should be guided by biomarker status and clinical scenario. Future research should focus on long-term outcomes, optimal combination strategies, and managing immune-related toxicity. Non-small cell lung cancer Immune checkpoint inhibitors Immunotherapy Systematic review Randomized controlled trials PD-1 PD-L1 CTLA-4 Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9240131","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":613688708,"identity":"b7eaa5c5-eeb2-4c3a-a8a7-5083b1ea023b","order_by":0,"name":"Moontasir Ahmed","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYBADHgb25oMPQAw+otQfAGnhOZZsANLCRqwWBgaJHDMJEE1Qi25787HHH2rqZMwbEswqv+bYybAxMD98dAOPFrMzx9INDhw7zCNz4EDabdltyUCHsRkb5+DTcgPongNsB3gkGBuO3ZbcxgzUwsMmTVjLvzoeCWbGtmLJbfVEajnYxswjwcbMxvhx22EitJw5liZxtu8wjwQPG7M047bjQIqQX443H5Oo+FZnLyH//uPHn9uq7fnZmx8+xqcFBTDzgElilYMA4w9SVI+CUTAKRsGIAQCgo0RknPA0FgAAAABJRU5ErkJggg==","orcid":"","institution":"Tangail Medical College Hospital","correspondingAuthor":true,"prefix":"","firstName":"Moontasir","middleName":"","lastName":"Ahmed","suffix":""},{"id":613688709,"identity":"6e2f421b-4644-4cca-acc3-021686ea091e","order_by":1,"name":"Shadman Newaz","email":"","orcid":"","institution":"Tangail Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shadman","middleName":"","lastName":"Newaz","suffix":""},{"id":613688710,"identity":"b8334be4-043b-4fb9-a4f1-7591f8d561d6","order_by":2,"name":"Jannatara Tina","email":"","orcid":"","institution":"Tangail Medical College Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jannatara","middleName":"","lastName":"Tina","suffix":""},{"id":613688711,"identity":"9dceaa42-13c6-4edb-8acc-c67ac0679dcf","order_by":3,"name":"M. 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This systematic review synthesizes the evidence from randomized controlled trials (RCTs) to evaluate the efficacy and safety of ICI-based therapies compared to chemotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe systematically searched PubMed for RCTs published between January 2015 and January 2026 that compared ICI monotherapy or combinations to chemotherapy in patients with advanced NSCLC. Data on overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were extracted. The risk of bias was assessed using the Cochrane Risk of Bias tool.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e96 RCTs were included. ICI-based regimens demonstrated a consistent and significant improvement in OS (Hazard Ratio [HR] range: ~0.40\u0026ndash;0.79) and PFS (HR range: ~0.37\u0026ndash;0.70) compared to chemotherapy. Benefit was observed across lines of therapy, from first-line metastatic to perioperative settings. High PD-L1 expression and tumor mutational burden (TMB) were key predictive biomarkers for greater efficacy. While ICIs were associated with a distinct profile of immune-related AEs, they generally showed a favorable safety profile compared to chemotherapy, with lower rates of severe hematological and gastrointestinal toxicities.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003e ICI-based therapies represent a superior standard of care for advanced NSCLC, offering significant and durable survival benefits over chemotherapy. Treatment decisions should be guided by biomarker status and clinical scenario. Future research should focus on long-term outcomes, optimal combination strategies, and managing immune-related toxicity.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of immune checkpoint inhibitors versus chemotherapy in advanced non-small cell lung cancer: A systematic review of randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-30 13:38:02","doi":"10.21203/rs.3.rs-9240131/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f3ed58b4-e9b2-49ba-9f8f-d5c86486d086","owner":[],"postedDate":"March 30th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T13:38:02+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-30 13:38:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9240131","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9240131","identity":"rs-9240131","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}