Dissociated response and treatment outcome with immune checkpoint blockade in advanced cancer

Dissociated response and treatment outcome with immune checkpoint blockade in advanced cancer | 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 Article Dissociated response and treatment outcome with immune checkpoint blockade in advanced cancer Yaping Guan, Yu Cui, Yanhong Gong, Xiuju Liang, Xinyue Han, Yingcui Chen, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4897806/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Dec, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Immune-related dissociated response (DR) has been recently recognized and have become a subject of ongoing interest. The purpose of the present study was to evaluate the frequency, treatment outcome, and predictors of DR in cancer patients with immune checkpoint inhibitors. We retrospectively collected clinicopathological data from a cohort of patients with cancer who received PD-1/PD-L1 inhibitor-based monotherapy or combination therapy at a single institution (developing cohort). An independent cohort of advanced non-small cell lung cancer (NSCLC) patients treated with immunotherapy at two institutions was used as the validating cohort. Progression‐free survival (PFS) and overall survival (OS) were used as outcome measures. The pantumor cohort included 177 patients. DR were observed in 12 (6.8%) patients. The median PFS and OS were significantly longer in patients with atypical response versus nonresponse but shorter versus true response. Patients with DR had a longer median PFS and OS than those with true PD. Local treatment seemed to have a positive influence on DR patient outcomes, with a median OS of 32.3 months versus 21.9 months for no local treatment. No clinical characteristics remained significant predictors for DR. In the NSCLC cohort, DR was observed in 10 (12.5%) patients. Inferior PFS and OS were validated in patients with real PD when compared with patients with DR. Patients who experience DR exhibit a relatively favorable prognosis. Some patients with DR may benefit from thecontinuation of ICI administration and local treatment to the growing lesions and achieve a longer survival. Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy Biological sciences/Cancer/Cancer imaging Atypical responses Pseudoprogression Dissociated response Programmed cell death protein-1 Immune checkpoint inhibitor Advanced cancer Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations No competing interests reported. Table 1 and 2 are available in the Supplementary Files section. Supplementary Files Table1.docx Table2.docx SupplementaryFigureS1.docx SupplementaryTableS1.docx SupplementaryTableS2.docx SupplementaryTableS3.docx SupplementaryTableS4.docx SupplementaryTableS5.docx Cite Share Download PDF Status: Published Journal Publication published 30 Dec, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 10 Dec, 2024 Reviews received at journal 29 Nov, 2024 Reviewers agreed at journal 17 Nov, 2024 Reviews received at journal 05 Nov, 2024 Reviewers agreed at journal 15 Oct, 2024 Reviewers invited by journal 17 Sep, 2024 Editor assigned by journal 17 Sep, 2024 Editor invited by journal 30 Aug, 2024 Submission checks completed at journal 30 Aug, 2024 First submitted to journal 12 Aug, 2024 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. 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05:44:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4897806/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4897806/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-84009-8","type":"published","date":"2024-12-30T15:57:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66937882,"identity":"1e87f4eb-5513-4604-a658-58808a323c78","added_by":"auto","created_at":"2024-10-18 08:35:13","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":137759,"visible":true,"origin":"","legend":"\u003cp\u003eObjective response rate, atypical response rate, frequencies of DR according to RECIST response and cancer types in the development cohort. (a) Objective response rate in all patients at the first radiographical assessment. (b) Atypical response rate, including PsPD and DR rates, in all patients. (c) Frequencies of DR according to RECIST response (PR, SD, and PD). (d) Frequencies of DR according to cancer types. (e) Percent change from baseline in target lesions in patients with DR. (f) Frequencies of DR according to the timepoint of radiological assessment. PsPD: pseudoprogressive disease; DR: dissociated response; CR, complete response; PR: partial response; SD: stable disease; PD: progressive disease; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; BL: baseline; TP: timepoint\u003c/p\u003e","description":"","filename":"Figure1.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1/a050167747eb3424c101b2fe.jpg"},{"id":66937889,"identity":"37e33b82-11aa-44a2-9e84-ac63a61adeda","added_by":"auto","created_at":"2024-10-18 08:35:13","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":236633,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan‒Meier survival curves in patients with different treatment responses in the development cohort. (a,b), PFS and OS for patients with nonresponse, atypical response, and true response. (c,d), PFS and OS for patients with DR, true SD, and true PD. (e-g) OS in patients with DR or true PD according to local treatment or in patients with real PD according to treatment beyond progression .\u003c/p\u003e","description":"","filename":"Figure2.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1/3ee52d1c9b574f00f29125ff.jpg"},{"id":66937881,"identity":"9b35b6e3-2687-463b-8192-842f09c97d84","added_by":"auto","created_at":"2024-10-18 08:35:13","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":83248,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan‒Meier survival curves in patients with different treatment responses in the validation cohort. (a,b) PFS and OS for patients with DR, CR/PR, true SD, and true PD.\u003c/p\u003e","description":"","filename":"Figure3.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1/e5db9b5431bd5bb251090c6c.jpg"},{"id":66939743,"identity":"2f445ba6-85a4-40e5-bb1a-e2aee97cad81","added_by":"auto","created_at":"2024-10-18 08:43:13","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":231232,"visible":true,"origin":"","legend":"\u003cp\u003ePretreatment and posttreatment circulating biomarkers in patients with AR, PsPD, DR, CR/PR, SD, and PD. (a) Pretreatment absolute lymphocyte count, lymphocyte percentage, NLR, and dNLR. (b) Pretreatment IL-6 levels. (c) Pretreatment LDH levels. (d) Posttreatment absolute lymphocyte count, lymphocyte percentage, NLR, and dNLR. AR, atypical response; PsPD: pseudoprogressive disease; DR: dissociated response; CR, complete response; PR: partial response; SD: stable disease; PD: progressive disease; NLR: neutrophil-to-lymphocyte ratio; dNLR: derived neutrophil-to-lymphocyte ratio; LDH: lactate dehydrogenase; IL-6: interleukin 6\u003c/p\u003e","description":"","filename":"Figure4.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1/03a669fc5c075607a78c3bdc.jpg"},{"id":66940695,"identity":"39f51378-be88-46a1-bc6a-69de9ff62622","added_by":"auto","created_at":"2024-10-18 08:51:13","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":126898,"visible":true,"origin":"","legend":"\u003cp\u003eResponse assessment per immune-related criteria and subsequent treatment recommendations for DR patients. Although CR/PR and PD can be identified for different target lesions, the overall response for a patient could be PR, SD, or PD, which is dependent on the extent of the change for responding and nonresponding lesions. The criteria should be recommended to\u003c/p\u003e\n\u003cp\u003edefine DR per iRECIST and imPERCIST. (a) The overall evaluation is PR, iPR, or PMR, and the patient has both CR/PR (at least a 30% decrease in some lesions) and progressive lesions (at least a 20% increase in other lesions) simultaneously. (b) The overall evaluation is SD, iSD, or SMD, and the patient has both CR/PR (at least a 30% decrease in some lesions) and progressive lesions (at least a 20% increase in other lesions) simultaneously. (c) The overall evaluation is PD, iUPD, or UPMD, and the patient has CR/PR/SD lesions but with the appearance of one or more new lesions or apparent deterioration of nontarget lesions. Given that DR patients have a relatively favorable survival outcome compared with real progressive patients, these patients may benefit from continued ICI administration and local therapy for lesions with progression. L1 and L2: target lesion. L3: new lesion or nontarget lesion. PR: partial response; iPR: immune partial remission; PMR: partial metabolic response; SD: stable disease; iSD: immune stable disease; SMD: stable metabolic disease; PD: progressive disease; iUPD: immune unconfirmed progressive disease; UPMD: unconfirmed progressive metabolic disease; RECIST: Response Evaluation Criteria in Solid Tumors; iRECIST: immuno-RECIST; imPERCIST: immunotherapy-modified PERCIST; ICI: immune checkpoint inhibitor\u003c/p\u003e","description":"","filename":"Figure5.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1/4d5754d75c468189fecaa7cc.jpg"},{"id":73095027,"identity":"e9ae0f25-244b-49e4-a6c7-39942ffe564d","added_by":"auto","created_at":"2025-01-06 16:24:37","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1190719,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptDR20240817.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1_covered_9c1081ec-b52d-470f-b850-6338a0cb70fc.pdf"},{"id":66937880,"identity":"f77be94a-95c7-4f3d-9bf3-a7864a7d5413","added_by":"auto","created_at":"2024-10-18 08:35:13","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23827,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1/c649fea059fb321de3a83ec8.docx"},{"id":66937884,"identity":"b483da59-d21e-48f1-8e39-11474f5492f1","added_by":"auto","created_at":"2024-10-18 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08:35:13","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":21279,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1/42aa48fefceab099003a5877.docx"},{"id":66937892,"identity":"ef04d346-20be-4d86-bab8-1172223db6a4","added_by":"auto","created_at":"2024-10-18 08:35:13","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":24893,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS4.docx","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1/0214fe53d341c739d9c07204.docx"},{"id":66939747,"identity":"fb51d8bd-521e-4903-b0f0-f24a9a219516","added_by":"auto","created_at":"2024-10-18 08:43:13","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":24174,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS5.docx","url":"https://assets-eu.researchsquare.com/files/rs-4897806/v1/b9a89a8e875ee0e925a36449.docx"}],"financialInterests":"\u003cp\u003eNo competing interests reported.\u003c/p\u003e\n\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e","formattedTitle":"Dissociated response and treatment outcome with immune checkpoint blockade in advanced cancer","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Atypical responses, Pseudoprogression, Dissociated response, Programmed cell death protein-1, Immune checkpoint inhibitor, Advanced cancer","lastPublishedDoi":"10.21203/rs.3.rs-4897806/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4897806/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Immune-related dissociated response (DR) has been recently recognized and have become a subject of ongoing interest. The purpose of the present study was to evaluate the frequency, treatment outcome, and predictors of DR in cancer patients with immune checkpoint inhibitors. We retrospectively collected clinicopathological data from a cohort of patients with cancer who received PD-1/PD-L1 inhibitor-based monotherapy or combination therapy at a single institution (developing cohort). An independent cohort of advanced non-small cell lung cancer (NSCLC) patients treated with immunotherapy at two institutions was used as the validating cohort. Progression‐free survival (PFS) and overall survival (OS) were used as outcome measures. The pantumor cohort included 177 patients. DR were observed in 12 (6.8%) patients. The median PFS and OS were significantly longer in patients with atypical response versus nonresponse but shorter versus true response. Patients with DR had a longer median PFS and OS than those with true PD. Local treatment seemed to have a positive influence on DR patient outcomes, with a median OS of 32.3 months versus 21.9 months for no local treatment. No clinical characteristics remained significant predictors for DR. In the NSCLC cohort, DR was observed in 10 (12.5%) patients. Inferior PFS and OS were validated in patients with real PD when compared with patients with DR. Patients who experience DR exhibit a relatively favorable prognosis. Some patients with DR may benefit from thecontinuation of ICI administration and local treatment to the growing lesions and achieve a longer survival.","manuscriptTitle":"Dissociated response and treatment outcome with immune checkpoint blockade in advanced cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-18 08:35:08","doi":"10.21203/rs.3.rs-4897806/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-11T04:55:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-29T09:46:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194527119157587342534458537974207892517","date":"2024-11-18T01:32:21+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-05T21:18:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62369756530906086770111376258530395813","date":"2024-10-15T20:38:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-17T11:04:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-17T11:00:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-08-30T06:07:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-30T04:58:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-08-12T05:41:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"312946f1-7520-4c06-8ef6-35840f55be5e","owner":[],"postedDate":"October 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":38104742,"name":"Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy"},{"id":38104743,"name":"Biological sciences/Cancer/Cancer imaging"}],"tags":[],"updatedAt":"2025-01-06T16:22:35+00:00","versionOfRecord":{"articleIdentity":"rs-4897806","link":"https://doi.org/10.1038/s41598-024-84009-8","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-12-30 15:57:00","publishedOnDateReadable":"December 30th, 2024"},"versionCreatedAt":"2024-10-18 08:35:08","video":"","vorDoi":"10.1038/s41598-024-84009-8","vorDoiUrl":"https://doi.org/10.1038/s41598-024-84009-8","workflowStages":[]},"version":"v1","identity":"rs-4897806","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4897806","identity":"rs-4897806","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}