Application of extended immunotherapy in advanced clear cell renal cell carcinoma treated with first-line combination of immune-checkpoint inhibitor and tyrosine kinase inhibitor

Application of extended immunotherapy in advanced clear cell renal cell carcinoma treated with first-line combination of immune-checkpoint inhibitor and tyrosine kinase inhibitor | 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 Research Article Application of extended immunotherapy in advanced clear cell renal cell carcinoma treated with first-line combination of immune-checkpoint inhibitor and tyrosine kinase inhibitor Qian Wang, Xingming Zhang, Qiyu zhu, Hong Zeng, Jindong Dai, Junru Chen, and 5 more This is a preprint; it has not been peer reviewed by a journal.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-5416848/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Dec, 2024 Read the published version in International Urology and Nephrology → Version 1 posted You are reading this latest preprint version Abstract Purpose To evaluate the efficacy and safety of extended immunotherapy in first-line immune checkpoint inhibitors (ICIs) - tyrosine kinase inhibitors (TKIs) combination treatment for advanced renal cell carcinoma (RCC). Patients and Methods: We retrospectively analyzed data from patients with advanced RCC who received first-line ICIs-TKIs combination treatment at West China Hospital of Sichuan University between October 2018 and July 2024. Patients who are assessed as having a disease control status after 2 years of continuous treatment will continue to receive immune checkpoint inhibitors until the inhibitors are discontinued due to disease progression or death. Result A total of 86 patients were screened and 14 patients diagnosed with clear cell RCC (ccRCC) were enrolled. After 65 months of follow-up, three-year progression-free survival (PFS) rate was 71.4% and 4-year PFS rate was 59.5%. The 5-year overall survival (OS) rate was 58.3%. During extended treatment, one patient (7.1%) experienced a transition from stable disease (SD) to partial response (PR) and two patients (14.3%) experienced a transition from PR to complete response (CR). The best tumor shrinkage rates presenting after 24 months had longer PFS and OS compared to those presenting within 24 months (median PFS: not reached vs. 36 months; Hazard Ratio (HR) = 0.10, 95%CI 0.01–0.80, P = 0.03). For safety, extended immunotherapy did not increase treatment-related toxicities compared to safety profile before 24 months. Conclusion Our analysis of real-world data indicates that patients with extended immunotherapy after 24 months had sustained survival benefits and manageable toxicity. Large-scale, prospective studies are still needed to further verify the conclusion. adverse events clear cell renal cell carcinoma extended therapy immune checkpoint inhibitor tyrosine kinase inhibitor Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Renal cell carcinoma (RCC) constitutes approximately 85% of all kidney cancers, making it the most common subtype [ 1 ] . According to the most recent reports, it was projected that there were approximately 430,000 new cases of kidney cancer worldwide in 2022, resulting in an estimated 150,000 deaths from the disease [ 2 ] . Despite advancements in techniques of early detection for RCC, about 25–30% of patients still present with metastatic disease upon initial diagnosis, while around 20% experience relapse or metastasis following nephrectomy [ 3 , 4 ] . With the emergence of the immunotherapy era, the combination therapy of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors(TKIs) has become the established first-line treatment for patients with advanced clear cell renal cell carcinoma (ccRCC) [ 5 – 7 ] . Although the combination therapy with ICIs has revolutionized the treatment of patients with advanced ccRCC and significantly improved clinical outcomes, there is currently no established standard protocol for the duration of ICIs use [ 8 ] . The discontinuation of ICIs may also lead to disease remission in cases where it has been observed in metastatic melanoma [ 9 ] . The continued utilization of ICIs is correlated with superior survival benefits compared to the discontinuation of ICIs in patients with advanced non-small cell lung cancer [ 10 , 11 ] . Although the efficacy of ICIs can be sustained in certain patients with advanced RCC, even after discontinuation, as demonstrated by these studies [ 12 ] ,the discontinuation of ICIs or the continuation of ICI therapy in patients with advanced ccRCC, who have achieved disease control or do not experience intolerable toxic effects, remains a subject of controversy regarding its impact on patient outcomes [ 13 ] . The objective of this study was to evaluate the efficacy and safety associated with continued ICIs therapy in real-world clinical practice. Methods Study design and patient population We conducted a retrospective analysis of data from patients with advanced ccRCC who underwent first-line TKIs-ICIs combination therapy at West China Hospital of Sichuan University between October 2018 and July 2024. The inclusion criteria encompassed adult patients aged ≥ 18 years with newly diagnosed stage IV or recurrent ccRCC. The first-line ICIs-TKIs combination was administered, and ICIs were utilized continuously for over 2 years. All patients exhibited measurable disease according to RECIST version 1.1 [ 14 ] and a Karnofsky performance status score of 70 or higher at baseline [ 15 ] . The exclusion criteria included symptomatic central nervous system metastasis, active autoimmune disease, uncontrolled hypertension (systolic blood pressure ≥ 150 mm Hg or diastolic blood pressure ≥ 90 mm Hg), ongoing systemic immunosuppressive therapy, as well as patients diagnosed with other malignant diseases or life-threatening major diseases were also excluded from the analysis. The study was approved by the Biomedical Research Ethics Committee of West China Hospital, Sichuan University. All procedures involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Treatment and outcome All enrolled patients were administered first-line combination therapy of ICIs-TKIs (such as axitinib plus pembrolizumab, axitinib plus sintilimab, axitinib plus toripalimab, etc.). Patients who are assessed as having a positive disease status (disease control status) after 2 years of continuous treatment will continue to receive immune checkpoint inhibitors until the inhibitors are discontinued due to disease progression or death. During the course of treatment, all patients underwent CT or MRI evaluations every 1–3 months until disease progression, discontinuation of immunological drugs or death occurred. All patients exhibited measurable disease according to RECIST version 1.1. The primary endpoints included PFS, OS and ORR. Secondary endpoints encompassed AEs related to immunotherapy. PFS was defined as the duration from initiation of ICIs-TKIs treatment to disease progression or death, while OS was defined as the duration from initiation of ICIs-TKIs treatment to death or loss of follow-up due to various causes. The objective response rate (ORR) was defined as the proportion of patients with a confirmed complete response (CR) or partial response (PR) among all treated patients, while the disease control rate (DCR) was defined as the proportion of patients with confirmed CR, PR or stable disease (SD) among all treated patient. The best objective response was defined as the reduction of the tumor to a minimal size or complete disappearance during treatment. The severity of treatment-related adverse events was assessed using the Common Terminology Criteria for AEs (CTCAE, version 5.0). Statistical analysis The quantitative variable data were compared using a t-test, while the categorical variable data were analyzed using a chi-square (χ2) test. Kaplan-Meier survival curves were utilized to illustrate the survival on prolongation therapy and differences in survival between different groups. Sankey charts and bar charts were employed to display the treatment response at various time points. All statistical analyses were conducted using Graph Pad Prism 8.0.1, SPSS version 26.0 software, and R (version 4.3.1). A P value < 0.05 was considered statistically significant. Result Characteristics of enrolled patients After screening of 86 patients, the study enrolled a total of 14 ccRCC patients (Fig. 1 ) and their baseline characteristics were summarized in Table 1 . The median follow-up was 40 months. 11 patients (78.6%) had received surgical removal of the primary lesion,including 4 patients with partial nephrectomy(PN) and 7 patients with radical nephrectomy(RN). The predominant sites of metastasis were the lung (64.3%) and lymph nodes (35.7%), liver (28.6%), pancreas (21.4%) and bone (14.3%). At the initiation of first-line treatment, 5 (35.7%), 8 (57.1%) and 1 (7.1%) patient were stratified into the high-risk, intermediate-risk, and low-risk categories according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Table 1 Baseline data regarding the clinical characteristics of patients Characteristic (N = 14) N (%) Age, years Median age (range) 53(37–79) < 65 10(71.4) ≥ 65 4(28.6) Gender Female 2(14.3) Male 12(85.7) WHO/ISUP < 3 4(28.6) ≥ 3 10(71.4) ECOG 0 5(35.7) 1 6(42.9) 2 3(21.4) IMDC risk group Favorable 5(35.7) Intermediate 8(57.1) Poor 1(7.1) T stage < 3 10(71.4) ≥ 3 4(28.6) Nephrectomy Yes 11(78.6) No 3(21.4) Metastatic sites Lung 9(64.3) lymph node 5(35.7) Liver 4(28.6) Others 4(28.6) Pancreas 3(21.4) Bone 2(14.3) Number of metastatic sites < 2 3(21.4) ≥ 2 11(78.6) Frist-line treatment Axitinib + Pembrolizumab 2(14.3) Axitinib + Sintilimab 5(35.7) Axitinib + Toripalimab 7(50.0) Response status at 24 months SD 5(35.7) PR 9(64.3) CR 0(0) The optimal time for tumor response ≤ 24 months 9(64.3) > 24 months 5(35.7) IMDC: International Metastatic Renal-Cell Carcinoma Database Consortium;SD:stable disease; PR:partial response; CR:complete response; ISUP:international society of urological pathology; ECOG:eastern cooperative oncology group. After 24 months of treatment with ICIs-TKIs, the response assessment showed that 5 cases (35.7%) were classified as SD, 9 cases (64.3%) were classified as PR. The treatment modality and tumor response for each patient are also outlined in Fig. 2 . Tumor response In the entire cohort, 12 patients (85.7%) achieved an optimal tumor response of PR and 2 patients (14.3%) achieved an optimal tumor response of CR. Specifically, 10 patients (71.4%) had an optimal tumor response of PR after ≤ 24 months of treatment, 10 patients(71.4%) had an optimal tumor response of PR and 2 patients(14.3%) had a response of CR after > 24 months of treatment. Notably, there was a change in tumor response from SD to PR in one patient (7.1%) and from PR to CR in two patients (14.3%) during extended therapy ( Fig. 3 ). After 3 months of extended ICIs treatment, disease progression occurred in four patients, and one patient experienced disease progression at 12 months. The initial diagnosis revealed distant metastases in 3 patients, who subsequently underwent primary reductive resection. During extended therapy, 5 patients(35.7%) transitioned to alternative ICIs due to PD, while 4 patients(80%) achieved PR following the switch ( Fig. 3 ) . Survival outcome In the overall population, 3-year PFS rate was 71.4% and 4-year PFS rate was 59.5%, with a median PFS that has not been reached ( Fig. 4 A ) . The 5-year OS rate was 58.3%, and the median OS has not been reached ( Fig. 4 B ) . Subgroup analyses were conducted to compare PFS and OS in patients with the best tumor shrinkage rates before and after 24 months of treatment. The findings indicated that patients who achieved the best tumor shrinkage rates after 24 months experienced longer PFS and OS compared to those who achieved the best tumor shrinkage rates 24 months earlier (median PFS not reached vs. 36months; Hazard Ratio (HR) = 0.10; 95%CI 0.01–0.80 P = 0.03; median OS not reached vs. 43months; HR = 0.18; 95%CI 0.02–2.13, P = 0.18; Supplement 1 ). Compared with patients whose disease status was SD assessed at 24 months of immunotherapy, patients assessed with PR had longer PFS on extended therapy (median PFS not reached vs. 3months; HR = 0.26; 95%CI 0.03–2.02 P = 0.20; Supplement 2 ) Safety of extended treatment During the course of treatment, all 14 patients experienced adverse events that were related to the treatment. There were 2 cases (14.3%) before treatment and 6 cases (42.9%) after treatment with grade ≥ 3AEs (P = 0.21). Adverse events such as hypertension, proteinuria, hyperlipidemia, and diarrhea were frequently observed both before and after the 24-month mark. Five patients (35.7%) experienced the onset of grade ≥ 3 hypertension after 24 months of treatment (Supplement 3). Discussion To the best of our knowledge, this is the inaugural real-world study to investigate the efficacy and toxicity of ICIs extended therapy. According to the study findings, patients who demonstrated a positive response to ICIs-TKIs for 2 years and continued ICIs treatment achieved favorable outcomes in terms of both efficacy and safety. One patient's tumor response transitioned from SD to PR during extended therapy, and two patients achieved CR during extended treatment. Four patients achieved PR after transitioning to alternative ICIs despite experiencing disease progression during extended treatment. The combination therapy of first-line ICIs-TKIs has significantly enhanced PFS and OS in patients with advanced renal cell carcinoma [ 5 , 16 – 18 ] . However, the duration of first-line ICIs-TKIs treatment in patients with advanced clear cell renal cell carcinoma remains uncertain due to the lack of clinical evidence [ 8 ] . In clinical trials, the duration of immunotherapy has varied due to a lack of standardized guidelines, with the majority discontinuing treatment as a result of disease progression or unacceptable toxicity [ 16 , 19 ] .The duration of immunotherapy in the KEYNOT-426 and CLEAR studies was intended to be two years [ 20 , 21 ] . In the KEYNOT-426 study, 120 patients completed the 2-year treatment cycle and then discontinued. The median PFS was 37.4 months, with a PFS rate of 55.2% at 36 months and a PFS rate of 32.8% at 60 months [ 21 ] .The two aforementioned trials discontinued the use of ICIs after 2 years of ICIs-TKIs treatment. The follow-up results indicated that there was some efficacy in terms of PFS, but it did not appear to confer any advantage in improving PFS compared to continuing ICI use after 2 years. The impact of ongoing versus discontinued ICIs treatment on PFS and OS was also compared across different cancer types. The discontinuation of ICIs may also lead to disease remission in cases where it has been observed in metastatic melanoma [ 10 ] . The KEYNOTE-010 and CA209-003 studies indicate that a fixed regimen of immunotherapy may also yield enduring benefits for patients with advanced NSCLC [ 22 , 23 ] .Studies on immunotherapy in advanced melanoma have demonstrated sustained survival benefits even after discontinuation of Pembrolizumab for 2 years. Subgroup analysis revealed that patients who were assessed with SD and PR at the time of discontinuation had slightly worse survival outcomes compared to those with CR [ 24 ] . The discontinuation of ICIs may also lead to disease remission in cases where it has been observed in metastatic melanoma [ 25 ] .The early recurrence observed after discontinuation of immunotherapy, regardless of tumor type, may be attributed to the cessation of PD-1/PD-L1 inhibition [ 26 ] . Upon discontinuation of chronic PD-1/PD-L1 blocking, resistance mechanisms may also emerge [ 27 ] . Although there may be a sustained survival benefit from discontinuation of immune drugs in certain tumor types, the decision to discontinue remains controversial when there was a positive response to treatment and no intolerable adverse effects [ 28 ] . There is an ongoing debate regarding the discontinuation of ICIs in advanced renal cell carcinoma, and currently, there are no clear criteria for stopping ICIs in the absence of disease progression or unacceptable toxicity. Our study demonstrated that patients who completed 2 years of ICIs-TKIs and exhibited a positive response experienced sustained survival benefits and favorable toxicity profiles during extended ICIs treatment. Meanwhile, our study also demonstrated that the best tumor shrinkage rates presenting within 24 months had longer PFS and OS compared to those presenting after 24 months. This suggests that patients with the best tumor shrinkage rates after 24 months can still derive significant survival benefits from continued combination therapy targeting immunization, even in the presence of tumor growth during ongoing treatment. Further subgroup analysis showed that compared with patients whose disease status was SD assessed at 24 months of immunotherapy, patients assessed with PR had longer PFS on extended therapy. This conclusion has also been confirmed in the treatment of advanced melanoma [ 24 ] .While studies in lung cancer and melanoma have shown sustained survival benefits after discontinuing ICIs [ 11 , 29 , 30 ] , in real-world practice, most patients opt to continue treatment when they achieve sustained disease control and acceptable toxicity. The limitations of this study are as follows: Firstly, the relatively small sample size and the nature of single-center studies may have led to selection bias. Secondly, we only demonstrated the efficacy of prolonged treatment without comparing it with patients who did not continue treatment, so the results should be interpreted with caution. The conclusions of this study need to be further validated in larger prospective controlled studies. Conclusion Our analysis of real-world data indicates that patients who estimated disease control after 2 years of ICIs-TKIs treatment demonstrate sustained survival benefits and manageable toxicity following extended ICIs therapy. Patients who achieve the optimal tumor shrinkage rates after 24 months of treatment, even if tumor size increases post-treatment, can still derive long-term benefits from ICIs-TKIs as long as they do not meet progression disease criteria. In the absence of a direct control group, large-scale clinical trials and long-term follow-up are necessary to determine the appropriateness of duration of ICIs treatment. Declarations Funding: This work was supported by the Natural Science Foundation of China (NSFC 82202901, 82203110, 82273047, 82172785, 82103097, 81902577, 81974398, 81872107 and 81872108), China Postdoctoral Science Foundation (2020M673239, 2021M692286 and 2021M692281), Research Foundation for the Postdoctoral Program of Sichuan University (2021SCU12014 and 2022SCU12042), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC21020), Science and Technology Support Program of Sichuan Province (2021YFS0119), the Natural Science Foundation of Si Chuan Province (2023NSFSC1856, 2023NSFSC1858, 2023NSFSC1857), Natural Science Foundation of Sichuan Province (23NSFSC2454), Post-Doctor Research Project, West China Hospital, Sichuan University (20HXBH026, 2021HXBH036 and 2021HXBH028). Author contributions: QW and XMZ performed data collection and analysis. QW and XMZ were responsible for design of this study and the first draft of this manuscript. QW, XMZ, QYZ,Hong Zeng and JDD interpreted the results and wrote the final version of this manuscript. JGZ, JRC, GXS and ZHL helped formatting the final manuscript. PFS and Hao Zeng provided methodology consultation and critical revision of this manuscript. PFS and Hao Zeng are the co-corresponding authors of this manuscript. All authors read and approved the final manuscript. Consent for publication: Not Applicable Conflict of interest: The authors declare that the study is conducted without any financial relationship and without competing conflicts of interest. Data availability statement: Original contributions in this study are included in the article/supplementary information, and further requests may be directed to the corresponding author. 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Supplementary Files Supplement1.jpg Supplement 1 The survival curve for comparing the best objective response appeared both before and after 24 months Progression-free survival(A) and Overall survival(B) mPFS: median progression-free survival; NR:not reached; HR:Hazard Ratio Supplement2.jpg Supplement 2 The survival curves for patients with stable disease (SD) or partial response (PR) at 24 months of immunotherapy. SD:stable disease; PR:partial response;NR:not reached; HR:Hazard Ratio; mPFS: median progression-free survival Supplement3.docx Supplement 3 Treatment-related adverse events in the overall population, Before the slash indicates adverse events occurring within ≤24 months, while after the slash indicates adverse events occurring beyond 24 months. 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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-5416848","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":379881276,"identity":"6de107ea-9b95-4c33-9359-9b8db10a7a1d","order_by":0,"name":"Qian Wang","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Wang","suffix":""},{"id":379881277,"identity":"d80e4edd-76be-4aa7-86f8-873cc2b711d3","order_by":1,"name":"Xingming Zhang","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Xingming","middleName":"","lastName":"Zhang","suffix":""},{"id":379881280,"identity":"a5880d57-be99-455c-9393-45eec99c85c6","order_by":2,"name":"Qiyu zhu","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Qiyu","middleName":"","lastName":"zhu","suffix":""},{"id":379881281,"identity":"274b9723-7382-4824-b7fe-2a63da86a3cf","order_by":3,"name":"Hong Zeng","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Hong","middleName":"","lastName":"Zeng","suffix":""},{"id":379881284,"identity":"ca80c7b2-896b-40c1-aa09-d532a12efafd","order_by":4,"name":"Jindong Dai","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Jindong","middleName":"","lastName":"Dai","suffix":""},{"id":379881285,"identity":"26fd6748-3655-417d-88b1-3f46892deb73","order_by":5,"name":"Junru Chen","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Junru","middleName":"","lastName":"Chen","suffix":""},{"id":379881286,"identity":"2504ea42-6f7d-4db2-98b0-51f32a580c74","order_by":6,"name":"Jinge Zhao","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Jinge","middleName":"","lastName":"Zhao","suffix":""},{"id":379881287,"identity":"c5e6e916-121c-40bc-a18c-b9537533a5c9","order_by":7,"name":"Guangxi Sun","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Guangxi","middleName":"","lastName":"Sun","suffix":""},{"id":379881288,"identity":"6661458e-c64c-47b7-b0b4-6f3caea0c62d","order_by":8,"name":"Zhenhua Liu","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Zhenhua","middleName":"","lastName":"Liu","suffix":""},{"id":379881289,"identity":"9b74e143-f7df-49e0-83f7-caa6881ee9dd","order_by":9,"name":"Hao Zeng","email":"","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Zeng","suffix":""},{"id":379881290,"identity":"2e3de3fb-8a96-41f6-ba05-ce6cfb9c3ec5","order_by":10,"name":"Pengfei Shen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsElEQVRIiWNgGAWjYFCCHAbmHwYScmzs7QdI0MJQYGPMx3MmgRQtH9IS50k4GBCngb8995h0gcHh9DYJhgSGHxXbCGuROPMu2XiGweHcNunGA4w9Z24T1mIgkWP4gAekReZAAjNjG3FaDA4AtaSzSSQYEK3F8DGPQVoC8VokzrwxNpxhYGPYBgzkg0T5hb89x0ziwx8Jefn29oMPflQQoQUFHCBR/SgYBaNgFIwCXAAAsUE6A+Dx6wAAAAAASUVORK5CYII=","orcid":"","institution":"West China Hospital of Sichuan University","correspondingAuthor":true,"prefix":"","firstName":"Pengfei","middleName":"","lastName":"Shen","suffix":""}],"badges":[],"createdAt":"2024-11-08 13:23:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5416848/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5416848/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11255-024-04344-7","type":"published","date":"2024-12-24T15:57:20+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":71483144,"identity":"a27dd6f1-5a35-4fea-a969-ad506eced7d4","added_by":"auto","created_at":"2024-12-16 06:19:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65171,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of included patients.\u003c/p\u003e\n\u003cp\u003emRCC:metastatic renal cell carcinoma; ICI:Immune checkpoint inhibitor; TKI:Tyrosine kinase inhibitor\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5416848/v1/869f5309c5aabfac5803a9f5.jpg"},{"id":71482840,"identity":"13458490-89c5-4005-95dd-86a89a936609","added_by":"auto","created_at":"2024-12-16 06:11:28","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":77332,"visible":true,"origin":"","legend":"\u003cp\u003eSwimmer plot representation of each patient outcomes.\u003c/p\u003e\n\u003cp\u003eSD:stable disease; PR:partial response; CR:complete response; partial response\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5416848/v1/5108383731b5b1e69badd316.jpg"},{"id":71482838,"identity":"999290d6-45df-4052-863d-c7eb3ed01a9d","added_by":"auto","created_at":"2024-12-16 06:11:28","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":114258,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in the disease response of each patient during extended treatment. The images depict alterations in disease progression in the case of ccRCC8.\u003cstrong\u003eNA:\u003c/strong\u003ePatients who did not achieve the scheduled follow-up time.\u003c/p\u003e\n\u003cp\u003eSD:stable disease; PR:partial response; CR:complete response; partial response; PD:progress disease\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5416848/v1/913e4f600b5c2ef601423fc3.jpg"},{"id":71483145,"identity":"91c86adc-bca3-4414-8405-2f2287f45409","added_by":"auto","created_at":"2024-12-16 06:19:28","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":47324,"visible":true,"origin":"","legend":"\u003cp\u003eThe overall population survival curve includes Progression-free survival(A) and Overall survival(B)\u003c/p\u003e\n\u003cp\u003ePFS:Progression-free survival; OS:Overall survival\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5416848/v1/dfdf2caa096c4fee8e4d7f8d.jpg"},{"id":72640543,"identity":"43b048e0-da15-45ae-96ac-bcddfdee2b84","added_by":"auto","created_at":"2024-12-30 16:06:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":837014,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5416848/v1/b7978081-d408-45fe-8b51-40aa06847fe3.pdf"},{"id":71482842,"identity":"35cbe52c-2d5a-4953-9929-3c669c40856e","added_by":"auto","created_at":"2024-12-16 06:11:28","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28698,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplement 1 \u003c/strong\u003eThe survival curve for comparing the best objective response appeared both before and after 24 months Progression-free survival(A) and Overall survival(B)\u003c/p\u003e\n\u003cp\u003emPFS: median progression-free survival; NR:not reached; HR:Hazard Ratio\u003c/p\u003e","description":"","filename":"Supplement1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5416848/v1/b963812b7f43cfaa8e6874d3.jpg"},{"id":71483143,"identity":"cd2e370a-b18a-4f7a-bc0e-29d8eb3ff5bd","added_by":"auto","created_at":"2024-12-16 06:19:28","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23926,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplement 2 \u003c/strong\u003eThe survival curves for patients with stable disease (SD) or partial response (PR) at 24 months of immunotherapy.\u003c/p\u003e\n\u003cp\u003eSD:stable disease; PR:partial response;NR:not reached; HR:Hazard Ratio; mPFS: median progression-free survival\u003c/p\u003e","description":"","filename":"Supplement2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5416848/v1/aeb1496182e907d9440370b8.jpg"},{"id":71482839,"identity":"90bdc7c3-1b57-4aa7-b0ca-60b37be25ba6","added_by":"auto","created_at":"2024-12-16 06:11:28","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":12647,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplement 3 \u003c/strong\u003eTreatment-related adverse events in the overall population, Before the slash indicates adverse events occurring within ≤24 months, while after the slash indicates adverse events occurring beyond 24 months.\u003c/p\u003e","description":"","filename":"Supplement3.docx","url":"https://assets-eu.researchsquare.com/files/rs-5416848/v1/27695037419e22285287473d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Application of extended immunotherapy in advanced clear cell renal cell carcinoma treated with first-line combination of immune-checkpoint inhibitor and tyrosine kinase inhibitor","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRenal cell carcinoma (RCC) constitutes approximately 85% of all kidney cancers, making it the most common subtype\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. According to the most recent reports, it was projected that there were approximately 430,000 new cases of kidney cancer worldwide in 2022, resulting in an estimated 150,000 deaths from the disease\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Despite advancements in techniques of early detection for RCC, about 25\u0026ndash;30% of patients still present with metastatic disease upon initial diagnosis, while around 20% experience relapse or metastasis following nephrectomy\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. With the emergence of the immunotherapy era, the combination therapy of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors(TKIs) has become the established first-line treatment for patients with advanced clear cell renal cell carcinoma (ccRCC)\u003csup\u003e[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough the combination therapy with ICIs has revolutionized the treatment of patients with advanced ccRCC and significantly improved clinical outcomes, there is currently no established standard protocol for the duration of ICIs use\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. The discontinuation of ICIs may also lead to disease remission in cases where it has been observed in metastatic melanoma\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. The continued utilization of ICIs is correlated with superior survival benefits compared to the discontinuation of ICIs in patients with advanced non-small cell lung cancer\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Although the efficacy of ICIs can be sustained in certain patients with advanced RCC, even after discontinuation, as demonstrated by these studies\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e,the discontinuation of ICIs or the continuation of ICI therapy in patients with advanced ccRCC, who have achieved disease control or do not experience intolerable toxic effects, remains a subject of controversy regarding its impact on patient outcomes\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. The objective of this study was to evaluate the efficacy and safety associated with continued ICIs therapy in real-world clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patient population\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective analysis of data from patients with advanced ccRCC who underwent first-line TKIs-ICIs combination therapy at West China Hospital of Sichuan University between October 2018 and July 2024. The inclusion criteria encompassed adult patients aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years with newly diagnosed stage IV or recurrent ccRCC. The first-line ICIs-TKIs combination was administered, and ICIs were utilized continuously for over 2 years. All patients exhibited measurable disease according to RECIST version 1.1\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e and a Karnofsky performance status score of 70 or higher at baseline\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. The exclusion criteria included symptomatic central nervous system metastasis, active autoimmune disease, uncontrolled hypertension (systolic blood pressure\u0026thinsp;\u0026ge;\u0026thinsp;150 mm Hg or diastolic blood pressure\u0026thinsp;\u0026ge;\u0026thinsp;90 mm Hg), ongoing systemic immunosuppressive therapy, as well as patients diagnosed with other malignant diseases or life-threatening major diseases were also excluded from the analysis.\u003c/p\u003e \u003cp\u003e The study was approved by the Biomedical Research Ethics Committee of West China Hospital, Sichuan University. All procedures involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment and outcome\u003c/h3\u003e\n\u003cp\u003eAll enrolled patients were administered first-line combination therapy of ICIs-TKIs (such as axitinib plus pembrolizumab, axitinib plus sintilimab, axitinib plus toripalimab, etc.). Patients who are assessed as having a positive disease status (disease control status) after 2 years of continuous treatment will continue to receive immune checkpoint inhibitors until the inhibitors are discontinued due to disease progression or death. During the course of treatment, all patients underwent CT or MRI evaluations every 1\u0026ndash;3 months until disease progression, discontinuation of immunological drugs or death occurred. All patients exhibited measurable disease according to RECIST version 1.1.\u003c/p\u003e \u003cp\u003eThe primary endpoints included PFS, OS and ORR. Secondary endpoints encompassed AEs related to immunotherapy. PFS was defined as the duration from initiation of ICIs-TKIs treatment to disease progression or death, while OS was defined as the duration from initiation of ICIs-TKIs treatment to death or loss of follow-up due to various causes. The objective response rate (ORR) was defined as the proportion of patients with a confirmed complete response (CR) or partial response (PR) among all treated patients, while the disease control rate (DCR) was defined as the proportion of patients with confirmed CR, PR or stable disease (SD) among all treated patient. The best objective response was defined as the reduction of the tumor to a minimal size or complete disappearance during treatment. The severity of treatment-related adverse events was assessed using the Common Terminology Criteria for AEs (CTCAE, version 5.0).\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe quantitative variable data were compared using a t-test, while the categorical variable data were analyzed using a chi-square (χ2) test. Kaplan-Meier survival curves were utilized to illustrate the survival on prolongation therapy and differences in survival between different groups. Sankey charts and bar charts were employed to display the treatment response at various time points. All statistical analyses were conducted using Graph Pad Prism 8.0.1, SPSS version 26.0 software, and R (version 4.3.1). A P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of enrolled patients\u003c/h2\u003e \u003cp\u003eAfter screening of 86 patients, the study enrolled a total of 14 ccRCC patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and their baseline characteristics were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median follow-up was 40 months. 11 patients (78.6%) had received surgical removal of the primary lesion,including 4 patients with partial nephrectomy(PN) and 7 patients with radical nephrectomy(RN). The predominant sites of metastasis were the lung (64.3%) and lymph nodes (35.7%), liver (28.6%), pancreas (21.4%) and bone (14.3%). At the initiation of first-line treatment, 5 (35.7%), 8 (57.1%) and 1 (7.1%) patient were stratified into the high-risk, intermediate-risk, and low-risk categories according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline data regarding the clinical characteristics of patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003cp\u003eN (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53(37\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(71.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(28.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(14.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12(85.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWHO/ISUP\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(28.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(71.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(35.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(42.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(21.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIMDC risk group\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFavorable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(35.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(57.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(7.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eT stage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(71.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(28.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNephrectomy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(78.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(21.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetastatic sites\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(64.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elymph node\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(35.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(28.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(28.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePancreas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(21.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(14.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of metastatic sites\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3(21.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11(78.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFrist-line treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAxitinib\u0026thinsp;+\u0026thinsp;Pembrolizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(14.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAxitinib\u0026thinsp;+\u0026thinsp;Sintilimab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(35.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAxitinib\u0026thinsp;+\u0026thinsp;Toripalimab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eResponse status at 24 months\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(35.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(64.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0(0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThe optimal time for tumor response\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;24 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(64.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;24 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(35.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eIMDC: International Metastatic Renal-Cell Carcinoma Database Consortium;SD:stable disease; PR:partial response; CR:complete response; ISUP:international society of urological pathology; ECOG:eastern cooperative oncology group.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAfter 24 months of treatment with ICIs-TKIs, the response assessment showed that 5 cases (35.7%) were classified as SD, 9 cases (64.3%) were classified as PR. The treatment modality and tumor response for each patient are also outlined in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eTumor response\u003c/h2\u003e \u003cp\u003eIn the entire cohort, 12 patients (85.7%) achieved an optimal tumor response of PR and 2 patients (14.3%) achieved an optimal tumor response of CR. Specifically, 10 patients (71.4%) had an optimal tumor response of PR after \u0026le;\u0026thinsp;24 months of treatment, 10 patients(71.4%) had an optimal tumor response of PR and 2 patients(14.3%) had a response of CR after \u0026gt;\u0026thinsp;24 months of treatment. Notably, there was a change in tumor response from SD to PR in one patient (7.1%) and from PR to CR in two patients (14.3%) during extended therapy \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter 3 months of extended ICIs treatment, disease progression occurred in four patients, and one patient experienced disease progression at 12 months. The initial diagnosis revealed distant metastases in 3 patients, who subsequently underwent primary reductive resection. During extended therapy, 5 patients(35.7%) transitioned to alternative ICIs due to PD, while 4 patients(80%) achieved PR following the switch\u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurvival outcome\u003c/h3\u003e\n\u003cp\u003eIn the overall population, 3-year PFS rate was 71.4% and 4-year PFS rate was 59.5%, with a median PFS that has not been reached \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA\u003cb\u003e)\u003c/b\u003e. The 5-year OS rate was 58.3%, and the median OS has not been reached \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSubgroup analyses were conducted to compare PFS and OS in patients with the best tumor shrinkage rates before and after 24 months of treatment. The findings indicated that patients who achieved the best tumor shrinkage rates after 24 months experienced longer PFS and OS compared to those who achieved the best tumor shrinkage rates 24 months earlier (median PFS not reached vs. 36months; Hazard Ratio (HR)\u0026thinsp;=\u0026thinsp;0.10; 95%CI 0.01\u0026ndash;0.80 P\u0026thinsp;=\u0026thinsp;0.03; median OS not reached vs. 43months; HR\u0026thinsp;=\u0026thinsp;0.18; 95%CI 0.02\u0026ndash;2.13, P\u0026thinsp;=\u0026thinsp;0.18; \u003cb\u003eSupplement 1\u003c/b\u003e). Compared with patients whose disease status was SD assessed at 24 months of immunotherapy, patients assessed with PR had longer PFS on extended therapy (median PFS not reached vs. 3months; HR\u0026thinsp;=\u0026thinsp;0.26; 95%CI 0.03\u0026ndash;2.02 P\u0026thinsp;=\u0026thinsp;0.20; \u003cb\u003eSupplement 2\u003c/b\u003e)\u003c/p\u003e\n\u003ch3\u003eSafety of extended treatment\u003c/h3\u003e\n\u003cp\u003eDuring the course of treatment, all 14 patients experienced adverse events that were related to the treatment. There were 2 cases (14.3%) before treatment and 6 cases (42.9%) after treatment with grade\u0026thinsp;\u0026ge;\u0026thinsp;3AEs (P\u0026thinsp;=\u0026thinsp;0.21). Adverse events such as hypertension, proteinuria, hyperlipidemia, and diarrhea were frequently observed both before and after the 24-month mark. Five patients (35.7%) experienced the onset of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 hypertension after 24 months of treatment \u003cb\u003e(Supplement 3).\u003c/b\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the inaugural real-world study to investigate the efficacy and toxicity of ICIs extended therapy. According to the study findings, patients who demonstrated a positive response to ICIs-TKIs for 2 years and continued ICIs treatment achieved favorable outcomes in terms of both efficacy and safety. One patient's tumor response transitioned from SD to PR during extended therapy, and two patients achieved CR during extended treatment. Four patients achieved PR after transitioning to alternative ICIs despite experiencing disease progression during extended treatment.\u003c/p\u003e \u003cp\u003eThe combination therapy of first-line ICIs-TKIs has significantly enhanced PFS and OS in patients with advanced renal cell carcinoma\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. However, the duration of first-line ICIs-TKIs treatment in patients with advanced clear cell renal cell carcinoma remains uncertain due to the lack of clinical evidence\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. In clinical trials, the duration of immunotherapy has varied due to a lack of standardized guidelines, with the majority discontinuing treatment as a result of disease progression or unacceptable toxicity\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.The duration of immunotherapy in the KEYNOT-426 and CLEAR studies was intended to be two years\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. In the KEYNOT-426 study, 120 patients completed the 2-year treatment cycle and then discontinued. The median PFS was 37.4 months, with a PFS rate of 55.2% at 36 months and a PFS rate of 32.8% at 60 months\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.The two aforementioned trials discontinued the use of ICIs after 2 years of ICIs-TKIs treatment. The follow-up results indicated that there was some efficacy in terms of PFS, but it did not appear to confer any advantage in improving PFS compared to continuing ICI use after 2 years.\u003c/p\u003e \u003cp\u003eThe impact of ongoing versus discontinued ICIs treatment on PFS and OS was also compared across different cancer types. The discontinuation of ICIs may also lead to disease remission in cases where it has been observed in metastatic melanoma\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The KEYNOTE-010 and CA209-003 studies indicate that a fixed regimen of immunotherapy may also yield enduring benefits for patients with advanced NSCLC\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e.Studies on immunotherapy in advanced melanoma have demonstrated sustained survival benefits even after discontinuation of Pembrolizumab for 2 years. Subgroup analysis revealed that patients who were assessed with SD and PR at the time of discontinuation had slightly worse survival outcomes compared to those with CR\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. The discontinuation of ICIs may also lead to disease remission in cases where it has been observed in metastatic melanoma\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.The early recurrence observed after discontinuation of immunotherapy, regardless of tumor type, may be attributed to the cessation of PD-1/PD-L1 inhibition\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Upon discontinuation of chronic PD-1/PD-L1 blocking, resistance mechanisms may also emerge\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. Although there may be a sustained survival benefit from discontinuation of immune drugs in certain tumor types, the decision to discontinue remains controversial when there was a positive response to treatment and no intolerable adverse effects\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere is an ongoing debate regarding the discontinuation of ICIs in advanced renal cell carcinoma, and currently, there are no clear criteria for stopping ICIs in the absence of disease progression or unacceptable toxicity. Our study demonstrated that patients who completed 2 years of ICIs-TKIs and exhibited a positive response experienced sustained survival benefits and favorable toxicity profiles during extended ICIs treatment. Meanwhile, our study also demonstrated that the best tumor shrinkage rates presenting within 24 months had longer PFS and OS compared to those presenting after 24 months. This suggests that patients with the best tumor shrinkage rates after 24 months can still derive significant survival benefits from continued combination therapy targeting immunization, even in the presence of tumor growth during ongoing treatment. Further subgroup analysis showed that compared with patients whose disease status was SD assessed at 24 months of immunotherapy, patients assessed with PR had longer PFS on extended therapy. This conclusion has also been confirmed in the treatment of advanced melanoma\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e.While studies in lung cancer and melanoma have shown sustained survival benefits after discontinuing ICIs\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e, in real-world practice, most patients opt to continue treatment when they achieve sustained disease control and acceptable toxicity.\u003c/p\u003e \u003cp\u003eThe limitations of this study are as follows: Firstly, the relatively small sample size and the nature of single-center studies may have led to selection bias. Secondly, we only demonstrated the efficacy of prolonged treatment without comparing it with patients who did not continue treatment, so the results should be interpreted with caution. The conclusions of this study need to be further validated in larger prospective controlled studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur analysis of real-world data indicates that patients who estimated disease control after 2 years of ICIs-TKIs treatment demonstrate sustained survival benefits and manageable toxicity following extended ICIs therapy. Patients who achieve the optimal tumor shrinkage rates after 24 months of treatment, even if tumor size increases post-treatment, can still derive long-term benefits from ICIs-TKIs as long as they do not meet progression disease criteria. In the absence of a direct control group, large-scale clinical trials and long-term follow-up are necessary to determine the appropriateness of duration of ICIs treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003eThis work was supported by the Natural Science Foundation of China (NSFC 82202901, 82203110, 82273047, 82172785, 82103097, 81902577, 81974398, 81872107 and 81872108), China Postdoctoral Science Foundation (2020M673239, 2021M692286 and 2021M692281), Research Foundation for the Postdoctoral Program of Sichuan University (2021SCU12014 and 2022SCU12042), 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC21020), Science and Technology Support Program of Sichuan Province (2021YFS0119), the Natural Science Foundation of Si Chuan Province (2023NSFSC1856, 2023NSFSC1858, 2023NSFSC1857), Natural Science Foundation of Sichuan Province (23NSFSC2454), Post-Doctor Research Project, West China Hospital, Sichuan University (20HXBH026, 2021HXBH036 and 2021HXBH028).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e QW and XMZ performed data collection and analysis. QW and XMZ were responsible for design of this study and the first draft of this manuscript. QW, XMZ, QYZ,Hong Zeng and JDD interpreted the results and wrote the final version of this manuscript. JGZ, JRC, GXS and ZHL helped formatting the final manuscript. PFS and Hao Zeng provided methodology consultation and critical revision of this manuscript. PFS and Hao Zeng are the co-corresponding authors of this manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e The authors declare that the study is conducted without any financial relationship and without competing conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e Original contributions in this study are included in the article/supplementary information, and further requests may be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eWe have secured the informed consent of all participants involved in the study and all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (name of institute/committee) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBarata P C, Rini B I. Treatment of renal cell carcinoma: Current status and future directions[J]. CA: A Cancer Journal for Clinicians, 2017, 67(6): 507\u0026ndash;524.\u003c/li\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, etc. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA: A Cancer Journal for Clinicians, 2024: caac.21834.\u003c/li\u003e\n\u003cli\u003eZnaor A, Lortet-Tieulent J, Laversanne M, etc. International Variations and Trends in Renal Cell Carcinoma Incidence and Mortality[J]. European Urology, 2015, 67(3): 519\u0026ndash;530.\u003c/li\u003e\n\u003cli\u003eRiaz I B, He H, Ryu A J, etc. A Living, Interactive Systematic Review and Network Meta-analysis of First-line Treatment of Metastatic Renal Cell Carcinoma[J]. European Urology, 2021, 80(6): 712\u0026ndash;723.\u003c/li\u003e\n\u003cli\u003eRini B I, Plimack E R, Stus V, etc. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma[J]. New England Journal of Medicine, 2019, 380(12): 1116\u0026ndash;1127.\u003c/li\u003e\n\u003cli\u003eEuropean Association of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update - PubMed[EB/OL]. /2024-04-10. https://pubmed.ncbi.nlm.nih.gov/35346519/.\u003c/li\u003e\n\u003cli\u003eMotzer R J, Tannir N M, McDermott D F, etc. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma[J]. New England Journal of Medicine, 2018, 378(14): 1277\u0026ndash;1290.\u003c/li\u003e\n\u003cli\u003eSingla N, Freifeld Y, Ghandour R A, etc. Rational Approaches to Treatment Duration with Immunotherapy in Metastatic Renal Cell Carcinoma[J]. European Urology Focus, 2020, 6(1): 31\u0026ndash;33.\u003c/li\u003e\n\u003cli\u003eRobert C, Marabelle A, Herrscher H, etc. Immunotherapy discontinuation - how, and when? Data from melanoma as a paradigm[J]. Nature Reviews Clinical Oncology, 2020, 17(11): 707\u0026ndash;715.\u003c/li\u003e\n\u003cli\u003eWaterhouse D M, Garon E B, Chandler J, etc. Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: CheckMate 153[J]. Journal of Clinical Oncology, 2020, 38(33): 3863\u0026ndash;3873.\u003c/li\u003e\n\u003cli\u003eFriedlaender A, Kim C, Addeo A. Rethinking the Optimal Duration of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer Throughout the COVID-19 Pandemic[J]. Frontiers in Oncology, 2020, 10: 862.\u003c/li\u003e\n\u003cli\u003eMcDermott D F, Drake C G, Sznol M, etc. Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab[J]. Journal of Clinical Oncology, 2015, 33(18): 2013\u0026ndash;2020.\u003c/li\u003e\n\u003cli\u003eTzeng A, Tzeng T H, Ornstein M C. Treatment-free survival after discontinuation of immune checkpoint inhibitors in metastatic renal cell carcinoma: a systematic review and meta-analysis[J]. Journal for ImmunoTherapy of Cancer, 2021, 9(10): e003473.\u003c/li\u003e\n\u003cli\u003eEisenhauer E A, Therasse P, Bogaerts J, etc. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)[J]. European Journal of Cancer, 2009, 45(2): 228\u0026ndash;247.\u003c/li\u003e\n\u003cli\u003eSchag C C, Heinrich R L, Ganz P A. Karnofsky performance status revisited: reliability, validity, and guidelines.[J]. Journal of Clinical Oncology, 1984, 2(3): 187\u0026ndash;193.\u003c/li\u003e\n\u003cli\u003eMotzer R, Alekseev B, Rha S-Y, etc. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma[J]. New England Journal of Medicine, 2021, 384(14): 1289\u0026ndash;1300.\u003c/li\u003e\n\u003cli\u003eChoueiri T K, Powles T, Burotto M, etc. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma[J]. New England Journal of Medicine, 2021, 384(9): 829\u0026ndash;841.\u003c/li\u003e\n\u003cli\u003eYan X Q, Ye M J, Zou Q, etc. Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study[J]. Annals of Oncology, 2024, 35(2): 190\u0026ndash;199.\u003c/li\u003e\n\u003cli\u003ePowles T, Plimack E R, Souli\u0026egrave;res D, etc. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial[J]. The Lancet Oncology, 2020, 21(12): 1563\u0026ndash;1573.\u003c/li\u003e\n\u003cli\u003eMotzer R J, Porta C, Eto M, etc. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study[J]. Journal of Clinical Oncology, 2024, 42(11): 1222\u0026ndash;1228.\u003c/li\u003e\n\u003cli\u003eASCO 2023: Pembrolizumab + Axitinib Versus Sunitinib as First-Line Therapy for Advanced Clear Cell RCC: 5-Year Analysis of KEYNOTE-426[EB/OL]. /2024-04-13. https://www.urotoday.com/conference-highlights/asco-2023/asco-2023-kidney-cancer/144965-asco-2023-pembrolizumab-axitinib-versus-sunitinib-as-first-line-therapy-for-advanced-clear-cell-rcc-5-year-analysis-of-keynote-426.html.\u003c/li\u003e\n\u003cli\u003eHerbst R S, Garon E B, Kim D-W, etc. Five Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel for Previously Treated, Programmed Death-Ligand 1-Positive Advanced NSCLC[J]. Journal of Thoracic Oncology, 2021, 16(10): 1718\u0026ndash;1732.\u003c/li\u003e\n\u003cli\u003eRobert C, Ribas A, Schachter J, etc. Five-Year Follow-Up of Nivolumab in Previously Treated Advanced Non\u0026ndash;Small-Cell Lung Cancer: Results From the CA209-003 Study[J]. The Lancet Oncology, 2019, 20(9): 1239\u0026ndash;1251.\u003c/li\u003e\n\u003cli\u003eGettinger S, Horn L, Jackman D, etc. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study[J]. Journal of Clinical Oncology, 2018, 36(17): 1675\u0026ndash;1684.\u003c/li\u003e\n\u003cli\u003eJansen Y, Rozeman E A, Foppen M G, etc. Real life outcome of advanced melanoma patients who discontinue pembrolizumab (PEMBRO) in the absence of disease progression.[J]. Journal of Clinical Oncology, Wolters Kluwer, 2017, 35(15_suppl): 9539\u0026ndash;9539.\u003c/li\u003e\n\u003cli\u003eArlauckas S P, Garris C S, Kohler R H, etc. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy[J]. Science Translational Medicine, 2017, 9(389): eaal3604.\u003c/li\u003e\n\u003cli\u003eRamos P, Bentires-Alj M. Mechanism-based cancer therapy: resistance to therapy, therapy for resistance[J]. Oncogene, 2015, 34(28): 3617\u0026ndash;3626.\u003c/li\u003e\n\u003cli\u003eBaik C S, Rubin E H, Forde P M, etc. Immuno-oncology Clinical Trial Design: Limitations, Challenges, and Opportunities[J]. Clinical Cancer Research, 2017, 23(17): 4992\u0026ndash;5002.\u003c/li\u003e\n\u003cli\u003eRobert C, Ribas A, Hamid O, etc. Durable Complete Response After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma[J]. Journal of Clinical Oncology, 2018, 36(17): 1668\u0026ndash;1674.\u003c/li\u003e\n\u003cli\u003eHamid O, Robert C, Daud A, etc. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001[J]. Annals of Oncology, 2019, 30(4): 582\u0026ndash;588.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"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},"keywords":"adverse events, clear cell renal cell carcinoma, extended therapy, immune checkpoint inhibitor, tyrosine kinase inhibitor","lastPublishedDoi":"10.21203/rs.3.rs-5416848/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5416848/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo evaluate the efficacy and safety of extended immunotherapy in first-line immune checkpoint inhibitors (ICIs) - tyrosine kinase inhibitors (TKIs) combination treatment for advanced renal cell carcinoma (RCC).\u003c/p\u003e\u003ch2\u003ePatients and Methods:\u003c/h2\u003e \u003cp\u003eWe retrospectively analyzed data from patients with advanced RCC who received first-line ICIs-TKIs combination treatment at West China Hospital of Sichuan University between October 2018 and July 2024. Patients who are assessed as having a disease control status after 2 years of continuous treatment will continue to receive immune checkpoint inhibitors until the inhibitors are discontinued due to disease progression or death.\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eA total of 86 patients were screened and 14 patients diagnosed with clear cell RCC (ccRCC) were enrolled. After 65 months of follow-up, three-year progression-free survival (PFS) rate was 71.4% and 4-year PFS rate was 59.5%. The 5-year overall survival (OS) rate was 58.3%. During extended treatment, one patient (7.1%) experienced a transition from stable disease (SD) to partial response (PR) and two patients (14.3%) experienced a transition from PR to complete response (CR). The best tumor shrinkage rates presenting after 24 months had longer PFS and OS compared to those presenting within 24 months (median PFS: not reached vs. 36 months; Hazard Ratio (HR)\u0026thinsp;=\u0026thinsp;0.10, 95%CI 0.01\u0026ndash;0.80, P\u0026thinsp;=\u0026thinsp;0.03). For safety, extended immunotherapy did not increase treatment-related toxicities compared to safety profile before 24 months.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur analysis of real-world data indicates that patients with extended immunotherapy after 24 months had sustained survival benefits and manageable toxicity. Large-scale, prospective studies are still needed to further verify the conclusion.\u003c/p\u003e","manuscriptTitle":"Application of extended immunotherapy in advanced clear cell renal cell carcinoma treated with first-line combination of immune-checkpoint inhibitor and tyrosine kinase inhibitor","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-16 06:11:23","doi":"10.21203/rs.3.rs-5416848/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":"590df19a-3690-4926-9237-e61bea62f4f4","owner":[],"postedDate":"December 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-30T16:00:38+00:00","versionOfRecord":{"articleIdentity":"rs-5416848","link":"https://doi.org/10.1007/s11255-024-04344-7","journal":{"identity":"international-urology-and-nephrology","isVorOnly":false,"title":"International Urology and Nephrology"},"publishedOn":"2024-12-24 15:57:20","publishedOnDateReadable":"December 24th, 2024"},"versionCreatedAt":"2024-12-16 06:11:23","video":"","vorDoi":"10.1007/s11255-024-04344-7","vorDoiUrl":"https://doi.org/10.1007/s11255-024-04344-7","workflowStages":[]},"version":"v1","identity":"rs-5416848","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5416848","identity":"rs-5416848","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}