Midterm outcomes of combination therapy with immune checkpoint inhibitors and VEGFR-TKIs in real-world patients with advanced renal cell carcinoma

Midterm outcomes of combination therapy with immune checkpoint inhibitors and VEGFR-TKIs in real-world patients with advanced renal cell carcinoma | 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 Midterm outcomes of combination therapy with immune checkpoint inhibitors and VEGFR-TKIs in real-world patients with advanced renal cell carcinoma Hiroki Ishihara, Nanaka Katsurayama, Yuki Nemoto, Shinsuke Mizoguchi, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7771726/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Limited data are available on the midterm outcomes of combination therapy with immune checkpoint inhibitors and VEGFR-TKIs (IO-TKI therapy) for advanced renal cell carcinoma (RCC) in real-world settings. Methods We retrospectively evaluated clinical data from 68 patients who received lenvatinib plus pembrolizumab (n = 14), cabozantinib plus nivolumab (n = 20), pembrolizumab plus axitinib (n = 23), or avelumab plus axitinib (n = 11) as first-line therapy for advanced RCC. All patients had a minimum follow-up of 3 years after treatment initiation. Effectiveness and safety profiles were assessed. Results During a median follow-up of 32.7 months, the median progression-free survival (PFS) and overall survival (OS) were 19.9 and 46.7 months, respectively. The objective response rate was 57%. In subgroup analysis, histology was associated with survival outcomes; median PFS (23.0 vs. 8.97 months, p = 0.0362) and OS (not reached vs. 32.1 months, p = 0.0005) were longer in patients with clear-cell RCC than in those with non-clear cell RCC. Regarding safety, grade ≥ 3 adverse events occurred in 44 patients (65%). Treatment discontinuation of both drugs was required in 14 patients (21%), and discontinuation of one drug in 21 patients (31%). High-dose corticosteroids (≥ 40 mg prednisone/day) were required in 10 patients (15%). Conclusion With a minimum of 3 years of follow-up, IO-TKI therapy demonstrated feasible effectiveness and manageable safety in patients with advanced RCC in real-world. More effective treatment strategies and novel therapeutic targets are needed for patients with non-clear cell RCC. Immuno-oncology immunotherapy PD-1 PD-L1 targeted therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Combination therapy with immune checkpoint inhibitors (ICIs) and VEGFR-TKIs (IO-TKI therapy) has been approved as a standard first-line systemic treatment for advanced renal cell carcinoma (RCC). To date, three regimens—lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, and pembrolizumab plus axitinib—have demonstrated improved overall survival (OS) compared with sunitinib in patients with previously untreated advanced RCC in randomized phase III clinical trials [ 1 – 3 ]. In these pivotal trials, extended follow-up has consistently shown sustained efficacy and manageable safety of IO-TKI therapy [ 4 – 7 ]. Long-term follow-up provides stronger evidence for outcomes, particularly OS and treatment-related toxicities. However, real-world reports remain limited, with most studies assessing outcomes only up to 2 years [ 8 – 14 ]. In real-world practice, some patients are considered trial-ineligible due to characteristics such as non-clear cell histology, severe organ dysfunction, or brain metastases [ 15 ]. Since these patients are generally excluded from randomized phase III trials, evidence regarding IO-TKI outcomes in this population is lacking. Importantly, their prognosis after systemic therapy, including ICIs, may be worse than that reported in clinical trials [ 15 ]. Therefore, extended real-world follow-up data are needed to clarify the outcomes of IO-TKI therapy. In this context, we retrospectively evaluated the midterm outcomes of IO-TKI therapy for previously untreated advanced RCC using a minimum 3-year follow-up dataset collected from multiple institutions in Japan. 2. Patients and methods 2.1. Patient selection and study design At Tokyo Women’s Medical University and four affiliated institutions (Tokyo Women’s Medical University Adachi Medical Center, Saiseikai Kawaguchi General Hospital, Saiseikai Kazo Hospital, and Jyoban Hospital), a total of 71 patients received IO-TKI therapy (lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, pembrolizumab plus axitinib, or avelumab plus axitinib) initiated on or before September 2022, ensuring a minimum follow-up of 3 years. Three patients were excluded due to incomplete baseline data, leaving 68 patients for evaluation in this retrospective observational study. Treatment was continued until radiographic disease progression or the occurrence of intolerable adverse events (AEs). ICI doses could not be modified; however, administration intervals could be adjusted based on toxicity or patient condition. For TKIs, both dose and administration interval could be modified as needed. Effectiveness was assessed by progression-free survival (PFS), OS, and objective response rate (ORR). PFS was defined as the time from treatment initiation to disease progression or death, whichever occurred first. OS was defined as the time from treatment initiation to death. The cutoff date for outcome assessment was September 2025. Patients lost to follow-up were censored at the date of last contact. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 [ 16 ]. Computed tomography of the chest, abdomen, and pelvis was performed at 4–12 week intervals after treatment initiation, depending on the patient's condition. Magnetic resonance imaging, positron emission tomography/computed tomography, and brain imaging were performed when clinically indicated. Safety was assessed by evaluating the incidence of AEs, treatment discontinuation, and corticosteroid use. AEs were graded using the Common Terminology Criteria for Adverse Events version 5.0 [ 17 ]. The study protocol was approved by the Institutional Ethics Review Board of Tokyo Women’s Medical University (ID: 2020-0009). The study was conducted in accordance with the principles of the Declaration of Helsinki (1964) and its later amendments. Clinical and laboratory data were obtained from electronic databases and patient medical records. 2.2. Protocol for IO-TKI combination therapy The protocol for IO-TKI therapy as first-line treatment has been described previously [ 18 , 19 ]. In practice, lenvatinib plus pembrolizumab or nivolumab plus cabozantinib are preferentially selected for patients who require rapid and/or substantial tumor shrinkage due to disease-related symptoms, for use as presurgical therapy (for example, deferred cytoreductive nephrectomy), or for those with non-clear cell histology. Pembrolizumab plus axitinib or avelumab plus axitinib may be considered for patients with a favorable International Metastatic RCC Database Consortium (IMDC) risk, older patients, those with multiple or severe comorbidities, or individuals intolerant to corticosteroids because of AEs. Due to the timing of approval under the Japanese insurance system, pembrolizumab plus axitinib and avelumab plus axitinib were primarily used in the early period. However, lenvatinib plus pembrolizumab and nivolumab plus cabozantinib have since become the main IO-TKI regimens. Despite these trends, no consensus-based criteria for treatment selection have been established across our affiliated institutions. 2.3. Statistical analysis Baseline characteristics were summarized as numbers (%) for categorical variables and as medians with interquartile ranges for continuous variables. Categorical variables were compared using Fisher’s exact test. Survival was estimated using the Kaplan–Meier method and compared with the log-rank test. Risks were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). All analyses were performed using JMP software, version 17 (SAS Institute Inc., Cary, NC, USA). Statistical significance was defined as p < 0.05. 3. Results 3.1. Patient characteristics Table 1 summarizes patient characteristics. Forty-two patients (62%) were ≥ 65 years old, and 50 (74%) were male. Prior nephrectomy was performed in 47 patients (69%), and 45 (66%) had clear-cell RCC. Lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, pembrolizumab plus axitinib, and avelumab plus axitinib were administered in 14 (21%), 20 (29%), 23 (34%), and 11 (16%) patients, respectively. Based on IMDC risk classification, 12 (18%), 42 (62%), and 14 (21%) patients were categorized as favorable, intermediate, and poor risk, respectively. The median follow-up period was 32.7 months (interquartile range: 18.5–39.4 months). 3.2. Effectiveness During follow-up, 51 patients (75%) experienced disease progression, and 24 (35%) died. The median PFS was 19.9 months (95% CI: 13.8–26.0), and the median OS was 46.7 months (95% CI: 38.8–not reached) (Figure 1). Univariate analysis of PFS and OS showed that histology was the only factor significantly associated with survival. Clear-cell histology was associated with improved PFS (HR: 0.54, 95% CI: 0.30–0.97, p = 0.0393) and OS (HR: 0.25, 95% CI: 0.11–0.58, p = 0.0011) (Figures 2 and 3, Supplementary Table 1). Patients with clear-cell RCC had longer PFS (median: 23.0 months, 95% CI: 18.3–32.6 vs. 8.97 months, 95% CI: 4.31–18.1, p = 0.0362) and OS (median: not reached, 95% CI: 46.7–not reached vs. 32.1 months, 95% CI: 17.8–40.6, p = 0.0005) compared with those with non-clear cell RCC or unknown histology (Figure 4). Regarding tumor response, the ORR was 57%, including 5 patients (7%) with complete response and 34 (50%) with partial response (Figure 5, Table 2). ORRs by regimen were 70% for nivolumab plus cabozantinib, 57% for lenvatinib plus pembrolizumab, 52% for pembrolizumab plus axitinib, and 45% for avelumab plus axitinib. The median best tumor response among 66 evaluable patients was -35.0% (interquartile range: -56.7% to -13.6%). When stratified by histology, ORR tended to be higher in patients with clear-cell RCC than in those with non-clear cell RCC or unknown histology (64% vs. 43%, p = 0.124). The median best tumor response was also greater in patients with clear-cell RCC (-42.3%, 95% CI: -60.7% to -20.5%) than in those with non-clear cell or unknown histology (-24.3%, 95% CI: -43.7 to -11.0%, p = 0.0329). 3.3. Safety At least one AE of any grade occurred in all patients (100%); in contrast, grade ≥ 3 AEs developed in 44 patients (65%) (Table 3). Treatment discontinuation of both drugs was required in 14 patients (21%), and discontinuation of one drug in 21 patients (31%). Corticosteroids were administered to 23 patients (34%), including 10 (15%) who required high-dose treatment (≥ 40 mg prednisone per day). 4. Discussion This retrospective, multi-institutional study with a minimum follow-up of 3 years demonstrated that IO-TKI therapy provides feasible effectiveness and manageable safety for patients with previously untreated advanced RCC. A midterm survival benefit was observed regardless of baseline characteristics, except for histological subtype. To our knowledge, this is the first study to report midterm, real-world outcomes of first-line IO-TKI therapy for RCC. The effectiveness observed in this cohort is broadly comparable to results from phase III randomized clinical trials. For example, in the CLEAR trial, lenvatinib plus pembrolizumab achieved a median OS of 53.7 months, a median PFS of 23.9 months, and an ORR of 71.3% with approximately 4 years of follow-up [ 20 ]. The CheckMate 9ER trial reported median OS and PFS of 49.5 and 16.6 months, respectively, and an ORR of 56% for nivolumab plus cabozantinib at a median follow-up of 44.0 months [ 5 ]. In the KEYNOTE-426 trial, median OS and PFS for pembrolizumab plus axitinib were 46 and 16 months, respectively, with an ORR of 60% at 43 months of follow-up [ 6 ]. Similarly, the JAVELIN Renal 101 trial reported median OS and PFS of 44.8 and 13.9 months, respectively, and an ORR of 59.7% during a median follow-up of 73 months for avelumab plus axitinib [ 7 ]. Several real-world studies have also evaluated IO-TKI outcomes with meaningful follow-up durations. The ARON-1 study, using multi-center retrospective data with a median follow-up of 15.1 months, showed that 202 patients receiving lenvatinib plus pembrolizumab had a 2-year OS rate of 67%, median PFS of 15.1 months, and ORR of 59% [ 8 ]. The same group reported that among 333 patients receiving nivolumab plus cabozantinib, the 2-year OS rate was 75%, median PFS was 33.7 months, and ORR was 58% with a 15.9-month median follow-up [ 10 ]. In Italy, a prospective study of pembrolizumab plus axitinib in 170 patients showed a 2-year OS rate of 62%, a median PFS of 19.2 months, and a disease control rate of 84.6% at 19.3 months [ 12 ]. The J-DART2 study from Japan reported that avelumab plus axitinib achieved a 2-year OS rate of 84.7%, median PFS of 17.1 months, and ORR of 53.3% with 18.7 months of follow-up [ 13 ]. Collectively, the results of our study are consistent with these prior findings, suggesting that IO-TKI therapy maintains clinical activity even in real-world patients. In this study, treatment effectiveness was not influenced by baseline patient characteristics, supporting the broad feasibility of IO-TKI therapy. However, patients with non-clear cell RCC had worse survival outcomes compared with those with clear-cell histology, consistent with previous reports in patients treated with pembrolizumab plus axitinib [ 12 ]. We previously reported similar findings with nivolumab plus ipilimumab, where patients with non-clear cell RCC experienced poorer outcomes than those with clear-cell RCC at a minimum of 3 years of follow-up [ 21 ]. A recent network meta-analysis using clinical trial data indicated notable activity of IO-TKI therapy in patients with non-clear cell RCC [ 22 ]. However, given the persistent survival disadvantage in this subgroup, more effective treatment strategies and novel therapeutic targets are urgently needed [ 23 , 24 ]. Regarding safety, the CLEAR trial reported grade ≥ 3 AEs in 82.4% of patients receiving lenvatinib plus pembrolizumab, with treatment discontinuation in 37.2% [ 1 ]. In the CheckMate 9ER trial, 66.9% of patients experienced grade ≥ 3 treatment-related AEs, 27.5% discontinued at least one agent [ 5 ], and 21.9% required prolonged corticosteroid therapy (≥ 40 mg prednisone daily) [ 5 ]. In the KEYNOTE-426 trial, 68% of patients receiving pembrolizumab plus axitinib developed grade ≥ 3 AEs [ 6 ], and 7% discontinued both drugs [ 25 ]. Similarly, in the JAVELIN Renal 101 trial, 66.8% of patients treated with avelumab plus axitinib developed grade ≥ 3 AEs, and 15.4% required high-dose corticosteroids [ 7 ]. The safety outcomes in our study align with these clinical trial data, which is noteworthy given that real-world patients may have comorbidities or organ dysfunction (for example, renal impairment) that increase vulnerability to treatment-related toxicity [ 15 , 26 ]. This study has some limitations. First, its retrospective design and small sample size inevitably introduce selection bias, which may affect the findings. Second, the follow-up duration may still be insufficient to fully assess OS, potentially limiting interpretation. Third, subgroup analyses were based on univariate analysis, which are susceptible to confounding factors. 5. Conclusion This multi-institutional, real-world study with midterm follow-up demonstrated that first-line IO-TKI combination therapy provides feasible effectiveness and a manageable safety profile for patients with previously untreated advanced RCC. The outcomes were generally comparable to those reported in clinical trials, supporting the use of IO-TKI therapy in real-world. Further studies with longer follow-up and larger sample sizes are needed to evaluate the long-term OS benefit of this treatment in real-world settings. Declarations Conflicts of interest Toshio Takagi received honorariums from Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., Merck KGaA, and Takeda Pharmaceutical Co., Ltd. Tsunenori Kondo received honoraria from Pfizer, Novartis, Bristol-Myers Squibb, and Ono Pharmaceutical Co., Ltd. Funding None. Acknowledgements None. References Motzer R, Alekseev B, Rha SY et al (2021) Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med 384:1289-1300 Choueiri TK, Powles T, Burotto M et al (2021) Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 384:829-841 Rini BI, Plimack ER, Stus V et al (2019) Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 380:1116-1127 Motzer RJ, Choueiri TK, Hutson T et al (2024) Characterization of Responses to Lenvatinib plus Pembrolizumab in Patients with Advanced Renal Cell Carcinoma at the Final Prespecified Survival Analysis of the Phase 3 CLEAR Study. Eur Urol 86:4-9 Powles T, Burotto M, Escudier B et al (2024) Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open 9:102994 Plimack ER, Powles T, Stus V et al (2023) Pembrolizumab Plus Axitinib Versus Sunitinib as First-line Treatment of Advanced Renal Cell Carcinoma: 43-month Follow-up of the Phase 3 KEYNOTE-426 Study. Eur Urol 84:449-454 Choueiri TK, Penkov K, Uemura H et al (2025) Avelumab + axitinib versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma: final analysis of the phase III JAVELIN Renal 101 trial. Ann Oncol 36:387-392 Porta C, Massari F, Taha T et al (2025) Pembrolizumab plus Lenvatinib in patients with metastatic Renal Cell Carcinoma: real-world evidences from the international ARON- 1 study. Cancer Immunol Immunother 74:196 Hara T, Suzuki K, Okamura Y et al (2024) Efficacy and safety of lenvatinib and pembrolizumab as first-line treatment for advanced renal cell carcinoma patients: real-world experience in Japan. Int J Clin Oncol 29:1931-1936 Bourlon MT, Galli L, Grande E et al (2025) Nivolumab plus cabozantinib in metastatic renal cell carcinoma: real-world evidence from the international ARON-1 study. Front Oncol 15:1605282 Harada KI, Sato R, Bando Y et al (2023) Efficacy and safety of pembrolizumab and axitinib as first-line treatment for patients with advanced renal cell carcinoma: Real-world experience in Japan. Int J Urol 30:772-777 Guida A, Gili A, Mosillo C et al (2024) Efficacy and Safety of Pembrolizumab plus Axitinib combination for Metastatic Renal Cell Carcinoma in a Real-World Scenario: Data From the Prospective ProPAXI Study. Clin Genitourin Cancer 22:102225 Kato T, Furukawa J, Hinata N et al (2025) Real-world outcomes of avelumab plus axitinib in patients with advanced renal cell carcinoma in Japan: long-term follow-up from the J-DART2 retrospective study. Int J Clin Oncol 30:99-109 Kato T, Nakano Y, Hongo F et al (2024) Real-world outcomes of avelumab plus axitinib as first-line therapy in patients with advanced renal cell carcinoma in Japan: A multicenter, retrospective, observational study (J-DART). Int J Urol 31:265-272 Gan CL, Stukalin I, Meyers DE et al (2021) Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials. Eur J Cancer 151:115-125 Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.4 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). Ishihara H, Omae K, Nemoto Y et al (2024) First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data. Int J Clin Oncol 29:473-480 Ishihara H, Omae K, Nemoto Y et al (2025) Comparison of real-world outcomes between nivolumab plus ipilimumab and lenvatinib plus pembrolizumab or nivolumab plus cabozantinib combination therapies for previously untreated advanced renal cell carcinoma. Urol Oncol Motzer RJ, Porta C, Eto M et al (2024) 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 Clin Oncol 42:1222-1228 Ishihara H, Yuki N, Ishiyama R et al (2024) Real-world outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma in Japanese patients: data with a minimum of 3 years of follow-up. Jpn J Clin Oncol 54:577-583 Petrelli F, Verri E, Ghidini A et al (2025) First-Line Therapy For Advanced Non-Clear Cell Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. JAMA Oncol 11:1064-1071 Nepali PR, Eraky A, Okhawere KE et al (2025) Molecular and therapeutic landscape of non-clear cell renal carcinoma. Nat Rev Urol Jikuya R, Fukagawa A, Ito D et al (2025) Translational Research Bridging Basic and Clinical Insights in Renal Cell Carcinoma: A Collaborative Review and Future Directions. Int J Urol 32:932-943 Powles T, Plimack ER, Soulières D et al (2020) 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. Lancet Oncol 21:1563-1573 Castro DV, Prajapati SR, Feng MI et al (2024) Assessment of eligibility criteria in renal cell carcinoma trials evaluating systemic therapy. BJU Int 133:297-304 Tables Table 1. Patient characteristics Variables All (n = 68) Age > 65 years (ref. ≤ 65 years) 42 (62%) Sex Male (ref. female) 50 (74%) Prior Nephrectomy Presence (ref. absence) 47 (69%) Histology Clear-cell renal cell carcinoma Non-clear cell renal cell carcinoma Unknown 45 (66%) 15 (22%) 8 (12%) Regimen Lenvatinib plus pembrolizumab Nivolumab plus cabozantinib Pembrolizumab plus axitinib Avelumab plus axitinib 14 (21%) 20 (29%) 23 (34%) 11 (16%) cM status cM1 (ref. cM0) 31 (46%) IMDC risk Favorable Intermediate Poor 12 (18%) 42 (62%) 14 (21%) Karnofsky performance status score ≤ 80 (ref. > 80) 11 (16%) Serum CRP levels > 1 mg/dL (ref. ≤ 1 mg/dL) 20 (29%) Serum neutrophil-to-lymphocyte ratio > 3 (ref. ≤ 3) 38 (56%) Chronic kidney disease Presence (ref. absence) 51 (75%) Lung metastasis Presence (ref. absence) 44 (65%) Bone metastasis Presence (ref. absence) 14 (21%) Liver metastasis Presence (ref. absence) 11 (16%) Lymph node metastasis Presence (ref. absence) 17 (25%) Follow-up period, months* 32.7 (18.5–39.4) *median (interquartile range) IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; CRP, C-reactive protein Table 2. Tumor response Variables All (n = 68) Best overall response Complete response Partial response Stable disease Progressive disease Not applicable 5 (7%) 34 (50%) 26 (38%) 2 (3%) 1 (1%) Objective response rate 57% Magnitude of best tumor response* -35.0 (-56.7 to -13.6) *66 patients were analyzed Table 3. Safety profile Variables All (n = 68) Any grade adverse events 68 (100%) Grade 3 or higher adverse events 44 (65%) Treatment discontinuation Both drugs Either drug 14 (21%) 21 (31%) Corticosteroid need Presence High-dose corticosteroid 23 (34%) 10 (15%) Supplementary Files IOTKI3ySupplyTablev2.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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1","display":"","copyAsset":false,"role":"figure","size":171536,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival after IO\u003c/strong\u003e-\u003cstrong\u003eTKI therapy initiation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Progression-free survival. (b) Overall survival.\u003c/p\u003e\n\u003cp\u003ePFS, progression-free survival; OS, overall survival; N.R., not reached\u003c/p\u003e","description":"","filename":"fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7771726/v1/43e4a8af408c8267b0658e15.jpg"},{"id":94846035,"identity":"593ed5b9-3b6b-4f37-a5e8-0b78ce47bed0","added_by":"auto","created_at":"2025-10-31 10:10:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":220749,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubgroup analysis of progression-free survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHR, hazard ratio; CI, confidence interval; Nx, nephrectomy; ccRCC, clear-cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma; unk, unknown; LP, lenvatinib plus pembrolizumab; NC, nivolumab plus cabozantinib; PA, pembrolizumab plus axitinib; AA, avelumab plus axitinib; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; KPS, Karnofsky Performance Status; CRP, C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; CKD, chronic kidney disease; LN, lymph node\u003c/p\u003e","description":"","filename":"fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7771726/v1/499c42800a61d738309350f4.jpg"},{"id":94846027,"identity":"e9e04fa4-0160-45be-b01b-6a9731677fba","added_by":"auto","created_at":"2025-10-31 10:10:50","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":220017,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubgroup analysis of overall survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHR, hazard ratio; CI, confidence interval; Nx, nephrectomy; ccRCC, clear-cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma; unk, unknown; LP, lenvatinib plus pembrolizumab; NC, nivolumab plus cabozantinib; PA, pembrolizumab plus axitinib; AA, avelumab plus axitinib; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; KPS, Karnofsky Performance Status; CRP, C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; CKD, chronic kidney disease; LN, lymph node\u003c/p\u003e","description":"","filename":"fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7771726/v1/c8f5876ea8bf93d0a3a7ca1d.jpg"},{"id":94985512,"identity":"4b266615-5cc6-446a-bfaf-8299f467a513","added_by":"auto","created_at":"2025-11-03 06:58:19","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":224835,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival after IO\u003c/strong\u003e-\u003cstrong\u003eTKI therapy initiation according to histology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Progression-free survival. (b) Overall survival.\u003c/p\u003e\n\u003cp\u003ePFS, progression-free survival; OS, overall survival; N.R., not reached; ccRCC, clear-cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma; unk, unknown\u003c/p\u003e","description":"","filename":"fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7771726/v1/0c21eef3eb1cfa1062553f69.jpg"},{"id":94985242,"identity":"8bab1bf1-5279-420e-a100-68fc75dfc624","added_by":"auto","created_at":"2025-11-03 06:57:45","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":236274,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWaterfall plot showing the magnitude of best tumor shrinkage\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) Overall. (b) By treatment regimens.\u003c/p\u003e","description":"","filename":"fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7771726/v1/211055d4fda063f2b277be88.jpg"},{"id":95802576,"identity":"fb742b83-6f82-46b5-aa52-cd1e46ad3fbe","added_by":"auto","created_at":"2025-11-13 08:27:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1794567,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7771726/v1/abdf1cf2-c1b7-451e-8c02-d38f3eab4821.pdf"},{"id":94984926,"identity":"b0d6e522-ab92-4e7a-8555-a0de13567658","added_by":"auto","created_at":"2025-11-03 06:56:56","extension":"docx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":22850,"visible":true,"origin":"","legend":"","description":"","filename":"IOTKI3ySupplyTablev2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7771726/v1/2d4ba5834122119215f8c411.docx"}],"financialInterests":"","formattedTitle":"Midterm outcomes of combination therapy with immune checkpoint inhibitors and VEGFR-TKIs in real-world patients with advanced renal cell carcinoma","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCombination therapy with immune checkpoint inhibitors (ICIs) and VEGFR-TKIs (IO-TKI therapy) has been approved as a standard first-line systemic treatment for advanced renal cell carcinoma (RCC). To date, three regimens\u0026mdash;lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, and pembrolizumab plus axitinib\u0026mdash;have demonstrated improved overall survival (OS) compared with sunitinib in patients with previously untreated advanced RCC in randomized phase III clinical trials [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn these pivotal trials, extended follow-up has consistently shown sustained efficacy and manageable safety of IO-TKI therapy [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Long-term follow-up provides stronger evidence for outcomes, particularly OS and treatment-related toxicities. However, real-world reports remain limited, with most studies assessing outcomes only up to 2 years [\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In real-world practice, some patients are considered trial-ineligible due to characteristics such as non-clear cell histology, severe organ dysfunction, or brain metastases [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Since these patients are generally excluded from randomized phase III trials, evidence regarding IO-TKI outcomes in this population is lacking. Importantly, their prognosis after systemic therapy, including ICIs, may be worse than that reported in clinical trials [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Therefore, extended real-world follow-up data are needed to clarify the outcomes of IO-TKI therapy.\u003c/p\u003e\u003cp\u003eIn this context, we retrospectively evaluated the midterm outcomes of IO-TKI therapy for previously untreated advanced RCC using a minimum 3-year follow-up dataset collected from multiple institutions in Japan.\u003c/p\u003e"},{"header":"2. Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Patient selection and study design\u003c/h2\u003e\u003cp\u003eAt Tokyo Women\u0026rsquo;s Medical University and four affiliated institutions (Tokyo Women\u0026rsquo;s Medical University Adachi Medical Center, Saiseikai Kawaguchi General Hospital, Saiseikai Kazo Hospital, and Jyoban Hospital), a total of 71 patients received IO-TKI therapy (lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, pembrolizumab plus axitinib, or avelumab plus axitinib) initiated on or before September 2022, ensuring a minimum follow-up of 3 years. Three patients were excluded due to incomplete baseline data, leaving 68 patients for evaluation in this retrospective observational study.\u003c/p\u003e\u003cp\u003eTreatment was continued until radiographic disease progression or the occurrence of intolerable adverse events (AEs). ICI doses could not be modified; however, administration intervals could be adjusted based on toxicity or patient condition. For TKIs, both dose and administration interval could be modified as needed.\u003c/p\u003e\u003cp\u003eEffectiveness was assessed by progression-free survival (PFS), OS, and objective response rate (ORR). PFS was defined as the time from treatment initiation to disease progression or death, whichever occurred first. OS was defined as the time from treatment initiation to death. The cutoff date for outcome assessment was September 2025. Patients lost to follow-up were censored at the date of last contact. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Computed tomography of the chest, abdomen, and pelvis was performed at 4\u0026ndash;12 week intervals after treatment initiation, depending on the patient's condition. Magnetic resonance imaging, positron emission tomography/computed tomography, and brain imaging were performed when clinically indicated. Safety was assessed by evaluating the incidence of AEs, treatment discontinuation, and corticosteroid use. AEs were graded using the Common Terminology Criteria for Adverse Events version 5.0 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e The study protocol was approved by the Institutional Ethics Review Board of Tokyo Women\u0026rsquo;s Medical University (ID: 2020-0009). The study was conducted in accordance with the principles of the Declaration of Helsinki (1964) and its later amendments. Clinical and laboratory data were obtained from electronic databases and patient medical records.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Protocol for IO-TKI combination therapy\u003c/h2\u003e\u003cp\u003eThe protocol for IO-TKI therapy as first-line treatment has been described previously [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In practice, lenvatinib plus pembrolizumab or nivolumab plus cabozantinib are preferentially selected for patients who require rapid and/or substantial tumor shrinkage due to disease-related symptoms, for use as presurgical therapy (for example, deferred cytoreductive nephrectomy), or for those with non-clear cell histology. Pembrolizumab plus axitinib or avelumab plus axitinib may be considered for patients with a favorable International Metastatic RCC Database Consortium (IMDC) risk, older patients, those with multiple or severe comorbidities, or individuals intolerant to corticosteroids because of AEs.\u003c/p\u003e\u003cp\u003eDue to the timing of approval under the Japanese insurance system, pembrolizumab plus axitinib and avelumab plus axitinib were primarily used in the early period. However, lenvatinib plus pembrolizumab and nivolumab plus cabozantinib have since become the main IO-TKI regimens. Despite these trends, no consensus-based criteria for treatment selection have been established across our affiliated institutions.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Statistical analysis\u003c/h2\u003e\u003cp\u003eBaseline characteristics were summarized as numbers (%) for categorical variables and as medians with interquartile ranges for continuous variables. Categorical variables were compared using Fisher\u0026rsquo;s exact test. Survival was estimated using the Kaplan\u0026ndash;Meier method and compared with the log-rank test. Risks were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). All analyses were performed using JMP software, version 17 (SAS Institute Inc., Cary, NC, USA). Statistical significance was defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.1.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; Patient characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 summarizes patient characteristics. Forty-two patients (62%) were ≥ 65 years old, and 50 (74%) were male. Prior nephrectomy was performed in 47 patients (69%), and 45 (66%) had clear-cell RCC. Lenvatinib plus pembrolizumab, nivolumab plus cabozantinib, pembrolizumab plus axitinib, and avelumab plus axitinib were administered in 14 (21%), 20 (29%), 23 (34%), and 11 (16%) patients, respectively. Based on IMDC risk classification, 12 (18%), 42 (62%), and 14 (21%) patients were categorized as favorable, intermediate, and poor risk, respectively. The median follow-up period was 32.7 months (interquartile range: 18.5–39.4 months).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.2.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; Effectiveness\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring follow-up, 51 patients (75%) experienced disease progression, and 24 (35%) died. The median PFS was 19.9 months (95% CI: 13.8–26.0), and the median OS was 46.7 months (95% CI: 38.8–not reached) (Figure 1). Univariate analysis of PFS and OS showed that histology was the only factor significantly associated with survival. Clear-cell histology was associated with improved PFS (HR: 0.54, 95% CI: 0.30–0.97, p = 0.0393) and OS (HR: 0.25, 95% CI: 0.11–0.58, p = 0.0011) (Figures 2 and 3, Supplementary Table 1). Patients with clear-cell RCC had longer PFS (median: 23.0 months, 95% CI: 18.3–32.6 vs. 8.97 months, 95% CI: 4.31–18.1, p = 0.0362) and OS (median: not reached, 95% CI: 46.7–not reached vs. 32.1 months, 95% CI: 17.8–40.6, p = 0.0005) compared with those with non-clear cell RCC or unknown histology (Figure 4).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegarding tumor response, the ORR was 57%, including 5 patients (7%) with complete response and 34 (50%) with partial response (Figure 5, Table 2). ORRs by regimen were 70% for nivolumab plus cabozantinib, 57% for lenvatinib plus pembrolizumab, 52% for pembrolizumab plus axitinib, and 45% for avelumab plus axitinib. The median best tumor response among 66 evaluable patients was -35.0% (interquartile range: -56.7% to -13.6%). When stratified by histology, ORR tended to be higher in patients with clear-cell RCC than in those with non-clear cell RCC or unknown histology (64% vs. 43%, p = 0.124). The median best tumor response was also greater in patients with clear-cell RCC (-42.3%, 95% CI: -60.7% to -20.5%) than in those with non-clear cell or unknown histology (-24.3%, 95% CI: -43.7 to -11.0%, p = 0.0329).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003e3.3.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp; Safety\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt least one AE of any grade occurred in all patients (100%); in contrast, grade ≥ 3 AEs developed in 44 patients (65%) (Table 3). Treatment discontinuation of both drugs was required in 14 patients (21%), and discontinuation of one drug in 21 patients (31%). Corticosteroids were administered to 23 patients (34%), including 10 (15%) who required high-dose treatment (≥ 40 mg prednisone per day).\u0026nbsp;\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis retrospective, multi-institutional study with a minimum follow-up of 3 years demonstrated that IO-TKI therapy provides feasible effectiveness and manageable safety for patients with previously untreated advanced RCC. A midterm survival benefit was observed regardless of baseline characteristics, except for histological subtype. To our knowledge, this is the first study to report midterm, real-world outcomes of first-line IO-TKI therapy for RCC.\u003c/p\u003e\u003cp\u003eThe effectiveness observed in this cohort is broadly comparable to results from phase III randomized clinical trials. For example, in the CLEAR trial, lenvatinib plus pembrolizumab achieved a median OS of 53.7 months, a median PFS of 23.9 months, and an ORR of 71.3% with approximately 4 years of follow-up [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The CheckMate 9ER trial reported median OS and PFS of 49.5 and 16.6 months, respectively, and an ORR of 56% for nivolumab plus cabozantinib at a median follow-up of 44.0 months [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In the KEYNOTE-426 trial, median OS and PFS for pembrolizumab plus axitinib were 46 and 16 months, respectively, with an ORR of 60% at 43 months of follow-up [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Similarly, the JAVELIN Renal 101 trial reported median OS and PFS of 44.8 and 13.9 months, respectively, and an ORR of 59.7% during a median follow-up of 73 months for avelumab plus axitinib [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSeveral real-world studies have also evaluated IO-TKI outcomes with meaningful follow-up durations. The ARON-1 study, using multi-center retrospective data with a median follow-up of 15.1 months, showed that 202 patients receiving lenvatinib plus pembrolizumab had a 2-year OS rate of 67%, median PFS of 15.1 months, and ORR of 59% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The same group reported that among 333 patients receiving nivolumab plus cabozantinib, the 2-year OS rate was 75%, median PFS was 33.7 months, and ORR was 58% with a 15.9-month median follow-up [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In Italy, a prospective study of pembrolizumab plus axitinib in 170 patients showed a 2-year OS rate of 62%, a median PFS of 19.2 months, and a disease control rate of 84.6% at 19.3 months [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The J-DART2 study from Japan reported that avelumab plus axitinib achieved a 2-year OS rate of 84.7%, median PFS of 17.1 months, and ORR of 53.3% with 18.7 months of follow-up [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Collectively, the results of our study are consistent with these prior findings, suggesting that IO-TKI therapy maintains clinical activity even in real-world patients. In this study, treatment effectiveness was not influenced by baseline patient characteristics, supporting the broad feasibility of IO-TKI therapy. However, patients with non-clear cell RCC had worse survival outcomes compared with those with clear-cell histology, consistent with previous reports in patients treated with pembrolizumab plus axitinib [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. We previously reported similar findings with nivolumab plus ipilimumab, where patients with non-clear cell RCC experienced poorer outcomes than those with clear-cell RCC at a minimum of 3 years of follow-up [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A recent network meta-analysis using clinical trial data indicated notable activity of IO-TKI therapy in patients with non-clear cell RCC [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, given the persistent survival disadvantage in this subgroup, more effective treatment strategies and novel therapeutic targets are urgently needed [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRegarding safety, the CLEAR trial reported grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs in 82.4% of patients receiving lenvatinib plus pembrolizumab, with treatment discontinuation in 37.2% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In the CheckMate 9ER trial, 66.9% of patients experienced grade\u0026thinsp;\u0026ge;\u0026thinsp;3 treatment-related AEs, 27.5% discontinued at least one agent [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and 21.9% required prolonged corticosteroid therapy (\u0026ge;\u0026thinsp;40 mg prednisone daily) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In the KEYNOTE-426 trial, 68% of patients receiving pembrolizumab plus axitinib developed grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and 7% discontinued both drugs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Similarly, in the JAVELIN Renal 101 trial, 66.8% of patients treated with avelumab plus axitinib developed grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs, and 15.4% required high-dose corticosteroids [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The safety outcomes in our study align with these clinical trial data, which is noteworthy given that real-world patients may have comorbidities or organ dysfunction (for example, renal impairment) that increase vulnerability to treatment-related toxicity [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study has some limitations. First, its retrospective design and small sample size inevitably introduce selection bias, which may affect the findings. Second, the follow-up duration may still be insufficient to fully assess OS, potentially limiting interpretation. Third, subgroup analyses were based on univariate analysis, which are susceptible to confounding factors.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis multi-institutional, real-world study with midterm follow-up demonstrated that first-line IO-TKI combination therapy provides feasible effectiveness and a manageable safety profile for patients with previously untreated advanced RCC. The outcomes were generally comparable to those reported in clinical trials, supporting the use of IO-TKI therapy in real-world. Further studies with longer follow-up and larger sample sizes are needed to evaluate the long-term OS benefit of this treatment in real-world settings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflicts of interest\u003c/h2\u003e\u003cp\u003eToshio Takagi received honorariums from Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., Merck KGaA, and Takeda Pharmaceutical Co., Ltd. Tsunenori Kondo received honoraria from Pfizer, Novartis, Bristol-Myers Squibb, and Ono Pharmaceutical Co., Ltd.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMotzer R, Alekseev B, Rha SY et al (2021) Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med 384:1289-1300\u003c/li\u003e\n\u003cli\u003eChoueiri TK, Powles T, Burotto M et al (2021) Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 384:829-841\u003c/li\u003e\n\u003cli\u003eRini BI, Plimack ER, Stus V et al (2019) Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 380:1116-1127\u003c/li\u003e\n\u003cli\u003eMotzer RJ, Choueiri TK, Hutson T et al (2024) Characterization of Responses to Lenvatinib plus Pembrolizumab in Patients with Advanced Renal Cell Carcinoma at the Final Prespecified Survival Analysis of the Phase 3 CLEAR Study. Eur Urol 86:4-9\u003c/li\u003e\n\u003cli\u003ePowles T, Burotto M, Escudier B et al (2024) Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised CheckMate 9ER trial. ESMO Open 9:102994\u003c/li\u003e\n\u003cli\u003ePlimack ER, Powles T, Stus V et al (2023) Pembrolizumab Plus Axitinib Versus Sunitinib as First-line Treatment of Advanced Renal Cell Carcinoma: 43-month Follow-up of the Phase 3 KEYNOTE-426 Study. Eur Urol 84:449-454\u003c/li\u003e\n\u003cli\u003eChoueiri TK, Penkov K, Uemura H et al (2025) Avelumab + axitinib versus sunitinib as first-line treatment for patients with advanced renal cell carcinoma: final analysis of the phase III JAVELIN Renal 101 trial. Ann Oncol 36:387-392\u003c/li\u003e\n\u003cli\u003ePorta C, Massari F, Taha T et al (2025) Pembrolizumab plus Lenvatinib in patients with metastatic Renal Cell Carcinoma: real-world evidences from the international ARON- 1 study. Cancer Immunol Immunother 74:196\u003c/li\u003e\n\u003cli\u003eHara T, Suzuki K, Okamura Y et al (2024) Efficacy and safety of lenvatinib and pembrolizumab as first-line treatment for advanced renal cell carcinoma patients: real-world experience in Japan. Int J Clin Oncol 29:1931-1936\u003c/li\u003e\n\u003cli\u003eBourlon MT, Galli L, Grande E et al (2025) Nivolumab plus cabozantinib in metastatic renal cell carcinoma: real-world evidence from the international ARON-1 study. Front Oncol 15:1605282\u003c/li\u003e\n\u003cli\u003eHarada KI, Sato R, Bando Y et al (2023) Efficacy and safety of pembrolizumab and axitinib as first-line treatment for patients with advanced renal cell carcinoma: Real-world experience in Japan. Int J Urol 30:772-777\u003c/li\u003e\n\u003cli\u003eGuida A, Gili A, Mosillo C et al (2024) Efficacy and Safety of Pembrolizumab plus Axitinib combination for Metastatic Renal Cell Carcinoma in a Real-World Scenario: Data From the Prospective ProPAXI Study. Clin Genitourin Cancer 22:102225\u003c/li\u003e\n\u003cli\u003eKato T, Furukawa J, Hinata N et al (2025) Real-world outcomes of avelumab plus axitinib in patients with advanced renal cell carcinoma in Japan: long-term follow-up from the J-DART2 retrospective study. Int J Clin Oncol 30:99-109\u003c/li\u003e\n\u003cli\u003eKato T, Nakano Y, Hongo F et al (2024) Real-world outcomes of avelumab plus axitinib as first-line therapy in patients with advanced renal cell carcinoma in Japan: A multicenter, retrospective, observational study (J-DART). Int J Urol 31:265-272\u003c/li\u003e\n\u003cli\u003eGan CL, Stukalin I, Meyers DE et al (2021) Outcomes of patients with solid tumour malignancies treated with first-line immuno-oncology agents who do not meet eligibility criteria for clinical trials. Eur J Cancer 151:115-125\u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247\u003c/li\u003e\n\u003cli\u003eNational Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v.4 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). \u003c/li\u003e\n\u003cli\u003eIshihara H, Omae K, Nemoto Y et al (2024) First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data. Int J Clin Oncol 29:473-480\u003c/li\u003e\n\u003cli\u003eIshihara H, Omae K, Nemoto Y et al (2025) Comparison of real-world outcomes between nivolumab plus ipilimumab and lenvatinib plus pembrolizumab or nivolumab plus cabozantinib combination therapies for previously untreated advanced renal cell carcinoma. Urol Oncol\u003c/li\u003e\n\u003cli\u003eMotzer RJ, Porta C, Eto M et al (2024) 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 Clin Oncol 42:1222-1228\u003c/li\u003e\n\u003cli\u003eIshihara H, Yuki N, Ishiyama R et al (2024) Real-world outcomes of nivolumab plus ipilimumab combination therapy for advanced renal cell carcinoma in Japanese patients: data with a minimum of 3 years of follow-up. Jpn J Clin Oncol 54:577-583\u003c/li\u003e\n\u003cli\u003ePetrelli F, Verri E, Ghidini A et al (2025) First-Line Therapy For Advanced Non-Clear Cell Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. JAMA Oncol 11:1064-1071\u003c/li\u003e\n\u003cli\u003eNepali PR, Eraky A, Okhawere KE et al (2025) Molecular and therapeutic landscape of non-clear cell renal carcinoma. Nat Rev Urol\u003c/li\u003e\n\u003cli\u003eJikuya R, Fukagawa A, Ito D et al (2025) Translational Research Bridging Basic and Clinical Insights in Renal Cell Carcinoma: A Collaborative Review and Future Directions. Int J Urol 32:932-943\u003c/li\u003e\n\u003cli\u003ePowles T, Plimack ER, Souli\u0026egrave;res D et al (2020) 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. Lancet Oncol 21:1563-1573\u003c/li\u003e\n\u003cli\u003eCastro DV, Prajapati SR, Feng MI et al (2024) Assessment of eligibility criteria in renal cell carcinoma trials evaluating systemic therapy. BJU Int 133:297-304\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Patient characteristics \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 68)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u0026gt; 65 years (ref. \u0026le; 65 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e42 (62%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Male (ref. female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e50 (74%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003ePrior Nephrectomy\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Presence (ref. absence)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eHistology\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Clear-cell renal cell carcinoma\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Non-clear cell renal cell carcinoma\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e45 (66%)\u003c/p\u003e\n \u003cp\u003e15 (22%)\u003c/p\u003e\n \u003cp\u003e8 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eRegimen\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Lenvatinib plus pembrolizumab\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Nivolumab plus cabozantinib\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Pembrolizumab plus axitinib\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Avelumab plus axitinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (21%)\u003c/p\u003e\n \u003cp\u003e20 (29%)\u003c/p\u003e\n \u003cp\u003e23 (34%)\u003c/p\u003e\n \u003cp\u003e11 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003ecM status\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;cM1 (ref. cM0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e31 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eIMDC risk\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Favorable\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Intermediate\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Poor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (18%)\u003c/p\u003e\n \u003cp\u003e42 (62%)\u003c/p\u003e\n \u003cp\u003e14 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eKarnofsky performance status score\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u0026le; 80 (ref. \u0026gt; 80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eSerum CRP levels\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u0026gt; 1 mg/dL (ref. \u0026le; 1 mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eSerum neutrophil-to-lymphocyte ratio\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u0026gt; 3 (ref. \u0026le; 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e38 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eChronic kidney disease\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Presence (ref. absence)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eLung metastasis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Presence (ref. absence)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e44 (65%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eBone metastasis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Presence (ref. absence)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eLiver metastasis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Presence (ref. absence)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eLymph node metastasis\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Presence (ref. absence)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 397px;\"\u003e\n \u003cp\u003eFollow-up period, months*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e32.7 (18.5\u0026ndash;39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*median (interquartile range)\u003c/p\u003e\n\u003cp\u003eIMDC, International Metastatic Renal Cell Carcinoma Database Consortium; CRP, C-reactive protein\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Tumor response \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"566\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 68)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eBest overall response\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Complete response\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Partial response\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Stable disease\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Progressive disease\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Not applicable\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (7%)\u003c/p\u003e\n \u003cp\u003e34 (50%)\u003c/p\u003e\n \u003cp\u003e26 (38%)\u003c/p\u003e\n \u003cp\u003e2 (3%)\u003c/p\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eObjective response rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e57%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 330px;\"\u003e\n \u003cp\u003eMagnitude of best tumor response*\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e-35.0 (-56.7 to -13.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*66 patients were analyzed\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Safety profile\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"566\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAll\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 68)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003eAny grade adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003e68 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003eGrade 3 or higher adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003e44 (65%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003eTreatment discontinuation\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Both drugs\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Either drug\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (21%)\u003c/p\u003e\n \u003cp\u003e21 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003eCorticosteroid need\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Presence\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;High-dose corticosteroid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 283px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e23 (34%)\u003c/p\u003e\n \u003cp\u003e10 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"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":"Immuno-oncology, immunotherapy, PD-1, PD-L1, targeted therapy","lastPublishedDoi":"10.21203/rs.3.rs-7771726/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7771726/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eLimited data are available on the midterm outcomes of combination therapy with immune checkpoint inhibitors and VEGFR-TKIs (IO-TKI therapy) for advanced renal cell carcinoma (RCC) in real-world settings.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe retrospectively evaluated clinical data from 68 patients who received lenvatinib plus pembrolizumab (n\u0026thinsp;=\u0026thinsp;14), cabozantinib plus nivolumab (n\u0026thinsp;=\u0026thinsp;20), pembrolizumab plus axitinib (n\u0026thinsp;=\u0026thinsp;23), or avelumab plus axitinib (n\u0026thinsp;=\u0026thinsp;11) as first-line therapy for advanced RCC. All patients had a minimum follow-up of 3 years after treatment initiation. Effectiveness and safety profiles were assessed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eDuring a median follow-up of 32.7 months, the median progression-free survival (PFS) and overall survival (OS) were 19.9 and 46.7 months, respectively. The objective response rate was 57%. In subgroup analysis, histology was associated with survival outcomes; median PFS (23.0 vs. 8.97 months, p\u0026thinsp;=\u0026thinsp;0.0362) and OS (not reached vs. 32.1 months, p\u0026thinsp;=\u0026thinsp;0.0005) were longer in patients with clear-cell RCC than in those with non-clear cell RCC. Regarding safety, grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events occurred in 44 patients (65%). Treatment discontinuation of both drugs was required in 14 patients (21%), and discontinuation of one drug in 21 patients (31%). High-dose corticosteroids (\u0026ge;\u0026thinsp;40 mg prednisone/day) were required in 10 patients (15%).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eWith a minimum of 3 years of follow-up, IO-TKI therapy demonstrated feasible effectiveness and manageable safety in patients with advanced RCC in real-world. More effective treatment strategies and novel therapeutic targets are needed for patients with non-clear cell RCC.\u003c/p\u003e","manuscriptTitle":"Midterm outcomes of combination therapy with immune checkpoint inhibitors and VEGFR-TKIs in real-world patients with advanced renal cell carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-31 10:10:45","doi":"10.21203/rs.3.rs-7771726/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":"9807bcdf-7aa7-4224-9b0d-e2911edb2b18","owner":[],"postedDate":"October 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-13T04:33:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-31 10:10:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7771726","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7771726","identity":"rs-7771726","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}