Prognostic significance of early tumor shrinkage in metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based combination therapy

Prognostic significance of early tumor shrinkage in metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based combination therapy | 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 Prognostic significance of early tumor shrinkage in metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based combination therapy Naoki Matsuyama, Takuto Hara, Hideto Ueki, Naoto Wakita, Yasuyoshi Okamura, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8567777/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background Immune checkpoint inhibitor (ICI)-based combination therapies have become the standard first-line treatment for metastatic renal cell carcinoma (mRCC). This study evaluated the prognostic significance of early tumor shrinkage in patients with mRCC treated with first-line ICI-based combination therapies. Methods We retrospectively reviewed 169 mRCC patients who received nivolumab plus ipilimumab, pembrolizumab (or avelumab) plus axitinib, pembrolizumab plus lenvatinib, or nivolumab plus cabozantinib at Kobe University Hospital and its affiliated institutions. Patients were stratified into four groups according to early tumor shrinkage at the first imaging assessment after therapy initiation. The association between early tumor shrinkage and the overall survival (OS) was analyzed. Results The median early tumor shrinkage rate was 17.8%. Twenty-one patients (12.4%) had 50%–100% shrinkage, 31 (18.3%) had 30%–<50% shrinkage, 81 (47.9%) had 0%–<30% shrinkage, and 36 (21.3%) showed progression. The median OS was 42.4 months. The corresponding median OS by shrinkage category above was not reached (NR), NR, 34.7 months, and 30.8 months, respectively (p = 0.023), with 2-year OS rates of 86.7%, 75.1%, 66.1%, and 60.5%, respectively. A univariate analysis identified a prior nephrectomy, International mRCC Database Consortium risk group, bone or liver metastasis, C-reactive protein level, histological subtype, and early tumor shrinkage as predictors of the OS. In the multivariate analysis, prior nephrectomy, bone or liver metastasis, histological subtype, and early tumor shrinkage remained independent. Conclusion Early tumor shrinkage was independently associated with the OS, suggesting its potential as a prognostic indicator in patients with mRCC treated with first-line ICI-based combination therapy. renal cell carcinoma early tumor shrinkage tumor burden immune checkpoint inhibitor prognosis overall survival Figures Figure 1 Figure 2 Figure 3 Introduction Kidney cancer is among the most common malignancies in developed countries, accounting for approximately 4% of all new cancer cases in the United States in 2025 and 3% in Europe in 2022[ 1 , 2 ]. Renal cell carcinoma (RCC) is the most common form of kidney cancer, accounting for > 90% of all cases[ 3 ]. Approximately one-third of patients with RCC are diagnosed with advanced or metastatic disease, and their prognosis has historically been poor, with 5-year survival rates of 15%–35% for patients with regional disease and < 10% for those with metastatic disease[ 4 , 5 ]. In recent years, the introduction of tyrosine kinase inhibitors (TKIs), followed by immune checkpoint inhibitors (ICIs), has remarkably changed the treatment paradigm for advanced and metastatic RCC (mRCC). Combination regimens of ICIs (nivolumab plus ipilimumab) and ICIs with TKIs (pembrolizumab [or avelumab] plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib) have demonstrated significantly improved outcomes compared to sunitinib monotherapy in randomized clinical trials[ 6 – 10 ] and are now established as the mainstay of treatment for advanced or metastatic RCC. These agents have improved the prognosis of patients with RCC; however, although the 5-year survival rate between 2015 and 2021 reached 76.4% for patients with regional disease, it remained at only 19.1% for those with metastatic disease[ 1 ]. Accordingly, reliable early predictors of outcomes in patients with mRCC receiving ICI-based combination therapies have been explored as practical indicators to guide treatment decisions. Several studies have investigated how baseline tumor burden or treatment-induced changes in tumor burden are associated with the post-treatment prognosis. During the TKI era, Miyake et al. reported that early tumor shrinkage could serve as a useful predictor of the OS in patients with mRCC receiving TKIs as the first-line therapy[ 11 ]. In the ICI era, Grünwald et al. showed that the depth of tumor response was associated with the OS in a landmark analysis of the phase 3 CLEAR trial of patients with advanced RCC treated with lenvatinib plus pembrolizumab[ 12 ]. However, no studies to date have examined the impact of early tumor shrinkage on survival outcomes in patients treated with ICI-based combination therapies. Furthermore, studies on tumor burden in the ICI era have mainly included patients enrolled in clinical trials[ 12 ]. Even among the limited number of real-world studies available, most have focused on nivolumab plus ipilimumab[ 13 , 14 ]. Consequently, these findings may not fully reflect the current standard of care for RCC, potentially introducing bias when applied in real-world practice. The present study thus evaluated the prognostic significance of early tumor shrinkage in patients with mRCC receiving first-line ICI-based combination therapies. Patients and Methods Patients Clinical and pathological data were collected from 223 consecutive mRCC patients who received first-line ICI-based combination therapy at Kobe University Hospital and its affiliated institutions between October 2015 and December 2024. Patients were excluded if they lacked data on measurable lesion size, had a follow-up period of less than two months, or did not undergo their first imaging evaluation at an appropriate time after initiating systemic therapy. The patients received one of the following regimens: nivolumab plus ipilimumab, pembrolizumab (or avelumab) plus axitinib, pembrolizumab plus lenvatinib, or nivolumab plus cabozantinib. The study protocol was approved by the Research Ethics Committee of our institution (No. B230087) and was conducted in accordance with the principles of the Declaration of Helsinki. The requirement for individual informed consent was waived because of the retrospective nature of the analysis. Treatments and Procedures Each regimen was initiated at a standard prescribed dose. Treatment was continued until disease progression or intolerable adverse events (AEs) developed. In general, dose modification of TKIs was considered in cases with treatment-associated AEs corresponding to grade ≥ 3. Dose reductions or temporary interruptions were allowed at the discretion of the treating physician in accordance with prescribing information and institutional guidelines. A radiological evaluation of the tumor was performed before and approximately every three months after the initiation of systemic therapy. Imaging data were obtained from chest and abdominal computed tomography (CT), and if CT was not available, magnetic resonance imaging, bone scintigraphy, or 18F-fluorodeoxyglucose-positron emission tomography was used instead. Tumor burden was defined as the sum of the largest diameters of the target lesions, according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Early tumor shrinkage was calculated as the percentage change in tumor burden from baseline to the first imaging assessment. Based on changes in tumor burden, patients were stratified into 4 subgroups according to our strategy: tumor shrinkage from 50% to 100%, 30% to < 50%, 0% to < 30%, and a gain in tumor burden. Statistical Analyses The OS was analyzed using the Kaplan-Meier method, and subgroup comparisons were performed using the log-rank test. Cox proportional hazards models were used for univariate and subsequent multivariate analyses to determine the independent prognostic value of the OS. All statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). All statistical tests were 2-sided, and a p-value < 0.05 was considered statistically significant. Results Among the 223 patients initially enrolled, 33 were excluded due to a lack of data on measurable lesion size, 8 due to a follow-up period of less than two months, and 20 due to the absence of a timely first imaging evaluation after the initiation of systemic therapy (with some overlap). After these exclusions, 169 patients were included in this study. The baseline characteristics of the overall patient cohort are summarized in Table 1 . The median age was 70.0 years old (interquartile range [IQR], 63.0–76.0), and the majority were male (78.7%). According to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, 10.1% were favorable risk, 52.7% were intermediate-risk, and 37.3% were poor-risk. More than half of the patients (56.2%) had previously undergone prior nephrectomy. The most frequently administered first-line regimen was nivolumab plus ipilimumab (43.8%). Table 1 Patient’s characteristics. Variables Overall n = 190 Age (years), median (IQR) 70.0 (63.0–76.0) Sex Male 133 (78.7) Female 36 (21.3) PS ≥ 80 139 (82.2) < 80 30 (17.8) Prior nephrectomy No 74 (43.8) Radical nephrectomy 91 (53.8) Partial nephrectomy 4 (2.4) IMDC risk group Favorable 17 (10.1) Intermediate 89 (52.7) Poor 63 (37.3) C-reactive protein (mg/dL) < 0.1 93 (55.0) ≥ 0.1 76 (45.0) Metastatic organ Lung 105 (62.1) Lymph node 58 (34.3) Bone 56 (33.1) Liver 25 (14.8) Adrenal gland 21 (12.4) Brain 11 (6.5) Pancreas 12 (7.1) Others 28 (16.6) Number of metastases 1 29 (17.2) ≥ 2 140 (82.8) Histological subtype Clear cell 131 (77.5) Non-clear cell 38 (22.5) Sarcomatoid feature No 151 (89.3) Yes 18 (10.7) First-line treatment Nivo/Ipi 74 (43.8) Ave/Axi 26 (15.4) Pem/Axi 12 (7.1) Nivo/Cab 22 (13.0) Pem/Len 35 (20.7) Baseline volume of metastasis (mm), median (IQR) 68.0 (28.0–129.0) Change in tumor burden (%), median (IQR) –17.8 (–36.8 to 0) Magnitude of early tumor shrinkage (four-group classification) 100% to 50% 21 (12.4) < 50% to 30% 31 (18.3) < 30% to 0% 81 (47.9) gain 36 (21.3) Data are expressed as n (%) unless otherwise specified Ave/Axi, avelumab plus axitinib; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IQR, interquartile range; Nivo/Cabo, nivolumab plus cabozantinib; Nivo/Ipi, nivolumab plus ipilimumab; Pem/Axi, pembrolizumab plus axitinib; Pem/Len, pembrolizumab plus lenvatinib; PS, performance status. With a median follow-up of 33.4 months (95% confidence interval [CI], 27.7–38.7; Kaplan–Meier estimate), the median PFS and OS for the entire cohort were 18.8 months (95% CI, 12.8–24.9) and 42.4 months (95% CI, 31.5–66.1), respectively (Fig. 1 ). Figure 2 A shows a waterfall plot of the change in tumor burden at the first imaging evaluation after the initiation of systemic therapy for individual patients. The median change for the entire cohort was − 17.8% (IQR, − 36.8% to 0%). Twenty-one patients (12.4%) experienced early tumor shrinkage of 50% to 100%, 31 patients (18.3%) experienced shrinkage of 30% to < 50%, 81 patients (47.9%) experienced shrinkage of 0% to < 30%, and 36 patients (21.3%) showed an increase in tumor burden. The median interval from treatment initiation to the first imaging evaluation was 8.7 weeks (IQR, 6.6–11.0): 9.3 weeks (IQR, 8.0–12.3) for the 100% to 50% group, 8.3 weeks (IQR, 7.0–10.2) for the < 50% to 30% group, 8.9 weeks (IQR, 6.9–10.9) for the < 30% to 0% group, and 7.1 weeks (IQR, 6.1–10.6) for the group with an increase in tumor burden. The corresponding median OS stratified according to early tumor shrinkage of 50% to 100%, 30% to < 50%, 0% to < 30%, and a gain in tumor burden was not reached (NR; 95% CI, NE–NE), NR (95% CI, 31.5 months–NE), 34.7 months (95% CI, 24.5–NE), and 30.8 months (95% CI, 19.6–42.4), respectively (p = 0.023; Fig. 2 B). The 2-year OS rates stratified according to early tumor shrinkage as described above were 86.7% (95% CI, 56.4%–96.5%), 75.1% (95% CI, 54.3%–87.4%), 66.1% (95% CI, 52.5%–76.7%), and 60.5% (95% CI, 42.6%–74.4%), respectively. A univariate analysis identified a history of prior nephrectomy, IMDC risk group, bone or liver metastasis, C-reactive protein (CRP) level, histological subtype, and early tumor shrinkage as significant predictors of the OS (Table 2 ). Furthermore, in the multivariate analysis, four factors remained independently associated with the OS: a history of prior nephrectomy, bone or liver metastasis, histological subtype, and early tumor shrinkage. Table 2 Univariate and multivariate analyses of factors associated with the overall survival. Variable Univariate analysis Multivariate analysis HR (95% CI) p value HR (95% CI) p value Age (≥ 65 vs. <65 years) 1.27 (0.77–2.09) 0.34 Sex (female vs. male) 1.61 (0.93–2.78) 0.086 History of a prior nephrectomy (no vs. yes) 3.77 (2.22–6.41) < 0.001 2.43 (1.34–4.41) 0.003 IMDC risk group (poor vs. others) 3.05 (1.86–5.01) < 0.001 1.10 (0.56–2.17) 0.78 Number of metastasis (≥ 2 vs. 1) 2.29 (0.99–5.31) 0.053 Lung metastasis (yes vs. no) 1.50 (0.89–2.52) 0.13 Bone or liver metastasis (yes vs. no) 2.65 (1.58–4.45) < 0.001 2.34 (1.33–4.11) 0.003 C-reactive protein, mg/dL (≥ 0.1 vs. <0.1) 3.51 (2.08–5.92) < 0.001 1.94 (0.94-4.00) 0.072 Histological subtype (non-clear cell vs. clear cell) 1.83 (1.04–3.19) 0.035 2.17 (1.18-4.00) 0.013 Sarcomatoid feature (yes vs. no) 1.15 (0.55–2.42) 0.71 First line treatment (ICI-ICI vs. ICI-TKI) 1.08 (0.65–1.82) 0.76 Early tumor shrinkage 0.010 100% to 50% reference < 50% to 30% 3.02 (0.65–14.01) 0.16 < 30% to 0% 4.71 (1.13–19.75) 0.034 gain 6.12 (1.44–26.01) 0.014 Early tumor shrinkage (< 30% vs. 100% to 30%) 2.38 (1.24–4.56) 0.009 2.25 (1.15–4.38) 0.018 ICI, immune checkpoint inhibitor; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; TKI, tyrosine kinase inhibitor; HR, hazard ratio; CI, confidence interval To refine the prediction of the OS, we stratified the 169 patients into 3 groups according to the number of risk factors identified in the multivariate analysis. Death occurred in 8 of 63 patients with 0 or 1 risk factor (12.7%), 28 of 58 patients with 2 risk factors (48.3%), and 28 of 48 patients with 3 or 4 risk factors (58.3%). The OS differed significantly across the 3 groups (p < 0.001) (Fig. 3 ). Discussion In the present study, we conducted a multicenter retrospective analysis of 169 patients in Japan and found that greater early tumor shrinkage was significantly associated with a longer OS in patients with mRCC treated with first-line ICI-based combination therapies. A multivariate analysis further identified early tumor shrinkage as an independent prognostic factor for the OS. To our knowledge, this is the first report to suggest that early tumor shrinkage may serve as a reliable outcome predictor in patients with mRCC receiving first-line ICI-based combination therapies. The PFS of 18.8 months and OS of 42.4 months observed in this study were comparable to those reported in previous randomized clinical trials of first-line ICI-based combination therapies[ 6 – 10 ]. A multivariate analysis identified several factors, including a history of prior nephrectomy, bone or liver metastases, and histological subtype as significant prognostic indicators, consistent with previous findings[ 11 , 14 , 15 ]. In addition, an early tumor shrinkage of 100% to 30% was found to be a prognostic factor, with a hazard ratio comparable to these established variables. Tumor burden has been reported to be a useful tool for outcome prediction in patients receiving systemic therapy for mRCC. Because the tumor burden can be easily assessed using routine radiological examinations, it is valuable for stratifying patients and guiding treatment selection. In the TKI era, factors such as baseline tumor burden, magnitude and timing of the best tumor response, and early tumor shrinkage have been reported as prognostic factors or surrogate markers[ 11 , 16 – 22 ]. In the context of ICI-based combination therapy, recent retrospective analyses primarily involving nivolumab plus ipilimumab have shown that baseline tumor burden, depth of tumor response, and maximum evaluable lesion size are associated with outcomes following systemic treatment.[ 12 – 14 , 23 ]. Our study expands upon these findings by indicating that early tumor shrinkage is a clinically relevant indicator not only in TKI regimens but also in ICI-ICI and ICI-TKI combination therapies. The significance of this study lies in its ability to stratify the patient prognosis at an early time point, specifically during the first imaging evaluation. The most widely used method for assessing tumor response remains RECIST, and previous studies have reported that outcome stratification based on the criteria is feasible in patients with mRCC receiving ICI-based combination therapy[ 24 ]. However, the time to the best tumor response is typically longer than the time to the initial response, indicating that RECIST-based evaluations are often performed at later stages of treatment. For example, in a phase 1b trial of pembrolizumab plus axitinib, the median time to response was 2.8 months, and many patients continued to experience further tumor shrinkage thereafter[ 25 ]. If the prognosis can be predicted at an earlier time point, patients who achieve tumor shrinkage may be more confident in continuing treatment, whereas non-responders could avoid unnecessary toxicity and be considered for alternative therapeutic strategies at an earlier stage. Furthermore, in patients with favorable prognostic features, such as the absence of bone or liver metastases, clear cell histology, and early tumor shrinkage after treatment initiation, the expectation of a prolonged OS may justify the consideration of deferred CN[ 26 – 28 ]. Nevertheless, early imaging assessments carry a potential risk of misclassification due to pseudoprogression under ICI therapy[ 29 ]. We set the cutoff value for early tumor shrinkage at 30% in the multivariate analyses. During the TKI era, a threshold of 10% was considered appropriate, which was higher than the 1% cutoff proposed for interferon-α therapy[ 21 ]. This discrepancy may reflect differences in antitumor activity and tumor-shrinking potential across treatment modalities. A similar rationale may apply to ICI-based combination therapy, which generally yields higher objective response rates than TKI monotherapy, suggesting that a cutoff greater than 10% may be reasonable[ 6 – 10 ]. Although we did not determine the optimal cutoff in this study, we adopted 30% to match the lower limit of partial response as defined by RECIST, offering both consistency and clinical utility. Kaplan–Meier analyses of the OS stratified by early tumor shrinkage showed that the survival curves for patients with a tumor size shrinkage of 0% to < 30% and those with a gain in tumor size were closely aligned in this study. This observation is consistent with the report by Seidel et al. from the TKI era, in which the Kaplan–Meier curves for patient cohorts with early tumor shrinkage of 59%–30%, 29%–0%, and a gain in tumor size of 1%–19% also exhibited similar distributions[ 17 ]. In the present study, the median interval from treatment initiation to the first imaging assessment was 8.8 months in the < 30% to 0% group and 7.1 months in the gain group, indicating that earlier imaging in the latter group may have led to an underestimation of tumor shrinkage due to the shorter treatment duration. Several limitations associated with the present study warrant mention. First, this was a retrospective analysis with a limited number of patients, which may not represent the overall population and could introduce potential biases. Therefore, prospective validation of the findings in an external cohort is warranted. Second, treatment selection, dose reductions, and interruptions were not uniformly based on predefined criteria, which may have influenced clinical outcomes. Third, tumor shrinkage was evaluated using RECIST rather than immune-related criteria, such as irRECIST or irRC. Therefore, a potential limitation is pseudo-progression during ICI therapy, in which an initial apparent tumor enlargement is followed by subsequent regression[ 29 ]. Premature discontinuation or treatment switching based solely on early imaging findings should be avoided, and clinical judgment in combination with additional clinical information is essential. Fourth, the cutoff values for early tumor shrinkage were not standardized. In fact, they vary across studies, and the validity of specific thresholds should be interpreted with caution. Individualized thresholds are needed, depending on the treatment regimen and patient population. Conclusion Our findings suggest that early tumor shrinkage is independently associated with favorable OS and may serve as a useful prognostic indicator in patients with mRCC treated with first-line ICI-based combination therapy. Declarations Acknowledgments The authors sincerely appreciate the contributions of all physicians and patients who participated in this study. Conflict of interests Hideaki Miyake received honoraria from Eisai, Merck, MSD, Ono, Pfizer and Takeda. Naoki Matsuyama, Takuto Hara, Hideto Ueki, Naoto Wakita, Yasuyoshi Okamura, Yukari Bando, Kotaro Suzuki, Tomoaki Terakawa, Koji Chiba, Akihisa Yao, Jun Teishima have no conflicts of interest that might be relevant to the contents of this article. Funding No external funding was used in the preparation of this article. Data availability statements The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval This study was conducted in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethical Committee of Kobe University Graduate School of Medicine (approval number: B230087). Informed consent Patient consent was obtained via an opt-out on the website. Authors’ contribution Conceptualization: Takuto Hara; Methodology: Naoki Matsuyama; Formal analysis and investigation: Naoki Matsuyama; Writing – original draft preparation: Naoki Matsuyama; Writing – review and editing: Takuto Hara; Resources: Hideto Ueki, Naoto Wakita, Yasuyoshi Okamura, Yukari Bando, Kotaro Suzuki, Tomoaki Terakawa, Koji Chiba, Akihisa Yao; Supervision: Hideaki Miyake References Cancer of the Kidney and Renal Pelvis - Cancer Stat Facts In: SEER. https://seer.cancer.gov/statfacts/html/kidrp.html . Accessed 19 Sept 2025 Cancer Today https://gco.iarc.who.int/today/ . Accessed 19 Sept 2025 Bukavina L, Bensalah K, Bray F et al (2022) Epidemiology of Renal Cell Carcinoma: 2022 Update. Eur Urol 82:529–542. https://doi.org/10.1016/j.eururo.2022.08.019 Padala SA, Barsouk A, Thandra KC et al (2020) Epidemiology of Renal Cell Carcinoma. 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Jpn J Clin Oncol 52:1208–1214. https://doi.org/10.1093/jjco/hyac099 van de Fransen EE, van den Brink L, Mansour MA et al (2023) Indications and Outcomes for Deferred Cytoreductive Nephrectomy Following Immune Checkpoint Inhibitor Combination Therapy: Can Systemic Therapy be Withdrawn in Patients with No Evidence of Disease? Eur Urol Open Sci 55:15–22. https://doi.org/10.1016/j.euros.2023.07.002 Chiou VL, Burotto M (2015) Pseudoprogression and Immune-Related Response in Solid Tumors. JCO 33:3541–3543. https://doi.org/10.1200/JCO.2015.61.6870 Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major revisions 17 Feb, 2026 Reviewers agreed at journal 23 Jan, 2026 Reviewers invited by journal 22 Jan, 2026 Editor assigned by journal 13 Jan, 2026 First submitted to journal 10 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8567777","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":578765947,"identity":"3babea84-8690-48c9-b20a-ee753c3232ce","order_by":0,"name":"Naoki Matsuyama","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYBACCRCRwGADZQEBYwNxWtJI1cLAcBihhSCQnH38msTDHecT+2c3H3zAUGPDwDybgDXSfDllEolnbifOuHMs2YDhWBoD45wD+LXI8fAkGyS23U5suJFjJsHYcJiBcUYCUVrOJc4nWos0D/vBB4ltBxI3EK1FsoeH8UHimWTjjTfSkg0SjqXxEPSLxBn2Bwd/7rCTnXcj+eCDDzU2coaEQoyBgccAFHuOYHVAJ/EYziCkg4H9AUiLPZwvT3ScjoJRMApGwUgBACWSRk9QFLi0AAAAAElFTkSuQmCC","orcid":"","institution":"Kobe University Hospital: Kobe Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":true,"prefix":"","firstName":"Naoki","middleName":"","lastName":"Matsuyama","suffix":""},{"id":578765948,"identity":"1560ce4d-399a-4b3c-8aa3-15882732e9e3","order_by":1,"name":"Takuto Hara","email":"","orcid":"https://orcid.org/0000-0003-4524-2815","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Takuto","middleName":"","lastName":"Hara","suffix":""},{"id":578765949,"identity":"035979f3-1e20-425f-ba08-59dceaf3bc73","order_by":2,"name":"Hideto Ueki","email":"","orcid":"","institution":"Kobe University Hospital: Kobe Daigaku Igakubu Fuzoku Byoin","correspondingAuthor":false,"prefix":"","firstName":"Hideto","middleName":"","lastName":"Ueki","suffix":""},{"id":578765950,"identity":"87066f36-4bc5-40c3-a154-21496f4f4d44","order_by":3,"name":"Naoto Wakita","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Naoto","middleName":"","lastName":"Wakita","suffix":""},{"id":578765951,"identity":"3996aa19-5479-4da5-94bd-affe3989a0d7","order_by":4,"name":"Yasuyoshi Okamura","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Yasuyoshi","middleName":"","lastName":"Okamura","suffix":""},{"id":578765952,"identity":"784eca1e-46bf-4e0e-831f-e7dcf0be2d72","order_by":5,"name":"Yukari Bando","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Yukari","middleName":"","lastName":"Bando","suffix":""},{"id":578765953,"identity":"121e2b42-8f18-46ca-a7d7-7e795ad34a9b","order_by":6,"name":"Kotaro Suzuki","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Kotaro","middleName":"","lastName":"Suzuki","suffix":""},{"id":578765954,"identity":"36891efa-5605-4e8a-baae-6f6fcfd2cf77","order_by":7,"name":"Tomoaki Terakawa","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Tomoaki","middleName":"","lastName":"Terakawa","suffix":""},{"id":578765955,"identity":"48314333-0c74-453c-8c03-1bf25365a58a","order_by":8,"name":"Koji Chiba","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Koji","middleName":"","lastName":"Chiba","suffix":""},{"id":578765956,"identity":"64af1cea-be49-4409-b0a2-a7403f4c34a8","order_by":9,"name":"Akihisa Yao","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Akihisa","middleName":"","lastName":"Yao","suffix":""},{"id":578765957,"identity":"88aecd5d-1603-4d06-b595-f7506ff6806e","order_by":10,"name":"Jun Teishima","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Teishima","suffix":""},{"id":578765958,"identity":"8bfd663e-5667-43a6-a308-c1d904311c7b","order_by":11,"name":"Hideaki Miyake","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine School of Medicine: Kobe Daigaku Daigakuin Igakukei Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Hideaki","middleName":"","lastName":"Miyake","suffix":""}],"badges":[],"createdAt":"2026-01-10 11:05:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8567777/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8567777/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101397971,"identity":"3d8fc262-8e94-4918-806d-070145eb4ce9","added_by":"auto","created_at":"2026-01-29 09:38:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":140527,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of the progression-free survival (A) and overall survival (B) in 169 patients with metastatic renal cell carcinoma treated with ICI-based combination therapy. ICI, immune checkpoint inhibitor.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8567777/v1/5384afed0b2d32c2cee86be9.png"},{"id":101362680,"identity":"cb53dcea-c173-4082-9da5-b8b5f9b12f1f","added_by":"auto","created_at":"2026-01-29 00:30:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":169678,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Waterfall plot showing the percentage change in tumor burden from baseline in 169 patients with metastatic renal cell carcinoma at the first imaging evaluation after initiation of first-line immune checkpoint inhibitor-based combination therapy. (B) Kaplan–Meier estimate of the overall survival in 169 patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitor-based combination therapy according to tumor shrinkage at the first imaging evaluation after their initiation. Based on the changes in the sum of the largest diameters of target lesions assessed by computed tomography, patients were stratified into four subgroups with tumor shrinkage from 100% to 50%, \u0026lt;50% to 30%, \u0026lt;30% to 0%, and a gain in the sum of the largest diameters. CI, confidence interval; ICI, immune checkpoint inhibitor; NE, not estimated; NR, not reached.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8567777/v1/452db03b9275377b6802c460.png"},{"id":101362679,"identity":"3dfb9520-c25b-404a-b348-5d2785771698","added_by":"auto","created_at":"2026-01-29 00:30:55","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":118474,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimate of the overall survival in 169 patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitor-based combination therapy according to the number of independent risk factors for the overall survival identified on a multivariate analysis, including prior nephrectomy, bone or liver metastasis, histological subtype, and early tumor shrinkage. CI, confidence interval; ICI, immune checkpoint inhibitor; NE, not estimated; NR, not reached.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8567777/v1/520eff28c78503531ecf0b76.png"},{"id":101751268,"identity":"271ce69a-11db-4f65-866a-eb974b73e502","added_by":"auto","created_at":"2026-02-03 10:18:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1176216,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8567777/v1/b740bd3c-0065-4884-a7b0-e1cdbfc98c44.pdf"}],"financialInterests":"","formattedTitle":"Prognostic significance of early tumor shrinkage in metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based combination therapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eKidney cancer is among the most common malignancies in developed countries, accounting for approximately 4% of all new cancer cases in the United States in 2025 and 3% in Europe in 2022[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Renal cell carcinoma (RCC) is the most common form of kidney cancer, accounting for \u0026gt;\u0026thinsp;90% of all cases[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Approximately one-third of patients with RCC are diagnosed with advanced or metastatic disease, and their prognosis has historically been poor, with 5-year survival rates of 15%\u0026ndash;35% for patients with regional disease and \u0026lt;\u0026thinsp;10% for those with metastatic disease[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In recent years, the introduction of tyrosine kinase inhibitors (TKIs), followed by immune checkpoint inhibitors (ICIs), has remarkably changed the treatment paradigm for advanced and metastatic RCC (mRCC). Combination regimens of ICIs (nivolumab plus ipilimumab) and ICIs with TKIs (pembrolizumab [or avelumab] plus axitinib, pembrolizumab plus lenvatinib, and nivolumab plus cabozantinib) have demonstrated significantly improved outcomes compared to sunitinib monotherapy in randomized clinical trials[\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and are now established as the mainstay of treatment for advanced or metastatic RCC. These agents have improved the prognosis of patients with RCC; however, although the 5-year survival rate between 2015 and 2021 reached 76.4% for patients with regional disease, it remained at only 19.1% for those with metastatic disease[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Accordingly, reliable early predictors of outcomes in patients with mRCC receiving ICI-based combination therapies have been explored as practical indicators to guide treatment decisions.\u003c/p\u003e \u003cp\u003eSeveral studies have investigated how baseline tumor burden or treatment-induced changes in tumor burden are associated with the post-treatment prognosis. During the TKI era, Miyake et al. reported that early tumor shrinkage could serve as a useful predictor of the OS in patients with mRCC receiving TKIs as the first-line therapy[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In the ICI era, Gr\u0026uuml;nwald et al. showed that the depth of tumor response was associated with the OS in a landmark analysis of the phase 3 CLEAR trial of patients with advanced RCC treated with lenvatinib plus pembrolizumab[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, no studies to date have examined the impact of early tumor shrinkage on survival outcomes in patients treated with ICI-based combination therapies. Furthermore, studies on tumor burden in the ICI era have mainly included patients enrolled in clinical trials[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Even among the limited number of real-world studies available, most have focused on nivolumab plus ipilimumab[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Consequently, these findings may not fully reflect the current standard of care for RCC, potentially introducing bias when applied in real-world practice.\u003c/p\u003e \u003cp\u003eThe present study thus evaluated the prognostic significance of early tumor shrinkage in patients with mRCC receiving first-line ICI-based combination therapies.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eClinical and pathological data were collected from 223 consecutive mRCC patients who received first-line ICI-based combination therapy at Kobe University Hospital and its affiliated institutions between October 2015 and December 2024. Patients were excluded if they lacked data on measurable lesion size, had a follow-up period of less than two months, or did not undergo their first imaging evaluation at an appropriate time after initiating systemic therapy. The patients received one of the following regimens: nivolumab plus ipilimumab, pembrolizumab (or avelumab) plus axitinib, pembrolizumab plus lenvatinib, or nivolumab plus cabozantinib.\u003c/p\u003e \u003cp\u003eThe study protocol was approved by the Research Ethics Committee of our institution (No. B230087) and was conducted in accordance with the principles of the Declaration of Helsinki. The requirement for individual informed consent was waived because of the retrospective nature of the analysis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatments and Procedures\u003c/h3\u003e\n\u003cp\u003eEach regimen was initiated at a standard prescribed dose. Treatment was continued until disease progression or intolerable adverse events (AEs) developed. In general, dose modification of TKIs was considered in cases with treatment-associated AEs corresponding to grade\u0026thinsp;\u0026ge;\u0026thinsp;3. Dose reductions or temporary interruptions were allowed at the discretion of the treating physician in accordance with prescribing information and institutional guidelines. A radiological evaluation of the tumor was performed before and approximately every three months after the initiation of systemic therapy. Imaging data were obtained from chest and abdominal computed tomography (CT), and if CT was not available, magnetic resonance imaging, bone scintigraphy, or 18F-fluorodeoxyglucose-positron emission tomography was used instead. Tumor burden was defined as the sum of the largest diameters of the target lesions, according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Early tumor shrinkage was calculated as the percentage change in tumor burden from baseline to the first imaging assessment. Based on changes in tumor burden, patients were stratified into 4 subgroups according to our strategy: tumor shrinkage from 50% to 100%, 30% to \u0026lt;\u0026thinsp;50%, 0% to \u0026lt;\u0026thinsp;30%, and a gain in tumor burden.\u003c/p\u003e\n\u003ch3\u003eStatistical Analyses\u003c/h3\u003e\n\u003cp\u003eThe OS was analyzed using the Kaplan-Meier method, and subgroup comparisons were performed using the log-rank test. Cox proportional hazards models were used for univariate and subsequent multivariate analyses to determine the independent prognostic value of the OS. All statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (R Foundation for Statistical Computing, Vienna, Austria). All statistical tests were 2-sided, and a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAmong the 223 patients initially enrolled, 33 were excluded due to a lack of data on measurable lesion size, 8 due to a follow-up period of less than two months, and 20 due to the absence of a timely first imaging evaluation after the initiation of systemic therapy (with some overlap). After these exclusions, 169 patients were included in this study. The baseline characteristics of the overall patient cohort are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age was 70.0 years old (interquartile range [IQR], 63.0\u0026ndash;76.0), and the majority were male (78.7%). According to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, 10.1% were favorable risk, 52.7% were intermediate-risk, and 37.3% were poor-risk. More than half of the patients (56.2%) had previously undergone prior nephrectomy. The most frequently administered first-line regimen was nivolumab plus ipilimumab (43.8%).\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\u003ePatient\u0026rsquo;s characteristics.\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\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;190\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years), median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70.0 (63.0\u0026ndash;76.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\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\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e133 (78.7)\u003c/p\u003e \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\u003e36 (21.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePS\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\u0026ge;\u0026thinsp;80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e139 (82.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (17.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior nephrectomy\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\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (43.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadical nephrectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e91 (53.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePartial nephrectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIMDC risk group\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\u003e17 (10.1)\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\u003e89 (52.7)\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\u003e63 (37.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein (mg/dL)\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;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93 (55.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;0.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (45.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic organ\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\u003e105 (62.1)\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\u003e58 (34.3)\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\u003e56 (33.1)\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\u003e25 (14.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdrenal gland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (12.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (6.5)\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\u003e12 (7.1)\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\u003e28 (16.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of metastases\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\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (17.2)\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\u003e140 (82.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistological subtype\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\u003eClear cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e131 (77.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-clear cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (22.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSarcomatoid feature\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\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e151 (89.3)\u003c/p\u003e \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\u003e18 (10.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-line treatment\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\u003eNivo/Ipi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (43.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAve/Axi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (15.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePem/Axi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (7.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNivo/Cab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (13.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePem/Len\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (20.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline volume of metastasis (mm), median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.0 (28.0\u0026ndash;129.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChange in tumor burden (%), median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ndash;17.8 (\u0026ndash;36.8 to 0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMagnitude of early tumor shrinkage (four-group classification)\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\u003e100% to 50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (12.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50% to 30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (18.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;30% to 0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81 (47.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003egain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (21.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eData are expressed as n (%) unless otherwise specified\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eAve/Axi, avelumab plus axitinib; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IQR, interquartile range; Nivo/Cabo, nivolumab plus cabozantinib; Nivo/Ipi, nivolumab plus ipilimumab; Pem/Axi, pembrolizumab plus axitinib; Pem/Len, pembrolizumab plus lenvatinib; PS, performance status.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWith a median follow-up of 33.4 months (95% confidence interval [CI], 27.7\u0026ndash;38.7; Kaplan\u0026ndash;Meier estimate), the median PFS and OS for the entire cohort were 18.8 months (95% CI, 12.8\u0026ndash;24.9) and 42.4 months (95% CI, 31.5\u0026ndash;66.1), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA shows a waterfall plot of the change in tumor burden at the first imaging evaluation after the initiation of systemic therapy for individual patients. The median change for the entire cohort was \u0026minus;\u0026thinsp;17.8% (IQR, \u0026minus;\u0026thinsp;36.8% to 0%). Twenty-one patients (12.4%) experienced early tumor shrinkage of 50% to 100%, 31 patients (18.3%) experienced shrinkage of 30% to \u0026lt;\u0026thinsp;50%, 81 patients (47.9%) experienced shrinkage of 0% to \u0026lt;\u0026thinsp;30%, and 36 patients (21.3%) showed an increase in tumor burden. The median interval from treatment initiation to the first imaging evaluation was 8.7 weeks (IQR, 6.6\u0026ndash;11.0): 9.3 weeks (IQR, 8.0\u0026ndash;12.3) for the 100% to 50% group, 8.3 weeks (IQR, 7.0\u0026ndash;10.2) for the \u0026lt;\u0026thinsp;50% to 30% group, 8.9 weeks (IQR, 6.9\u0026ndash;10.9) for the \u0026lt;\u0026thinsp;30% to 0% group, and 7.1 weeks (IQR, 6.1\u0026ndash;10.6) for the group with an increase in tumor burden. The corresponding median OS stratified according to early tumor shrinkage of 50% to 100%, 30% to \u0026lt;\u0026thinsp;50%, 0% to \u0026lt;\u0026thinsp;30%, and a gain in tumor burden was not reached (NR; 95% CI, NE\u0026ndash;NE), NR (95% CI, 31.5 months\u0026ndash;NE), 34.7 months (95% CI, 24.5\u0026ndash;NE), and 30.8 months (95% CI, 19.6\u0026ndash;42.4), respectively (p\u0026thinsp;=\u0026thinsp;0.023; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The 2-year OS rates stratified according to early tumor shrinkage as described above were 86.7% (95% CI, 56.4%\u0026ndash;96.5%), 75.1% (95% CI, 54.3%\u0026ndash;87.4%), 66.1% (95% CI, 52.5%\u0026ndash;76.7%), and 60.5% (95% CI, 42.6%\u0026ndash;74.4%), respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA univariate analysis identified a history of prior nephrectomy, IMDC risk group, bone or liver metastasis, C-reactive protein (CRP) level, histological subtype, and early tumor shrinkage as significant predictors of the OS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Furthermore, in the multivariate analysis, four factors remained independently associated with the OS: a history of prior nephrectomy, bone or liver metastasis, histological subtype, and early tumor shrinkage.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analyses of factors associated with the overall survival.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026ge;\u0026thinsp;65 vs. \u0026lt;65 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.27 (0.77\u0026ndash;2.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (female vs. male)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.61 (0.93\u0026ndash;2.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.086\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistory of a prior nephrectomy (no vs. yes)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3.77 (2.22\u0026ndash;6.41)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e2.43 (1.34\u0026ndash;4.41)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIMDC risk group (poor vs. others)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3.05 (1.86\u0026ndash;5.01)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.10 (0.56\u0026ndash;2.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of metastasis (\u0026ge;\u0026thinsp;2 vs. 1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.29 (0.99\u0026ndash;5.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung metastasis (yes vs. no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.50 (0.89\u0026ndash;2.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBone or liver metastasis (yes vs. no)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2.65 (1.58\u0026ndash;4.45)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e2.34 (1.33\u0026ndash;4.11)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eC-reactive protein, mg/dL (\u0026ge;\u0026thinsp;0.1 vs. \u0026lt;0.1)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3.51 (2.08\u0026ndash;5.92)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.94 (0.94-4.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHistological subtype (non-clear cell vs. clear cell)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1.83 (1.04\u0026ndash;3.19)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.035\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e2.17 (1.18-4.00)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSarcomatoid feature (yes vs. no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.15 (0.55\u0026ndash;2.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst line treatment (ICI-ICI vs. ICI-TKI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08 (0.65\u0026ndash;1.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEarly tumor shrinkage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.010\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e100% to 50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50% to 30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.02 (0.65\u0026ndash;14.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;30% to 0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.71 (1.13\u0026ndash;19.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003egain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.12 (1.44\u0026ndash;26.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEarly tumor shrinkage (\u0026lt;\u0026thinsp;30% vs. 100% to 30%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2.38 (1.24\u0026ndash;4.56)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e2.25 (1.15\u0026ndash;4.38)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eICI, immune checkpoint inhibitor; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; TKI, tyrosine kinase inhibitor; HR, hazard ratio; CI, confidence interval\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTo refine the prediction of the OS, we stratified the 169 patients into 3 groups according to the number of risk factors identified in the multivariate analysis. Death occurred in 8 of 63 patients with 0 or 1 risk factor (12.7%), 28 of 58 patients with 2 risk factors (48.3%), and 28 of 48 patients with 3 or 4 risk factors (58.3%). The OS differed significantly across the 3 groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, we conducted a multicenter retrospective analysis of 169 patients in Japan and found that greater early tumor shrinkage was significantly associated with a longer OS in patients with mRCC treated with first-line ICI-based combination therapies. A multivariate analysis further identified early tumor shrinkage as an independent prognostic factor for the OS. To our knowledge, this is the first report to suggest that early tumor shrinkage may serve as a reliable outcome predictor in patients with mRCC receiving first-line ICI-based combination therapies.\u003c/p\u003e \u003cp\u003eThe PFS of 18.8 months and OS of 42.4 months observed in this study were comparable to those reported in previous randomized clinical trials of first-line ICI-based combination therapies[\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A multivariate analysis identified several factors, including a history of prior nephrectomy, bone or liver metastases, and histological subtype as significant prognostic indicators, consistent with previous findings[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In addition, an early tumor shrinkage of 100% to 30% was found to be a prognostic factor, with a hazard ratio comparable to these established variables.\u003c/p\u003e \u003cp\u003eTumor burden has been reported to be a useful tool for outcome prediction in patients receiving systemic therapy for mRCC. Because the tumor burden can be easily assessed using routine radiological examinations, it is valuable for stratifying patients and guiding treatment selection. In the TKI era, factors such as baseline tumor burden, magnitude and timing of the best tumor response, and early tumor shrinkage have been reported as prognostic factors or surrogate markers[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In the context of ICI-based combination therapy, recent retrospective analyses primarily involving nivolumab plus ipilimumab have shown that baseline tumor burden, depth of tumor response, and maximum evaluable lesion size are associated with outcomes following systemic treatment.[\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Our study expands upon these findings by indicating that early tumor shrinkage is a clinically relevant indicator not only in TKI regimens but also in ICI-ICI and ICI-TKI combination therapies.\u003c/p\u003e \u003cp\u003eThe significance of this study lies in its ability to stratify the patient prognosis at an early time point, specifically during the first imaging evaluation. The most widely used method for assessing tumor response remains RECIST, and previous studies have reported that outcome stratification based on the criteria is feasible in patients with mRCC receiving ICI-based combination therapy[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, the time to the best tumor response is typically longer than the time to the initial response, indicating that RECIST-based evaluations are often performed at later stages of treatment. For example, in a phase 1b trial of pembrolizumab plus axitinib, the median time to response was 2.8 months, and many patients continued to experience further tumor shrinkage thereafter[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. If the prognosis can be predicted at an earlier time point, patients who achieve tumor shrinkage may be more confident in continuing treatment, whereas non-responders could avoid unnecessary toxicity and be considered for alternative therapeutic strategies at an earlier stage. Furthermore, in patients with favorable prognostic features, such as the absence of bone or liver metastases, clear cell histology, and early tumor shrinkage after treatment initiation, the expectation of a prolonged OS may justify the consideration of deferred CN[\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Nevertheless, early imaging assessments carry a potential risk of misclassification due to pseudoprogression under ICI therapy[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe set the cutoff value for early tumor shrinkage at 30% in the multivariate analyses. During the TKI era, a threshold of 10% was considered appropriate, which was higher than the 1% cutoff proposed for interferon-α therapy[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This discrepancy may reflect differences in antitumor activity and tumor-shrinking potential across treatment modalities. A similar rationale may apply to ICI-based combination therapy, which generally yields higher objective response rates than TKI monotherapy, suggesting that a cutoff greater than 10% may be reasonable[\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although we did not determine the optimal cutoff in this study, we adopted 30% to match the lower limit of partial response as defined by RECIST, offering both consistency and clinical utility.\u003c/p\u003e \u003cp\u003eKaplan\u0026ndash;Meier analyses of the OS stratified by early tumor shrinkage showed that the survival curves for patients with a tumor size shrinkage of 0% to \u0026lt;\u0026thinsp;30% and those with a gain in tumor size were closely aligned in this study. This observation is consistent with the report by Seidel et al. from the TKI era, in which the Kaplan\u0026ndash;Meier curves for patient cohorts with early tumor shrinkage of 59%\u0026ndash;30%, 29%\u0026ndash;0%, and a gain in tumor size of 1%\u0026ndash;19% also exhibited similar distributions[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In the present study, the median interval from treatment initiation to the first imaging assessment was 8.8 months in the \u0026lt;\u0026thinsp;30% to 0% group and 7.1 months in the gain group, indicating that earlier imaging in the latter group may have led to an underestimation of tumor shrinkage due to the shorter treatment duration.\u003c/p\u003e \u003cp\u003eSeveral limitations associated with the present study warrant mention. First, this was a retrospective analysis with a limited number of patients, which may not represent the overall population and could introduce potential biases. Therefore, prospective validation of the findings in an external cohort is warranted. Second, treatment selection, dose reductions, and interruptions were not uniformly based on predefined criteria, which may have influenced clinical outcomes. Third, tumor shrinkage was evaluated using RECIST rather than immune-related criteria, such as irRECIST or irRC. Therefore, a potential limitation is pseudo-progression during ICI therapy, in which an initial apparent tumor enlargement is followed by subsequent regression[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Premature discontinuation or treatment switching based solely on early imaging findings should be avoided, and clinical judgment in combination with additional clinical information is essential. Fourth, the cutoff values for early tumor shrinkage were not standardized. In fact, they vary across studies, and the validity of specific thresholds should be interpreted with caution. Individualized thresholds are needed, depending on the treatment regimen and patient population.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings suggest that early tumor shrinkage is independently associated with favorable OS and may serve as a useful prognostic indicator in patients with mRCC treated with first-line ICI-based combination therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors sincerely appreciate the contributions of all physicians and patients who participated in this study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConflict of interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eHideaki Miyake received honoraria from Eisai, Merck, MSD, Ono, Pfizer and Takeda. Naoki Matsuyama, Takuto Hara, Hideto Ueki, Naoto Wakita, Yasuyoshi Okamura, Yukari Bando, Kotaro Suzuki, Tomoaki Terakawa, Koji Chiba, Akihisa Yao, Jun Teishima have no conflicts of interest that might be relevant to the contents of this article.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNo external funding was used in the preparation of this article.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData availability statements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics approval\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Ethical Committee of Kobe University Graduate School of Medicine (approval number: B230087).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInformed consent\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatient consent was obtained via an opt-out on the website.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026rsquo; contribution\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Takuto Hara; Methodology: Naoki Matsuyama; Formal analysis and investigation: Naoki Matsuyama; Writing \u0026ndash; original draft preparation: Naoki Matsuyama; Writing \u0026ndash; review and editing: Takuto Hara; Resources: Hideto Ueki, Naoto Wakita, Yasuyoshi Okamura, Yukari Bando, Kotaro Suzuki, Tomoaki Terakawa, Koji Chiba, Akihisa Yao; Supervision: Hideaki Miyake\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCancer of the Kidney and Renal Pelvis - Cancer Stat Facts In: SEER. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://seer.cancer.gov/statfacts/html/kidrp.html\u003c/span\u003e\u003cspan address=\"https://seer.cancer.gov/statfacts/html/kidrp.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 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JCO 33:3541\u0026ndash;3543. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/JCO.2015.61.6870\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2015.61.6870\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"renal cell carcinoma, early tumor shrinkage, tumor burden, immune checkpoint inhibitor, prognosis, overall survival","lastPublishedDoi":"10.21203/rs.3.rs-8567777/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8567777/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eImmune checkpoint inhibitor (ICI)-based combination therapies have become the standard first-line treatment for metastatic renal cell carcinoma (mRCC). This study evaluated the prognostic significance of early tumor shrinkage in patients with mRCC treated with first-line ICI-based combination therapies.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e We retrospectively reviewed 169 mRCC patients who received nivolumab plus ipilimumab, pembrolizumab (or avelumab) plus axitinib, pembrolizumab plus lenvatinib, or nivolumab plus cabozantinib at Kobe University Hospital and its affiliated institutions. Patients were stratified into four groups according to early tumor shrinkage at the first imaging assessment after therapy initiation. The association between early tumor shrinkage and the overall survival (OS) was analyzed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median early tumor shrinkage rate was 17.8%. Twenty-one patients (12.4%) had 50%\u0026ndash;100% shrinkage, 31 (18.3%) had 30%\u0026ndash;\u0026lt;50% shrinkage, 81 (47.9%) had 0%\u0026ndash;\u0026lt;30% shrinkage, and 36 (21.3%) showed progression. The median OS was 42.4 months. The corresponding median OS by shrinkage category above was not reached (NR), NR, 34.7 months, and 30.8 months, respectively (p\u0026thinsp;=\u0026thinsp;0.023), with 2-year OS rates of 86.7%, 75.1%, 66.1%, and 60.5%, respectively. A univariate analysis identified a prior nephrectomy, International mRCC Database Consortium risk group, bone or liver metastasis, C-reactive protein level, histological subtype, and early tumor shrinkage as predictors of the OS. In the multivariate analysis, prior nephrectomy, bone or liver metastasis, histological subtype, and early tumor shrinkage remained independent.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEarly tumor shrinkage was independently associated with the OS, suggesting its potential as a prognostic indicator in patients with mRCC treated with first-line ICI-based combination therapy.\u003c/p\u003e","manuscriptTitle":"Prognostic significance of early tumor shrinkage in metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based combination therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 00:30:50","doi":"10.21203/rs.3.rs-8567777/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2026-02-17T05:47:15+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-01-23T13:14:14+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-22T13:00:30+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-13T14:35:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2026-01-10T06:04:46+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a93ef31c-a268-4c26-8125-1641bf5ff8b3","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-15T06:12:31+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-29 00:30:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8567777","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8567777","identity":"rs-8567777","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}