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BACKGROUND AND OBJECTIVE: The role of cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) has been called into question on the basis of clinical trial data from the tyrosine kinase inhibitor (TKI) era. Comparative analyses of CN for patients treated with immuno-oncology (IO) versus TKI agents are sparse. Our objective was to compare CN timing and outcomes among patients who received TKI versus IO therapy. METHODS: This was a multicenter retrospective analysis of patients who underwent CN using data from the REMARCC (Registry of Metastatic RCC) database. The cohort was divided into TKI versus IO first-line therapy groups. The primary outcome was all-cause mortality (ACM). Secondary outcomes included cancer-specific mortality (CSM). Multivariable analysis was used to identify factors predictive for ACM and CSM. The Kaplan-Meier method was used to analyze 5-yr overall survival (OS) and cancer-specific survival (CSS) with stratification by primary systemic therapy and timing in relation to CN. KEY FINDINGS AND LIMITATIONS: We analyzed data for 189 patients (148 TKI + CN, 41 IO +CN; median follow-up 23.2 mo). Multivariable analysis revealed that a greater number of metastases (hazard ratio [HR] 1.06; p = 0.015), greater primary tumor size (HR 1.10; p = 0.043), TKI receipt (HR 2.36; p = 0.015), and initiation of systemic therapy after CN (HR 1.49; p = 0.039) were associated with worse ACM. A greater number of metastases at diagnosis (HR 1.07; p = 0.011), greater primary tumor size (HR 1.12; p = 0.018), TKI receipt (HR 5.43; p = 0.004), and initiation of systemic therapy after CN (HR 2.04; p

Simple Summary: ICI-based combinations have led to a significant change in mRCC medical treatment. However, data from real-world (RW) cohorts are rare. In this multicenter study, we evaluated the safety and effectiveness of cabozantinib plus nivolumab in real-world cohorts from centers in Germany, Switzerland, and Austria. The median PFS in the overall cohort was 18.6 months. We also analyzed subgroups in relation to the IMDC, histology, and with regard to the presence of bone metastasis. In summary, our real-word data support the promising efficacy data of the pivotal trials, particularly in patients with non-ccRCC and those without bone metastases at the start of the treatment. Introduction: Combinations of immune-checkpoint inhibitors (ICIs) are the standard of care (SOC) for treatment-naive metastatic renal cell carcinoma (mRCC) patients. In this multicenter study, we evaluated the RW safety and efficacy of cabozantinib plus nivolumab in mRCC patients. Methods: Data were retrospectively collected from twelve cancer centers in Germany, Switzerland, and Austria. Patients with advanced or mRCC were eligible. The investigator-based objective response rate (ORR) and progression free survival (PFS) were calculated from the start of the treatment to progression or death. Descriptive statistics and Kaplan–Meier (KM) plots were utilized where appropriate. Results: In total, 96 eligible patients (66.6% male) with a median age of 66.0 years were included. The most common histology was clear-cell RCC (ccRCC) in 63.4% (n = 61). A prior nephrectomy was performed in 60.4% (n = 58). ECOG 0-1 was 68.8% (n = 66). A partial response was documented in 43.8% of patients (n = 42), a stable disease in 32.3% (n = 31), and a progressive disease in 8.3% (n = 8) as the best overall response. Response data were not evaluable in 13.5% (n = 13). The median follow-up time was 12.7 months (95% CI, 10.0–15.3). The PFS rate at 6 months was 89.8% in the overall population (86.8% for ccRCC; 90.0% for non-ccRCC). Adverse events (AEs) were reported in 82.3% (n = 79) for all grades and 41.7% (n = 40) for grades 3–5. Elevated liver enzymes (34.4%), diarrhea (31.3%), and hand–foot syndrome (29.2%) were the three most frequent AEs of any grade and causality. Discussion/Conclusions: In this real-world cohort of mRCC patients, the application of cabozantinib plus nivolumab was shown to be safe and feasible. Our data support the use of cabozantinib plus nivolumab as a first-line standard therapy in mRCC patients. Major limitations were the retrospective data capture and short follow-up time of our study. [ABSTRACT FROM AUTHOR]

Background: Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment. Materials and methods: A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses. Results: A total of 571 patients with a median age of 61 years (range 17–85) were included in the analysis. With a median follow-up of 22.1 (1.0–89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders. Conclusion: This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the continuous therapeutic efforts metastatic renal cell carcinoma (mRCC) is a dreadful disease, but the many options available provide an horizon of hope for these patients. Sequential therapy based on vascular endothelial growth factor-tyrosine kinase inhibitors (VEGFR-TKI) continues in use. We present a nomogram for a more individualized and accurate estimation of cancer-specific survival (CSS) for patients with clear-cell (CC) mRCC treated with nephrectomy and VEGFR-TK, based on four independent clinical predictors: Eastern Cooperative Oncology Group (ECOG) status; International Metastatic RCC Database Consortium (IMDC) score; Morphology, Attenuation, Size and Structure (MASS) and Response Evaluation Criteria in Solid Tumors (RECIST) response criteria. This tool may be useful to clinicians assessing risk and prognosis of patients with mRCC. (1) Objective: To develop a clinically useful nomogram that may provide a more individualized and accurate estimation of cancer-specific survival (CSS) for patients with clear-cell (CC) metastatic renal cell carcinoma (mRCC) treated with nephrectomy and vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI)-based sequential therapy. (2) Methods: A prospectively maintained database of 145 patients with mRCC treated between 2008 and 2018 was analyzed to predict the CSS of patients receiving sunitinib and second- and third-line therapies according to current standards of practice. A nomogram based on four independent clinical predictors (Eastern Cooperative Oncology Group status, International Metastatic RCC Database Consortium score, the Morphology, Attenuation, Size and Structure criteria and Response Evaluation Criteria in Solid Tumors response criteria) was calculated. The corresponding 1- to 10-year CSS probabilities were then determined from the nomogram. (3) Results: The median age was 60 years (95% CI 57.9–61.4). The disease was metastatic at diagnosis in 59 (40.7%), and 86 (59.3%) developed metastasis during follow-up. Patients were followed for a median 48 (IQR 72; 95% CI 56–75.7) months after first-line VEGFR-TKI initiation. The concordance probability estimator value for the nomogram is 0.778 ± 0.02 (mean ± SE). (4) Conclusions: A nomogram to predict CSS in patients with CC mRCC that incorporates patient status, clinical risk classification and response criteria to first-line VEGFR-TKI at 3 months is presented. This new tool may be useful to clinicians assessing the risk and prognosis of patients with mRCC. [ABSTRACT FROM AUTHOR]

This article discusses a case study from Addenbrooke's Hospital in Cambridge, UK, where a patient with metastatic renal cell carcinoma (RCC) and inferior vena cava (IVC) tumor thrombus had a successful response to combined immunotherapy and tyrosine kinase inhibitor therapy. The patient was able to undergo surgery after the treatment, resulting in the removal of the tumor. The article explores the ongoing debate surrounding the management of metastatic RCC with IVC tumor thrombus and the potential benefits of systemic therapy and immediate surgery. The case study demonstrates the effectiveness of immunotherapy and targeted therapy in reducing the tumor size and enabling surgical intervention. The article also emphasizes the need for further research to determine the optimal approach for treating metastatic RCC with venous tumor thrombus. [Extracted from the article]

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection. [ABSTRACT FROM AUTHOR]

Aim: Assess the time-to-treatment discontinuation (TTD) and overall survival (OS) in a Swedish metastatic renal cell carcinoma (mRCC) nationwide cohort who received second-line axitinib. Methods: Retrospective analysis of 110 patients with mRCC treated with second-line axitinib in Sweden (2012–2019). Patients included in the study received axitinib after mainly first-line sunitinib or pazopanib. Results: The median (95% CI) TTD of patients who received second-line axitinib was 5.2 (3.7–6.1) months with 6 (5.5%) patients still receiving treatment at the time of analysis. Median (95% CI) OS was 12.2 (7.7–14.2) months. Conclusion: The results are consistent with previous findings in mRCC and add to the evidence demonstrating efficacy of second-line axitinib, after failure of a prior anti-angiogenic therapy in a real-world setting. Clinical Trial Registration:NCT04669366 (ClinicalTrials.gov) Article highlights The aim of this study was to assess the time-to-treatment discontinuation (TTD) and overall survival (OS) in a Swedish metastatic renal cell carcinoma (mRCC) national cohort who received second-line axitinib. A retrospective analysis of patients with mRCC treated with second-line axitinib in Sweden (2012–2019). A total of 110 patients with mRCC received second-line treatment with axitinib in the full population; 53 patients received first-line sunitinib, 53 patients received first-line pazopanib and the remaining four patients received another permitted first-line treatment. The median (95% CI) TTD in patients who received second-line axitinib was 5.2 (3.7–6.1) months with 6 (5.5%) patients still receiving treatment at the time of analysis. The median OS (95% CI) for all patients who received second-line axitinib was 12.2 (7.7–14.2) months; 28 (25.5%) patients remained censored at the time of analysis. The results are consistent with previous findings in mRCC and add to the evidence demonstrating efficacy of second-line axitinib, after failure of a prior anti-angiogenic therapy in a real-world setting. [ABSTRACT FROM AUTHOR]

Objective: A novel systemic immune-inflammation index (SII), based on the neutrophils, lymphocytes, and platelet counts, is associated with the prognosis of several cancers, including non-metastatic renal cell carcinoma (RCC). In the present study, we evaluate the prognostic significance of SII in patients with metastatic RCC (mRCC) treated with systemic therapy. Method: Relevant studies were searched comprehensively from Web of Science, PubMed, Embase and the Cochrane Library up to January 2024. The pooled hazard ratio (HR) and 95% confidence interval (CI) were extracted from each study to evaluate the prognostic value of SII in patients with mRCC treated with tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI). Results: A total of 12 studies including 4,238 patients were included in the final analysis. High SII was significantly correlated to poor overall survival (OS, HR = 1.88; 95% CI 1.60-2.21; P < 0.001) and progression-free survival (PFS, HR = 1.66; 95% CI 1.39-1.99; P < 0.001). Stratified by therapy, high SII was also related to the poor OS (TKI: HR = 1.63, P < 0.001; ICI: HR = 2.27, P < 0.001) and PFS (TKI: HR = 1.67, P < 0.001; ICI: HR = 1.88, P = 0.002). Conclusion: In conclusion, high SII could serve as an unfavorable factor in patients with mRCC treated with systemic therapy. Stratified by therapies, the elevated SII was also associated with worse prognosis. Whereas, more prospective and large-scale studies are warranted to validate our findings. [ABSTRACT FROM AUTHOR]