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Background: About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care., Objective: This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy., Methods: The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models., Results: Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively)., Conclusions: Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management., (© 2024. The Author(s).)

Background: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking., Method: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy., Results: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008)., Conclusions: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males., (© 2024. The Author(s).)

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47-0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39-0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling., (© 2024. The Author(s).)

Background: Systemic treatment with immune combinations is the gold standard for metastatic renal cell carcinoma (mRCC) worldwide. The systemic immune-inflammation index (SII) is a prognostic marker for several types of malignant neoplasms, including mRCC, in the era of tyrosine kinase inhibitor (TKI) treatment. Data regarding the prognostic value of the SII in patients with mRCC treated with immunotherapy are scarce and controversial.  METHODS: We retrospectively collected the data of patients with mRCC from 56 centers in 18 countries. SII (Platelet × Neutrophil/Lymphocyte count) was calculated prior to the first systemic treatment and cut-off was defined by a survival receiver operating characteristic (ROC) analysis. The primary objective of our retrospective study was to assess the outcomes of patients treated with first-line immunotherapy.  RESULTS: Data from 1034 mRCC patients was collected and included in this analysis. The SII cut-off value was 1265. After a follow-up of 26.7 months, and the overall survival (OS) and progression-free survival (PFS) were 39.8 and 15.7 months, respectively. According to SII (low vs. high), patients with low-SII had longer OS (55.7 vs. 22.2 months, P < .001), better PFS (20.8 vs. 8.5 months, P < .001), and higher overall response rate (52 vs. 37%, P = .033)., Conclusion: A high SII is associated with poor oncological outcomes in patients with mRCC. SII could be an easily accessible prognostic indicator for use in clinical practice., Competing Interests: Disclosure Fernando Sabino M. Monteiro: Research support was provided by Janssen (Merck Sharp Dome). Honoraria from Janssen, Ipsen, Bristol Myers Squibb, and Merck Sharp Dome. Ownership: BIO, Brazilian Information Oncology; Ondrej Fiala: Received honoraria from Roche, Janssen, MSD, Pierre Fabre, GSK, and Pfizer for consultations and lectures unrelated to this project; Francesco Massari: Personal fees from Astellas, BMS, Janssen, Ipsen, MSD, and Pfizer; Jindrich Kopecky: Consulting fees from Bristol Myers Squibb, Ipsen, Novartis, MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol-Myers Squibb, MSD, Pfizer, Merck, and Novartis; Jakub Kuchartz: Honoraria: Angelini, Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, IPSEN, Janssen, Merck MSD, Novartis, Pfizer, Research Funding: Novartis; Enrique Grande: Honoraria: Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, NanoString Technologies, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, and Thermo Fisher Scientific. Funding: Pfizer, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals; Maria T. Bourlon: Honoraria/advisory board: Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Eisai, IPSEN, Janssen, Merck, MSD, Novartis, Pfizer, Roche. Funding: Pfizer; Javier Molina-Cerrillo: Consultant, advisory, or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, Eisai, MSD, and BMS. JMC has received research grants from Pfizer, IPSEN, Janssen, and Roche; Tomas Buchler: Research support: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck KGaA, MSD, and Novartis; consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol-Myers Squibb, AstraZeneca, Roche, Servier, Accord, MSD, and Pfizer; Emmanuel Seront: Consultancy: MSD, BMS, Pfizer, Ipsen; Aristotelis Bamias: Honoraria, Advisory, Research support: Pfizer, Roche, MSD, BMS, and Ipsen; Camillo Porta: Honoraria: Angelini Pharma, Astra Zeneca, Bristol Myers Squibb, Eisai, Ipsen, MSD; Andre Poisl Fay: Honoraria: Pfizer, Astellas, BMS, Novartis, Roche, Astra-Zeneca, Janssen, MSD, Ipsen. Scientific Advisory Board: Janssen, Novartis, Roche, Ipsen, Pfizer, Bayer, MSD. Research Grant: CAPES - CNPq, BMS, Roche, Astra-Zeneca, MSD, Foundation Medicine, Ipsen. Ownership: BIO, Brazilian Information Oncology. All other authors do not have relationships to disclose. All authors except Ondrej Fiala are unrelated to this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions., Objective: The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC., Design, Setting, and Participants: Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected., Outcome Measurements and Statistical Analysis: Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method., Results and Limitations: The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature., Conclusions: Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations., Patient Summary: Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC)., Patients and Methods: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival., Results: A total of 675 patients were included; BMI was >25 kg/m 2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m 2 versus those with BMI ≤25 kg/m 2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI ≤25 kg/m 2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002)., Conclusion: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The upfront treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by the introduction of immune-based combinations. The role of cytoreductive nephrectomy (CN) in these patients is still debated. The ARON-1 study (NCT05287464) was designed to globally analyze real-world data of mRCC patients receiving first-line immuno-oncology combinations. This sub-analysis is focused on the role of upfront or delayed partial or radical CN in three geographical areas (Western Europe, Eastern Europe, America/Asia)., Methods: We conducted a multicenter retrospective observational study in mRCC patients treated with first-line immune combinations from 55 centers in 19 countries. From 1152 patients in the ARON-1 dataset, we selected 651 patients with de novo mRCC. 255 patients (39%) had undergone CN, partial in 14% and radical in 86% of cases; 396 patients (61%) received first-line immune-combinations without previous nephrectomy., Results: Median overall survival (OS) from the diagnosis of de novo mRCC was 41.6 months and not reached (NR) in the CN subgroup and 24.0 months in the no CN subgroup, respectively (P<0.001). Median OS from the start of first-line therapy was NR in patients who underwent CN and 22.4 months in the no CN subgroup (P<0.001). Patients who underwent CN reported longer OS compared to no CN in all the three geographical areas., Conclusions: No significant differences in terms of patients' outcome seem to clearly emerge, even if the rate CN and the choice of the type of first-line immune-based combination varies across the different Cancer Centers participating in the ARON-1 project.

Background: Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC)., Objective: The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients., Patients and Methods: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB)., Results: A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p = 0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p < 0.001)., Conclusions: Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations., Clinical Trial Registration: NCT05287464., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Patients with metastatic renal cell carcinoma (mRCC) are often elderly and have various comorbidities, including cardiovascular diseases. Although these patients have extensive co-exposure to targeted therapy and cardiovascular drugs, the impact of this co-exposure on outcomes for patients with mRCC remains unclear., Objective: Our objective was to evaluate the association between the use of cardiovascular medication and survival of patients with mRCC., Methods: The study included 343 consecutive patients with mRCC treated with sunitinib or pazopanib in the first line. Clinical data obtained from the Renal Cell Carcinoma Information System (RENIS) clinical registry and hospital information systems were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were compared according to the use of common medications, including antihypertensives (i.e., β-blockers [BBs], angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics), acetylsalicylic acid (aspirin), statins, and proton pump inhibitors., Results: The univariate Cox analysis evaluating the impact of the assessed comedications on patient survival revealed that only BBs were significantly associated with PFS (hazard ratio [HR] 0.533, p < 0.001) and OS (HR 0.641, p = 0.006). The median PFS and OS for users of BBs was 18.39 and 37.60 months versus 8.16 and 20.4 months for patients not using BBs (p < 0.001 and p < 0.001, respectively). The Cox multivariate analysis showed that the use of BBs was a significant factor for both PFS (HR 0.428, p = 0.001) and OS (HR 0.518, p = 0.001)., Conclusions: The results of this retrospective study suggest that the use of BBs is associated with favorable outcomes for patients with mRCC treated with sunitinib or pazopanib in the first line., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)