BACKGROUND: The optimal first-line therapy for metastatic renal cell carcinoma (mRCC) remains uncertain, despite recent advancements in immune-based combinations. This retrospective study compares the effectiveness of pembrolizumab plus axitinib (PA) and nivolumab plus cabozantinib (NC) as first-line treatments for mRCC in a real-world setting. METHODS: Patient data were collected from 55 centers across 16 countries, encompassing individuals diagnosed with mRCC receiving first-line treatment with PA or NC between January 2016 and October 2023. Clinical and tumor features and treatment responses were recorded. The primary endpoints were overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to second progression. Statistical analyses included Kaplan-Meier survival estimates, Cox proportional hazard models, and chi-square tests. RESULTS: A total of 760 patients with a median age of 64 years (range, 29-88) were included. Of them, 607 received PA, and only 153 NC. In the overall study population, ORR was 59% for and 49% for PA. Median OS was 55.7 months and not reached (NR) for PA and NC, respectively (P = .51), while median PFS was longer with NC (27.6 months) than for PA (16.2 months, P = .003). Subgroup analysis suggested a PFS benefits for NC in male, younger patients, intermediate risk group, clear cell histology, and lung involvement, as well as ORR favored NC in good risk patients. Multivariate analysis identified first-line therapy as a significant factor associated with PFS. CONCLUSIONS: In this certainly biased retrospective comparison, NC demonstrated superior ORR and longer PFS compared to PA in mRCC. These findings underscore the importance of considering individual patient characteristics and risk profiles when selecting first-line therapy for mRCC.

• Keywords
• ARON-1 study, Axitinib plus pembrolizumab, Cabozantinib plus nivolumab, Immune-oncology combinations,
• MeSH
• Anilides * therapeutic use   pharmacology   administration & dosage   MeSH
• Axitinib * therapeutic use   pharmacology   administration & dosage   MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized * therapeutic use   pharmacology   administration & dosage   MeSH
• Carcinoma, Renal Cell * drug therapy   mortality   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Kidney Neoplasms * drug therapy   pathology   mortality   MeSH
• Nivolumab * therapeutic use   pharmacology   administration & dosage   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Pyridines therapeutic use   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Comparative Study MeSH
• Names of Substances
• Anilides * MeSH
• Axitinib * MeSH
• cabozantinib MeSH Browser
• Antibodies, Monoclonal, Humanized * MeSH
• Nivolumab * MeSH
• pembrolizumab MeSH Browser
• Pyridines MeSH

INTRODUCTION: Renal cell carcinoma (RCC) is one of the most common types of urogenital cancer. The introduction of immune-based combinations, including dual immune-checkpoint inhibitors (ICI) or ICI plus tyrosine kinase inhibitors (TKIs), has radically changed the treatment landscape for metastatic RCC, showing varying efficacy across different prognostic groups based on the International Metastatic RCC Database Consortium (IMDC) criteria. MATERIALS AND METHODS: This retrospective multicenter study, part of the ARON-1 project, aimed to evaluate the outcomes of favorable-risk metastatic RCC patients treated with immune-based combinations or sunitinib. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate. We carried out a survival analysis by a Cox regression model. RESULTS: A total of 524 favorable-risk patients were included in the analysis. After a median follow-up of 37.2 months, the median OS in the overall population was 56.1 months. There was no significant difference in OS between patients receiving sunitinib and those receiving TKI + ICI combinations (p = 0.761). Patients on TKI + ICI had significantly longer PFS compared to patient treated with sunitinib (30.7 vs 22.9 months, p = 0.007). Analysis of OS and PFS based on metastatic site revealed that patients with bone metastases benefited more from ICI plus TKI (56 patients with bone metastases receiving IO + TKI, 38 received pembrolizumab plus axitinib, 15 cabozantinib plus nivolumab and 3 pembrolizumab plus lenvatinib), while sunitinib was more effective for pancreatic and glandular metastases. Additionally, the number of metastatic sites played a role, with TKI plus ICI showing superiority in patients with a single metastatic site. The time from RCC diagnosis to metastatic disease also impacted outcomes, with TKI plus ICI being more effective in patients with a shorter interval (i.e., < 36 months). CONCLUSIONS: The choice between upfront combination or monotherapy for metastatic favorable prognosis RCC remains a current issue. While combination therapy offers prolonged PFS, it does not necessarily translate to improve OS compared to sunitinib. This real-world study supports the superiority in terms of PFS of TKI plus ICI vs TKI monotherapy but not in OS. Probable, other clinical factors should be taking into account to make clinical treatment decisions in this setting.

• Keywords
• ARON-1 study, Good favorable-risk IMDC criteria, Immune-based combinations, Immunotherapy, Renal cell carcinoma,
• MeSH
• Quinolines therapeutic use   administration & dosage   MeSH
• Adult MeSH
• Phenylurea Compounds therapeutic use   administration & dosage   MeSH
• Immune Checkpoint Inhibitors * therapeutic use   MeSH
• Protein Kinase Inhibitors therapeutic use   MeSH
• Carcinoma, Renal Cell * drug therapy   immunology   mortality   MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Metastasis MeSH
• Kidney Neoplasms * drug therapy   immunology   mortality   pathology   MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Pyridines MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Sunitinib * therapeutic use   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Comparative Study MeSH
• Names of Substances
• cabozantinib MeSH Browser
• Quinolines MeSH
• Phenylurea Compounds MeSH
• Immune Checkpoint Inhibitors * MeSH
• Protein Kinase Inhibitors MeSH
• lenvatinib MeSH Browser
• Pyridines MeSH
• Sunitinib * MeSH

BACKGROUND: Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (Pref), face dismal outcomes. OBJECTIVE: Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of Pref patients. METHODS: This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve. RESULTS: In our study, the Pref rate was 19%. Nivolumab/ipilimumab showed the highest Pref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-Pref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for Pref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of Pref. This study presents limitations, mainly because of its retrospective design. CONCLUSIONS: The ARON-1 study provides valuable insights into Pref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.

• MeSH
• Drug Resistance, Neoplasm MeSH
• Adult MeSH
• Carcinoma, Renal Cell * drug therapy   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Kidney Neoplasms * drug therapy   pathology   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH