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Real-world outcome of patients with advanced renal cell carcinoma and intermediate- or poor-risk international metastatic renal cell carcinoma database consortium criteria treated by immune-oncology combinations: Differential effectiveness by risk group?

  • Matteo Santoni,
  • Sebastiano Buti,
  • Zin W. Myint,
  • Marco Maruzzo,
  • Roberto Iacovelli,
  • Martin Pichler,
  • Jindrich Kopecky,
  • Jakub Kucharz,
  • Mimma Rizzo,
  • Luca Galli,
  • Thomas Büttner,
  • Ugo De Giorgi,
  • Ravindran Kanesvaran,
  • Ondřej Fiala,
  • Enrique Grande,
  • Paolo Andrea Zucali,
  • Ray Manneh Kopp,
  • Giuseppe Fornarini,
  • Maria T. Bourlon,
  • Sarah Scagliarini,
  • Javier Molina-Cerrillo,
  • Gaetano Aurilio,
  • Marc R. Matrana,
  • Renate Pichler,
  • Carlo Cattrini,
  • Tomas Büchler,
  • Francesco Massari,
  • Emmanuel Seront,
  • Fabio Calabrò,
  • Alvaro Pinto,
  • Rossana Berardi,
  • Anca Zgura,
  • Giulia Mammone,
  • Jawaher Ansari,
  • Francesco Atzori,
  • Rita Chiari,
  • Aristotelis Bamias,
  • Orazio Caffo,
  • Giuseppe Procopio,
  • Kaisa Sunela,
  • Maria Bassanelli,
  • Cinzia Ortega,
  • Francesco Grillone,
  • Johannes Landmesser,
  • Michele Milella,
  • Carlo Messina,
  • Zsófia Küronya,
  • Alessandra Mosca,
  • Dipen Bhuva,
  • Daniele Santini,
  • Nuno Vau,
  • Franco Morelli,
  • Lorena Incorvaia,
  • Sara Elena Rebuzzi,
  • Giandomenico Roviello,
  • Andrey Soares,
  • Renato Bisonni,
  • Davide Bimbatti,
  • Ignacio Ortego Zabalza,
  • Alessandro Rizzo,
  • Veronica Mollica,
  • Giulia Sorgentoni,
  • Fernando Sabino M. Monteiro,
  • Nicola Battelli,
  • Sergio Bracarda,
  • Camillo Porta

Publication: European Urology Oncology, February 2024


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.


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.


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.

Commentary by Dr. Riccardo Bertolo

In the retrospective study by Santoni et al, 930 patients from 58 centres across 20 countries were analysed (from the ARON-1 study – NCT05287464 – designed to collect real-world data globally on the use of immuno-combinations as first-line therapy for metastatic renal cell carcinoma – RCC – patients). The outcomes of first-line immune combinations or immune-oncology (IO)-tyrosine kinase inhibitors (TKIs) for advanced RCC were assessed. Categorising patients into intermediate (654) and poor risk (276) based on International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria, the study explored various parameters, including sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localisation.


Significant differences in overall survival (OS) and progression-free survival (PFS) emerged in the intermediate-risk subgroup. Patients treated with IO + TKI exhibited notably longer OS, suggesting an advantage in combining immunotherapy with antiangiogenic therapy. However, no such distinctions were observed in the poor-risk subgroup, emphasising the complexity of treatment responses across risk categories.


The findings underscore the importance of tailoring treatment strategies based on risk stratification in metastatic RCC. For the substantial intermediate-risk patient population, the study advocates a preference for IO + TKI combinations over double immunotherapy, emphasising the need for a nuanced approach in daily practice.


The observed differences between IO + TKI and IO + IO combinations in the intermediate-risk subgroup may be influenced by the distinct biological profiles associated with antiangiogenic and immunogenic therapies. IO + TKI represents a dual approach targeting both the immune system and the VEGF pathway. This combination disrupts new blood vessel formation, limiting the tumour’s blood supply and enhancing immune responses. In contrast, double immunotherapy lacks direct antiangiogenic effects seen in IO + TKI combinations. The interplay between the tumour microenvironment, immune system, and angiogenic pathways contributes to differences in OS and PFS. The observed longer OS and PFS in the IO + TKI group in the intermediate-risk setting suggest synergistic effects of immune activation and angiogenesis inhibition. In the poor-risk subgroup, aggressive tumour nature may override therapeutic nuances, leading to no significant differences in outcomes between IO + TKI and IO + IO.


Consideration of distinct molecular profiles further enhances our understanding. Tumours with angiogenic signatures rely on VEGF pathways, targeted by antiangiogenic TKIs, leading to improved outcomes. Immunogenic signatures, with higher antigen expression, may respond favourably to immunotherapy. The study's intricate interplay between molecular signatures and therapeutic approaches suggests that combining IO with antiangiogenic therapy effectively targets tumours emphasising both angiogenic and immunogenic characteristics. However, in the poor-risk subgroup, molecular features may limit responsiveness to either strategy, highlighting tumour aggressiveness and heterogeneity.


Despite its retrospective nature, the study provides valuable real-world evidence. Acknowledging limitations, including the absence of randomisation and potential biases, warrants cautious interpretation. Future prospective studies should validate and refine observed treatment disparities, considering additional influencing factors.


In conclusion, this study contributes essential insights into advanced RCC treatment dynamics. The observed differences in outcomes between IO + TKI and IO + IO combinations underscore the importance of personalised approaches, particularly in the intermediate-risk population. As RCC therapeutics evolve, these findings guide clinicians in optimising patient outcomes in the complex landscape of advanced RCC.