Our multicentric analysis included 760 patients treated between 2016 and 2023 across 55 centers in 16 countries. This wide geographical and clinical heterogeneity provides an important degree of external validity, reflecting diverse treatment patterns and patient profiles. Most patients (n=607) received pembrolizumab-axitinib, while 153 were treated with nivolumab-cabozantinib.
Key Findings and Clinical Interpretation
Data on efficacy and survival are summarized in Table 1 and Figure 1. While overall survival (OS) was comparable between groups (median OS not reached for nivolumab-cabozantinib; 55.7 months for pembrolizumab-axitinib; p = 0.512), a clear advantage emerged in progression-free survival (PFS) for patients treated with nivolumab-cabozantinib (p = 0.003). Median PFS reached 27.6 months in the nivolumab-cabozantinib arm versus 16.2 months in the pembrolizumab-axitinib arm (Figure 1).
Figure 1. Synthesis of efficacy and survival of PA vs NC.
Summary Table: PA vs NC in First-line Treatment for mRCC
This difference was particularly pronounced in specific patient subgroups. In our subgroup analysis, patients with intermediate-risk disease according to IMDC criteria, clear cell histology, and lung metastases derived a greater PFS benefit from the nivolumab-cabozantinib combination (Figure 2). Interestingly, in patients with favorable-risk features, the objective response rate (ORR) appeared to favor nivolumab-cabozantinib as well, suggesting a broader efficacy spectrum than previously anticipated.
Multivariate Cox analysis further supported the robustness of these findings, identifying the choice of first-line regimen as an independent predictor of PFS. These results imply that personalized treatment strategies—based on clinical and pathological factors—may optimize outcomes in mRCC beyond guideline-based recommendations.
Real-World Value and Future Directions
ARON-1 provides a unique perspective into how these combinations perform outside of tightly controlled clinical trials. The broad inclusion criteria and international patient representation (Figure 3) enhance the translational relevance of the findings for clinicians navigating complex treatment decisions.
Nevertheless, as a retrospective observational study, limitations must be acknowledged, particularly the absence of central radiological review and data on treatment-related toxicity, quality of life, and subsequent lines of therapy. Future prospective head-to-head trials and biomarker-driven approaches are warranted to validate and expand upon our results.
Conclusion
In conclusion, the ARON-1 study offers clinically meaningful insights into the comparative performance of pembrolizumab-axitinib and nivolumab-cabozantinib in the first-line treatment of mRCC. Our findings support the preferential use of nivolumab-cabozantinib in selected subgroups and underscore the importance of individualized therapy selection in mRCC management.
We hope this analysis will support clinicians in making more informed and patient-tailored therapeutic decisions in an increasingly complex oncologic landscape.
Written by: Matteo Santon,1 Giandomenico Roviello,2 Enrique Grande,3 Camillo Porta,4 Kaisa Sunela,5 and Francesco Massari6
- Oncology Unit, Macerata Hospital, Macerata, Italy
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini 6, Florence 50139, Italy
- Department of Medical Oncology, MD Anderson Cancer Center Madrid, Madrid, Spain
- Chair of Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy
- Finnish Medicines Agency Fimea Department of Oncology, Tays Cancer Center, Tampere University Hospital, Tampere, Finland
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni - 15, Bologna – Italia