Immune-based Combinations in Intermediate-/Poor-risk Patients with Non–clear Cell Renal Cell Carcinoma: Results from the ARON-1 Study

Background and objective: Non–clear cell renal cell carcinoma (nccRCC) lacks direct comparisons of immune-based combinations, presenting an unmet need for defining optimal treatment for this specific population. This study aimed to assess the real-world efficacy of immune-based combinations in intermediate-/poor-risk nccRCC. Methods: We conducted a multicenter, retrospective study of patients (≥18 yr) with metastatic nccRCC treated with first-line immune-based combinations across 56 centers in 17 countries between January 2021 and December 2024. Patients received pembrolizumab/lenvatinib, pembrolizumab/axitinib, nivolumab/cabozantinib, or nivolumab/ipilimumab. The primary endpoints were overall survival (OS) and progression-free survival (PFS), analyzed using Kaplan-Meier and Cox proportional-hazard models, and overall response rate (ORR) evaluated as per RECIST 1.1 criteria. Key findings and limitations: Among the 323 patients analyzed (median follow-up: 21.2 mo), the median OS was 31.1 mo (95% confidence interval [CI] 24.6–40.4), with a 2-yr OS rate of 58%. The ORR was 38% (2% complete response and 36% partial response), and the median PFS was 13.0 mo (95% CI 10.0–17.4). Immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) significantly outperformed ICI doublets across efficacy metrics. Limitations include retrospective design and a selection bias. Conclusions and clinical implications: Our analysis suggests ICI/TKI combinations as the optimal strategy for intermediate-/poor-risk nccRCC, with pembrolizumab/lenvatinib showing marked benefits. Further studies are needed to validate these findings.