Brain metastases (BrM) in metastatic clear-cell renal cell carcinoma (m-ccRCC) are resistant to most systemic therapies, but respond better to cabozantinib. We documented intracranial response on common systemic therapies for m-ccRCC, described molecular mechanisms underlying efficacy or resistance and performed whole transcriptome sequencing on primary ccRCC-tumors and metastatic lesions in distinct host organs, including the brain. 30 patients with BrM were available for the evaluation of intracranial response on 39 systemic therapy lines. No partial responses (PR) were observed upon ipilimumab/nivolumab (0%), and pazopanib (0%). PRs were rare upon nivolumab (14%), sunitinib (25%), axitinib (28%) and axitinib/pembrolizumab (33%), but higher upon cabozantinib/nivolumab (50%) and cabozantinib in monotherapy (64%). Median time-to-intracranial-progression was the longest (not reached) with cabozantinib and cabozantinib/nivolumab and the shortest with nivolumab and ipilimumab/nivolumab (2.5 months). mRNA-expression analysis showed higher cMET- and AXL-expression in BrM compared to the primary tumor and other metastatic sites, lower angiogenesis and immune scores, less CD8 + T-cells and more M2-like (anti-inflammatory) macrophages. Based on this translational and clinical data, cabozantinib is the optimal systemic therapy for m-ccRCC patients with BrM. As the presence of BrM impacts the choice of first-line treatment, we advise to screen for BrM at baseline, even in asymptomatic patients.
© 2026. The Author(s).