Systemic therapies in renal cell carcinoma with brain metastases: A comparative meta-analysis of immunotherapy and tyrosine kinase inhibitors.

559 Background: Renal cell carcinoma (RCC) with brain metastases presents a clinical challenge. Management remains unclear, as systemic therapy data are limited and many trials exclude patients with active brain metastases. Current treatment primarily involves CNS-targeted radiation (e.g., stereotactic radiosurgery and whole-brain radiation therapy), while systemic therapies like tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are underexplored. This meta-analysis evaluates the efficacy of systemic treatments and whether these patients should continue to be excluded from clinical trials. Methods: A systematic search of PubMed, CENTRAL, MEDLINE, and Google Scholar was conducted through October 2024, focusing on studies of mRCC patients with brain metastases treated with ICIs, TKIs, or their combination. ICI therapies included nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab, while TKIs included sorafenib, sunitinib, and cabozantinib. Case reports, ongoing trials, narrative reviews, and meta-analyses were excluded. Primary endpoints were complete response (CR), partial response (PR), objective response rate (ORR), and overall survival (OS). Statistical analyses used fixed/random-effects models based on heterogeneity. Results: Nineteen studies involving 947 mRCC patients with brain metastases were included. The pooled analysis showed an ORR for ICIs of 29.9%, with a CR of 3.4% and PR of 28.9%. Brain-specific ORR, CR, and PR for ICIs were 27.5%, 10.8%, and 17.9%. TKIs alone showed a pooled ORR of 11.7%, with a CR of 1.3% and PR of 11.6%. Brain-specific ORR, CR, and PR for TKIs alone were 38.1%, 6.9%, and 29.5%. Only one study reported on ICI-TKI combinations, with an ORR of 0%. Survival analysis showed significantly worse OS for brain metastasis patients treated with ICIs plus TKIs (HR: 2.06, p=0.001) and TKIs alone (HR: 2.51, p=0.02) compared to those without brain metastases. Conclusions: ICIs had superior overall response rates compared to TKIs and ICI-TKI combinations in mRCC patients with brain metastases. Brain-specific response rates were similar between ICIs and TKIs. Given the poor prognosis of brain metastasis patients treated with TKIs, further research is needed to determine if they should continue to be excluded from trials. Larger prospective studies are required to confirm these findings and optimize treatment.