Efficacy of systemic treatments for advanced non-clear cell renal cell carcinoma: A single-arm systematic review and meta-analysis.

550 Background: Non-clear cell renal cell carcinoma (nccRCC) represents a genetically and histologically diverse subset of renal cancers, accounting for 15–30% of all renal malignancies. Patients with nccRCC generally face poorer prognoses compared to those with clear cell renal cell carcinoma (ccRCC). While many therapies, such as tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitors, and immune checkpoint inhibitors (ICI), have broadened treatment options for nccRCC, high-quality randomized controlled trials (RCTs) assessing these treatments remain scarce. Consequently, RCT-based reviews provide an incomplete understanding of systemic therapy in nccRCC. In contrast, single-arm trials (SATs), more commonly conducted in nccRCC patients, offer additional insights into therapeutic efficacy. This study aims to synthesize evidence from both RCTs and SATs to comprehensively evaluate the efficacy of systemic treatments for nccRCC. Methods: We conducted a systematic review and meta-analysis of SATs and arms of RCTs, retrieving studies from PubMed, MEDLINE, EMBASE, and the Cochrane Library up to October 1, 2024. Primary outcome was objective response rate (ORR), and secondary outcomes were progression-free survival (PFS), and overall survival (OS). A random-effects meta-analysis was employed to pool data, and subgroup analyses were conducted based on treatment regimens. Results: Thirty-two studies encompassing 1,958 patients were included in the meta-analysis. The pooled ORR across all treatments and therapy lines for nccRCC was 20% (95% CI 15%–26%). The median PFS and OS were 5.56 months (95% CI 4.03–7.09 months) and 17.25 months (95% CI 12.48–22.01 months), respectively. Among them, the pooled ORR for TKI and ICI monotherapy was 19% (95% CI 10%–30%) and 19% (95% CI 13%–26%), respectively, while the pooled ORR for TKI and ICI combination therapy was 39% (95% CI 28%–51%). For first-line therapy, the ORR was 20% (95% CI 12%–28%). Combination therapies (e.g., TKI+ICI, TKI+mTOR and ICI+ICI) demonstrated a higher pooled ORR of 32% (95% CI 19%–46%), while monotherapies (TKI, mTOR or ICI) had an ORR of 14% (95% CI 8%–21%). In papillary RCC (pRCC), the ORR for first-line therapy was 17% (95% CI 9%–26%). Combination therapies showed an ORR of 31% (95% CI 14%–51%), and single-agent therapies had an ORR of 12% (95% CI 6%–21%). Conclusions: This meta-analysis provides evidence supporting the efficacy of existing systemic therapies, particularly combination therapies, in advanced nccRCC. However, the inherent limitations of single-arm analysis necessitate further large-scale, multicenter trials to validate these findings and guide future clinical practice.