Defining second-line sequencing in advanced renal cell carcinoma: A systematic review and meta-analysis.

4539 Background: In the absence of head-to-head comparative trials, the optimal sequencing of second-line systemic therapy for advanced renal cell carcinoma (RCC) remains undefined. As immune checkpoint inhibitor (ICI) based regimens now represent the dominant first-line standard, second-line treatment decisions increasingly rely on indirect data. We conducted a systematic review and meta-analysis to assess the comparative clinical reliability, defined as consistency of benefit across trials, of commonly adopted second-line strategies in RCC. Methods: Randomized phase II–III and prospective trials evaluating second-line systemic therapies in advanced RCC were identified through a systematic literature search. 13 trials encompassing approximately 5,000 patients were included, predominantly post TKI and post immunotherapy. Treatments were grouped by mechanism of action, including tyrosine kinase inhibitor (TKI) based regimens, mTOR inhibitor based therapies, immune-based approaches, and targeted combinations. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled using inverse-variance random-effects models, with heterogeneity assessed using the I² statistic. Results: TKI based strategies demonstrated the most consistent benefit across endpoints, with significant improvement in OS (pooled HR 0.77, 95% CI 0.67–0.87; p<0.0001) and favorable PFS (HR 0.56, 95% CI 0.50-0.63; p<0.0001). Targeted combination strategies achieved consistent PFS benefit (HR 0.66, 95% CI 0.53–0.81; p<0.0001), which did not translate into OS advantage. In contrast, mTOR inhibitor based regimens were associated with modest PFS improvement but failed to demonstrate OS benefit (HR 1.13, 95% CI 0.95–1.35), while immune based approaches showed heterogeneous outcomes. To contextualize these findings within contemporary clinical practice, analyses restricted to patients previously treated with first line ICI based regimens demonstrated a consistent treatment pattern, with TKI based therapies retaining a robust PFS benefit (HR 0.57, 95% CI 0.51–0.64), while targeted combinations maintained a significant PFS improvement without a corresponding OS signal (HR 0.66, 95% CI 0.51–0.85). Conclusions: In the absence of head to head sequencing trials, this systematic synthesis of prospective evidence supports TKI based therapies as the most reliable reference second line strategy in advanced RCC, showing consistent benefit across both OS and PFS, including the immunotherapy first setting. In contrast, mTOR inhibitor based approaches and targeted combinations were associated with greater heterogeneity and did not demonstrate a consistent survival benefit despite improvements in PFS. These findings provide clinically actionable guidance for second-line treatment selection after ICI failure and underscore the need for prospective sequencing focused trials.