ABSTRACT
INTRODUCTION: Deciding on the optimal second-line (2L) treatment for metastatic clear-cell renal cell carcinoma (ccRCC) remains challenging due to the limited information comparing each of the available options and the influence of the newly expanding first-line (1L) agents. PATIENTS AND METHODS: We identified phase II/III randomized controlled trials (RCTs) evaluating 2L treatments in metastatic ccRCC. This Network Meta-analysis (NMA) evaluates the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and severe adverse events (SAE). We used normal likelihood model to incorporate log hazard ratios (HRs), odds ratios (OR), and 95%-confidence-intervals (CI). Treatment p-scores were used for ranking. Data was analyzed in a fixed-effects model using the netmeta package in R v.1.5-0. RESULTS: All therapies demonstrated some benefits over placebo. Lenvatinibâ¯+â¯everolimus ranked first for OS (HRâ¯=â¯0.44; 95%CIâ¯=â¯0.24-0.82; p-scoreâ¯=â¯0.92), PFS (HRâ¯=â¯0.13; 95%CIâ¯=â¯0.07-0.24, p-scoreâ¯=â¯0.98), and ORR (ORâ¯=â¯35.95; 95%CIâ¯=â¯11.55-111.87; p-scoreâ¯=â¯0.93) compared to placebo, though with a higher SAE (ORâ¯=â¯5.27; p-scoreâ¯=â¯0.23). Cabozantinib ranked second for OS (HRâ¯=â¯0.57, p-scoreâ¯=â¯0.80), PFS (HRâ¯=â¯0.19; p-scoreâ¯=â¯0.86), and ORR (ORâ¯=â¯27.24, p-scoreâ¯=â¯0.84). Nivolumab was third for ORR (p-scoreâ¯=â¯0.79), fourth for OS (p-scoreâ¯=â¯0.69), fifth for PFS (p-scoreâ¯=â¯0.61), and last for SAE (p-scoreâ¯=â¯0.83). Lenvatinib monotherapy ranked worst SAE (ORâ¯=â¯5.89, p-scoreâ¯=â¯0.17) and third for OS and PFS. The latest drug, tivozanib, was sixth for PFS, OS, and ORR. The NMA matrix revealed no differential OS benefit between cabozantinib, lenvatinibâ¯+â¯everolimus, and nivolumab. Other regimens had no significant OS benefit when compared to placebo. CONCLUSION: Based on OS and PFS, the lenvtatinibâ¯+â¯everolimus combination yielded superior, followed by cabozantinib and Lenvatinib monotherapies; all were limited by a worse SAE profile. Nivolumab and pazopanib had the lowest odds of SAEs.