Background: Due to the ever-changing front-line landscape therapeutic options for m-ccRCC, the second-line (2L) treatment decision remains challenging due to limited information comparing each of the options. We present a survival, efficacy, and safety comparison of the 2L treatment regimens based on the most recent drug approvals for m-ccRCC. Methods: Inclusion criteria for our NMA included phase II/III RTCs that evaluated 2L and beyond for metastatic ccRCC. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and severe adverse events (SAE) hazard ratios (HRs), odds ratios (OR), and 95% confidence intervals (CI) of the treatment differences were abstracted. The p-scores were used to rank treatments. Data were analyzed in a fixed effects model using the netmeta package in R v.1.5-0. Results: Nine studies with 10 therapies included demonstrated some level of efficacy over placebo (Table). Pairwise comparisons using the NMA matrix revealed no differential OS benefit between axitinib (A), cabozantinib (C), lenvatinib+everolimus (LE), and nivolumab (N). Other regimens had no OS benefit when compared to placebo. Table was ordered based on p-score ranking the certainty that one treatment is better than another averaged over all competing treatments for OS. Placebo represents the reference of 1. Conclusions: LE had the lowest safety profile, although did prove to have the best OS and efficacy based on PFS/ORR. C and N, both had significant improvement in OS and efficacy over placebo with lower rates of SAEs compared to LE. Therefore, while further direct comparison studies are warranted to inform clinical practice, for now, we rely on the limitations inherent in indirect treatment comparisons of a NMA.