Background: The combination of immuno-oncology agents (IO) ipilimumab and nivolumab (IPI-NIVO) and combinations of IO with vascular endothelial growth factor targeted therapies (IOVE) have demonstrated efficacy in clinical trials for the first-line treatment of mRCC. This study seeks to establish real-world clinical benchmarks based on the International mRCC Database Consortium (IMDC) criteria using vascular endothelial growth factor targeted therapy (VEGF-TT) treated patients for context. Methods: The IMDC database (IMDConline.com) was used to identify patients with mRCC who received first-line IPI-NIVO, IOVE (axitinib/pembrolizumab, lenvatinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab) and VEGF-TT (sunitinib or pazopanib) from 2002-2021. The primary endpoint was overall survival (OS) and was calculated from time of initiation of first-line therapy to death or last follow up. Log-rank tests were conducted to compare favorable, intermediate, and poor risk OS outcomes within treatment groups. Overall response rates (ORR) and complete response (CR) rates were calculated based on physician assessment of best clinical response. Results: In total, 692 patients received IPI-NIVO, 244 received IOVE, and 7152 received VEGF-TT. Baseline characteristics for IPI-NIVO, IOVE, and VEGF-TT, respectively, were as follows: median age (interquartile range) 63 (56-69), 64 (57-70), and 63 (56-70); male 72%, 74%, and 72% (p=0.74); non-clear cell histology 15%, 10%, and 13% (p=0.15); sarcomatoid features 24%, 15%, and 13% (p<0.0001); brain metastasis 8%, 4%, and 8% (p=0.04); liver metastasis 18%, 14%, and 18% (p=0.17); underwent nephrectomy 61%, 79% and 80% (p<0.0001). OS and ORR are reported in the table. P-values (log rank) for OS between risk groups were significant for IPI-NIVO (p<0.0001), IOVE (p=0.0005), and VEGF-TT (p<0.0001). Conclusions: These findings provide real-world survival and response benchmarks for contemporary first-line mRCC treatments and could be helpful for patient counselling. In addition, these findings mirror the efficacy of combination therapies established in clinical trials against VEGF-TT monotherapy. IMDC criteria continue to risk stratify patients in these novel combination therapies.

*IPI-NIVO is not indicated in favorable risk patients and must be interpreted with caution.