Background: Immuno-Oncology (IO) combinations, either an IO/IO (ipilimumab/nivolumab) or an IO/TKI combination (pembrolizumab/axitinib, avelumab/axitinib, nivolumab/cabozantinib, and pembrolizumab/lenvatinib), have emerged as the standard of care for frontline treatment of metastatic clear cell renal cell carcinoma (mccRCC) since 2018. Here we present uptake trends and efficacy of IO combinations in the United States from 2018 to 2022 using American Society of Clinical Oncology’s (ASCO) CancerLinQ Discovery database (CLQD). Methods: Patients diagnosed with mccRCC treated with frontline IO-based combinations from 2018-2022 were identified in the CLQD kidney dataset. The Kaplan-Meier survival method was used to present time to treatment discontinuation (TTD) and overall survival (OS) stratified by International mRCC Database Consortium (IMDC) risk. Results: There were 515 mccRCC patients who received frontline IO agents in 2018-2022: 228 (44.3%) patients received ipilimumab/nivolumab, 153 (29.7%) patients received IO/TKI (139 out of 153 received pembrolizumab/axitinib), and 122 (23.7%) patients received IO monotherapy (nivolumab or pembrolizumab). 385 (75%) were IMDC intermediate/poor risk and 97 (19%) were favorable risk patients. The median age was 69 (interquartile range: 61-79) and 59% were male. There was an increasing trend of use of IO/TKI from 2019 to 2021 [30.8%, 42.8%, 44.3%, respectively; analysis for 2022 was limited by sample size (n = 8)]. The median follow-up for ipilimumab/nivolumab and pembrolizumab/axitinib was 13.1 and 11.8 months (mos), respectively. The mTTD for ipilimumab/nivolumab and pembrolizumab/axitinib was 8.5 vs 11.0 mos, respectively. The median OS (mOS) was not reached (NR) in either regimen. The TTD and OS stratified by IMDC risk are presented in Table 1. Conclusions: Uptake of frontline IO combinations therapy in mccRCC and in particular IO/TKI combinations increased in the United States since 2018. Compared to progression-free survival (PFS) from the landmark trials, this analysis demonstrated shorter TTD, indicating either underestimation of the true PFS or worse outcomes in a non-clinical trial setting. Integration of radiologic response into this dataset could help clarify outcomes.