Background: The first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC) includes an immuno-oncology (IO) based combination. The current standard regimens include a PD-1 inhibitor plus either (1) an anti-CTLA-4 inhibitor (IO/IO), or (2) an anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) (IO/TKI). Currently, there is no level 1 evidence to guide physician’s choice between an IO/IO versus IO/TKI combination. The phase III IMmotion 151 trial performed RNA-seq from 823 ccRCC tumors and established seven biologically distinct gene expression clusters of ccRCC (Motzer and Rini et al., Cancer Cell 2020). The seven clusters showed differential responses to immune checkpoint inhibitor and may serve as a predictive biomarker to select frontline treatment. Methods: This trial is a phase II, multicenter study using the established biologic clusters to assign patients with mccRCC to either an IO/IO (ipilimumab/nivolumab) or an IO/TKI (nivolumab/cabozantinib) regimen. Patients diagnosed with mccRCC without prior systemic therapy (including in the neoadjuvant or adjuvant setting) and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. RNA-seq will be performed on metastatic tumor specimens and used to assign tumor clusters. Patients with cluster 1/2 tumors will be assigned to the nivolumab/cabozantinib arm; patients with cluster 4/5 tumors will be assigned to the ipilimumab/nivolumab arm. Cluster 3/6/7 will be excluded. The primary endpoint is overall response rate (ORR) per RECIST 1.1. The hypothesis is that use of tumor clusters to assign front-line therapy to either nivolumab/cabozantinib or ipilimumab/nivolumab will lead to a 20% greater ORR compared to unselected historical controls in CheckMate 9ER (ORR: 55%) or CheckMate 214 (ORR: 40%). This trial adopts Simon’s MiniMax two-stage design (power: 80%, one-sided α: 0.1). For the nivolumab/cabozantinib arm, stage I will enroll 12 eligible patients. If there are 7 or more responders in the first 12 patients, the trial will continue for stage II to enroll additional 14 patients (total n=26). The primary endpoint will be met if there are 18 or more responders (ORR ≥75%). For the ipilimumab/nivolumab arm, stage I will enroll 16 eligible patients. If there are 7 or more responders in the first 16 patients, the trial will continue for stage II to enroll additional 12 patients (total n=28). The primary endpoint will be met if there are 15 or more responders (ORR ≥60%). Key secondary endpoints include progression-free survival (PFS), depth of response>80%, and rate of immune-related adverse events (irAEs). This trial is funded by the Department of Defense Kidney Cancer Research Program Clinical Trial Award (W81XWH-22-1-1033) (NCT05361720). Clinical trial information: NCT05361720.