TPS4600 Background: XL092 is a novel oral inhibitor of receptor tyrosine kinases, including MET, VEGFR2, and TAM kinases (AXL, MER), which are implicated in tumor growth, metastasis, angiogenesis, and immune suppression of the tumor microenvironment. XL092 has a relatively short half-life (̃21h) to support convenient daily dosing and help manage tolerability. Preclinical studies of XL092 with an anti‒PD-1 immune checkpoint inhibitor (ICI) demonstrated antitumor activity in tumor models, and BEMPEG (IL-2 pathway agonist) showed synergy with anti‒PD-L1 and anti‒CTLA-4 agents. This phase 1b trial will evaluate the safety and clinical activity of XL092 alone and in combination with NIVO (anti‒PD-1 mAb) ±IPI (anti‒CTLA-4 mAb) or ±BEMPEG in pts with advanced solid tumors including genitourinary cancers. Presented here is the study design. Methods: This multicenter phase 1b, open-label study (NCT05176483) will enroll pts with unresectable advanced or metastatic solid tumors in dose-escalation and expansion stages. In the dose-escalation stage, ̃36 pts will be enrolled in three XL092 combination therapy cohorts using a rolling 6 design. Cohort A: XL092 (starting dose [SD] 100 mg PO QD) + NIVO (360 mg IV Q3W); Cohort B: XL092 (SD 80 mg PO QD) + NIVO (3 mg/kg IV Q3W × 4, then 480 mg IV Q4W) + IPI (1 mg/kg Q3W × 4); Cohort C: XL092 (SD 100 mg PO QD) + NIVO (360 mg IV Q3W) + BEMPEG (0.006 mg/kg IV Q3W). The primary objective of the dose-escalation stage is to determine the recommended doses of XL092 with the NIVO regimens to be used in the expansion stage. The expansion stage will include cohorts of advanced genitourinary tumors: Cohort 1, clear-cell renal cell carcinoma (ccRCC), no prior systemic therapy; Cohort 2, ccRCC, 1 prior ICI combination regimen; Cohort 3, metastatic castration-resistant prostate cancer (mCRPC), 1 prior novel-hormonal therapy; Cohort 4, urothelial carcinoma (UC), 1 prior platinum-based regimen, ICI-naïve; Cohort 5, UC, ≤2 prior systemic regimens, ICI-experienced; Cohort 6, non-ccRCC, no prior systemic therapy. In each cohort, pts will be randomized to one of the following treatments (based on tumor cohort): single-agent XL092 (Cohorts 2‒6); XL092+NIVO (Cohorts 1‒6); NIVO+IPI (Cohort 1); XL092+NIVO+IPI (Cohorts 1, 3, 6); NIVO+BEMPEG (Cohort 1), XL092+NIVO+BEMPEG (Cohort 1, 2, 4‒6). Thirty pts will be enrolled in each single-agent XL092 arm and 40 pts in each combination therapy arm. Expansion stage objectives are to assess preliminary efficacy, safety, and pharmacokinetics of XL092 alone or in combination in each tumor-specific cohort. Primary efficacy endpoints include objective response rate by investigator per RECIST v1.1 and progression-free survival by blinded independent radiology committee per Prostate Working Group 3 criteria (mCRPC cohort only). The study is currently enrolling pts. Clinical trial information: NCT05176483.