Background: Patients with locally advanced renal cell carcinoma (RCC) may experience recurrence after surgery. In the phase 3 KEYNOTE-564 (NCT03142334) trial, adjuvant pembrolizumab demonstrated significant improvement in disease-free survival (DFS) in ccRCC, leading to FDA approval of pembrolizumab (November 17, 2021) for adjuvant treatment of patients with RCC at intermediate-high or high risk for recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. Despite benefit of pembrolizumab, there is an unmet need for more effective adjuvant treatment for patients at risk for recurrence after definitive surgery. The HIF-2α inhibitor belzutifan (MK-6482) has shown activity and good tolerability in patients with advanced ccRCC and von Hippel-Lindau (VHL) disease–associated RCC. Combining belzutifan with pembrolizumab may be a therapeutic option as adjuvant treatment of ccRCC. This global, multicenter, double-blind, randomized, phase 3 study LITESPARK-022 (NCT05239728) is designed to compare the efficacy and safety of belzutifan + pembrolizumab with that of placebo + pembrolizumab as adjuvant treatment of ccRCC after nephrectomy. Methods: Approximately 1600 patients with histologically or cytologically confirmed RCC (intermediate-high [pT2, grade 4 or sarcomatoid, N0, M0 or pT3, any grade, N0, M0], high [pT4, any grade, N0, M0 or pT, any stage/grade, N+, M0] or M1 NED [patients who present with the primary kidney tumor and solid, isolated, soft tissue metastases that can be resected at the time of nephrectomy or ≤2 years from nephrectomy) with a clear cell component and had not previously received systemic therapy will be enrolled. Patients must have undergone nephrectomy and/or metastasectomy ≤12 weeks before randomization and be tumor free, confirmed by CT/MRI. Stratification factors are tumor grade (1 or 2 vs 3 or 4) and risk type (intermediate-high vs high vs M1 NED). Patients will be randomly assigned 1:1 to receive belzutifan 120 mg orally once daily + pembrolizumab 400 mg IV every 6 weeks (Q6W) or oral placebo + pembrolizumab 400 mg IV Q6W. Pembrolizumab treatment will be administered for up to 9 doses (̃1 year); belzutifan and placebo may be continued for a maximum of 54 weeks. Disease recurrence will be evaluated radiologically Q12W from randomization through year 2, Q16W in years 3-5, and Q24W in years 6 and beyond. Adverse events (AEs) will be monitored by NCI CTCAE v5.0 through 30 days (90 days for serious AEs) after cessation of study drug. The primary end point is DFS, as assessed by investigator, defined as time from randomization to first documented event of local recurrence, occurrence of distant kidney cancer metastasis, or death from any cause, whichever occurs first. The key secondary end point is overall survival. Other secondary end points are safety, disease recurrence–specific survival and patient-reported outcomes. Clinical trial information: NCT05239728.