Background: Radical metastasectomy and other local treatment strategies (including definitive radiotherapy, RT) can be carried out instead of systemic therapies for selected metastatic renal cell carcinoma (mRCC) patients (pts) with the aim of healing the patient even in an advanced disease stage. Recent data suggests a potential benefit from perioperative immunotherapy with immune checkpoint inhibitors (ICIs), as shown by the significant efficacy of adjuvant pembrolizumab in the M1 NED subgroup of the KEYNOTE-564 trial. Moreover, important activity of a short course of pembrolizumab has been demonstrated also in oligometastatic mRCC pts in combination with stereotactic ablative RT in the RAPPORT study. To date, no randomized trial has evaluated the concomitant use of pembrolizumab with surgery or definitive RT in mRCC compared to local therapy alone, which is the aim of our study. Methods: PE-PE study (NCT05578664) is a randomized, open-label, multicenter, phase 2 study evaluating the efficacy of pembrolizumab in delaying tumor progression in pts with oligometastatic mRCC who are candidates for radical surgery and/or definitive RT of the metastases. Eligible pts should have undergone previous nephrectomy and have maximum three metastases considered eligible for radical metastasis directed therapy (MDT; either metastasectomy or RT) and new disease must have appeared within 5 years from prior nephrectomy or metastasectomy. Pts will be randomized 2:1 to receive pembrolizumab at flat dose of 400 mg every six weeks for a total of 9 cycles (one year of therapy) and MDT from day 21 to day 42 of the cycle 1 (ARM A); or MDT alone within 42 days from randomization (ARM B). The primary endpoint is to assess the relapse free survival (RFS) defined as the length of time from randomization to the appearance of radiological progression in pts who receive pembrolizumab compared to those who do not. Secondary endpoints include: distant RFS (defined as the time from randomization to the appearance of distant metastases other those treated with surgery or RT), overall survival, and safety. Exploratory biomarkers analysis will be performed. The trial is actively recruiting. Clinical trial information: NCT05578664.