Background: Brain metastasis incidence has historically ranged from 2%-15%, whereas modern series post-immunotherapy (IO) have found incidences as high as 29%. Despite the revolution of the RCC treatment landscape with the discovery of targeted therapy and IO agents, treating RCC patients with brain metastasis remains challenging. Our snRNA-seq studies showed that brain metastases have a unique immunosuppressive environment with a layer of neuronal regulation, which is targetable by inhibiting FGFR2. Moreover, neuronal cells have proliferative signaling on tumor cells through FGFR4 signaling, which is targetable by a multi-target tyrosine kinase inhibitor of VEGFR, FGFR1-4, PDGFR and other receptors. Additionally, Keynote-146 showed efficacy of pembrolizumab+lenvatinib on extracranial metastasis sites in patients who progressed on immunotherapy alone. Based on these findings we hypothesize that pembrolizumab+lenvatinib can modulate the immunosuppressive brain metastasis microenvironment and is safe and effective in patients with renal cell carcinoma (RCC) and brain metastasis who were previously treated with immune checkpoint blockade. Methods: This is a multi-center, open-label phase II study evaluating the efficacy and safety of pembrolizumab+Lenvatinib in patients with RCC and untreated brain metastasis who were previously treated with immune checkpoint blockade. The study will implement a Bayesian design with 40 patients, with futility monitoring based on a null hypothesis median intracranial progression free survival (icPFS) of 4.8 months with a target improvement of median PFS equal to 8.7 months. Pembrolizumab (200 mg IV Q3W) and lenvatinib (20 mg PO QD) will be administered in 21-day cycles for a maximum of 24 months (or 35 cycles) in the absence of disease progression or until unacceptable toxicity, death, withdrawal of consent, or discontinuation from the study treatment for any other reason. The primary endpoint is icPFS as assessed by Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) criteria. The key secondary endpoints are intracranial objective response rate (ORR) of non-irradiated measurable (tumor diameter 0.5-3.0 cm on magnetic resonance imaging (MRI)) brain metastases and distant brain failure rate defined by the recurrence of new brain metastases outside of the radiation field, as assessed by RANO-BM, and overall survival (OS). Other secondary endpoints are safety, extracranial ORR, extracranial PFS, as assessed by the RECIST 1.1 and iRECIST. Exploratory analyses will include evaluation of tissue, blood-based and cerebrospinal fluid immune-related correlates, identification of imaging characteristics of treatment, evaluation of the neurological and cognitive function, seizure reduction, steroid, and opiate pain medication. Clinical trial information: N/A.