492 Background: The incidence of brain metastases(mets) in patients (pts) with advanced renal cell carcinoma (aRCC) is approximately 12%. Brain mets carry a poor prognosis, with treatment largely limited to surgery and radiation. Although systemic therapies including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICIs) have been explored in aRCC pts with brain mets, prospective data is lacking. Cabozantinib is FDA-approved for aRCC with intracranial activity. The phase III COSMIC-313 trial demonstrated cabozantinib in combination with nivolumab and ipilimumab significantly improved progression-free survival (PFS) in previously untreated pts with aRCC. However, the role of this combination in aRCC pts with brain mets remains undefined. We evaluated the safety and efficacy of cabozantinib in combination with nivolumab and ipilimumab in RCC pts with untreated brain mets in a phase II trial. Methods: This phase II trial enrolls pts with asymptomatic and untreated brain mets from RCC. Planned accrual is 20 pts. Prior systemic therapy for aRCC permitted without prior anti–CTLA-4, cabozantinib, or MET inhibitor treatment. Pts will receive nivolumab (3mg/kg) and ipilimumab (1mg/kg) IV every 3 weeks for 4 doses and cabozantinib 40mg daily followed by nivolumab 480mg IV Q 4 weeks and cabozantinib 40mg daily until disease progression(PD), unacceptable toxicity, or withdrawal of consent. Salvage CNS radiation and surgery are indicated for intracranial PD. The primary objective is intracranial progression free survival (iPFS). Secondary objectives include intracranial safety, Intracranial objective response rate(iORR) by modified RECIST v1.1, extracranial objective response rate(eORR) by RECIST v1.1, extracranial PFS (ePFS) and overall survival(OS). Clinical trial information: NCT05048212. Results: Between February 2023 and December of 2024, 11 pts were enrolled onto this trial. Median age was 61 years (range 38-75), 8 pts had clear cell histology. Only 1 pt received prior therapy with lenvatinib and pembrolizumab. median follow up was 19.5 months. Median iPFS was 12 months (95% CI: 6.5, NA), iORR was 54.5% with 4 complete response(CR), 2 partial response(PR), 4 stable disease(SD) and 1 non CR/non PD. eORR is 36% with 4 PR and 7 SD. ePFS was 8.5 months (95% CI: 6.5, NA). median OS is 13 months (95% CI: 11.3, NA). There was one case of grade 3 encephalitis, with no other CNS adverse events(AEs) reported. 195 AEs of any grade were deemed related to treatment. 26(13.3%) were grade 3 or 4 AEs. There was 1 grade 4 AE (hypophysitis). Conclusions: The combination of nivolumab and ipilimumab with cabozantinib showed encouraging intracranial activity in pts with untreated brain mets from RCC , with acceptable central nervous system toxicities observed. This trial indicates that the combination of ICIs and a TKI is a promising strategy for controlling intracranial disease in RCC pts. Clinical trial information: NCT05048212 .
Wang et al. (2026) studied this question.