Background: Symptomatic radiation necrosis rates in patients treated with immune checkpoint inhibitor (ICI) therapy and concomitant single-fraction stereotactic radiosurgery (SRS) are as high as 20% (PMID: 29327059). We present updated results from the Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) trial following completion of an a priori interim analysis, aimed to identify reduced-dose SRS that is safe and efficacious for this patient population. Methods: RADREMI (clinicaltrials.gov, NCT04047602) is a prospective multicenter single arm Phase I trial involving patients age > 18 receiving ICI with SRS for 1-10 brain metastases on MRI. Patients had biopsy-confirmed primary malignancy with disease-specific graded prognostic assessment estimated median survival of at least 6 months and no previous whole brain radiation therapy. Six-month symptomatic radiation necrosis (radiographic radiation necrosis + clinical symptoms requiring steroid administration and/or operative intervention) was the primary endpoint, based on an expected rate of 5% and a historical rate of 16%. Secondary endpoints included 6-month local control and radiographic radiation necrosis. Response Assessment in Neuro-Oncology criteria defined local control; findings were compared to historical 6-month local control of 87-91% with RTOG 90-05 SRS dosing. A pre-determined interim futility analysis (based on the null hypothesis of no fewer than 15 of the first 20 patients reaching the primary endpoint achieving 6-month local control for RADREMI dosing) was performed using the Fisher’s exact test. Results: Between December 18, 2019 and September 10, 2021, 43 lesions were treated in 16 patients receiving ICI delivered within 30 days before SRS who were enrolled on trial and met the primary endpoint (median follow-up = 9.1 months). All patients received RADREMI SRS dosing (18 Gy for lesions 0-2 cm, 14 Gy for lesions 2.1-3 cm, and 12 Gy for lesions 3.1-4 cm). The most common ICI used was single-agent pembrolizumab (51% of lesions, 56% of patients), followed by single-agent nivolumab (28% of lesions, 13% of patients). The six-month rates of symptomatic and radiographic radiation necrosis were zero; the six-month local control rate was 98% per treated lesion (42/43), and 94% per treated patient (15/16), comparable to historical controls (p > 0.05) and sufficient to not reject the interim futility analysis null hypothesis. Conclusions: Interim analysis reveals that the safety and efficacy of RADREMI dosing for reducing SRS dose in brain metastasis patients receiving concomitant ICI persists with excellent local control and no morbidity in a multi-institutional collaborative trial. Further results following completion of trial enrollment will provide additional evidence regarding the safety and efficacy of RADREMI SRS dosing. Clinical trial information: NCT04047602.