Background: The rate of symptomatic radiation necrosis in patients treated with immune checkpoint inhibitor (ICI) therapy and concomitant single-fraction stereotactic radiosurgery (SRS) is as high as 20% (Martin et al., JAMA Oncology 2018). Here, we present the first results from the Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) trial, aimed to identify reduced-dose SRS that is safe and efficacious for this patient population. Methods: RADREMI is a prospective multicenter, single arm phase I pilot study. Patients age > 18 receiving ICI with SRS for 1-10 brain metastases on MRI from biopsy-confirmed primary malignancy with estimated median survival of at least 6 months (by disease-specific graded prognostic assessment) and no history of whole brain radiation therapy were eligible. The primary endpoint was six-month symptomatic radiation necrosis (defined as a six-month rate of clinical symptomatology requiring steroid administration and/or operative intervention concomitant with imaging findings consistent with radiation necrosis), based on a historical six-month symptomatic radiation necrosis rate of 16% and an expected rate of 5%. Secondary endpoints included six-month local control and six-month radiographic radiation necrosis. Local control was defined according to Response Assessment in Neuro-Oncology (RANO) criteria, and was compared to historical controls of 87-91% six-month local control with RTOG 90-05 SRS dosing. The Fisher’s exact test was used for statistical analysis. This trial is registered at clinicaltrials.gov, NCT04047602. Results: Between December 18, 2019 and January 21, 2021, 39 lesions were treated in 17 patients receiving ICI delivered within 30 days before SRS from whom we recruited and obtained consent. All patients were treated with RADREMI dosing, which involved SRS doses of 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 (49% of lesions, 59% of patients), followed by single-agent nivolumab (31% of lesions, 12% of patients). For the 11 lesions (six patients) meeting the primary endpoint (median follow-up = 259 days), the six-month symptomatic radiation necrosis rate was 0% per treated lesion, and 0% per treated patient, which was not significantly different from historical controls (p = 0.478). The six-month local control rate was 100% per treated lesion, and 100% per treated patient, comparable to historical controls (p = 0.476). Conclusions: In the first prospective trial to investigate dose-reduced SRS with concomitant ICI in treating metastatic brain disease, early results support the safety and efficacy of RADREMI dosing in this patient population. These findings warrant further multi-institutional collaborative trials of RADREMI dosing for this population. Clinical trial information: NCT04047602