Abstract PS5-03-01: Phase I Study of Stereotactic Radiation and Sacituzumab Govitecan with Zimberelimab in the Management of Metastatic Triple Negative Breast Cancer with Brain Metastases

Abstract Background: The prognosis and quality of life for triple negative breast cancer (TNBC) brain metastases remains poor. Sacituzumab govitecan (SG) has shown potential blood brain barrier (BBB) penetration in preclinical and clinical settings with anti-tumor activity in the phase III ASCENT Trial (NCT02574455). Radiotherapy can open the BBB and has been shown to be safe in combination with anti-PD-1 therapy in our previous study (NCT03807765). Combining radiation with the anti-PD-1 monoclonal antibody, zimberelimab, and SG may provide a synergistic anti-tumor approach. Methods: The study is designed as a single-arm, nonrandomized, open-label, phase I/II trial of SG and zimberelimab with stereotactic radiosurgery (SRS) among patients with metastatic TNBC with brain metastases. The primary endpoint is neurologic toxicity defined by CTCAE v5 criteria (phase I) assessed via a 3+3 design. Eligibility includes TNBC patients ≥ 18 years old with brain metastases eligible for SRS with at least one measurable lesion ≥ 0.5 cm per RANO-BM criteria. Treatment is initiated with SRS followed 1 week later by SG on days 1 and 8 (10 mg/kg) with zimberelimab on day 1 (360 mg IV) repeated every 3 weeks. Phase I results are reported, clinical trial information: NCT06238921. Results: Three patients were enrolled between December 2024 through April 2025. Median age was 56 (range: 49-57) with a baseline KPS of 90 in 2 patients and 70 in 1 patient. Median lines of prior systemic therapy in the stage IV setting was 1 (range 0-2). No intracranial dose limiting toxicities were noted. The most common grade ≥ 2 adverse events were neutropenia in 3 patients (100%) (grade 4 in 1 and grade 2 in 2 patients) and grade 2 fatigue in 1 patient. The best RANO-BM intracranial response has been a partial response (PR) in 3 patients (100%). The best irRECIST systemic response has been a PR (n=1), stable disease (n=1), and progressive disease (n=1). Two patients continue study therapy currently. No deaths have occurred. Conclusions: Results from the phase I portion reveals safety of a combined approach. Efficacy continues to be assessed in the phase II portion. Citation Format: K. A. Ahmed, Y. Kim, R. Dowell, D. Oliver, M. Mills, R. Nair, A. Armaghani, R. Costa, T. O'Connor, G. Rajasekaran Rathnakumar, H. Soliman, A. Soyano, E. Tan-Chiu, P. Forsyth, J. Arrington, H. Yu, H. Han. Phase I Study of Stereotactic Radiation and Sacituzumab Govitecan with Zimberelimab in the Management of Metastatic Triple Negative Breast Cancer with Brain Metastases [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-03-01.