Intracranial activity of sacituzumab govitecan in HER2-negative breast cancer brain metastases: A systematic review and meta-analysis.

Abstract

e14009 Background: Patients with HER2-negative metastatic breast cancer who develop brain metastases face a critical therapeutic gap, as most systemic agents show limited central nervous system (CNS) penetration and intracranial efficacy. Sacituzumab govitecan (SG), a TROP-2–directed antibody–drug conjugate, has demonstrated survival benefit in advanced breast cancer, yet its intracranial activity remains poorly characterized. We conducted the first systematic review and meta-analysis focused specifically on the intracranial efficacy of SG in breast cancer brain metastases (BCBMs). Methods: We systematically searched PubMed, Embase, and Cochrane databases through November 2025 for clinical trials and observational studies reporting outcomes of SG in patients with documented BCBMs. Endpoints included overall survival (OS), progression-free survival (PFS), intracranial PFS (IC-PFS), overall response rate (ORR), disease control rate (DCR), intracranial ORR (IC-ORR), and intracranial DCR (IC-DCR). All analyses were restricted to cohorts with confirmed brain metastases. Random-effects models were applied, and heterogeneity was assessed using I² statistics. The protocol was registered in PROSPERO (CRD420251161992). Results: Eleven studies (2 prospective trials, 9 observational cohorts) comprising 313 patients with BCBMs were included. Median age ranged from 48 to 61.5 years, with median follow-up of 6.7–17.5 months. Among evaluable patients, 75% had stable brain metastases at treatment initiation. The pooled median OS was 8.4 months (95% CI 6.7–10.5; I²=0%), and median PFS was 3.8 months (95% CI 2.8–5.3; I²=67.8%). Importantly, SG demonstrated consistent intracranial activity, with a pooled median IC-PFS of 2.9 months (95% CI 1.7–4.9; I²=0%). While the pooled systemic ORR was modest at 10.7% (95% CI 0–37.9; I²=86.8%), the intracranial ORR reached 31.7% (95% CI 15.5–54.0; I²=58.2%). Disease control was more consistent across studies, with a pooled DCR of 45.4% (95% CI 33.9–57.5; I²=0%) and an IC-DCR of 55.6% (95% CI 42.2–68.1; I²=0%). Conclusions: SG demonstrates reproducible intracranial disease control and a clinically meaningful intracranial response rate in patients with HER2-negative BCBMs, an area of profound unmet need. Despite modest systemic response rates, the disproportionate intracranial activity observed supports SG as one of the few systemic therapies with potential CNS efficacy in this population. These findings provide a strong rationale for prospective trials incorporating brain-specific endpoints.