BACKGROUND: Adenoid cystic carcinoma (ACC) with NOTCH-activating mutations presents a clinical challenge due to its poor prognosis. NOTCH inhibitors have emerged as a potential therapy for ACC patients with NOTCH activation. This study aimed to evaluate the efficacy of NOTCH inhibitors in this patient population. METHODS: A retrospective analysis was conducted on patients with metastatic ACC harboring NOTCH pathway activation, who received NOTCH inhibitors at MD Anderson Cancer Center. NOTCH inhibitors included AL101, a gamma-secretase inhibitor, and brontictuzumab, an antibody targeting NOTCH1. NOTCH pathway activation was assessed through genomic analysis for NOTCH-activating mutations or immunohistochemistry for NOTCH1 intracellular domain (NICD1). Efficacy endpoints included best overall response (BOR) and progression-free survival (PFS) per RECIST or MD Anderson bone response criteria. RESULTS: Twenty-nine patients were included, with a predominance of solid histology (86%). NOTCH-activating mutations were identified in 82% of patients, and 95% showed positive NICD1 staining. BOR revealed partial response in 17% of patients, stable disease in 55%, and progressive disease in 28%. Median response duration was longer for AL101 compared to brontictuzumab (9.9 vs. 1.7 months, p = 0.04). Median PFS with NOTCH inhibitor was 4.2 months (95% CI 2.7-8.6 months). Progression of nontarget lesions occurred in 34% of patients. Comparison with prior therapy showed longer PFS with NOTCH inhibitors (HR 0.38, 95% CI 0.19-0.78, p = 0.0065). CONCLUSION: NOTCH inhibitors demonstrate activity in NOTCH-activated ACC, surpassing the efficacy of observation or prior systemic therapies. However, limited PFS and progression of nontarget lesions suggest the potential need for combination therapy to address ACC heterogeneity.