Clinical Outcomes With Notch Inhibitors in Notch-Activated Recurrent/Metastatic Adenoid Cystic Carcinoma.

backgroundAdenoid 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.

methodsA 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.

resultsTwenty-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).

conclusionNOTCH 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.