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

Area of Science:

• Oncology
• Molecular Biology
• Drug Development

Background:

• Adenoid cystic carcinoma (ACC) with NOTCH-activating mutations presents a significant clinical challenge due to its poor prognosis.
• NOTCH inhibitors are being investigated as a targeted therapy for ACC patients with NOTCH pathway activation.

Purpose of the Study:

• To evaluate the efficacy of NOTCH inhibitors in patients with metastatic ACC harboring NOTCH pathway activation.
• To compare the efficacy of different NOTCH inhibitors (AL101 and brontictuzumab) in this patient population.

Main Methods:

• Retrospective analysis of 29 metastatic ACC patients with NOTCH pathway activation treated with NOTCH inhibitors.
• Assessment of NOTCH pathway activation via genomic analysis or NICD1 immunohistochemistry.
• Efficacy evaluation based on best overall response (BOR) and progression-free survival (PFS).

Main Results:

• NOTCH-activating mutations and NICD1 staining were prevalent (82% and 95%, respectively).
• Partial response was observed in 17% of patients, with stable disease in 55%.
• Median PFS was 4.2 months, and NOTCH inhibitors showed longer PFS compared to prior therapies (HR 0.38, p=0.0065).

Conclusions:

• NOTCH inhibitors demonstrate clinical activity in NOTCH-activated ACC, outperforming observation or prior systemic treatments.
• Limited progression-free survival and progression in nontarget lesions indicate a need for combination therapies to overcome ACC heterogeneity.