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

Abstract

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.

FIGURE 1

NOTCH signaling pathway and NOTCH inhibitor targets. NOTCH is a transmembrane receptor activated by cleavage by intracellular gamma‐secretase. Following cleavage, the released NOTCH intracellular domain (NICD) translocates to the nucleus and modulates transcription. The monoclonal antibody brontictuzumab targets NOTCH1, inhibiting pathway activation. AL101 inhibits NOTCH activation by inhibiting gamma secretase, disrupting intracellular release of NICD. EGF, epidermal growth factor repeats; NRR, negative regulatory region; PEST, PEST domain.

FIGURE 2

Representative images of mixed responses to NOTCH inhibitor. (A, B) Computerized tomography (CT) of the chest (top) and abdomen (bottom) at baseline (A; yellow circle and arrow) and at the second re‐staging at 16 weeks (B) demonstrates response in the mediastinal nodal metastasis (white circles and arrows) but development of new liver metastases (red arrows). (C, D) CT of the abdomen in another NOTCH inhibitor trial patient at baseline (C; yellow circle and arrow) and at second re‐staging at 16 weeks (D) demonstrates response in a hepatic lesion (white arrows), but progression of a peritoneal metastasis (red circles).

FIGURE 3

Univariate and multivariate analyses of PFS on NOTCH inhibitor. (A) Nonsolid histology was associated with longer PFS than solid histology. (B) NOTCH‐wild‐type ACC was associated with longer PFS than NOTCH‐mutant ACC. (C) AL101 was associated with numerically longer PFS than brontictuzumab, but this difference was not significant on univariate analysis. (D) On multivariate analysis, AL101 was associated with longer PFS than brontictuzumab. HR, hazard ratio; Ni, NOTCH inhibitor.

FIGURE 4

Efficacy of NOTCH inhibitor compares favorably to the efficacy of pre‐NOTCH‐inhibitor systemic therapy or observation. (A) For the 23 patients eligible for PFS analysis before NOTCH inhibitor therapy, NOTCH inhibitor significantly increased PFS when compared to immediately before NOTCH inhibitor therapy, including patients receiving prior systemic therapy or observation. (B) For the 13 patients receiving a prior systemic therapy, median PFS on NOTCH inhibitor was numerically longer than on prior systemic therapy. (C) For the 10 patients under observation before NOTCH inhibitor therapy, median PFS on NOTCH inhibitor was statistically significantly longer than on prior observation. HR, hazard ratio.