900P - Notch inhibitor AL101 prior to surgery in patients (pts) with Notch1 activated adenoid cystic carcinoma (ACC): Safety and efficacy in a window of opportunity study

Background

ACC with NOTCH1 pathway activation (ACC-N1) have poor prognosis. AL101 inhibits gamma secretase-mediated Notch signaling. In a prior study of AL101 in metastatic NOTCH mutant ACC, the response rate (ORR) was 15% and disease control rate was 71% at the 4 mg dose. Here we conducted a window of opportunity study to gain insights on the biological impact of AL101 on ACC-N1 and to guide combinatorial therapy.

Methods

AL101 at 4 mg Q1W was administered for 4 to 8 weeks in ACC-N1 pts prior to surgery. Notch1 pathway activation was determined by Notch1-Intracellular domain (NICD1) IHC; nuclear staining in ≥ 70% of the tumor cells was considered positive and trial eligible. ORR evaluation per RECIST occurred prior to surgery. Treatment-related adverse events (AEs) were recorded per CTCAE v5.0. The co-primary objectives were to assess safety and feasibility of pre-operative AL101, and to determine NICD1 tumor expression changes with treatment. We assumed that AL101 would decrease NICD1 expression with an effect size of 0.8. With 12 evaluable patients, the study power is 82% with a 5% type I error.

Results

13 pts enrolled from Nov/21 to Dec/23, 7 female, median age 45, 8 were newly diagnosed. Median doses of AL101 were 6 (range: 4–7), the most common primary site was maxillary sinus (n=4). There were no grade 3-5 AEs. Most common AEs were ALT increase (n=12), diarrhea (n=10), and hypophosphatemia (n=10). One pt had a PR (ORR=7.7%), 11 (84.6%) had SD (2 SD had >20% shrinkage in target lesion), and 1 pt had PD in non-target lesion. There were no surgical delays due to AEs; 12 pts underwent planed surgery, 4 occurred > 72 hs after last AL101 infusion. One pt did not undergo surgery despite SD (+2%) in the setting of metastatic disease. There were no unexpected surgical complications. No significant decrease in NICD1 expression was noted in the post-treatment compared to pre-treatment specimens.

Conclusions

Pre-operative AL101 was safe and feasible in ACC-N1 pts. Tumor NICD1 expression was not significantly reduced following AL101 treatment. Paired tissue and blood samples analyzes are ongoing. This first-of-its-kind study in ACC has implications for future drug development.

Clinical trial identification

NCT04973683.

Editorial acknowledgement

Legal entity responsible for the study

MD Anderson Cancer Center.

Funding

Department of Defense and Ayala Pharmaceuticals.

Disclosure

R. Ferrarotto: Financial Interests, Personal, Advisory Board: Regeneron-Sanofi, Ayala Pharmaceuticals, Bicara Therapeutics, Prelude Therapeutics, Guidepoint, Elevar Therapeutics, G1 Therapeutics, ExpertConnect, Remix; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Royalties: UptoDate; Financial Interests, Institutional, Coordinating PI: Merck, Gennentech, Pfizer, Ayala, EMD Serono; Financial Interests, Institutional, Other, Co-PI: Rakuten, Nanobiotix; Financial Interests, Institutional, Local PI: Prelude, ISA Therapeutics; Non-Financial Interests, Advisory Role: Cellestia. All other authors have declared no conflicts of interest.