908P - Efficacy of NOTCH inhibitors (Ni) relative to prior systemic therapy or observation in patients (pts) with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC)

Background

ACC is a heterogeneous malignancy with no standard treatment for R/M disease. Around 20% of ACC carry NOTCH1 (N1) activating mutations associated with poor prognosis. We hypothesized that Ni is an active therapy for ACC pts with N1 mutation or pathway activation.

Methods

Retrospective study of 29 R/M ACC pts with N1 mutation or pathway activation (assessed by cleaved N1 IHC) treated with Ni at MD Anderson (MDA). Ni included AL101, a gamma-secretase inhibitor, or OMP-52M51, an antibody targeting N1. Efficacy endpoints were objective response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS) per RECIST or MDA bone criteria (for pts with bone disease only). These endpoints were assessed at two timepoints: during Ni therapy and immediately prior to Ni (pre-Ni) during systemic therapy or observation for the same pts.

Results

Out of the 29 ACC pts, 18 (62%) were males with median age 45 y (26-72 y). Of 24 genotyped ACC, 23 (96%) had N1 mutation. 15 (75%) of 20 pts with reported ACC histology had a solid component. 18 (62%) pts received AL101 and 11 (38%) received OMP-52M51. Ni was given in 2^nd line or beyond in 18 (62%) pts, with the most common prior regimen being platinum-based chemotherapy (55%). The ORR to Ni was 17% (5/29), CBR was 72% (21/29) and median PFS was 4.2 mos (95%CI 2.9-8.6 mos). Tumor progression on Ni occurred on non-target lesions in 10/29 (34%) pts. 23 of 29 (79%) pts were eligible for PFS analysis immediately prior to Ni; 13 (57%) had received systemic therapy and 10 (43%) were under close observation. The median PFS on Ni vs. pre-Ni was 4.2 vs. 3 mos, respectively (HR 0.42 [95%CI 0.22-0.81], p=0.0076). Considering only the 13 pts who were on systemic therapy pre-Ni, ORR pre-Ni was 0% (0/13) and CBR was 8% (1/13). Median PFS on Ni vs. prior systemic therapy was 3.7 vs. 2.1 mos, respectively (HR 0.34 [95%CI 0.13-0.93], p= 0.029).

Conclusions

Ni has activity in ACC pts with N1 mutation or pathway activation. The efficacy of Ni compares favorably with efficacy of systemic therapies administered prior to Ni. The limited PFS and high rate of tumor progression on non-target lesions suggests Ni combination therapy may be necessary to address ACC heterogeneity.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The University of Texas MD Anderson Cancer Center.

Funding

Has not received any funding.

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.