A phase 2 study of novel MDM2 inhibitor alrizomadlin (APG-115) with or without toripalimab in patients (pts) with advanced adenoid cystic carcinoma (ACC) or other solid tumors.

Abstract

6102 Background: Alrizomadlin, an investigational MDM2 inhibitor, has shown a manageable safety profile with preliminary efficacy in liposarcoma (LPS) and ACC and in combination with a PD-1/PD-L1 inhibitor in advanced solid tumors. Methods: This multicenter trial (APG115XC102) assessed alrizomadlin (± toripalimab) in pts with advanced ACC, malignant peripheral nerve sheath tumor (MPNST), LPS, biliary-tract cancer (BTC), or other solid tumors in China. Enrolled pts had an ECOG PS 0-1 and were without central nervous system metastases. Alrizomadlin was administered orally at 50, 100, or 150 mg every other day for 2 weeks, with 1 week off, in repeated 21-day cycles, and combined with toripalimab 240 mg IV for 30 minutes on Day 1 of repeated 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was RP2D for the combination. ORR was assessed per RECIST v1.1. Results: As of January 5, 2025, 54 pts were enrolled. In the monotherapy arm, 22 pts were treated with alrizomadlin 150 mg; common treatment-related adverse events (TRAEs) included nausea (68.2%), decreased appetite (45.5%), thrombocytopenia (40.9%), white blood cell count decreased (40.9%), neutropenia (36.4%), and hypoalbuminemia (22.7%). Grade ≥ 3 TRAEs included neutropenia (13.6%) and thrombocytopenia (9.1%). No treatment-related serious adverse events (SAEs) were reported. In the combination arm, 32 pts were treated with alrizomadlin at 50 (n = 3), 100 (n = 3), or 150 mg (n = 26). No DLT was observed; the expansion dose was 150 mg plus toripalimab. Common TRAEs at 150 mg included nausea (73.1%), thrombocytopenia (65.4%), neutropenia (50.0%), decreased appetite (42.3%), and anemia (38.5%). Grade ≥ 3 TRAEs included thrombocytopenia (38.5%) and neutropenia (34.6%). Treatment-related SAEs were reported in 8 pts, including 6 thrombocytopenia, 1 neutropenia, 1 intestinal fistula, and 1 peptic ulcer. One pt (3.8%) discontinued treatment because of grade 4 thrombocytopenia; no treatment-related death was reported. Regarding efficacy, in the monotherapy arm, 14 pts were evaluable, with 2 unconfirmed partial responses (PRs) in 9 pts with ACC (ORR 22.2%, DCR 100%). All 5 pts with MPNST achieved SD (DCR 100%). In the combination arm, 28 pts were evaluable: 1 of 5 pts with BTC had a confirmed PR, and the ORR (CR + PR) was 20% and DCR 80%; 1 unconfirmed PR was reported in 6 pts with LPS, for an ORR of 16.7% and DCR of 66.7%. Pts with MPNST had an ORR of 14.3% and a DCR of 53.6%, and 2 pts with MPNST had confirmed PRs with prolonged PFS (1 pt > 60 weeks, 1 > 96 weeks). Conclusions: Alrizomadlin monotherapy showed promising antitumor activity in pts with advanced ACC or MPNST. Alrizomadlin combined with toripalimab was also well tolerated, showing antitumor activity in MPNST, BTC, and LPS and an acceptable safety profile (NCT04785196). Clinical trial information: NCT04785196 .