RINGSIDE: A phase 3 randomized, placebo-controlled trial of varegacestat for treatment of progressing desmoid tumors.

11506 Background: Desmoid tumors (DT) are rare, locally aggressive tumors with few effective treatments. Varegacestat (VAR) is an investigational, once daily, oral gamma secretase inhibitor that previously showed antitumor activity in pts with DT in the RINGSIDE Phase 2 study. Methods: RINGSIDE Phase 3 was a double-blind, placebo (PBO)-controlled study in adults with progressing DT per RECIST v1.1 (NCT04871282). 156 pts were randomized 1:1 to once daily oral VAR 1.2 mg (n=79) or PBO (n=77). Imaging-based tumor response was assessed per RECIST v1.1 by blinded independent central review. The primary endpoint was progression-free survival (PFS). Alpha-controlled secondary endpoints were confirmed objective response rate (ORR), change in tumor volume (TV) at Week 24, and change in patient-reported worst pain intensity (WPI) at Week 12. Results: Demographics and disease characteristics were balanced between treatment arms. As of Oct 7, 2025, median duration of exposure was 20.3 months (range 0.8 – 34.6) for VAR and 11.1 months (range 0.2 – 34.6) for PBO. VAR demonstrated significantly better PFS compared with PBO (hazard ratio [HR]: 0.16 [95% CI: 0.07, 0.38; P