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

Abstract

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 <0.0001]). PFS consistently favored VAR in all subgroups analyzed. ORR was significantly better with VAR vs PBO (55.7% vs 9.1%; P <0.0001), with 3 CRs in the VAR arm and 1 CR in the PBO arm. Median duration of response was not reached in either arm. All alpha-controlled secondary endpoints demonstrated statistically and clinically significant superiority for VAR compared with PBO (Table). Overall, 95% of adverse events (AEs) were Grade 1-2 and there were no Grade 5 AEs. Grade 3/4 AEs were reported in 57% of VAR pts and 17% of PBO pts. AEs led to dose reduction in 63 (80%) VAR pts and 7 (9%) PBO pts; 16 (20%) VAR pts and 5 (7%) PBO pts discontinued due to AEs. In the VAR arm, the most frequently reported AEs were diarrhea (82%), fatigue (44%), and rash (43%). Ovarian toxicity occurred in 20/36 (56%) premenopausal women on VAR, resolved in 11/20 (55%), and did not lead to dose interruption or drug withdrawal. Conclusions: VAR demonstrated statistically significant and clinically meaningful antitumor activity and pain relief, achieving the highest ORR reported in a Phase 3 trial of systemic DT therapy, with no new safety signals. Clinical trial information: NCT04871282 . RINGSIDE phase 3 trial outcomes. VAR (n=79) PBO (n=77) HR (95% CI) or Difference; P value Median PFS (95% CI) - radiographic, months NE (NE, NE) 24.9 (13.8, NE) 0.16 (0.07, 0.38); P<0.0001 Confirmed ORR, n (%) 44 (55.7) 7 (9.1) P<0.0001 TV change (cm 3 ) at Week 24, LS mean (SE) -109.6 (40.64) 122.8 (42.72) -232.4 (57.39); P<0.0001 WPI (pain) change at Week 12, LS mean (SE) -2.24 (0.27) 0.18 (0.27) -2.42 (0.37); P<0.0001 Median best % change in TV* -83.4 11.3 * 1-year PFS, % (95% CI)* 94.2 (85.3, 97.8) 65.6 (52.3, 76.0) * 2-year PFS, % (95% CI)* 88.9 (77.9, 94.6) 56.7 (42.6, 68.6) * LS, least square; SE, standard error. *Not alpha-controlled endpoint.