Subgroup analysis of the phase 2 part of the RINGSIDE phase 2/3 trial of varegacestat for treatment of desmoid tumors.

This is the authors' abstract. We don't add key points for this paper.

11516 Background: Gamma secretase inhibitors (GSIs) have shown antitumor activity against desmoid tumors (DT). The RINGSIDE Phase 2 study (NCT04871282) demonstrated early and continued response to three dose regimens of varegacestat (AL102) in patients with DTs. We evaluated treatment response in key subgroups. Methods: RINGSIDE Phase 2 is an open-label, dose-finding study in adults with progressing DT (≥10% unidimensional growth ≤18 months or DT-related pain requiring non-opioid medication). Participants were randomized to three dose regimens: 1.2 mg once daily (n=14), 2 mg intermittent (n=14) or 4 mg intermittent (n=14) (intermittent = 2 days on, 5 days off). In the open-label extension (OLE) period, all active participants began receiving 1.2 mg once daily. We performed descriptive analyses of objective response rate (ORR) in the following subgroups with at least 5 participants: age (≤40 years vs. >40 years), tumor size (<70 mm vs. ≥70 mm), prior lines of therapy (0, 1, or 2+), tumor location (intra-abdominal vs. extra-abdominal) and mutational biomarkers ( APC vs CTNNB1 ). Subgroups were analyzed by pooling across dose regimens. Results: RINGSIDE Phase 2 enrolled 42 participants, of whom 29 (69%) entered the OLE. As of April 10, 2024, median time on treatment was 23.1 months (range 0.7 – 26.6) and 23 participants (55%) were still on treatment. Median age was 38.5 years (range 19 – 72), 74% were women, and 69% received prior DT therapy. ORR ranged from 43% to 78% across age, tumor size, prior therapy, tumor location and mutation subgroups (Table). Response rates were comparable across all subgroups examined. Conclusions: Comparable, objective tumor responses to oral varegacestat therapy were shown in all subgroups examined. These findings support continued evaluation of all desmoid tumor patients independent of subgroups in the ongoing, double-blind, randomized, placebo-controlled Phase 3 study of varegacestat (RINGSIDE NCT04871282). Clinical trial information: NCT04871282 . Varegacestat response in subgroups. Subgroups ORRResponder (%) Age ≤40 years (n=22) vs. >40 years (n=14) 13 (59) vs. 10 (71) Tumor size <70 mm (n=18) vs. ≥70 mm (n=14) 13 (72) vs. 9 (64) Prior lines of therapy: 0 (n=11), 1 (n=16), or 2+ (n=9) 6 (55), 10 (63), 7 (78) Intra-abdominal (n=9) vs. extra-abdominal (n=27) 4 (44) vs. 19 (70) APC (n=7) vs CTNNB1 (n=19) mutation 3 (43) vs. 13 (68)