(P 315) ANALYSIS OF CHANGES IN T2-WEIGHTED SIGNAL INTENSITY AND TUMOR VOLUME AND EXPOSURE-RESPONSE IN THE RINGSIDE PHASE 2 STUDY OF VAREGACESTAT FOR DESMOID TUMORS

Objective: T2-weighted signal intensity (T2W) and tumor volume (TV) on MRI may be more sensitive than RECIST for assessing treatment effect in desmoid tumors (DT). On T2W images, hyperintense areas are associated with active fibroblast proliferation and hypointense areas with tumor cell loss and increased collagenous tissue. RINGSIDE Phase 2 (NCT04871282) showed safety and early and continued MRI changes in DTs with oral varegacestat (AL102). We report exploratory analyses of T2W, TV, and exposure-response (ER).

Methods: Adults with progressing DT and ≥10% unidimensional growth in ≤18 mo or DT pain requiring non-opioid medication were randomized to 3 varegacestat doses: 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, active pts received 1.2 mg once daily. T2W, TV and RECIST sum of diameters (SOD) were evaluated at screening, Week 16 and every 12 weeks thereafter. Linear correlations were evaluated with Pearson correlation coefficient. ER modeling evaluated time course of drug effect on TV to support selection of 1.2 mg once daily for further study.

Results: As of Jan. 6, 2025, median time on treatment was 23.3 mo (range 0.7–38.8) and 12 (29%) pts were still on treatment. By Week 16, median % change was -39% for T2W, -24% for TV and -8% for SOD. Median best % change was -96% for T2W, -86% for TV and -48% for SOD. Correlations were observed for best % changes in T2W vs SOD (R=0.67), TV vs SOD (R=0.81), and T2W vs TV (R=0.93). In 25 pts with PR/CR, median best % change was -99% for T2W, -91% for TV and -56% for SOD. In 10 pts with SD, median best % change was -82% for T2W, -39% for TV and -8% for SOD. Preliminary ER analysis predicted median time to 30% TV decrease of 3 mo with 1.2 mg once daily.

Conclusion: Substantial early and rapid reductions in T2W and TV preceded subsequent varegacestat responses by RECIST in adults with DT, adding to evidence that T2W and TV may play a role in evaluating DT treatment response.

© 2025 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2025 ASCO Annual Meeting. All rights reserved.