Real-world efficacy of nirogacestat compared to prior standard-of-care (SOC) systemic agents in desmoid tumors.

Abstract

e23542 Background: Desmoid tumors are rare, locally aggressive fibroblastic neoplasms for which systemic therapy has historically included tyrosine kinase inhibitors (e.g., sorafenib, pazopanib) and hormonal/anti-inflammatory approaches. Nirogacestat, a gamma-secretase inhibitor, was recently proven effective versus placebo in a phase III trial and approved for desmoid tumors. We performed a real-world comparison of nirogacestat versus other systemic therapies. Methods: We retrospectively analyzed 31 UCI Health patients treated from 2019–2025 (nirogacestat n=18; other SOC: sorafenib/pazopanib/tamoxifen+sulindac n=13). Response was assessed by RECIST v1.1. ORR (CR+PR) was compared with Fisher’s exact test. PFS was estimated by Kaplan–Meier and compared by log-rank; HRs were calculated with Cox regression. Results: Median follow-up was 8.3 months (range, 1.57–22.87) with nirogacestat and 41.6 months (2.8–207.2) with other SOC. ORR was 44.4% with nirogacestat versus 23.1% with other therapies, a difference not statistically significant (p=0.45). Among responders with available dates, median time to response was 6.4 months (3.7–10.0; n=6) vs 6.7 months (3.4–22.1; n=3). Median PFS was not reached with nirogacestat and was 58.0 months with other SOC (95% CI, 11.5–104.5); log-rank p=0.685. Univariable Cox regression showed no significant PFS difference (HR 0.73, 95% CI 0.16–3.41; p=0.686). No deaths were observed during follow-up; OS was not estimable. Conclusions: Nirogacestat showed a higher tumor response rate than other systemic therapies(sorafenib, pazopanib, or tamoxifen/sulindac) in this real-world analysis. However, no significant PFS improvement was observed, likely due to the small sample size and shorter follow-up for the nirogacestat group. These findings support the activity of nirogacestat in desmoid tumors and warrant validation in larger, long-term studies. Best overall response and time to response with nirogacestat versus other standard systemic therapies in desmoid tumors (real-world, retrospective cohort). Outcome Nirogacestat (n=18) Other SOC* (n=13) CR, n (%) 1 (5.6) 1 (7.7) PR, n (%) 7 (38.9) 2 (15.4) SD, n (%) 7 (38.9) 8 (61.5) PD, n (%) 3 (16.7) 2 (15.4) ORR (CR+PR), n (%) 8 (44.4) 3 (23.1) Median time to response among responders, months (range)† 6.4 (3.7–10.0) 6.7 (3.4–22.1) *Other SOC includes sorafenib, pazopanib, or tamoxifen+sulindac. †Time to response calculated among responders with available response dates. Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; SOC, standard of care.