Nirogacestat Tops Standard-of-Care Response Rate in Desmoid Tumors

Nirogacestat (Ogsiveo; SpringWorks Therapeutics) achieved an improved objective response rate compared with prior standard-of-care (SOC) systemic agents in a real-world, single-center analysis of patients with desmoid tumors. The difference, however, did not reach statistical significance, which investigators attributed to limited sample size and shorter follow-up in the nirogacestat cohort, according to a poster presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

What the UCI Health Real-World Analysis Found

Researchers at University of California Irvine (UCI) Health conducted a retrospective analysis of 31 patients treated between 2019 and 2025, comparing 18 patients who received nirogacestat with 13 treated with other systemic agents, including sorafenib, pazopanib, and the tamoxifen-plus-sulindac combination historically used for desmoid tumors.¹ Response was assessed by RECIST v1.1 criteria.

The objective response rate (ORR), defined as complete plus partial responses, was 44.4% with nirogacestat vs 23.1% with the SOC comparator group (P = .45). Among patients who responded, median time to response was nearly identical across both arms, with data showing a response time of 6.4 months with nirogacestat and 6.7 months with other therapies. Median progression-free survival (PFS) was not reached in the nirogacestat group, compared with 58.0 months (95% CI, 11.5-104.5) in the SOC group, with a log-rank P value of .685. A univariable Cox regression model showed no significant PFS difference between arms (HR, 0.73; 95% CI, 0.16-3.41; P = .686). No deaths were recorded during follow-up.

A key limitation is the substantial disparity in median follow-up of 8.3 months for the nirogacestat cohort vs 41.6 months for patients on prior SOC regimens. This gap makes PFS comparisons inherently difficult to interpret.

How Nirogacestat Fits Into the Evolving Desmoid Treatment Landscape

Desmoid tumors are rare, locally aggressive fibroblastic neoplasms with an estimated incidence of 3 to 5 cases per million person-years. Their morphologic heterogeneity and variable clinical presentation contribute to misdiagnosis rates as high as 30% to 40%, often resulting in delayed or inappropriate treatment.² Before the approval of nirogacestat, systemic options were limited to tyrosine kinase inhibitors such as sorafenib and pazopanib, as well as hormonal and anti-inflammatory combinations.

Nirogacestat, a γ-secretase inhibitor that blocks Notch pathway activation, received FDA approval in November 2023 on the strength of the phase 3 DeFi trial (NCT03785964), which demonstrated a 71% reduction in the risk of disease progression vs placebo (HR, 0.29; 95% CI, 0.15-0.55) along with significantly higher response rates, including complete responses not observed in the placebo arm.³

Long-term DeFi data reported in early 2026 reinforced the durability of those benefits, showing sustained tumor shrinkage, durable responses, and a safety profile that improved over time as adverse event frequency and severity declined after the first year of therapy.⁴

What Real-World Evidence Adds—and Where Gaps Remain

The UCI Health analysis is among the first to attempt a direct real-world comparison of nirogacestat against the agents it has effectively supplanted in clinical practice. While the ORR signal—44.4% compared with 23.1%—is directionally consistent with DeFi's trial-based superiority findings, the absence of statistical significance and the wide Cox regression CIs (0.16-3.41) underscore the constraints of small retrospective cohorts in rare disease settings.

The authors called for validation in larger, prospective cohorts with longer follow-up to better characterize nirogacestat's PFS and overall survival benefit relative to prior SOC in real-world populations. Given the rarity of desmoid tumors, multi-institutional registry efforts may be necessary to generate the sample sizes needed for definitive conclusions.

References

1. Kim H, Chow WA. Real-world efficacy of nirogacestat compared to prior standard-of-care systemic agents in desmoid tumors. J Clin Oncol. 2026;44(suppl 16):Abstr e23542. doi:10.1200/JCO.2026.44.16_suppl.e23542
2. AJMC Staff. Desmoid tumors: advancements and emerging therapies. AJMC^®. 2026. Accessed June 2, 2026. https://www.ajmc.com/view/desmoid-tumors--advancements-and-emerging-therapies
3. Caffrey M, Steinzor P. FDA approves nirogacestat for treatment of desmoid tumors. AJMC. November 27, 2023. Accessed June 2, 2026. https://www.ajmc.com/view/fda-approves-nirogacestat-for-treatment-of-desmoid-tumors
4. AJMC Contributor. Long-term trial shows durable efficacy, sustained QOL gains with nirogacestat in desmoid tumors. AJMC. January 1, 2026. Accessed June 2, 2026. https://www.ajmc.com/view/long-term-trial-shows-durable-efficacy-sustained-qol-gains-with-nirogacestat-in-desmoid-tumors