Long-Term Trial Shows Durable Efficacy, QOL Gains With Nirogacestat in Desmoid Tumors

New long-term data from the phase 3 DeFi trial provide the most comprehensive picture to date of how continuous nirogacestat (Ogsiveo; SpringWorks) therapy performs in adults with desmoid tumors, showing not only sustained treatment benefit but also ongoing tumor shrinkage, durable responses, and a safety profile that becomes more favorable over time.¹

The analysis, spanning up to 5 years of therapy, represents the largest prospective dataset ever collected on long-term systemic treatment for this rare, locally aggressive type of tumor. Researchers recently published the findings in the Journal of Clinical Oncology.

Nirogacestat, a gamma-secretase inhibitor, is the first therapy approved in the US for adults with progressing desmoid tumors requiring systemic treatment.² Earlier results from the DeFi trial demonstrated significant improvements in progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PROs) compared with placebo. The long-term analysis builds on that foundation, offering critical insights into how patients fare with extended continuous treatment.¹

Of the 70 patients originally randomized to nirogacestat, 39 continued into the open-label extension phase. Median exposure to the drug increased substantially from 20.6 months at the primary analysis to 33.6 months (range: 0.3-61.8 months). Notably, 33 patients remained on therapy for at least 3 years, and 15 reached 4 years or more, allowing the research team to assess multiyear treatment dynamics rarely captured in systemic therapy trials for desmoid tumors.

Efficacy outcomes remained strong. Median PFS was still not reached at the final cutoff, and after year 2, no additional patients experienced progression or death. The ORR continued to rise with prolonged therapy, reaching 45.7% after up to 4 years of treatment. This included 24 partial responses (PRs) and 8 complete responses (CRs)—3 more CRs and 3 more PRs than reported in the primary analysis. Most patients experienced further tumor shrinkage over time, and some patients who initially had stable disease transitioned to PR or CR after extended therapy.

PROs, an area of high importance given the pain and functional impairment associated with desmoid tumors, also demonstrated durable benefit. Multiple validated instruments, including the Brief Pain Inventory–Short Form and the GODDESS symptom and impact scales, showed rapid improvement early in treatment, followed by sustained or further enhanced symptom relief during long-term therapy. These effects were consistent across pain intensity, physical functioning, and daily activity domains, providing compelling evidence that prolonged nirogacestat use not only controls tumor growth but improves lived experience for patients. Supporting graphics in the supplemental figures show tight clustering of improved scores maintained over years.

The long-term safety profile was generally consistent with earlier findings but with a notable trend: treatment-emergent side effects became less frequent and less severe after the first year. Most common side effects, such as diarrhea, nausea, and fatigue, occurred early and decreased with continued therapy. Hypophosphatemia remained one of the more frequent laboratory abnormalities, but also decreased in incidence over time. Despite the long treatment duration, few new serious side effects emerged. Between years 2 and 4, only 4 patients discontinued due to side effects.

Ovarian toxicity, an established class effect of gamma-secretase inhibitors, was monitored closely. After year 3, one new event occurred in a patient without prior hormone changes, and 3 patients with previously resolved events experienced recurrence.

“Three of the 4 OT events that occurred since the primary analysis were recurrent events in patients with previous resolved OT, indicating that some women might experience fluctuations in reproductive hormone values or symptoms even after apparent resolution of previous events,” wrote the researchers.

Nonmelanoma skin cancers were rare, with 2 new cases reported after the primary analysis. These events occurred in patients with known risk factors such as older age, sun-exposure history, and prior radiation. All were managed with lesion removal, and none led to treatment discontinuation.

References:

1. Ratan R, Kasper B, Alcindor T, et al. Efficacy and safety of long-term continuous nirogacestat treatment in adults with desmoid tumors: results from the DeFi trial. J Clin Oncol. Published online October 20, 2025.

2. FDA approves nirogacestat for desmoid tumors. FDA. Last updated November 28, 2023. Accessed December 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nirogacestat-desmoid-tumors