Updated data from the phase 3 DeFi trial show that nirogacestat (Ogsiveo) provides deepening and durable responses with long-term treatment in patients with desmoid tumors, offering new hope for patients with this rare, locally aggressive soft tissue tumor.
The findings, presented at the 2025 ESMO Sarcoma and Rare Cancers Congress, demonstrate that patients who received nirogacestat for up to four years experienced improved objective response rates (ORR) and sustained quality-of-life benefits compared to those treated for shorter periods.
Deepening Responses Over Time
According to lead study author Dr. Bernd Kasper of the Sarcoma Unit at the University of Heidelberg and Mannheim University Medical Center, "These results show the long-term efficacy and safety of continuous use of nirogacestat with a median exposure of 33.6 months, extended from 20.6 months at the primary analysis."
The landmark analysis revealed that patients who received nirogacestat for up to four years achieved an ORR of 45.7% (complete response [CR], 11.4%; partial response [PR], 34.3%), compared to 34.3% (CR, 4.3%; PR, 30.0%) in those treated for up to one year. Notably, additional complete and partial responses continued to emerge during years three and four of treatment.
The median best change in target tumor size also improved with longer treatment duration:
- -32.3% with at least 1 year of treatment
- -42.5% with at least 2 years of treatment
- -51.3% with at least 3 years of treatment
- -75.8% with at least 4 years of treatment
DeFi Trial Design and Patient Population
The DeFi trial enrolled 142 patients across North America and Europe with progressive desmoid tumors, defined as documented 20% growth within the past 12 months. Dr. Nam Quoc Bui, a trial investigator, emphasized that "these were patients with the highest-risk desmoid disease."
Patients were randomized to receive either nirogacestat (150 mg twice daily) or placebo in a double-blind portion, followed by an open-label extension where eligible placebo patients could cross over to nirogacestat.
The trial population had several notable characteristics:
- Approximately 75% of tumors were extra-abdominal
- About 40% of patients had multifocal disease
- Median tumor size was 91.6 mm for nirogacestat and 115.7 mm for placebo
- 16-18% had familial adenomatous polyposis
- 60% had CTNNB1 mutations
- Most patients were heavily pretreated (median of 2 prior therapies)
- 39-43% had uncontrolled pain at baseline
Significant Survival and Symptom Benefits
The primary analysis of DeFi demonstrated that nirogacestat significantly improved progression-free survival (PFS) compared to placebo, with a hazard ratio of 0.29 (95% CI, 0.15-0.55; P<.001). The median PFS was not reached for nirogacestat, whereas it was 15.1 months for placebo.
The likelihood of being progression-free at two years was 76% for nirogacestat versus 44% for placebo. The disease control rate was impressive at 91% for nirogacestat compared to 85% for placebo.
Perhaps most importantly for patients, nirogacestat provided rapid and sustained improvement in symptoms, particularly pain. Dr. Bui noted, "I've noticed that pain improves very quickly—within 2 weeks, patients are off opioids and feeling better. The MRI may not change much initially, but it does over time."
Patient-reported outcomes showed sustained benefits across multiple measures, including pain intensity, symptom scores, physical functioning, and overall quality of life.
Safety Profile and Manageable Side Effects
The updated safety analysis confirmed that most treatment-emergent adverse effects (TEAEs) were grade 1 or 2, with the incidence and severity of common TEAEs decreasing after year one.
The most common side effect was diarrhea, affecting 84% of patients, though investigators noted it was generally manageable with standard medications or dose reductions. Other common TEAEs included nausea, fatigue, hypophosphatemia, and headache.
Addressing Ovarian Toxicity Concerns
An important finding for the predominantly young female patient population was the characterization of ovarian toxicity. Approximately 75% of female patients on nirogacestat experienced ovarian dysfunction compared to 0% on placebo, with a median onset of 8.9 weeks and median duration of 21 weeks.
Dr. Bui emphasized that "of the 11 patients who stopped nirogacestat, all recovered ovarian function, so this is not permanent. We can tell patients it's unlikely they'll be permanently postmenopausal."
The updated analysis identified three patients who experienced an additional instance of ovarian toxicity following a previously reported event, and one patient who experienced first-time ovarian toxicity.
FDA Approval and Clinical Implications
The FDA approved nirogacestat in November 2023 for adult patients with progressing desmoid tumors who require systemic treatment, based on the primary DeFi trial results.
These long-term data provide clinicians with valuable information about the benefits of continued treatment, though questions remain about optimal treatment duration. As Dr. Bui noted, "The question is, when do you stop these drugs? These questions aren't answered in these pivotal trials. It will require post-marketing data and collaborations between investigators to pool data and figure it out."
For now, the deepening responses over time suggest potential benefits to continued treatment for appropriate patients, with careful monitoring and management of side effects.
