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Final DeFi trial results show sustained responses, improved PROs, and a stable safety profile with long-term nirogacestat in desmoid tumors.
Long-term findings from the phase 3 DeFi trial (NCT03785964) demonstrated sustained efficacy and a consistent safety profile with nirogacestat (Ogsiveo), an oral γ-secretase inhibitor, for the treatment of adult patients with progressing desmoid tumors requiring systemic therapy, according to results published in the Journal of Clinical Oncology.1,2
In November 2023, the FDA approved nirogacestat for the treatment of adult patients with progressing desmoid tumors who require systemic treatment based on earlier findings from the DeFi trial.3
Consistent with the primary analysis, long-term follow-up from the trial demonstrated that median progression-free survival (PFS) was not reached as of the final data cutoff. No additional progression or death events occurred beyond 2 years of continued nirogacestat treatment, reinforcing the sustained disease control observed with long-term therapy.2
The objective response rate (ORR) improved over time, indicating that ongoing exposure to nirogacestat led to continued tumor shrinkage and deepening responses. Among 70 patients treated, ORR increased from 34.3% after 1 year to 41.4%, 44.3%, and 45.7% after 2, 3, and 4 years of treatment, respectively. Across years 3 and 4, three additional partial responses (PRs) and 3 complete responses (CRs) were recorded, resulting in a total of 24 PRs (34.3%) and 8 CRs (11.4%).
“Desmoid tumors are locally aggressive and complex tumors whose unpredictable growth can cause significant pain, functional impairment, and emotional distress. For many patients, these tumors disrupt daily life in ways that are often underestimated, so advancing treatment options that offer durable symptom relief and tumor control can make a meaningful difference for patients,” Ravin Ratan, MD, MEd, an associate professor in the Department of Sarcoma Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, and lead author of the publication shared in a news release.1
The phase 3 DeFi trial was a global, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of nirogacestat in adults with progressing desmoid tumors. A total of 142 patients were enrolled and randomly assigned to receive either oral nirogacestat at 150 mg twice daily via continuous 28-day cycles or placebo during the double-blind phase.2
Patients continued treatment until imaging-based or clinical disease progression, discontinuation for any reason, death, or completion of the study. Following the double-blind phase, eligible patients were permitted to enter an open-label extension (OLE) phase, which evaluated the long-term safety and efficacy of nirogacestat. Individuals initially assigned to nirogacestat in the double-blind phase were eligible to continue the same regimen in the OLE phase after either the completion of the primary analysis or upon experiencing disease progression per independent central review, provided they continued to derive clinical benefit without significant toxicity as determined by the investigator.
The final data cutoff for the long-term analysis was December 19, 2024. The primary end point was PFS; key secondary end points included ORR and patient-reported outcomes (PROs).
Among the 69 patients included in the safety population, the median duration of exposure to nirogacestat was 33.6 months (range, 0.3-61.8). The frequency and severity of treatment-emergent adverse effects (TEAEs) decreased with continued treatment beyond the first year. The most commonly reported grade 1/2 TEAEs during the first year included diarrhea (48%), nausea (45%), ovarian toxicity (38%), fatigue (32%), hypophosphatemia (29%), and headache (23%). These rates declined substantially after year 1, with few new effects reported during later years of therapy.
Dose modifications and discontinuations were infrequent. Five additional patients required dose reductions after the primary analysis, although no dose reductions occurred beyond year 3. Four patients discontinued treatment between years 2 and 4 due to adverse effects. Ovarian toxicity remained a key area of interest: one new event (menopause) occurred after 3 years of therapy in a 54-year-old patient without prior ovarian toxicity, and 3 patients who had previously resolved ovarian toxicity events reported recurrence during years 3 and 4.The most frequently reported treatment-related adverse effect across years 3 and 4 was diarrhea, consistent with earlier findings.
Notably, 5 nonmelanoma skin cancers (NMSCs) were reported over the study period, including 3 during the primary analysis (two squamous cell carcinomas [SCC] and 1 basal cell carcinoma [BCC]) and 2 additional cases (1 BCC in year 3 and 1 SCC in year 4). All NMSCs were successfully excised and resolved without treatment discontinuation. Identified risk factors included prior radiation exposure, White race, older age, and a history of sun exposure or sunburns.
“[Although] the optimal duration of therapy may vary for many patients and is best decided between individual patients and their physicians, the new data published in the JCO provide physicians with additional information regarding the long-term safety and efficacy of nirogacestat, and will help inform treatment decisions and improve patient care,” Ratan concluded.