Long-term results from the phase 3 DeFi trial (NCT03785964) have shown sustained efficacy and a reliable safety profile for nirogacestat (Ogsiveo), an oral γ-secretase inhibitor designed for adult patients with progressing desmoid tumors requiring systemic therapy. These findings were published in the Journal of Clinical Oncology.
In November 2023, the FDA granted approval for nirogacestat based on earlier conclusions from the DeFi trial. The long-term follow-up data corroborated the initial analysis, indicating that the median progression-free survival (PFS) had not been reached by the final data cutoff. Notably, there were no new cases of disease progression or fatalities after two years of continuous nirogacestat treatment, reinforcing the drug”s ability to maintain disease control over an extended period.
The objective response rate (ORR) for patients improved over time, demonstrating that prolonged treatment with nirogacestat led to continued tumor shrinkage and enhanced responses. Of the 70 patients treated, the ORR rose from 34.3% after one year to 41.4%, 44.3%, and 45.7% after two, three, and four years of treatment, respectively. Between years three and four, three additional partial responses and three complete responses were documented, bringing the total to 24 partial responses (34.3%) and eight complete responses (11.4%).
“Desmoid tumors are locally aggressive and complex, with unpredictable growth that can lead to significant pain, functional impairment, and emotional distress. For many patients, these tumors disrupt daily life in ways that are often underestimated. Thus, advancing treatment options that provide durable symptom relief and tumor control can make a significant difference,” stated Dr. Ravin Ratan, an associate professor at the Department of Sarcoma Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston and the lead author of the publication.
The phase 3 DeFi trial was a global, multicenter, randomized, double-blind, placebo-controlled study aimed at assessing nirogacestat”s safety and efficacy in adults with progressing desmoid tumors. A total of 142 patients participated, receiving either 150 mg of oral nirogacestat twice daily or a placebo during the double-blind phase. Patients continued their treatment until they experienced imaging-based or clinical disease progression, discontinued for any reason, passed away, or completed the study.
After the double-blind phase, eligible participants could enter an open-label extension (OLE) phase to further evaluate nirogacestat”s long-term safety and efficacy. Those assigned to nirogacestat in the double-blind portion could continue their regimen in the OLE phase if they completed the primary analysis or experienced disease progression per independent review, provided they continued to benefit clinically without significant toxicity as assessed by the investigator. The last data cutoff for this long-term analysis was December 19, 2024.
The primary endpoint was PFS, while key secondary endpoints included ORR and patient-reported outcomes (PROs). Among the 69 patients in the safety population, the median duration of nirogacestat exposure was 33.6 months. The frequency and severity of treatment-emergent adverse effects (TEAEs) decreased with continued treatment beyond the first year. Common 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 dropped significantly after the first year, with minimal new adverse effects reported in subsequent years. Dose modifications and treatment discontinuations were rare.
Five patients required dose reductions after the primary analysis, but no reductions were noted beyond year three. Four patients stopped treatment between years two and four due to adverse effects. Ovarian toxicity remained a notable concern; one new event (menopause) was reported after three years of treatment in a 54-year-old patient without previous ovarian toxicity, and three patients who previously experienced ovarian toxicity had recurrences during years three and four. The most frequently reported treatment-related adverse effect during years three and four was diarrhea, consistent with earlier findings. Additionally, five cases of nonmelanoma skin cancers (NMSCs) were documented during the study, including three during the primary analysis and two in subsequent years. All NMSCs were successfully excised, and treatment was not discontinued.
Identified risk factors for NMSCs included prior radiation exposure, Caucasian ethnicity, older age, and a history of sun exposure or sunburns. Dr. Ratan concluded, “While the optimal duration of therapy may differ among patients and should be determined collaboratively by patients and their healthcare providers, the new data published in the JCO offer vital information regarding the long-term safety and efficacy of nirogacestat, contributing to informed treatment decisions and improved patient care.”
