1. There is a 71% lower risk of disease progression or death in the nirogacestat group than in the placebo group

2. Adverse events were almost all low grade, but ovarian dysfunction occurred in 75% of women who received nirogacestat.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Desmoid tumors are rare, locally aggressive, and invasive soft-tissue tumors that have been shown to overexpress Notch1 which is implicated in a pathway that amplifies oncogenic growth. Currently, there are no approved therapies, however, nirogacestat, a selective γ-secretase inhibitor that blocks Notch signaling, has shown antitumor activity and palliation of pain in phase 1 and 2 trials. This is a phase 3 trial for patients with progressing desmoid tumors. The primary endpoint of the trial was progression-free survival (PFS), and secondary endpoints included objective response (OR), patient-reported outcomes, and adverse events. This study found that there is a 71% lower risk of disease progression or death in the nirogacestat group than in the placebo group. The median progression-free survival was not calculated in the nirogacestat group due to the low number of events, but was 15.1 months in the placebo group. The 1 and 2 year event free likelihoods were estimated as 85% and 76% for the nirogacestat group and 53% and 44% in the placebo group respectively. OR rates were 41% in the nirogacestat group and 8% in the placebo group. Patient-reported outcomes showed improvements in pain, total symptoms, physical functioning, and quality of life. Common adverse events (grade 1-2) included diarrhea, nausea, fatigue, hypophosphatemia, maculopapular rash, stomatitis, headache, dermatitis acneiform, and vomiting. Ovarian dysfunction occurred in 75% of women who received nirogacestat. The only serious adverse event (grade 3 or higher) was premature menopause. The strengths of this study included tracking a range of outcome measures but the limitations included a small sample size. Overall, this study provides some evidence for the effectiveness of nirogacestat in treating desmoid tumors.

Click to read the study in NEJM

Relevant Reading: A Phase I, Dose-Finding Study in Patients with Advanced Solid Malignancies of the Oral γ-Secretase Inhibitor PF-03084014

In-Depth [randomized controlled trial]: This phase 3, international, randomized, placebo-controlled trial investigated oral nirogacestat 150mg (70 patients) vs placebo (72) taken twice daily in 28-day cycles until a defined event in adults with histologically confirmed progressing desmoid tumors. Patients were stratified according to the location of the tumor. Defined events included death, trial completion, clinical progression, intolerable adverse event, or discontinuation. The median follow-up for progression-free survival was 15.9 months. Between the groups, the risk of disease progression or death was 71% lower in the nirogacestat group than in the placebo group (HR 0.29; 95%CI, 0.15 to 0.55; P<0.001). Median progression-free survival is unknown in the nirogacestat group due to the low number of events, but was 15.1 months (95%CI, 8.4 to NA) in the placebo group. The 1 and 2 year event free likelihoods were estimated as 85% (95%CI, 73 to 92) and 76% (95%CI, 61 to 87) for the nirogacestat group and 53% (95%CI, 40 to 64) and 44% (95%CI, 32 to 56) in the placebo group respectively. Results were generally consistent across subgroups. OR rates were 41% in the nirogacestat group and 8% in the placebo group (P<0.001) with complete responses observed in 7% in the nirogacestat group and no patients in the placebo group. The median time to first response was 5.6 months with nirogacestat and 11.1 months with placebo. Patient-reported outcomes were assessed at cycle 10 and showed improvements in pain, total symptoms, physical functioning, and quality of life, all with P<0.001. Common adverse events (grade 1-2) included diarrhea, nausea, fatigue, hypophosphatemia, maculopapular rash, stomatitis, headache, dermatitis acneiform, and vomiting. Ovarian dysfunction occurred in 75% of women who received nirogacestat. The only serious adverse event (grade 3 or higher) was premature menopause (in 3 patients). Overall, this study provides some evidence for the effectiveness of nirogacestat in treating desmoid tumors.

Image: PD

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