Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors

by Selleckchem | Jul 12 2023

Background: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments.

Methods: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival.

Results: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%).

Conclusions: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade.

Comments:

The information you provided is a summary of a phase 3 clinical trial conducted to evaluate the effectiveness and safety of nirogacestat, an oral γ-secretase inhibitor, in treating adults with progressing desmoid tumors. Here's a breakdown of the key findings from the study:

Study Design: The trial was a double-blind, randomized, placebo-controlled study involving 70 patients receiving nirogacestat and 72 patients receiving a placebo. The primary endpoint of the trial was progression-free survival.

Progression-Free Survival: Nirogacestat demonstrated a significant progression-free survival benefit compared to the placebo. The hazard ratio for disease progression or death was 0.29, indicating a lower risk of disease progression or death in the nirogacestat group. The likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo.

Objective Response: The percentage of patients who had an objective response (partial or complete response) was significantly higher in the nirogacestat group (41%) compared to the placebo group (8%). The median time to response was 5.6 months for nirogacestat and 11.1 months for placebo. The percentage of patients with a complete response was 7% in the nirogacestat group and 0% in the placebo group.

Patient-Reported Outcomes: Secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, showed significant improvements in the nirogacestat group compared to the placebo group (P≤0.01).

Adverse Events: Common adverse events associated with nirogacestat included diarrhea (84% of patients), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%). The majority (95%) of adverse events were of grade 1 or 2, indicating mild to moderate severity. Among women of childbearing potential receiving nirogacestat, 27 out of 36 (75%) experienced adverse events consistent with ovarian dysfunction, but these resolved in 20 women (74%).

In conclusion, nirogacestat demonstrated significant benefits in terms of progression-free survival, objective response, and various patient-reported outcomes in adults with progressing desmoid tumors. However, it's important to note that adverse events were common, albeit mostly of low grade.