On November 27, 2023, the Food and Drug Administration approved nirogacestat for adult patients with progressing desmoid tumours who require systemic treatment. This is the first approved treatment for desmoid tumours.

Efficacy was evaluated in DeFi (NCT03785964), an international, multicenter, randomised (1:1), double-blind, placebo-controlled trial in 142 patients with progressing desmoid tumours not amenable to surgery. Patients were eligible if the desmoid tumour had progressed within 12 months of screening. Patients were randomised to receive 150 mg nirogacestat or placebo orally twice daily until disease progression or unacceptable toxicity.

The major efficacy outcome measure was progression-free survival (PFS) based on RECIST v1.1 as assessed by blinded independent central review or on clinical progression by the investigator (and adjudicated by independent review). Median PFS was not reached (NR) in the nirogacestat arm (95% CI: NR, NR) and 15.1 months (95% CI: 8.4, NR) in the placebo arm (hazard ratio [HR] 0.29 [95% CI: 0.15, 0.55]; p-value=<0.001). An exploratory analysis of PFS based on only radiographic progression demonstrated a hazard ratio of 0.31 (95% CI: 0.16, 0.62).

Objective response rate (ORR) was an additional efficacy outcome measure. ORR was 41% (95% CI: 29.8, 53.8) in the nirogacestat arm and 8% (95% CI: 3.1, 17.3) for those receiving placebo (p-value=<0.001). Additionally, efficacy results were supported by change from baseline in patient-reported worst pain favouring the nirogacestat arm.

The most common adverse reactions were diarrhoea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea.

The recommended nirogacestat dose is 150 mg administered orally twice daily with or without food until disease progression or unacceptable toxicity. Each 150 mg dose consists of three 50 mg tablets.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, breakthrough designation, fast track designation, and orphan drug designation. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Full prescribing information for nirogacestat will be posted here.

Source: FDA