On November 27, 2023, the FDA approved nirogacestat (Ogsiveo; SpringWorks Therapeutics) for adults with progressing desmoid tumors who require systemic treatment. Desmoid tumors (also known as aggressive fibromatosis or desmoid fibromatosis) are rare, locally invasive, noncancerous soft-tissue tumors that cause pain and disability, and in rare cases when vital structures are impacted, may be life-threatening. The FDA granted this application priority review and breakthrough therapy, fast track, and orphan drug designations.
Nirogacestat, an oral, selective, small-molecule gamma secretase inhibitor, is the first approved treatment for desmoid tumors.
The approval was based on the results of the phase 3 DeFi (NCT03785964) clinical trial, an international, multicenter, randomized, double-blind, placebo-controlled study in 142 patients with progressing desmoid tumors that are not amenable to surgery. Patients with a desmoid tumor that had progressed within 12 months of screening were eligible for inclusion in the study. Patients were randomized 1:1 to 150-mg nirogacestat or placebo orally twice daily until disease progression or unacceptable adverse events.
The primary end point was progression-free survival (PFS). The secondary end point was objective response rate (ORR). Nirogacestat met the primary end point, demonstrating a significant improvement versus placebo, with a 71% reduction in the risk for disease progression (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.15-0.55; P<.001). The median PFS was not reached in the nirogacestat arm and was 15.1 months in the placebo arm. An exploratory analysis of PFS based solely on radiographic progression showed an HR of 0.31 (95% CI, 0.16-0.62).
The ORR was significantly higher with nirogacestat compared with placebo (41% vs 8%, respectively; P<.001), with median times to response of 5.6 months and 11.1 months, respectively. Nirogacestat also demonstrated PFS and ORR benefits regardless of baseline characteristics, including sex, tumor location, treatment status, previous treatments, and a history of familial adenomatous polyposis. In addition, nirogacestat showed early and sustained improvements in patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life.
The most common (≥15%) adverse events with nirogacestat were diarrhea, ovarian adverse events, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection, and dyspnea. Serious adverse events occurring in ≥2% of patients included ovarian adverse events (4%). The most common (≥15%) laboratory abnormalities were decreased phosphate and potassium, and increased urine glucose, urine protein, aspartate aminotransferase, and alanine aminotransferase.
“Desmoid tumors can have a significant impact on people’s lives and are difficult to manage due to their invasive nature and high rates of recurrence. Ogsiveo is a highly innovative therapy with efficacy data demonstrating both meaningful antitumor activity and a significant improvement in desmoid tumor symptoms,” said Mrinal M. Gounder, MD, Sarcoma Medical Oncologist at Memorial Sloan Kettering Cancer Center, New York, and an investigator in the DeFi trial, in a press release. “As a treating physician, it was encouraging to see in the DeFi trial that Ogsiveo achieved statistically significant and clinically meaningful improvements across the primary and all key secondary end points, while also having a manageable safety profile. This approval represents an important therapeutic advance for patients,” he added.
The recommended dose of nirogacestat is 150 mg orally twice daily with or without food until disease progression or unacceptable adverse events. Each 150-mg dose consists of three 50-mg tablets.