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Nirogacestat was found to significantly improve progression-free survival over placebo when used in the treatment of adult patients with progressing desmoid tumors, meeting the primary end point of the phase 3 DeFi trial.
Nirogacestat (PF-03084014), was found to significantly improve progression-free survival (PFS) over placebo when used in the treatment of adult patients with progressing desmoid tumors, meeting the primary end point of the phase 3 DeFi trial (NCT03785964).1
The agent reduced the risk of disease progression or death by 71% in this patient population (HR, 0.29; 95% CI, 0.15-0.55; P < .001). Nirogacestat was also found to significantly improve objective response rate (ORR) and patient-reported outcomes (PROs), meeting all key secondary end points of the trial.
Moreover, nirogacestat had an acceptable toxicity profile and proved to be generally well tolerated, although most women of childbearing potential experienced toxicities that were consistent with ovarian dysfunction.
“Desmoid tumors are aggressive soft tissue tumors that can lead to severe negative outcomes for patients, including long-lasting pain, disfigurement, and amputation. In rare cases, when vital organs are impacted, desmoid tumors can also be life threatening,” Saqib Islam, chief executive officer of SpringWorks Therapeutics Inc., stated in a press release. “Today’s announcement represents a significant milestone toward our goal of bringing the first approved therapy to the desmoid tumor community.”
Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor. Gamma secretase is a protease complex that cleaves Notch and other transmembrane proteins. When Notch is dysregulated, it can activate pathways that are known to contribute to desmoid tumor growth.2 The agent is being explored as a monotherapy in those with progressing desmoid tumors, and as part of novel BCMA combination regimens for patients with multiple myeloma.
In September 2019, nirogacestat received fast track and breakthrough therapy designations from the FDA for use in adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatoisis.3 The agent has also received an orphan designation from the FDA for use in those with desmoid tumors, and from the European Commission for use in those with soft tissue sarcoma.
These designations are supported by data from a phase 1 trial (NCT00878189), which demonstrated the initial clinical activity of the agent in desmoid tumors.4-6
At the time of publication, the median PFS had not yet been reached with the agent because of a lack of tumor progression events. The disease control rate was 100%, and the ORR was 71.4% among 7 evaluable patients with desmoid tumors. Moreover, the median duration of treatment was 49.5 months at the time of publication, and none of the 7 patients discontinued treatment due to toxicities.
The designation was also supported by findings from a phase 2 trial (NCT01981551), in which 17 patients with desmoid tumors were given oral nirogacestat at a twice-daily dose of 150 mg in 3-week treatment cycles.7 All patients had progressing tumors at the time of enrollment, and they had received a median of 4 prior lines (range, 1-9) of systemic therapy.4 Sixteen of the 17 patients were determined to be evaluable for response, and 29% experienced a confirmed partial response with the agent.7
Again, the median PFS had not yet been reached at the time of the publication data because of a lack of tumor progression events.4 Nirogacestat elicited an ORR of 29.4%, with no progressive disease observed. Moreover, 59% of patients were still receiving treatment for longer than 2 years; 71% stayed on the agent for over 1 year. The median duration of treatment was greater than 25 months at the time of publication, and the agent was determined to be well tolerated.
Based on these early data, investigators launched the double-blind, placebo-controlled, phase 3 DeFi trial, which enrolled adult patients with progressing desmoid tumors. To participate, patients needed to have experienced tumor progression by at least 20% per RECIST v1.1 criteria within 12 months before their first dose of study treatment.
A total of 142 patients were randomized 1:1 to receive nirogacestat at a twice-daily dose of 150 mg or matching placebo. Treatment continued until disease progression. Those on the placebo arm were able to cross to open-label nirogacestat, given at a twice-daily dose of 150 mg, upon disease progression. All patients were entered into follow-up following progression.
The primary end point was PFS per blinded independent central review, and key secondary end points were ORR and changes in PROs. Other end points of interest included safety and tolerability, duration of response, and changes in tumor volume per magnetic resonance imaging assessment.
The trial was initiated in May 2019, and fully enrolled in July 2020. Additional findings from the trial will be shared at an upcoming medical meeting in the second half of 2022, according to a press release issued by SpringWorks Therapeutics, Inc., the drug developer.
The clinical-stage biopharmaceutical company also announced plans to submit a new drug application to the FDA for the agent in this indication in the second half of 2022.