Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.