Dr Kasper on the FDA Approval of Nirogacestat in Desmoid Tumors

Bernd Kasper, MD, PhD, chair, Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, University of Heidelberg, discusses the significance of the FDA approval of nirogacestat (Ogsiveo) for patients with desmoid tumors.

 for the treatment of adult patients with progressing desmoid tumors who require systemic treatment. This approval was supported by findings from the phase 3 DeFi trial (NCT03785964), in which nirogacestat elicited an estimated 2-year progression-free survival (PFS) rate of 76% vs 44% with placebo in patients with desmoid tumors who were not amenable to surgery. The median PFS was not reached (NR; 95% CI, NR-NR) in the nirogacestat arm and was 15.1 months (95% CI, 8.4-NR) in the placebo arm. The hazard ratio for progression or death was 0.29 (95% CI, 0.15-0.55; 

 < .001). At a median follow-up of 15.9 months, 49 events of disease progression or death occurred. Of these,12 occurred in the nirogacestat arm and 37 were observed in the placebo arm. These PFS results were generally consistent across prespecified subgroups, including tumor location, sex, focality, previous treatments, genetic mutation status, and history of familial adenomatous polyposis.

The overall response rate was 41% (95% CI, 29.8%-53.8%) with nirogacestat vs 8% (95% CI, 3.1%-17.3%) with placebo (

 < .001), with respective median times to response of 5.6 months and 11.1 months. Seven percent of patients in the nirogacestat arm achieved a complete response compared with 0% of patients in the placebo arm.

Secondary patient-reported outcomes, including symptom burden, pain, physical or role functioning, and health-related quality of life, favored the nirogacestat arm (

 ≤ 0.01). Common adverse effects (AEs) associated with nirogacestat included diarrhea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%). Ninety-five percent of the AEs observed in the nirogacestat arm were grade 1/2.

Prior to this regulatory decision, no drugs were approved for patients with desmoid tumors, Kasper says. Nirogacestat is the first agent to be approved for the treatment of patients with desmoid tumors who require systemic therapy, and will thus become the standard of care, Kasper concludes.

Videos

Bernd Kasper, MD, PhD, discusses the significance of the FDA approval of nirogacestat for patients with desmoid tumors.

Bernd Kasper, MD, PhD, professor, Mannheim University Medical Center, discusses the effect of nirogacestat on tumor volume and T2 hyperintensity in patients with desmoid tumors.

Patients with desmoid tumors are known to experience substantial disease-related pain symptoms that greatly decrease their quality of life, Kasper begins. The phase 3 DeFi trial (NCT03785964) assessed the ability of the novel gamma secretase inhibitor nirogacestat to improve survival outcomes and reduce aspects of disease-related pain for patients with progressing desmoid tumors when compared with placebo, Kasper states.

Initial findings from the DeFi trial were reported 

, and showed that patients with progressing desmoid tumors experienced a statistically significant progression-free survival (PFS) increase with nirogacestat (n = 70) vs placebo (n = 72; HR, 0.29; 95% CI, 0.15–0.55; 

the FDA granted priority review status to a new drug application (NDA) for nirogacestat

The impact of nirogacestat on MRI tumor volume and T2 hypersensitivity in patients enrolled in the DeFi study was reported at the 2023 ASCO Annual Meeting, Kasper continues. Changes in MRI tumor volume or T2 signal intensity were hypothesized to have prognostic or predictive value for responses in this space. This is the largest dataset to prospectively evaluate these metrics in desmoid tumors, Kasper notes.

Imaging-based results showed that nirogacestat significantly reduced tumor volume and T2 hypersensitivity vs placebo, he reports. Patients in the nirogacestat arm and placebo arm had similar ratios of T2 hyperintensity, which were 95% and 97% respectively. However, this ratio changed from greater than 90% at baseline to less than 90% at any time after baseline in 34% of patients in the nirogacestat arm and 15% of those in the placebo arm.

These exploratory findings are consistent with improvements in overall response rate seen with nirogacestat and indicate that these measures can help guide the evaluation of treatment responses for patients with desmoid tumors.

Dr. Kaspar reports serving as a consultant or in an advisory role for Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehringer Ingelheim, GlaxoSmithKline, and SpringWorks Therapeutics; he received honoraria from Bayer, GlaxoSmithKline, and Pharmamar-zeltia

Bernd Kasper, MD, PhD, professor, Universitätsmedizin Mannheim, Mannheim, discusses the effect of nirogacestat on tumor volume and T2 hyperintensity in patients with desmoid tumors.

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Dr Kasper on the Evaluation of Nirogacestat in Desmoid Tumors in the DeFi Trial

Bernd Kasper, MD, PhD, professor, Universitätsmedizin Mannheim, discusses future treatment approaches in the field of sarcoma and the potential role of imatinib (Gleevac).

There are interesting data looking at Notch inhibition with a gamma secretase inhibitor in a small, phase II study of 17 patients, which demonstrated an overall response rate of 29%. Hopefully, this will lead to a larger study, Kasper adds, that could show that this could be an effective treatment option for patients.

Moreover, tyrosine kinase inhibitors, such as imatinib could also hold promise in patients with desmoid tumors, specifically in those who have progressive disease. However, this needs to be built into a strategy and used appropriately on an individualized basis, Kasper explains.

Bernd Kasper, MD, PhD, professor, Universitätsmedizin Mannheim, Mannheim, discusses future treatment approaches in the field of sarcoma and the potential role of imatinib (Gleevac).

Dr. Kasper on Future Treatment Approaches in Sarcoma

Bernd Kasper, MD, PhD, professor, Universitätsmedizin Mannheim, Mannheim, discusses imatinib (Gleevac) versus sorafenib (Nexavar) as treatments for patients with sarcoma.

There are 4 studies which used imatinib, explains Kasper. The most positive results from those studies demonstrate a treatment duration of 2 years and an overall response rate of 90%.

There is a retrospective study with sorafenib (Nexavar), which determined an overall response rate of 80% but demonstrated more toxicities than imatinib for patients being treated with sarcoma.

Bernd Kasper, MD, PhD, professor, Universitätsmedizin Mannheim, Mannheim, discusses imatinib (Gleevac) versus sorafenib (Nexavar) as treatments for patients with sarcoma. 


Dr. Kasper on Imatinib Versus Sorafenib in Sarcoma

Bernd Kasper, MD, PhD, professor, Universitätsmedizin Mannheim, Mannheim, discusses results of a phase II study exploring the efficacy of imatinib (Gleevac) in patients with resistant progressive desmoid tumors.

The German Interdisciplinary Sarcoma Group explored imatinib in patients with desmoid tumors. Overall, results showed that imatinib had sustained activity over a treatment period of 2 years. This is the longest treatment period published thus far for this group of patients, Kasper explains.

Prior results showed that 65% of patients had stable disease at 6 months, he adds. Additionally, one of the key inclusion criteria to enroll on the trial was that patients must have had progressive disease, which underlines these meaningful results, Kasper said.

Bernd Kasper, MD, PhD, professor, Universitätsmedizin Mannheim, Mannheim, discusses results of a phase II study exploring the efficacy of imatinib (Gleevac) in patients with racist progressive demoed tumors.

Bernd Kasper, MD, PhD

Articles

Dr Kasper on the FDA Approval of Nirogacestat in Desmoid Tumors

Dr Kasper on the Evaluation of Nirogacestat in Desmoid Tumors in the DeFi Trial

Dr. Kasper on Future Treatment Approaches in Sarcoma

Dr. Kasper on Imatinib Versus Sorafenib in Sarcoma

Dr. Kasper on Imatinib in Resistant Progressive Desmoid Tumors