FDA-Approved Nirogacestat Demonstrates Improved Patient Outcomes in Desmoid Tumor Management

Desmoid tumors (DTs), also referred to as aggressive fibromatosis or desmoid-type fibromatosis, are connective tissue neoplasms characterized by a propensity for local invasion and a variable clinical course.¹ These benign yet aggressive entities can affect patients of all ages, imposing significant functional and psychosocial burdens. The heterogeneity in their clinical behavior has rendered the existing therapeutic options—from surgical resection to cytotoxic chemotherapy—suboptimal, and recurrence is a common and challenging outcome.^1-3

In recent clinical trials, the gamma-secretase inhibitor nirogacestat has improved patient outcomes.^2,4 Based on these trials, the US Food and Drug Administration (FDA) approved the use of nirogacestat (Ogsiveo, SpringWorks Therapeutics Inc.) for adults with progressing DTs who require systemic treatment. Nirogacestat is the first FDA-approved treatment for patients with DTs beyond surgery and radiation options.⁵ Nirogacestat addresses pressing therapeutic gaps in DT management, potentially heralding a new era of treatment tailored to the molecular foundations of the disease.

Understanding Desmoid Tumors

DTs are rare, with reported incidence ranging from 2.10 to 5.36 cases per million person-years. Even though DTs primarily occur in patients aged 20 to 44 years, they can develop in patients of any age.^1,2 Generally, women are 2.2 to 3.9 times more likely to have DTs than men. Risk factors for development of DTs include antecedent trauma and estrogen level; women taking oral contraceptives or who have been recently pregnant (within 24 months) are at higher risk for developing DTs.^2,6

The development of DTs is intricately linked to the interplay of the canonical Wnt/β-catenin/APC and Notch signaling pathways. Mutations in the CTNNB1 and APC genes lead to an accumulation of β-catenin, resulting in dysregulation of the Wnt pathway. Concurrently, the Notch pathway, involving critical cleavages at Notch receptors by ADAM10 and gamma-secretase, is also implicated. The interaction between these pathways, particularly the activation of the Notch pathway due to dysregulation in the Wnt pathway, is a significant factor in DT development.^2,7

Clinically, DTs can occur in any part of the body and are often classified as either intra-abdominal or extra-abdominal tumors. Despite their classification as nonmalignant, DTs can have locally aggressive and infiltrative growth, affecting organs and adjacent structures and compressing blood vessels.² This leads to a considerable clinical burden that impacts the health-related quality of life of patients.^2,8 In some cases, DTs may even result in fatal outcomes when they are located around vital organs.²

The clinical challenge with DTs lies not only in their aggressive nature but also in their tendency to recur. Recurrence rates vary considerably, depending on tumor location and trauma, such as surgical interventions. For example, DTs on extremities have reported recurrence rates ranging from 24% to 77%.²

Advances in understanding these tumors and developing treatment options have been made, yet local recurrence remains a persistent issue. This necessitates ongoing research and development of new therapeutic approaches to improve the management and prognosis of patients with DTs.

Current Management of Desmoid Tumors

The management of DTs presents a complex challenge due to the lack of a universal standard of care and the heterogeneity of the disease.^3,4,9 Treatment strategies are diverse and tailored to individual patient circumstances, including tumor location, symptoms, and progression rate. Options range from conservative active surveillance for asymptomatic or stable tumors to more aggressive interventions for those that are symptomatic or rapidly growing.^3,4,9,10

Surgical resection has traditionally been a cornerstone of DT management, particularly for abdominal wall tumors, but this is now reserved for specific scenarios in which morbidity from surgery is expected to be low. This shift is partly due to reported postsurgery recurrence rates, which vary widely from 5% to 63%, with higher rates observed in recurrent DT management.³

Radiation therapy, cryoablation, and high-intensity focused ultrasound represent other localized treatment modalities, each with varying degrees of efficacy and associated risks.^2,10-13 Systemic therapies, including hormonal agents, nonsteroidal anti-inflammatory drugs, cytotoxic chemotherapy, and tyrosine kinase inhibitors, such as sorafenib, imatinib, pazopanib, and sunitinib, are employed for unresectable, symptomatic, or advanced DTs. The aggressiveness of the tumors and the urgency for treatment response guide the choice of systemic therapy, and conventional chemotherapy is preferred for a rapid response.^2,10

Despite these therapeutic options, the limitations and challenges of current therapies significantly impact patient quality of life. The potential for recurrence, side effects of systemic treatments, and the psychological burden of living with a chronic condition necessitate a multidisciplinary approach to care that emphasizes the need for personalized treatment plans and supportive care strategies.^2,9,10,14

Nirogacestat, a New Targeted Therapy for Progressing DT

Nirogacestat, an oral gamma-secretase inhibitor initially developed as a potential Alzheimer’s disease treatment, targets the Notch signaling pathway. The Notch pathway is implicated in cell differentiation and proliferation, and DTs have high expression of the Notch1 protein; by blocking this pathway, nirogacestat may inhibit DT growth and progression.⁴

Nirogacestat was evaluated in the DeFi clinical trial (NCT03785964), a double-blind, randomized, placebo-controlled trial that included a diverse cohort of 142 patients aged 18 to 76 years, spanning 37 sites across the United States, Canada, and Europe. The trial’s objective was to evaluate the safety and efficacy of nirogacestat in adults with histologically confirmed, progressing DTs.⁴

Eligibility criteria included patients with DTs that had progressed by ≥20% per RECIST version 1.1 who were either treatment-naïve for progressing DTs not suitable for surgical intervention or had experienced refractory or recurrent DTs following ≥1 line of therapy. Stratification was based on tumor location, distinguishing between intra-abdominal and extra-abdominal tumors.⁴

Patients were randomized in a 1:1 ratio to receive either 150 mg of nirogacestat or a placebo orally twice daily over 28-day cycles. The primary end point was progression-free survival (PFS), defined as the time from randomization to imaging-based or clinical progression, or death. Secondary efficacy end points included the rate of confirmed objective responses, patient-reported pain levels, and health-related quality-of-life metrics.⁴

The median PFS was not reached in the nirogacestat group due to a lower incidence of progression or death versus a median PFS of 15.1 months in the placebo cohort. The 2-year event-free probability was significantly higher with nirogacestat at 76% compared with 44% for the placebo group. Notably, the risk of disease progression or death was reduced by 71% in the nirogacestat group (hazard ratio, 0.29; 95% confidence interval, 0.15-0.55; P<.001).⁴

Objective response rates further underscored the potential of nirogacestat, with 41% of patients in the treatment group achieving a confirmed response versus 8% in the placebo group (P<.001). Complete responses were observed in 7% of the nirogacestat-treated patients, and no complete responses were reported in the placebo group.⁴ Even with long-term follow-up of patients receiving nirogacestat for more than 7 years, the objective response rate remained high, and no RECIST disease progression was observed.¹⁵

Safety data indicated that adverse events such as diarrhea, nausea, and fatigue were more common in the nirogacestat group, affecting at least 20% of patients. Serious adverse events were rare, with premature menopause reported in 3 patients. Ovarian dysfunction was noted in 75% of women of childbearing potential receiving nirogacestat, which typically resolved on treatment cessation.⁴ Nevertheless, the FDA warns that women of reproductive potential be advised of the potential risks for ovarian adverse events and embryo-fetal toxicity. Additional FDA warnings and precautions include diarrhea, hepatotoxicity, nonmelanoma skin cancers, and electrolyte abnormalities.¹⁶

The DeFi trial’s outcomes suggest that nirogacestat may offer substantial therapeutic benefits in the management of DTs, with favorable effects on disease progression and patient-reported outcomes. However, the treatment’s safety, particularly concerning reproductive health, warrants careful consideration and further study.

Conclusion

Nirogacestat addresses significant unmet needs in DT management. By targeting the Notch signaling pathway—a key factor in DT pathogenesis—this gamma-secretase inhibitor offers a targeted patient-centric therapy that may curtail tumor growth and enhance quality of life. The DeFi clinical trial’s data underscore the potential of integrating nirogacestat therapy into clinical practice. Yet, alongside its promising efficacy, the drug’s safety profile, particularly regarding reproductive health in women, demands further evaluation. Nirogacestat may provide some patients with more effective DT management while decreasing the risk of recurrence associated with invasive techniques.

As clinicians consider nirogacestat in DT management, its potential benefits must be weighed against the necessity for patient selection and disease monitoring. This balance is pivotal for the nuanced incorporation of nirogacestat, potentially bridging the gap in DT treatment between active surveillance, invasive procedures, and chemotherapy, marking a paradigm shift toward more targeted, molecularly informed interventions.

References

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