The U.S. Food and Drug Administration (FDA) has accepted SpringWorks Therapeutics’ New Drug Application (NDA) for nirogacestat*, also known as PF-03084014, an investigational tetralin imidazole γ- (gamma-) secretase inhibitor (a proteolytic enzyme complex mediating processing of several integral membrane proteins including amyloid precursor protein and Notch), for the treatment of adults with desmoid tumors, a rare mesenchymal neoplasm.
Desmoid tumors are rare, aggressive, locally invasive, and potentially morbid tumors of the soft/connective tissues or fibroblasts. While they do not metastasize, and are generally slow growing, desmoid tumors are associated with a high rate of recurrence. Sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis, these soft or connective tissue tumors can be serious, debilitating, and, in rare cases when vital structures are impacted, they can be life-threatening, leading to severe morbidity and loss of function. 
Desmoid tumors are most commonly diagnosed in patients between the ages of 20 and 44 years, with a two-to-three times higher prevalence in females. It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.
Current treatment approach
Historically, desmoid tumors were treated with surgical resection, but this approach has become less favored due to a high recurrence rate after surgery. There are currently no FDA-approved therapies for the treatment of desmoid tumors.
However, as part of the evolution of therapy away from primary surgical approaches to less invasive options, image-guided ablation has been accepted as less morbid and include cryoablation and high-intensity focused ultrasound. In addition, systemic therapy options currently include hormonal agents, nonsteroidal anti-inflammatory drugs, tyrosine kinase inhibitors, and anthracycline-based regimens. The goals of systemic therapy is toonly to promote tumor shrinkage, leading to, for example, subsequent resection, and to induce growth arrest and tumor stabilization.
Among these approaches, hormonal agents and nonsteroidal anti-inflammatory drugs have a benign side effect profile but also a limited efficacy. In contrast, anthracycline-based therapies are limited by the risk of secondary malignancies as well as cardiomyopathy.
Tyrosine kinase inhibitors, including sorafenib (Nexavar®; Bayer), imatinib (Gleevec®; Novartis) and pazopanib (Votrient®; Novartis) are well studied, and utilized therapies, however, they are limited by their side effect profiles.
And as a result of disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors, there is a major unmet medical need, highlighting the need to develop effective systemic treatments for this disease.
The NDA was granted Priority Review and has been given a Prescription Drug User Fee Act (PDUFA) action date of August 27, 2023. The FDA’s Priority Review designation is given to investigational medicines that treat a serious condition and offer significant improvements in safety or effectiveness. In addition, the FDA has stated that it is not currently planning to hold an advisory committee meeting to discuss the application.
“People with desmoid tumors can experience severe pain and other debilitating morbidities, and we are excited by the opportunity to potentially transform the standard of care for these patients,” said Saqib Islam, Chief Executive Officer of SpringWorks.
“The acceptance of our NDA for nirogacestat with Priority Review represents a significant milestone in our ambition to provide the first approved therapy for patients with desmoid tumors. We look forward to working closely with the FDA during the review process and remain focused on ensuring that we are well-positioned to expeditiously serve the desmoid tumor patient and the physician communities following approval.”
The investigational drug, an oral, selective, small molecule gamma secretase inhibitor, is in Phase 3 clinical development for the treatment of desmoid tumors and in Phase 2 clinical development for ovarian granulosa cell tumors. In these studies, the safety and efficacy of the treatment have not been established.
The Notch pathway is an important developmental signaling pathway, which is aberrantly activated in tumor angiogenesis. Activation of Notch receptors is mediated through gamma secretase, a target amenable to inhibition with small molecules.
Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to growth of desmoid and ovarian granulosa cell tumors.
Gamma secretase has also been shown to directly cleave membrane-bound B cell maturation antigen (BCMA), resulting in the release of the BCMA extracellular domain (ECD) from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies.
Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. Researchers at SpringWorks is evaluating nirogacestat as a BCMA potentiator and has several collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities.
The company has also formed research collaborations with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA-directed therapies using a variety of preclinical multiple myeloma models.
Nirogacestat has received Orphan Drug designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.
Nirogacestat is investigated in the DeFi (NCT03785964) study, a global, randomized (1:1), double-blind, placebo-controlled Phase 3 trial evaluating the efficacy, safety and tolerability of nirogacestat in adult patients with progressing desmoid tumors. The double-blind phase of the study randomized 142 patients (nirogacestat, n=70; placebo n=72) to receive 150 mg of nirogacestat or placebo twice daily.
Key eligibility criteria included tumor progression by ≥20% as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) within 12 months prior to screening. The primary endpoint was progression-free survival, as assessed by blinded independent central review, or death by any cause. Secondary and exploratory endpoints included safety and tolerability measures, objective response rate (ORR), duration of response, changes in tumor volume assessed by magnetic resonance imaging (MRI), and changes in patient-reported outcomes (PROs). DeFi includes an open-label extension phase, which is ongoing.
Data from the DeFi study were presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2022.
The DeFi trial met its primary endpoint of improving progression-free survival (PFS), as assessed by blinded independent central review, demonstrating a statistically significant improvement for nirogacestat over placebo, with a 71% reduction in the risk of disease progression (hazard ratio (HR) = 0.29 (95% CI: 0.15, 0.55); p< 0.001). The median Kaplan-Meier estimate of PFS was not reached in the nirogacestat arm and was 15.1 months in the placebo arm. A PFS benefit was observed across all prespecified subgroups, including gender, tumor location, prior treatment or surgery, and mutational status. Confirmed objective response rate (complete response + partial response) based on RECIST v1.1 was 41% with nirogacestat versus 8% with placebo (p<0.001).
The complete response rate was 7% in the nirogacestat arm and 0% in the placebo arm. Nirogacestat demonstrated statistically significant and clinically meaningful improvements in patient-reported outcomes (PRO), which were key secondary endpoints of the study. Specifically, nirogacestat significantly reduced pain (p<0.001) and other DT-specific symptoms (p<0.001) and also significantly improved physical/role functioning (p<0.001) and overall health-related quality of life (p=0.007). Most PRO benefits were observed as early as Cycle 2, which was the first timepoint for post-treatment evaluation, and were sustained over the duration of the study.
At the time of primary analysis in April 2022), the median duration of treatment was 20.6 months for participants on nirogacestat and 11.4 months for those on placebo, with the majority of nirogacestat patients continuing on treatment. Nirogacestat exhibited a manageable safety profile in the DeFi trial, with 95% of all treatment-emergent adverse events (TEAEs) reported as Grade 1 or 2.
The most frequently reported TEAEs in participants receiving nirogacestat as compared to the placebo arm were diarrhea (84% vs 35%), nausea (54% vs 39%), and fatigue (51% vs 36%). Forty-two percent of patients in the nirogacestat arm vs 0% in the placebo arm required dose reductions due to TEAEs and 20% of patients in the nirogacestat arm vs 1% in the placebo arm discontinued treatment due to TEAEs. Ovarian dysfunction, which was defined by investigator-reported events of amenorrhea, premature menopause, menopause, and ovarian failure, was observed in 75% (27/36) of women of childbearing potential receiving nirogacestat. These events resolved in 74% (20/27) of the affected participants, including 64% (9/14) of such participants who remained on nirogacestat treatment and 100% (11/11) of those participants who discontinued treatment for any reason.
Real-Time Oncology Review
The NDA is being reviewed under the FDA’s Real-Time Oncology Review (RTOR) program and is based on the previously announced positive results from the Phase 3 DeFi trial.  The FDA granted Fast Track and Breakthrough Therapy designations to nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. Nirogacestat has also received Orphan Drug designation from the FDA for the treatment of desmoid tumors.
Note: * In 2017 Pfizer licensed nirogacestat*, also known as PF-03084014, to Pfizer-spinoff SpringWorks.
Nirogacestat for Adults With Desmoid Tumor/Aggressive Fibromatosis (DT/AF) (DeFi) – NCT03785964
Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis – NCT01981551
Highlights of prescribing information
Sorafenib (Nexavar®; Bayer)[Prescribing Information]
Imatinib (Gleevec®; Novartis)[Prescribing Information]
Pazopanib (Votrient®; Novartis)[Prescribing Information]
 Kasper B, Baumgarten C, Garcia J, et al; Desmoid Working Group. An update on the management of sporadic desmoid-type fibromatosis: a European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG). Ann Oncol. 2017;28(10):2399-2408. doi: 10.1093/annonc/mdx323.
 Penel N, Chibon F, Salas S. Adult desmoid tumors: biology, management and ongoing trials. Curr Opin Oncol. 2017;29(4):268-274. doi: 10.1097/CCO.0000000000000374.
 Xie Y, Xie K, Gou Q, He J, Zhong L, Wang Y. Recurrent desmoid tumor of the mediastinum: a case report. Oncol Lett. 2014;8(5):2276-2278. doi: 10.3892/ol.2014.2431.
 Skubitz KM. Biology and treatment of aggressive fibromatosis or desmoid tumor. Mayo Clin Proc. 2017;92(6):947-964. doi: 10.1016/j.mayocp.2017.02.012.
 Joglekar SB, Rose PS, Sim F, Okuno S, Petersen I. Current perspectives on desmoid tumors: the Mayo Clinic approach. Cancers (Basel). 2011;3(3):3143-3155. doi: 10.3390/cancers3033143.
 Penel N, Coindre JM, Bonvalot S, et al. Management of desmoid tumours: a nationwide survey of labelled reference centre networks in France. Eur J Cancer. 2016;58:90-96. doi: 10.1016/j.ejca.2016.02.008.
 van Broekhoven DLM, Grünhagen DJ, den Bakker MA, van Dalen T, Verhoef C. Time trends in the incidence and treatment of extra-abdominal and abdominal aggressive fibromatosis: a population-based study. Ann Surg Oncol. 2015;22(9):2817-2823. doi: 10.1245/s10434-015-4632-y.
 Anneberg M, Svane H, Fryzek J, et al. The Epidemiology of Desmoid Tumors in Denmark. Cancer Epidemiol. 2022; 77:1-7. doi.org/10.1016/j.canep.2022.102114.
 Orphanet Report Series: Rare Diseases collection. Prevalence and incidence of rare diseases: bibliographic data. Number 1, January 2022. Last accessed on February 26, 2023. [Report]
 The Desmoid Tumor Working Group. The management of desmoid tumors: a joint global evidence-based consensus guideline approach for adult and pediatric patients. Accessed April 10, 2022.[Report]
 Zhou MY, Bui NQ, Charville GW, Ghanouni P, Ganjoo KN. Current management and recent progress in desmoid tumors. Cancer Treat Res Commun. 2022;31:100562. doi: 10.1016/j.ctarc.2022.100562. Epub 2022 Apr 16. PMID: 35460976.
 Kasper B, Ratan R, Alcindor T Schoeffski P, Van Der Graaf WTA, Wilky BA, Riedel RF, et al. DeFi: A phase III, randomized controlled trial of nirogacestat versus placebo for progressing desmoid tumors (DT).LBA2. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089 [Article]
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