On September 10, 2022 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biogress 2022 (Press release, SpringWorks Thpharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported that data from the Phase 3 DeFi trial of nirogacestat, an investigational oral gamma secretase inhibitor, in adult patients with progressing desmoid tumors, as a late-breaking oral presentation during a Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Conerapeutics, SEP 10, 2022, View Source [SID1234619351]).

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"Desmoid tumors can have a debilitating impact on patients’ lives and there is an urgent need for a new standard-of-care treatment," said Saqib Islam, Chief Executive Officer of SpringWorks. "DeFi is the largest and most robust Phase 3 trial conducted to date in patients with desmoid tumors and we believe these positive data bring us a step closer toward potentially introducing the first approved therapy for this underserved community. We look forward to completing our full NDA filing package by the end of the year, which will be submitted for review under FDA’s RTOR program."

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 (April 7, 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.

"The DeFi study enrolled patients with progressing desmoid tumors at baseline and included a high proportion of patients with multifocal disease and uncontrolled pain, representing a very difficult-to-treat patient population," said Bernd Kasper, M.D., Ph.D., University of Heidelberg, Mannheim Cancer Center, Mannheim, Germany and Principal Investigator of the DeFi trial. "The consistently positive data generated across progression-free survival, objective response rate, and patient-reported outcomes, coupled with a safety profile that is suitable for long-term dosing, support the potential for nirogacestat to become an important and much needed treatment for patients with desmoid tumors."

ESMO Oral Presentation Details

Title: DeFi: A Phase 3, Randomized Controlled Trial of Nirogacestat Versus Placebo for Progressing Desmoid Tumors (DT)
Presentation Number: LBA2
Presenter: Bernd Kasper, M.D., Ph.D., University of Heidelberg, Mannheim Cancer Center, Mannheim, Germany
Session/Type: Presidential Symposium 1, Proffered Paper Session
Date: Saturday, September 10, 2022
Time: 4:55-5:10 p.m. CEST (10:55-11:10 a.m. ET)

Investor Event Details

Presenters: SpringWorks’ management team will be joined by Bernd Kasper, M.D., Ph.D., University of Heidelberg, Mannheim Cancer Center, Mannheim, Germany and Principal Investigator of the DeFi trial.
Date: Sunday, September 11, 2022
Time: 4:00 p.m. CEST (10:00 a.m. ET)
Instructions: To join the live webcast and view corresponding slides, please visit the Events & Presentations page within the Investors & Media section of the Company’s website at View Source To join via audio teleconference, please register here. Once registration is complete, participants will be provided with a dial-in number and conference code to access the call. A replay will be available on the Company’s website for a limited time following the event.

About the DeFi Trial

DeFi (NCT03785964) is 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 the first dose of study treatment. The primary endpoint is progression-free survival, as assessed by blinded independent central review. Secondary and exploratory endpoints include 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.

About Desmoid Tumors

Desmoid tumors are rare, aggressive, locally invasive, and potentially morbid tumors of the soft tissues.1,2 While they do not metastasize, desmoid tumors are associated with a high rate of recurrence.2,3,4 Sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis, these soft tissue tumors can be serious, debilitating, and, in rare cases when vital structures are impacted, they can be life-threatening.2,5

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.4,6,7,8 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.7,8,9

Historically, desmoid tumors were treated with surgical resection, but this approach has become less favored due to a high recurrence rate after surgery.1,4,10 There are currently no FDA-approved therapies for the treatment of desmoid tumors.

About Nirogacestat

Nirogacestat is an investigational, oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth.

In addition, gamma secretase has 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. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has eight collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies, three bispecific antibodies and a monoclonal antibody. SpringWorks 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. SpringWorks plans to submit a New Drug Application (NDA) to the FDA in the second half of 2022, which will be submitted for review under the FDA’s Real-Time Oncology Review (RTOR) program.