On November 1, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported the presentation of additional data from the Phase 3 DeFi trial at the 2023 Connective Tissue Oncology Society (CTOS) Annual Meeting, being held November 1-4, 2023 (Press release, SpringWorks Therapeutics, NOV 1, 2023, View Source [SID1234636658]). These data demonstrate the impact of nirogacestat, an investigational gamma secretase inhibitor, on physical and role functioning in adults with desmoid tumors. Data from the DeFi trial demonstrated statistically significant and clinically meaningful improvements across all primary and key secondary endpoints and were previously presented at leading medical congresses and published in the March 9, 2023 edition of the New England Journal of Medicine.1-3
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"Desmoid tumors are locally aggressive and invasive soft tissue tumors that can cause severe pain and functional impairment. These impairments can be physical, such as difficulty walking or carrying out daily tasks, or role-related, such as difficulty caring for children or working, and they severely impact the day-to-day lives of patients," said Jim Cassidy, M.D., Ph.D., Chief Medical Officer of SpringWorks. "We are pleased that the robust data from our Phase 3 DeFi trial demonstrated that nirogacestat provided clinically meaningful improvements in key patient-reported outcomes, including pain as well as both physical and role functioning. We look forward to the opportunity to bring this important new medicine to the desmoid tumor community following anticipated U.S. regulatory approval."
Poster Presentation at the 2023 CTOS Meeting
Impact of Nirogacestat on Functional Status in Patients with Desmoid Tumors: Results from the Phase 3 DeFi Study
Abstract #: 1571083
Poster #: P 188
Poster Session Date and Time: Thursday, November 2, 5:30-6:30 p.m. CEST
As previously reported in the DeFi trial (NCT03785964), nirogacestat met its primary endpoint of significantly improving progression-free survival compared to placebo in adult patients with progressing desmoid tumors (hazard ratio: 0.29 [95% CI, 0.15–0.55]; P<0.001). Nirogacestat also achieved a significant and clinically meaningful improvement in physical and role functioning status, a key secondary endpoint, compared with placebo at Cycle 10 (p<0.001). The most frequently reported treatment-emergent adverse events that occurred in participants receiving nirogacestat were diarrhea (84%), ovarian dysfunction (75% of women of childbearing potential), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%).
During the DeFi study, the impact of nirogacestat on functional status was evaluated. Changes from baseline in physical and role functioning were compared between nirogacestat and placebo at Cycle 10, the prespecified time point for key secondary endpoints. Statistically significant and clinically meaningful improvements in physical and role functioning were observed with nirogacestat compared with placebo at Cycle 10 across all three assessment tools used: the GOunder/Desmoid Tumor Research Foundation DEsmoid Impact Scale (GODDESS DTIS) Physical Functioning (PF) subscale, the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) PF and Role Functioning (RF) subscales, and the Patient-Reported Outcomes Measurement Information System Physical Function Short Form 10a (PROMIS PF10a) tool. Improvements in functional status were rapid, becoming evident as early as Cycle 2 (the first post-treatment time point evaluated) and these improvements were maintained through Cycle 24 across multiple tools measuring physical and role functioning.
The following results are being presented at CTOS:
Nirogacestat significantly improved mean physical functioning score from baseline per the GODDESS DTIS PF domain compared with placebo at the pre-specified time point. The GODDESS DTIS PF domain captures varying degrees of vigorous and moderate daily activity, including moving and reaching.
Nirogacestat significantly improved mean physical functioning score from baseline per the EORTC QLQ-C30 PF subscale compared with placebo at the pre-specified time point. The EORTC QLQ-C30 PF subscale captures the concepts of strenuous activities, taking a long walk, taking a short walk, need to stay in a bed or chair, and help with eating, dressing, washing, and using the toilet.
Nirogacestat significantly improved mean role functioning score from baseline per the EORTC QLQ-C30 RF subscale compared with placebo at the pre-specified time point. The EORTC QLQ-C30 RF subscale captures the concepts of work or other daily activities and hobbies or leisure activities.
At Cycle 10, patients receiving nirogacestat were five times more likely to have a clinically meaningful improvement in physical functioning (GODDESS DTIS Physical Functioning and EORTC QLQ-C30 Physical Functioning), and twice as likely to have a clinically meaningful improvement in role functioning (EORTC QLQ-C30 Role Functioning) than those receiving placebo. By Cycle 4, the mean PROMIS PF10a score in the nirogacestat arm reached the average physical function observed in the general U.S. population whereas the score of the placebo arm did not.
"Treatment goals for patients with desmoid tumors often focus on tumor growth endpoints, such as progression-free survival, but reducing pain and improving functioning are also very important since these have a significant impact on patients’ quality of life," said Bernd Kasper, M.D., Ph.D., University of Heidelberg, Mannheim Cancer Center, Mannheim, Germany and Principal Investigator of the DeFi trial. "It is very encouraging that patients experienced meaningful improvements in their functional status while on nirogacestat and that these improvements were sustained over the course of the study."
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 screening. The primary endpoint was progression-free survival, as assessed by blinded independent central review, or death by any cause. 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, potentially morbid tumors of the soft tissues.4,5 While they do not metastasize, desmoid tumors are associated with a high rate of recurrence.4-6 Sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis, these soft tissue tumors can be serious, debilitating, and in rare cases when vital organs are impacted, they can be life-threatening.5,8
Desmoid tumors are most commonly diagnosed in patients between the ages of 20 to 44 years, with a two-to-three times higher prevalence in females.7-10 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.10-12
Historically, desmoid tumors were treated with surgical resection, but this approach has become less favored due to a high recurrence rate after surgery.4,7,13 There are currently no FDA-approved therapies for the treatment of desmoid tumors.
About Nirogacestat
Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors. SpringWorks is also evaluating nirogacestat as a potential treatment for patients with ovarian granulosa cell tumors and for patients with multiple myeloma as part of several B-cell maturation agent (BCMA) combination therapy regimens in collaboration with leaders in industry and academia. Nirogacestat is an investigational drug for which safety and efficacy have not been established.
The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for nirogacestat for the treatment of adults with desmoid tumors, which is being reviewed under the FDA’s Real-Time Oncology Review program. The NDA has been given a Prescription Drug User Fee Act (PDUFA) action date of November 27, 2023. The FDA also 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. In addition, nirogacestat has received Orphan Drug Designation from the FDA for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma.