– Long-term follow-up data highlight further reductions in tumor size, increase in ORR with additional CRs, sustained improvement in desmoid tumor symptoms, and consistent safety profile, now with a median duration of therapy of approximately 3 years –
Nov. 07, 2024 -- SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, today announced that long-term efficacy and safety data from the Phase 3 DeFi trial of nirogacestat in adults with progressing desmoid tumors will be presented as a late-breaking oral presentation at the Connective Tissue Oncology Society (CTOS) 2024 Annual Meeting, being held November 13-16, 2024, in San Diego, CA. These results, utilizing an August 2024 data cutoff date, showed that longer-term treatment with nirogacestat was associated with further reductions in tumor size, increase in objective response rate (ORR) with additional partial responses (PRs) and complete responses (CRs), sustained improvements in desmoid tumor symptoms including pain, and a consistent safety profile compared to the April 2022 data cut utilized for the primary results of the trial.
“Our findings demonstrate that longer-term nirogacestat treatment was associated with durable tumor size reductions, evidence of deepening responses, and sustained benefits in pain, physical functioning and other desmoid tumor symptoms,” said Ravin Ratan, M.D., M.Ed., Associate Professor, Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, and DeFi study investigator presenting the data at CTOS. “Given the oftentimes persistent and debilitating nature of desmoid tumors, these results are meaningful for patients and clinicians as they provide valuable insights on the longer-term use of this medicine.”
“We are pleased that the growing body of evidence from the DeFi trial continues to support the significant benefits that OGSIVEO is providing for patients with desmoid tumors,” said Jim Cassidy, M.D., Ph.D., Chief Medical Officer of SpringWorks Therapeutics. “It is also gratifying that feedback from the real-world setting is consistent with our clinical trial experience, with patients reporting rapid, sustained and continued symptomatic relief, which is contributing to their overall improved quality of life.”
Additional DeFi data to be presented at CTOS include an oral presentation of a post-hoc analysis assessing the effect of nirogacestat in subgroups of patients with desmoid tumors who have risk factors associated with poor prognosis and a poster on patients with CTNNB1 and APC mutations.
Oral Presentations at the CTOS 2024 Annual Meeting
Nirogacestat treatment in adult patients with desmoid tumors: Long-term efficacy and safety from the Phase 3 DeFi trial
Date and Time: November 16, 3:30-4:30 p.m. PT (6:30-7:30 p.m. ET)
As previously reported, 70 patients were randomized to nirogacestat in the double-blind (DB) portion of the Phase 3 DeFi trial (NCT03785964); these patients achieved statistically and clinically significant improvement in progression-free survival (PFS) and ORR, as well as rapid and sustained improvement in pain, physical functioning, role functioning and overall quality of life, as compared to those randomized to placebo. At the primary analysis data cut-off date (April 2022), the median (range) duration of nirogacestat treatment was 20.6 (0.3-33.6) months. Following the DB portion of the study, patients could continue to receive nirogacestat as part of the open-label extension (OLE). As of this long-term follow-up analysis (August 2024 data cut-off date), the median (range) duration of nirogacestat treatment in these patients was 33.6 (0.3 to 60) months. The data being presented at CTOS evaluated the overall efficacy and safety of continuous nirogacestat treatment in patients initially randomized to nirogacestat in DeFi and further explored safety and efficacy analyses at milestones of one, two, three, and four years on treatment.
Results demonstrated that:
Three new PRs and three new CRs were reported using the August 2024 versus the April 2022 data cut-off date, resulting in an ORR of 45.7% (34.3% PR, 11.4% CR) (N=70).
The median best percent reduction from baseline in target tumor size by RECIST 1.1 with continuous nirogacestat treatment was −32.3% at year one (n=46) and −75.8% for patients completing at least four years (n=15) of treatment.
Improvement in patient reported outcomes (PROs) of pain, desmoid tumor-specific symptom severity, and desmoid tumor-specific physical functioning, which occurred early (at Cycle 2, the first post-treatment timepoint evaluated as disclosed at the primary analysis) and were sustained with up to 45 months of treatment with nirogacestat.
The most frequently reported treatment emergent adverse events (TEAEs) that occurred in >20% of patients receiving nirogacestat over the entire treatment period were diarrhea, nausea, fatigue, hypophosphatemia, and headache, and were generally consistent between the April 2022 and August 2024 data cutoffs. Most events were Grade 1 or 2, with first onset occurring in the first year of treatment for most patients. Overall, the incidence and severity of frequently reported TEAEs decreased through years two, three and four of treatment.
Efficacy of nirogacestat in patients with poor prognostic factors for desmoid tumors: patient-reported outcomes, progression-free survival, and objective response in the phase 3 DeFi trial
Date and Time: November 16, 3:30-4:30 p.m. PT (6:30-7:30 p.m. ET)
A post hoc analysis of the DeFi trial was conducted to assess the effect of nirogacestat on PFS, ORR and PROs in subgroups of patients with desmoid tumors who have risk factors associated with a poor prognosis: larger tumor size (>10 cm), younger age (≤30 years), specific types of CTNNB1 gene mutations, and presence of pain at baseline. Results include:
Treatment with nirogacestat led to consistent improvements in PFS, ORR and PROs versus placebo regardless of the patient subgroups.
The ORR risk difference between nirogacestat and placebo ranged from 18.1% to 56.0%, favoring nirogacestat.
Compared with placebo, patients treated with nirogacestat generally reported greater improvement from baseline at cycle 10 in PROs (pain, desmoid tumor-specific symptom burden, physical and role functioning, and overall quality of life) across subgroups of patient-related and tumor-related poor prognostic factors.
The authors concluded that nirogacestat demonstrates uniform efficacy and consistent improvement in PROs across the desmoid tumor population.
Poster Presentations at the CTOS 2024 Annual Meeting
Descriptive evaluation of patients with desmoid tumor and co-occurring somatic mutations of CTNNB1 and APC in the Phase 3 DeFi trial
Date and Time: November 14, 5:45-6:45 p.m. PT (8:45-9:45 p.m. ET)
This analysis identified three patients with desmoid tumors enrolled in the DeFi trial who had co-occurring somatic mutations of CTNNB1 and APC, including two treated with nirogacestat. Both patients achieved a best overall response of partial response (with time to response of 6.0 and 13.8 months). Although the small number of patients limited a formal analysis, descriptive results suggest that patients with this mutational profile benefit from nirogacestat treatment in a manner that is generally consistent with the overall DeFi study population but may take longer to experience a treatment response.
DeFi (NCT03785964) is a global, randomized (1:1), multicenter, double-blind, placebo-controlled pivotal 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 (PFS), 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.
Desmoid tumors (sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis) are rare, aggressive, locally invasive tumors of the soft tissues that can be serious, debilitating, and, in rare cases when vital structures are impacted, life-threatening.1,2
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.3,4 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.4,5,6
Although they do not metastasize, desmoid tumors are associated with recurrence rates of up to 77% after surgical resection.3,7.8 Desmoid tumor experts and treatment guidelines now recommend systemic therapies as first-line intervention instead of surgery for most tumor locations requiring treatment.8
OGSIVEO (nirogacestat) is an oral, selective, small molecule gamma secretase inhibitor approved in the United States for the treatment of adult patients with progressing desmoid tumors who require systemic treatment.
OGSIVEO is not approved for the treatment of any other indication in the United States, or for any indication in any other jurisdiction by any other health authority.
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.
SpringWorks is a commercial-stage biopharmaceutical company applying a precision medicine approach to developing and delivering life-changing medicines for people with severe rare diseases and cancer. OGSIVEO® (nirogacestat), approved in the United States for the treatment of adult patients with progressing desmoid tumors who require systemic treatment, is the Company’s first FDA-approved therapy. SpringWorks also has a diversified targeted therapy pipeline spanning solid tumors and hematological cancers, with programs ranging from preclinical development through advanced clinical trials. In addition to its wholly owned programs, SpringWorks has also entered into multiple collaborations with innovators in industry and academia to unlock the full potential for its portfolio and create more solutions for patients in need.
References
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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.
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.
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.
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U.S. Department of Commerce. News Blog. U.S. population estimated at 332,403,650 on Jan. 1, 2022. Accessed November 5, 2024. https://www.commerce.gov/news/blog/2022/01/us-population-estimated-332403650-jan-1-2022.
Easter DW, Halasz NA. Recent trends in the management of desmoid tumors. Summary of 19 cases and review of the literature. Ann Surg. 1989;210(6):765-769. doi:10.1097/00000658-198912000-00012.
Gronchi A, Kasper B, et al. Desmoid Tumor Working Group. The management of desmoid tumours: a joint global consensus-based guideline approach for adult and paediatric patients. Eur J Cancer. 2020;127:96-107. doi:10.1016/j.ejca.2019.11.013.
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