SpringWorks to Present Long-Term Efficacy and Safety Data from Phase 3 DeFi Trial of Ogsiveo

SpringWorks to present long-term efficacy and safety data from phase 3 DeFi trial of Ogsiveo in adults with desmoid tumours at CTOS 2024 meeting

Overview

SpringWorks Therapeutics, Inc., a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, announced that long-term efficacy and safety data from the phase 3 DeFi trial of nirogacestat in adults with progressing desmoid tumours 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, Califoria. 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 tumour symptoms including pain, and a consistent safety profile compared to the April 2022 data cut utilized for the primary results of the trial.

From The University of Texas

• Our findings demonstrate that longer-term nirogacestat treatment was associated with durable tumour size reductions, evidence of deepening responses, and sustained benefits in pain, physical functioning and other desmoid tumour 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 tumours, these results are meaningful for patients and clinicians as they provide valuable insights on the longer-term use of this medicine.

Words CMO: SpringWorks Therapeutics 

• •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 Data Presentation

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 tumours 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 tumours: 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).

The Process

• 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 tumour 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 tumour-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.

Reported Adverse Events

• The most frequently reported treatment emergent adverse events (TEAEs) that occurred in >20% of patients receiving nirogacestat over the entire treatment period were diarrhoea, 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

Efficacy of nirogacestat in patients with poor prognostic factors for desmoid tumours: 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).

The Post Hoc Analysis

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 tumours who have risk factors associated with a poor prognosis: larger tumour 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%, favouring nirogacestat.
•  Compared with placebo, patients treated with nirogacestat generally reported greater improvement from baseline at cycle 10 in PROs (pain, desmoid tumour-specific symptom burden, physical and role functioning, and overall quality of life) across subgroups of patient-related and tumour-related poor prognostic factors.
• The authors concluded that nirogacestat demonstrates uniform efficacy and consistent improvement in PROs across the desmoid tumour population.

Poster Presentations at the CTOS 2024 Annual Meeting:

• Descriptive evaluation of patients with desmoid tumour 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)

Analysis on Patient with Desmoid Tumours

• This analysis identified three patients with desmoid tumours 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 Phase 3 Trial

• 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 tumours. 
• 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 tumour progression by =20% as measured by Response Evaluation Criteria in Solid Tumours (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 tumour 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 Tumours

• Desmoid tumours (sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis) are rare, aggressive, locally invasive tumours of the soft tissues that can be serious, debilitating, and, in rare cases when vital structures are impacted, life-threatening.
• Desmoid tumours 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.
• Although they do not metastasize, desmoid tumours are associated with recurrence rates of up to 77% after surgical resection. 
• Desmoid tumour experts and treatment guidelines now recommend systemic therapies as first-line intervention instead of surgery for most tumour locations requiring treatment.

About Ogsiveo

• 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 tumours 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 on Nirogacestat

• SpringWorks is also evaluating nirogacestat as a potential treatment for patients with ovarian granulosa cell tumours 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.

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