SpringWorks Therapeutics announced long-term efficacy and safety data from the Phase 3 DeFi trial of OGSIVEO (nirogacestat) in adults with progressing desmoid tumors. The data, presented at the Connective Tissue Oncology Society (CTOS) 2024 Annual Meeting, highlight further reductions in tumor size, an increase in objective response rate (ORR), sustained improvements in desmoid tumor symptoms, and a consistent safety profile with a median therapy duration of approximately 3 years.
Durable Tumor Reduction and Deepening Responses
The results, utilizing an August 2024 data cutoff, demonstrated that longer-term treatment with nirogacestat was associated with durable tumor size reductions and evidence of deepening responses. Ravin Ratan, M.D., M.Ed., from The University of Texas MD Anderson Cancer Center, noted that the findings demonstrate sustained benefits in pain, physical functioning, and other desmoid tumor symptoms, providing valuable insights for patients and clinicians.
Specifically, the data showed three new partial responses (PRs) and three new complete responses (CRs) compared to the April 2022 data cutoff, resulting in an ORR of 45.7% (34.3% PR, 11.4% CR) among 70 patients. The median best percent reduction from baseline in target tumor size by RECIST 1.1 was -32.3% at year one (n=46) and -75.8% for patients completing at least four years (n=15) of treatment.
Sustained Symptomatic Relief and Improved Quality of Life
Patients reported early and sustained improvements in pain, desmoid tumor-specific symptom severity, and physical functioning, maintained for up to 45 months of treatment with nirogacestat. Jim Cassidy, M.D., Ph.D., Chief Medical Officer of SpringWorks Therapeutics, highlighted that real-world feedback aligns with clinical trial experiences, with patients reporting rapid, sustained symptomatic relief contributing to improved quality of life.
Safety Profile
The most frequently reported treatment-emergent adverse events (TEAEs) occurring in >20% of patients receiving nirogacestat over the entire treatment period included diarrhea, nausea, fatigue, hypophosphatemia, and headache. These were generally consistent between the April 2022 and August 2024 data cutoffs, with most events being Grade 1 or 2 and first onset occurring in the first year of treatment. The incidence and severity of frequently reported TEAEs decreased through years two, three, and four of treatment.
Subgroup Analysis
A post-hoc analysis assessed the effect of nirogacestat in subgroups of patients with desmoid tumors who have risk factors associated with poor prognosis, including larger tumor size (>10 cm), younger age (≤30 years), specific types of CTNNB1 gene mutations, and presence of pain at baseline. Results indicated that treatment with nirogacestat led to consistent improvements in progression-free survival (PFS), ORR, and patient-reported outcomes (PROs) versus placebo, regardless of the patient subgroups.
About the DeFi Trial
The Phase 3 DeFi trial is a global, randomized (1:1), multicenter, double-blind, placebo-controlled study evaluating the efficacy, safety, and tolerability of nirogacestat in adult patients with progressing desmoid tumors. The trial randomized 142 patients (nirogacestat, n=70; placebo n=72) to receive 150 mg of nirogacestat or placebo twice daily. The primary endpoint was progression-free survival (PFS).
About Desmoid Tumors
Desmoid tumors are rare, aggressive, locally invasive soft tissue tumors that can be serious and debilitating. They are most commonly diagnosed in patients between 20 and 44 years old, with an estimated 1,000-1,650 new cases diagnosed annually in the United States. Systemic therapies are now recommended as first-line intervention instead of surgery for most tumor locations requiring treatment.
