SpringWorks Therapeutics announced new long-term efficacy and safety data from the Phase 3 DeFi trial of nirogacestat (Ogsiveo) in adult patients with progressing desmoid tumors. The data, presented at the Connective Tissue Oncology Society (CTOS) 2024 Annual Meeting, highlight the sustained benefits of nirogacestat, including further tumor size reduction, increased objective response rates, and consistent safety over an extended treatment period.
The DeFi trial (NCT03785964) is a global, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy, safety, and tolerability of nirogacestat in adult patients with progressing desmoid tumors. In the double-blind phase, 142 patients were randomized (1:1) to receive either 150 mg of nirogacestat or placebo twice daily. Key eligibility criteria included tumor progression of ≥20% within 12 months prior to screening, as measured by RECIST 1.1. The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review.
Sustained Tumor Reduction and Improved Response Rates
The updated analysis, utilizing an August 2024 data cutoff, revealed that longer-term treatment with nirogacestat was associated with further reductions in tumor size. 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. The objective response rate (ORR) also increased, with three new partial responses (PRs) and three new complete responses (CRs) reported, resulting in an ORR of 45.7% (34.3% PR, 11.4% CR) (N=70).
Symptom Relief and Quality of Life
Patients treated with nirogacestat experienced early and sustained improvements in patient-reported outcomes (PROs), including pain, desmoid tumor-specific symptom severity, and physical functioning. These improvements were observed as early as Cycle 2 and sustained for up to 45 months of treatment.
According to Ravin Ratan, M.D., M.Ed., Associate Professor at The University of Texas MD Anderson Cancer Center and DeFi study investigator, "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... 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."
Consistent Safety Profile
The most frequently reported treatment-emergent adverse events (TEAEs) occurring in >20% of patients receiving nirogacestat over the entire treatment period were diarrhea, nausea, fatigue, hypophosphatemia, and headache. These events 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.
Efficacy Across Subgroups with Poor Prognostic Factors
A post-hoc analysis of the DeFi trial assessed 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, including larger tumor size (>10 cm), younger age (≤30 years), specific types of CTNNB1 gene mutations, and presence of pain at baseline. The analysis demonstrated that 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.
Desmoid Tumors: A Rare and Debilitating Condition
Desmoid tumors are rare, aggressive, locally invasive soft tissue tumors that can cause serious debility and, in rare cases, can be life-threatening if vital structures are impacted. While they do not metastasize, desmoid tumors have high recurrence rates after surgical resection. Current treatment guidelines recommend systemic therapies as first-line intervention instead of surgery for most tumor locations requiring treatment.
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.
