Desmoid tumors, also known as desmoid-type fibromatosis, are rare, locally aggressive soft tissue tumors characterized by infiltrative growth, high recurrence rates, and substantial morbidity despite their non-metastatic nature. Patients frequently experience chronic pain, functional impairment, and reduced quality of life, while existing systemic treatment options remain limited and variably effective.
Gamma secretase inhibitors (GSIs), which target aberrant Notch signaling implicated in desmoid tumor biology, have emerged as a promising therapeutic strategy. Varegacestat (formerly AL102) is an investigational, oral, once-daily GSI developed to provide durable disease control with a manageable safety profile. The global Phase 3 RINGSIDE trial was designed as a registrational study to definitively evaluate the efficacy and safety of varegacestat in patients with progressing desmoid tumors.
On December 15, 2025, Immunome announced positive topline results from RINGSIDE, demonstrating robust clinical benefit across multiple efficacy endpoints.
“RINGSIDE is the largest and most comprehensive clinical trial conducted to date in patients with desmoid tumors, and the topline results represent the highest objective response rate observed in a randomized clinical trial in this patient population. These findings demonstrate the potential of varegacestat to offer best-in-class results in a convenient, once-daily, oral medicine that may help patients reclaim their lives.”
said Immunome’s CEO, Clay Siegall, Ph.D.
Photo from Immunome
Methods and Study Design
RINGSIDE (NCT04871282) is a global, randomized, double-blind, placebo-controlled Phase 3 trial conducted in patients with progressing desmoid tumors.
A total of 156 patients were randomized to receive either:
- Varegacestat 1.2 mg orally once daily, or
- Placebo,
administered until disease progression or death.
Endpoints
The primary endpoint was progression-free survival (PFS) as assessed by blinded independent central review. Key secondary endpoints included objective response rate (ORR) per RECIST v1.1, change in tumor volume, and patient-reported pain intensity. Additional secondary endpoints evaluated duration of response, best tumor volume reduction, quality-of-life measures, and safety and tolerability. The study also includes an ongoing open-label extension phase.
“Desmoid tumors can have a devastating physical and emotional impact on patients given their unpredictable nature and the limitations of current treatment options. The progression-free survival benefit, high response rate and reduction in tumor volume with varegacestat in the RINGSIDE trial are striking. These findings elevate the role of GSIs and confirm varegacestat could become standard of care in the treatment of desmoid tumors.”
said Mrinal M. Gounder, M.D., sarcoma medical oncologist at Memorial Sloan Kettering Cancer Center and primary investigator of RINGSIDE.
Photo from Memorial Sloan Kettering Cancer Center
Results
The RINGSIDE trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival with varegacestat compared with placebo. Treatment with varegacestat resulted in an 84% reduction in the risk of disease progression or death, with a hazard ratio of 0.16 (95% CI: 0.071–0.375; p<0.0001).
All key secondary endpoints were also met. The confirmed objective response rate was 56% in the varegacestat arm versus 9% with placebo (p<0.0001), as assessed by blinded independent central review. In an exploratory analysis, varegacestat achieved a median best tumor volume reduction of –83%, compared with a +11% increase in the placebo group. Significant improvements were additionally observed in landmark tumor volume reduction and worst pain intensity, underscoring both radiographic and symptomatic benefit.
Varegacestat was generally well tolerated, with a safety profile consistent with the GSI class. The most common treatment-emergent adverse events included diarrhea, fatigue, rash, nausea, and cough, with the majority reported as grade 1 or 2 in severity.
Conclusion
The Phase 3 RINGSIDE trial represents the largest and most comprehensive randomized study conducted to date in desmoid tumors and demonstrates unprecedented efficacy for varegacestat in this setting. The magnitude of PFS benefit, high objective response rate, substantial tumor volume reduction, and meaningful improvements in pain collectively support varegacestat as a potential new standard of care for patients with progressing desmoid tumors.
Based on these results, Immunome plans to submit a New Drug Application to the U.S. FDA in Q2 2026, with additional data from RINGSIDE expected to be presented at an upcoming major medical conference.
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