Varegacestat: Shaping the Future of GSI Therapy for Desmoid Tumors
Varegacestat is an investigational once-daily oral gamma-secretase inhibitor (GSI) being developed to provide meaningful clinical benefit for patients with progressing desmoid tumors.1,2
Varegacestat: Shaping the Future of GSI Therapy for Desmoid Tumors
Varegacestat is an investigational once-daily oral gamma-secretase inhibitor (GSI) being developed to provide meaningful clinical benefit for patients with progressing desmoid tumors.1,2
Varegacestat: A Once-Daily Oral GSI2
Desmoid tumor biology is largely influenced by β-catenin accumulation and subsequent impact on crosstalk between the Wnt and Notch signaling pathways.1 By inhibiting Notch signaling, GSIs, which include varegacestat, have been shown in preclinical research to reduce β-catenin activity and affect tumor cell behavior.1
RINGSIDE Is the Largest Global Phase 3 Trial in Adults With Desmoid Tumors3
The RINGSIDE trial is a pivotal Phase 2/3 trial evaluating investigational new drug varegacestat for the treatment of patients with progressing desmoid tumors.3 The trial seeks to expand the availability of targeted systemic therapies and potentially improve outcomes, addressing the continuing unmet need for the treatment of desmoid tumors.3
RINGSIDE trial design: Phase 33,4
Global Phase 3
Double-Blind Placebo-Controlled
Key Inclusion Criteria
- Progressed within last 12 months*
- Treatment-naive or recurrent/refractory disease appropriate for systemic treatment
Key Endpoints
- Primary: Progression-free survival† (PFS)
- Key secondary endpoints
- Overall response rate (ORR)
- Tumor volume‡ at Week 24
- Worst pain intensity at Week 12§
- Safety and tolerability
- Additional exploratory efficacy assessments, including median best percent change in tumor volume‡
OLE: open-label extension
QD: once daily
R: randomization
- Progression was defined as ≥20% increase per RECIST v1.1.
- PFS was defined as time from randomization until the date of assessment of radiographic progression as assessed by Blinded Independent Central Review (BICR) based on RECIST v1.1 or death by any cause.
- Measured by T2 weighted magnetic resonance imaging (MRI) or computed tomography (CT) per BICR based on RECIST v1.1.
- Measured using Desmoid Tumor Symptom Scale Item 1 from the Gounder/Desmoid Tumor Research Foundation Desmoid Tumor Symptom/Impact Scale (GODDESS).
RINGSIDE trial design: Phase 22,4,5
A Trial of Varegacestat in Patients With Progressing Desmoid Tumors (RINGSIDE)
Phase 2 - PART A
RINGSIDE trial design: Phase 22,4,5
A Trial of Varegacestat in Patients With Progressing Desmoid Tumors (RINGSIDE)
RINGSIDE: Varegacestat in Progressing Desmoid Tumors
Multicenter, randomized, 2-part Phase 2/3 trial
Part A (Phase 2): Open-label, dose-finding; Part B (Phase 3): Double-blind, placebo-controlled
Primary endpoint: Safety
Secondary endpoints: Tumor volume reduction*2 days on/5 days off.
Phase 2 - PART A
RINGSIDE trial design: Phase 22,4,5
A Trial of Varegacestat in Patients With Progressing Desmoid Tumors (RINGSIDE)
RINGSIDE:
Varegacestat in Progressing Desmoid TumorsMulticenter, randomized, 2–part Phase 2/3 trial
Part A (Phase 2): Open-label, dose-finding; Part B (Phase 3): Double-blind, placebo-controlled
Primary endpoint: Safety
Secondary endpoints: Tumor volume reduction
*2 days on/5 days off.
BIW: intermittent dosing (2 days on/5 days off)
PD: progressive disease
QD: once daily
R/R: relapse/refractory
A Closer Look
Unmet Need in Desmoid Tumors
Desmoid tumors (aggressive fibromatosis) are rare, locally aggressive connective tissue tumors that can arise throughout the body.1 In the United States, up to 1,650 patients are diagnosed each year, most commonly young adults, with a higher proportion occurring in women.1,3 Desmoid tumors can cause significant morbidity, including chronic pain, functional impairment, deformity, and serious complications depending on tumor location.1
Historically, surgery was a common treatment approach.1 Today, treatment of patients with desmoid tumors has shifted toward systemic therapy, given the high risk of recurrence challenges associated with achieving clear surgical margins.1 This shift underscores the need for effective, well-tolerated treatment options that address both disease tumor shrinkage and quality of life.
“
Desmoid tumors can profoundly affect every aspect of a person’s life, often during the prime of adulthood, impacting physical health, emotional well-being, careers, and families. While progress has been made in understanding the disease, patients and caregivers continue to face significant unmet needs that affect quality of life.”
Katie Doyle Myers – Executive Director, DTRF
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References:
- Federman N. Molecular pathogenesis of desmoid tumor and the role of γ-secretase inhibition. JCO Precision Oncology (JCO PO). 2022;62:1-8.
- Chugh R, Gounder MM, Singh AS, et al. Subgroup analysis of the phase 2 part of the RINGSIDE phase 2/3 trial of varegacestat for treatment of desmoid tumors. J Clin Oncol. 2025;43:11516.
- Immunome announces positive topline results from phase 3 RINGSIDE trial of varegacestat in patients with desmoid tumors. News details. Immunome Inc. December 15, 2025. Accessed December 31, 2025. https://investors.immunome.com/immunome-announces-positive-topline-results-from-phase-3-ringside-trial-of-varegacestat-in-patients-with-desmoid-tumors/
- ClinicalTrials.gov. A study of AL102 in patients with progressing desmoid tumors (RINGSIDE). ClinicalTrials.gov identifier: NCT04871282. Updated 2025. Accessed December 29, 2025. https://clinicaltrials.gov/study/NCT04871282
- Gounder M, Kasper B, Chugh R, et al. Change in T2-weighted signal intensity, tumor volume, and exposure–response in desmoid tumors: RINGSIDE phase 2 study of varegacestat. Poster 40. ASCO Annual Meeting; May 30–Jun 3, 2025; Chicago, IL.
