Journal of Clinical Oncology October 08, 2026

RINGSIDE Phase II Study of Varegacestat for Treatment of Desmoid Tumors: A Randomized Dose-Finding Clinical Trial

Rashmi Chugh et al.

Bottom Line

In a phase II open-label randomized trial, the gamma-secretase inhibitor varegacestat showed clinically meaningful tumor volume reduction and a manageable safety profile in adults with progressive desmoid tumors, with the 1.2-mg once-daily dose exhibiting the greatest efficacy.

Key Findings

1. Treatment-related adverse events were reported in 97.6% (41 of 42) of participants, with 21.4% (9) reporting grade 3 events; there were no serious adverse events and no grade 4 or 5 events.

2. At week 16, median tumor volume reduction was most pronounced in the 1.2-mg once-daily arm (-51.91%), compared with the 2-mg intermittent (-15.25%) and 4-mg intermittent (-9.50%) dose arms.

3. The confirmed objective response rate (ORR) during the initial randomized phase was 35.7% for the 1.2-mg daily dose versus 21.4% for both intermittent dose arms.

4. Among the 29 participants (69%) who entered the open-label extension and received 1.2-mg once daily (median exposure 102.0 weeks), median best percent tumor volume change reached -85.88%, and the confirmed ORR increased to 57.1%.

Study Design

Design

Phase II Randomized Trial

Open-Label

Sample

Patients

Duration

50.5 wk

Median

Setting

Multicenter

Population Adults with histologically confirmed desmoid tumors and disease progression.

Intervention Oral varegacestat 1.2-mg once daily, 2-mg intermittent (once daily for 2 consecutive days with 5 consecutive days off), or 4-mg intermittent.

Comparator Other dosing regimens of varegacestat (dose-finding design).

Outcome Safety (incidence of adverse events).

Study Limitations

• Small sample size (42 randomized patients, 14 per arm) intrinsic to a phase II dose-finding study in a rare disease setting.

• Open-label design without a placebo or active standard-of-care control arm.

• Long-term safety, sustained efficacy, and impact on functional outcomes or quality of life require validation in the subsequent phase III trial.

Clinical Significance

Desmoid tumors are rare, locally invasive, and highly morbid neoplasms with limited treatment options. By demonstrating robust and deep tumor volume reductions (up to -85.88% with extended therapy) and a 57.1% long-term ORR, varegacestat provides compelling proof of concept for targeting Notch signaling via gamma-secretase inhibition. This study successfully de-risked the compound and identified 1.2 mg once daily as the optimal dosage regimen, establishing the foundation for its phase III evaluation.

Historical Context

Historically, aggressive fibromatosis (desmoid tumors) were treated surgically, but high recurrence rates led to a paradigm shift toward systemic therapies such as TKIs (e.g., sorafenib) and chemotherapy. Because desmoid tumors are driven by Wnt/beta-catenin mutations that cross-talk with Notch signaling, gamma-secretase inhibitors (GSIs) emerged as a targeted class. Nirogacestat became the first FDA-approved GSI for desmoid tumors in late 2023. The 2026 publication of the RINGSIDE phase II trial evaluates varegacestat (formerly AL102), another novel GSI, attempting to expand targeted therapeutic options with optimized dosing.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Desmoid tumors are classically driven by mutations in the Wnt/beta-catenin pathway (e.g., CTNNB1 or APC). Varegacestat is a gamma-secretase inhibitor (GSI). What is the primary target of GSIs, and what is the mechanistic rationale for using them in desmoid tumors?

Key Response

GSIs primarily block the cleavage of Notch receptors, preventing the release of the Notch intracellular domain (NICD). In desmoid tumors, there is significant cross-talk between the Notch and Wnt/beta-catenin pathways. Inhibiting Notch signaling suppresses the proliferation of desmoid tumor cells, making GSIs an effective targeted therapy despite the primary oncogenic driver being Wnt/beta-catenin.

Resident

Based on the safety profiles of gamma-secretase inhibitors, what specific adverse event requires careful pre-treatment counseling and monitoring in young female patients being treated for desmoid tumors?

Key Response

Gamma-secretase inhibitors (like varegacestat and nirogacestat) have been associated with ovarian toxicity, specifically premature ovarian insufficiency (POI). Given that desmoid tumors disproportionately affect women of childbearing age (often post-pregnancy), counseling on fertility preservation and monitoring menstrual cycles and hormone levels (FSH, estradiol) is a critical management step.

Fellow

In evaluating tumor response for desmoid tumors in trials like RINGSIDE, why is tumor volume reduction (often measured by MRI) considered a more clinically meaningful endpoint than standard RECIST v1.1 criteria?

Key Response

Desmoid tumors are irregularly shaped, infiltrative, and can undergo significant internal changes (like increased collagen deposition or decreased cellularity) without immediate changes in 1-dimensional size. Standard RECIST v1.1, which measures the longest unidimensional diameter, often underestimates clinical benefit. Volumetric MRI assessment and T2-weighted signal intensity changes correlate better with symptom relief and true biological response.

Attending

With active surveillance currently being the frontline approach for asymptomatic desmoid tumors, how should the availability of highly effective systemic agents like varegacestat alter our threshold to intervene in a patient with a stable but anatomically precarious tumor?

Key Response

The paradigm has shifted away from morbid surgical resections toward active surveillance. However, the emergence of highly active, well-tolerated medical therapies like GSIs lowers the threshold for intervention in tumors near critical structures (e.g., mesenteric root, neurovascular bundles) before they cause irreversible organ compromise, shifting the focus from reactive palliation to proactive organ preservation.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The RINGSIDE study is an open-label, randomized dose-finding Phase II trial. What are the specific statistical and methodological challenges of using tumor volume reduction as a primary endpoint in an open-label setting for a spontaneously regressing tumor model?

Key Response

Desmoid tumors have a known natural history of spontaneous regression in up to 20-30 percent of cases. Without a placebo control in this phase II design, attributing volumetric reduction solely to the drug is confounded by natural disease biology. Additionally, open-label designs can introduce assessment bias in radiographic interpretation if the central review is not strictly blinded to treatment arm and dose level.

Journal Editor

As a reviewer for this phase II dose-finding study, what critical safety and efficacy trade-offs would you scrutinize when evaluating the authors' conclusion that the 1.2-mg once-daily dose exhibits the greatest clinical utility?

Key Response

A stringent reviewer would analyze the dose-response relationship to ensure the 1.2-mg dose genuinely offers superior volumetric reduction compared to lower doses without disproportionately increasing dose-limiting toxicities (like severe diarrhea or hepatotoxicity). Since GSIs often have narrow therapeutic windows, justifying the chosen Phase III dose requires robust demonstration that the incremental efficacy is worth the toxicity cost.

Guideline Committee

Current NCCN guidelines for desmoid tumors list nirogacestat as a preferred systemic therapy alongside active surveillance and TKIs like sorafenib. What level of evidence does this Phase II varegacestat trial provide, and what subsequent data is required to warrant its inclusion as a Category 1 recommendation?

Key Response

As a Phase II trial, this provides Level 2A evidence at best. To achieve a Category 1 recommendation and be incorporated into guidelines alongside or in preference to existing therapies, varegacestat would require a well-powered, double-blind, placebo-controlled Phase III trial (similar to the DeFi trial for nirogacestat) demonstrating significant improvements in progression-free survival (PFS) and validated patient-reported outcomes (PROs) regarding pain and quality of life.

Clinical Landscape

Noteworthy Related Trials

2018

Alliance A091105 Trial

n = 87 · NEJM

Tested

Sorafenib 400 mg daily

Population

Patients with progressive or symptomatic desmoid tumors

Comparator

Placebo

Endpoint

Progression-free survival

Key result: Sorafenib significantly improved progression-free survival compared to placebo, with a 2-year rate of 81 percent versus 36 percent.

2019

DESMOPAZ Trial

n = 72 · Lancet Oncol

Tested

Pazopanib 800 mg daily

Population

Adults with progressive desmoid tumors

Comparator

Methotrexate plus vinblastine

Endpoint

Progression-free survival at 6 months

Key result: Pazopanib demonstrated an 83.7 percent 6-month progression-free survival rate, establishing it as an active treatment over chemotherapy.

2023

DeFi Trial

n = 142 · NEJM

Tested

Nirogacestat 150 mg twice daily

Population

Adults with progressing desmoid tumors

Comparator

Placebo

Endpoint

Progression-free survival

Key result: Nirogacestat significantly prolonged progression-free survival and reduced the risk of disease progression by 71 percent compared to placebo.

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