EMA Validates Varegacestat Application for Desmoid Tumors

The European Medicines Agency (EMA) has validated a marketing authorization application seeking approval of varegacestat in adult patients with desmoid tumors, clearing the way for the agency to begin its centralized review.¹

The application is backed by findings from the phase 3 RINGSIDE trial (NCT04871282), in which varegacestat improved progression-free survival (PFS) vs placebo, reducing the risk of disease progression or death by 84% (HR, 0.16; 95% CI, 0.07-0.38; P < .0001).^1,2 The confirmed objective response rates (ORRs) were 55.7% in the varegacestat arm and 9.1% in the placebo arm (P < .0001).

“The EMA's validation of our MAA for varegacestat is an important step in our efforts to bring this treatment to patients with desmoid tumors globally,” Clay Siegall, PhD, president and chief executive officer of Immunome, stated in a news release.¹ "The application is supported by the robust efficacy and safety data generated from the phase 3 RINGSIDE trial,"

What is the mechanism of action of varegacestat?

Varegacestat is an investigational gamma-secretase inhibitor administered orally once per day. By blocking gamma-secretase, the agent disrupts Notch signaling.

In desmoid tumors, β-catenin accumulates and the Wnt and Notch pathways interact to drive tumor biology; gamma-secretase inhibitors act on the Notch arm of this network. Immunome has reported that, in preclinical studies, Notch inhibition with agents in this class can dampen β-catenin activity and alter tumor cell behavior.

Although desmoid tumors do not metastasize, those that progress can lead to pain, loss of function, and other complications, which is the rationale for evaluating varegacestat as a systemic therapy in this setting.

How was the RINGSIDE trial designed?

RINGSIDE is a global phase 2/3 study with an initial dose-finding component followed by a randomized, double-blind, placebo-controlled phase 3 component.²

The phase 3 portion enrolled 156 patients with progressing desmoid tumors, who were randomly assigned 1:1 to oral varegacestat 1.2 mg once daily (n = 79) or placebo (n = 77). Responses were evaluated by blinded independent central review (BICR) per RECIST 1.1 criteria.

An open-label extension is also part of the study, enabling continued assessment of efficacy and tolerability.

PFS served as the primary end point of the phase 3 portion and was defined as the time from randomization to BICR-assessed radiographic progression or death from any cause.

Key secondary end points, which were statistically controlled, comprised confirmed ORR, change in tumor volume at week 24, and change in patient-reported worst pain intensity at week 12; pain was measured with the Gounder/Desmoid Tumor Research Foundation Desmoid Tumor Symptom/Impact Scale. Other assessments included duration of response, additional patient-reported outcomes, and safety and tolerability.

What additional efficacy findings support the application?

At week 12, the mean change from baseline in worst pain intensity was −2.24 with varegacestat compared with +0.18 with placebo, for a treatment difference of −2.42 (P < .0001). A clinically meaningful difference of more than 2 points emerged as early as the first assessment at week 4.

Mean tumor volume decreased by 109.6 cm³ with varegacestat and increased by 122.8 cm³ with placebo at week 24, a difference of −232.4 cm³ (P < .0001). In an exploratory analysis, the median best change in tumor volume was approximately −83% in the varegacestat arm vs +11% in the placebo arm.

What safety findings were reported?

Diarrhea (82%), fatigue (44%), and rash (43%) were the most common adverse effects (AEs) observed with varegacestat. Most individual AEs (95%) were grade 1 or 2; however, grade 3/4 AEs were reported in 57% of patients in the varegacestat arm compared with 17% of those in the placebo arm.

Dose reductions due to AEs occurred in 80% of patients given varegacestat vs 9% of those given placebo, and AE-related discontinuations occurred in 20% vs 7%, respectively. There were no grade 5 AEs.

Among 36 premenopausal women treated with varegacestat, 20 experienced ovarian toxicity, which resolved in 11 of the 20. No patients required dose interruption or treatment withdrawal because of this event.

What is the status of the US application?

Separate from the EMA review, the FDA has already accepted Immunome's new drug application for varegacestat and set a Prescription Drug User Fee Act target action date of April 28, 2027.¹

References

1. Immunome announces EMA validation of marketing authorization application for varegacestat for the treatment of adults with desmoid tumors. News release. Immunome, Inc. October 30, 2026. Accessed October 30, 2026. https://www.businesswire.com/news/home/20261030925417/en/Immunome-Announces-EMA-Validation-of-Marketing-Authorization-Application-for-Varegacestat-for-the-Treatment-of-Adults-with-Desmoid-Tumors
2. Gounder MM, Rutkowski P, Jones RL, et al. RINGSIDE: a phase 3 randomized, placebo-controlled trial of varegacestat for treatment of progressing desmoid tumors. J Clin Oncol. 2026;44(suppl 16):11506. doi:10.1200/JCO.2026.44.16_suppl.11506