Varegacestat Achieves PFS Gains, Deep Shrinkage of Desmoid Tumors

Varegacestat, an investigational gamma secretase inhibitor (GSI), delivered clinically meaningful improvements in efficacy outcomes vs placebo in patients with progressing desmoid tumors, according to topline data from the phase 3 RINGSIDE trial (NCT04871282).¹

Notably, treatment with varegacestat significantly improved progression-free survival (PFS) compared with placebo, slashing the risk of disease progression or death by 84% (HR, 0.16; 95% CI, 0.071–0.375; P <.0001).

The agent also successfully delivered on the trial’s secondary end points, achieving not only high response rates, but also clinically meaningful reductions in tumor volume and worst pain intensity compared with placebo. The confirmed objective response rates (ORR) with varegacestat and placebo were 56% and 9%, respectively (P <.0001). Additionally, an exploratory analysis revealed a median best change in tumor volume of –83% with varegacestat vs +11% with placebo, demonstrating deep tumor shrinkage with varegacestat.

The safety profile of varegacestat was deemed manageable and consistent with the GSI class, with the most common adverse events being diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), and cough (34%). Most events were grades 1 or 2.

In 2023, varegacestat, then known as AL102, received orphan drug designation from the FDA in recognition of its therapeutic potential in desmoid tumors, a rare condition which can cause substantial pain and detriment to patient quality of life. With varegacestat’s oral, once-daily delivery, these latest findings further highlight the agent’s potential to offer a convenient, potentially new standard-of-care option for desmoid tumors.

“Desmoid tumors can have a devastating physical and emotional impact on patients given their unpredictable nature and the limitations of current treatment options,” said Mrinal M. Gounder, MD, Memorial Sloan Kettering Cancer Center and RINGSIDE primary investigator, in a news release.¹ “The [PFS] 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.”

Based on these data, Immunome, trial sponsor, has revealed plans for submission of a new drug application to the FDA in 2026 and noted that additional RINGSIDE trial data will be shared at an upcoming medical conference.

About the RINGSIDE Trial

The RINGSIDE trial is an open-label, multicenter phase 2/3 trial investigating the efficacy and safety of varegacestat in patients with progressive desmoid tumors.²

In the ongoing randomized, double-blind, placebo-controlled phase 3 portion, 156 patients have been enrolled and randomized to receive either 1.2-mg daily doses of varegacestat or placebo. The trial’s primary end point is PFS per blinded independent central review. Key secondary end points include ORR per RECIST, change in tumor volume at week 24, and change in pain intensity; other secondary end points include duration of response, best reduction in tumor volume, patient-reported outcomes, and safety and tolerability.

Findings from the preceding phase 2 portion showed early tumor responses among 42 patients with relapsed/refractory or treatment-naive desmoid tumors treated with varegacestat, with objective responses seen across age, tumor size, number of prior lines of therapy, tumor location, and mutational subgroups (ORR range, 43%–78%).³

REFERENCES

1. Immunome announces positive topline results from Phase 3 RINGSIDE trial of varegacestat in patients with desmoid tumors. News release. Immunome. December 15, 2025. Accessed December 15, 2025. https://tinyurl.com/myre7znx

2. A study of AL102 in patients with progressing desmoid tumors (RINGSIDE). ClinicalTrials.gov. Updated June 5, 2025. Accessed December 15, 2025. https://clinicaltrials.gov/study/NCT04871282

3. 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(16_suppl):11516-11516. doi:10.1200/jco.2025.43.16_suppl.11516