Varegacestat Hits Phase 3 PFS End Point in Progressing Desmoid Tumors

Treatment with the investigational, oral, once-daily γ-secretase inhibitor varegacestat (AL102) led to statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with placebo in patients with progressing desmoid tumors, meeting the primary end point of the phase 2/3 RINGSIDE trial (NCT04871282).^1,2

Findings announced by Immunome, the developer of varegacestat, showed that the agent reduced the risk of disease progression or death by 84% vs placebo (HR, 0.16; 95% CI, 0.071-0.375; P < .0001).

Additionally, Immunome announced that RINGSIDE met all key secondary end points, with varegacestat yielding statistically significant improvements in landmark tumor volume reduction and pain intensity.¹ Patients treated with varegacestat achieved an objective response rate (ORR) of 56% per RECIST 1.1 criteria compared with 9% for those given placebo (P < .0001). Data from an exploratory analysis revealed that the median best change in tumor volume was –83% with varegacestat vs 11% with placebo.

Regarding safety, the profile of varegacestat was consistent with γ-secretase inhibition. Most adverse effects were grade 1 or 2, and the most common toxicities reported in the experimental arm included diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), and cough (34%). Notably, 55.6% of premenopausal women treated with varegacestat experienced ovarian toxicity.² No deaths due to toxicity were reported.

Findings from RINGSIDE will support a new drug application for varegacestat, which Immunome intends to submit to the FDA in the second quarter of 2026.^1,2

“Overall, these data support the potential for varegacestat to become another standard of care in the treatment of [patients with] desmoid tumors,” Mrinal M. Gounder, MD, a sarcoma medical oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York, and primary investigator of RINGSIDE, said during a webinar hosted by Immunome.² “The PFS, high response rate, and tumor volume reduction [with varegacestat] are best in class.”

How was the RINGSIDE trial of varegacestat in desmoid tumors designed?

RINGSIDE was a phase 2/3, global, randomized, double-blind, placebo-controlled trial.^1,2 Phase 2/part A was an open-label, dose-finding trial that led into the placebo-controlled portion in phase 3/part B.³

During phase 3, patients needed to be 12 years or older, weigh at least 40 kg, have a histologically confirmed desmoid tumor with aggressive fibromatosis per local pathologist assessment, and have disease that had progressed by at least 20% per RECIST 1.1 criteria within 12 months of the screening visit scan. Key inclusion criteria comprised measurable disease per RECIST 1.1 criteria.

“Desmoid tumors are rare. They’re nonmetastatic, [and] they’re locally aggressive sarcomas of fibroblastic or myofibroblastic origin,” Gounder said.² “As patients progress or become symptomatic, the need for active intervention increases.”

Patients were excluded if they had an ECOG performance status of 2 or higher, had abnormal organ or bone marrow function, or had received any treatment for desmoid tumors within 4 weeks before the first study treatment.³ Patients with uncontrolled active infection that required systemic antibacterial, antiviral, or antifungal therapy within 7 days of study initiation were also excluded.

During phase 3, investigators randomly assigned patients (n = 156) to receive varegacestat at 1.2 mg once per day or placebo.^1,2 Treatment continued until disease progression or death.

Along with the primary end point of PFS, secondary end points were ORR, change in tumor volume, duration of response, patient-reported outcomes, and safety.³

“RINGSIDE is the largest and most comprehensive clinical trial conducted to date in patients with desmoid tumors, and the topline results represent the highest ORR observed in a randomized clinical trial in this patient population,” Clay Siegall, PhD, Immunome CEO, said in a news release.¹ “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.”

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 24, 2025. https://investors.immunome.com/immunome-announces-positive-topline-results-from-phase-3-ringside-trial-of-varegacestat-in-patients-with-desmoid-tumors/
2. Topline results of the RINGSIDE phase 3 study of varegacestat in desmoid tumors. Immunome. December 15, 2025. Accessed December 24, 2025. https://edge.media-server.com/mmc/p/kw6gej7y/
3. A study of AL102 in patients with progressing desmoid tumors (RINGSIDE). ClinicalTrials.gov. Updated June 5, 2025. Accessed December 24, 2025. https://clinicaltrials.gov/study/NCT04871282