Varegacestat Exhibits Improved Efficacy in Progressing Desmoid Tumors

Varegacestat (AL102), an oral gamma secretase inhibitor (GSI), improved efficacy outcomes, including progression-free survival (PFS), among patients with progressing desmoid tumors in the phase 2/3 RINGSIDE trial (NCT04871282), according to a news release from the developer, Immunome.¹ As a result of these findings, they plan to submit an FDA application for the investigational agent in this patient group in the second quarter of 2026.

Findings from the RINGSIDE trial revealed that the oral agent displayed an 84% reduction in the risk of disease progression or death vs placebo (HR, 0.16; 95% CI, 0.071-0.375; P < .0001), which met the study’s primary end point of PFS. Additionally, the confirmed objective response rate (ORR) was 56% among patients treated with varegacestat compared with 9% of patients treated with placebo (P < .0001) per blinded independent central review (BICR). Additionally, in an exploratory analysis, the investigational agent elicited a median best change in tumor volume of –83% vs +11% with placebo.

“Desmoid tumors can have a devastating physical and emotional impact on patients given their unpredictable nature and the limitations of current treatment options,” Mrinal M. Gounder, MD, sarcoma medical oncologist and drug development specialist at Memorial Sloan Kettering Cancer Center, and RINGSIDE primary investigator, stated in the news release on the RINGSIDE data.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.”

In the phase 2/3 RINGSIDE trial, patients were randomly assigned 1:1 to receive varegacestat at 1.2 mg daily or placebo until disease progression or death.² In the phase 2 portion of the study, patients received 1.2 mg of daily varegacestat, or 2 to 4 mg of the agent intermittently, with the former selected as the recommended dose regimen for the phase 3 portion of the trial.

The primary end point of the trial was PFS per BICR. Secondary end points included ORR per RECIST v1.1 criteria, change in tumor volume at week 24, change in pain intensity per patient-reported outcome instrument, duration of response, and safety.

According to the developers, varegacestat was well-tolerated, and its safety profile was consistent with other GSI agents. The most common adverse effects included diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), and cough (34%). Events were primarily grade 1 or 2 in severity.

Patients 18 years and older were eligible for study participation if they had histologically confirmed desmoid tumors per local pathologist assessment and disease progression defined as: unidimensional growth of desmoid tumors by at least 10% within 18 months of screening; and/or having desmoid tumor-related pain not adequately controlled with nonopioid medication. Additional inclusion criteria included having at least 1 measurable lesion, treatment-naive or recurrent/refractory disease following prior therapy, agreement to provide formalin-fixed paraffin embedded archival or fresh tumor tissue, and the ability to swallow whole capsules.

“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,” Immunome’s chief executive officer, Clay Siegall, PhD, stated.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 16, 2025. https://tinyurl.com/wcy3r7et
2. A study of AL102 in patients with progressing desmoid tumors (RINGSIDE). ClinicalTrials.gov. Updated June 5, 2025. Accessed December 16, 2025. https://tinyurl.com/5cbntmw3