2 Clarke Drive
Suite 100
Cranbury, NJ 08512
© 2025 MJH Life Sciences™ and OncLive - Clinical Oncology News, Cancer Expert Insights. All rights reserved.
Varegacestat improved progression-free survival vs placebo in patients with progressing desmoid tumors.
Treatment with the investigational, oral, once-daily gamma 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 3 RINGSIDE trial (NCT04871282).1
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. 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 gamma 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%).
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.
“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, a sarcoma medical oncologist and drug development specialist at Memorial Sloan Kettering Cancer Center, and primary investigator of RINGSIDE, stated in a news release. “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 gamma secretase inhibitors and confirm varegacestat could become standard of care in the treatment of desmoid tumors.”
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.2
During phase 3, patients needed to be at least 12 years of age with a body weight of at least 40 kg with histologically confirmed desmoid tumor with aggressive fibromatosis per local pathologist assessment, and disease that 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.
Patients were excluded if they had an ECOG performance status of 2 or higher; abnormal organ or bone marrow function; or received any treatment for desmoid tumors within 4 weeks of first study treatment. Patients with uncontrolled, active infection, requiring systemic anti-bacterial, anti-viral, 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 Treatment continued until disease progression or death.
Along with the primary end point of PFS, secondary end points comprised ORR, change in tumor volume, duration of response, patient-reported outcomes, and safety.2
“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, chief executive officer of Immunome, added 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.”