Treatment with varegacestat (AL102) significantly improved progression-free survival (PFS) and objective response rate (ORR) vs placebo in patients with progressing desmoid tumors, according to data from the phase 3 RINGSIDE trial (NCT04871282) presented at the
The trial met its primary end point, with varegacestat (n = 79) reducing the risk of disease progression or death by 84% vs placebo (n = 77; HR, 0.16; 95% CI, 0.07-0.38; P < .0001). The median PFS was not estimable (NE; 95% CI, NE-NE) in the varegacestat arm vs 24.87 months (95% CI, 13.80-NE) in the placebo arm.
“Taken together, [RINGSIDE] data suggest that varegacestat has the potential to become a standard of care for patients with desmoid tumors requiring systemic therapies,” lead study author Mrinal M. Gounder, MD, said in a presentation of the data.
Gounder is a sarcoma medical oncologist and an early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York.
In April 2026,
RINGSIDE was a global, randomized, double-blind, placebo-controlled, phase 3 trial that enrolled adult patients with histologically confirmed desmoid tumors that had progressed in the past 12 months per RECIST 1.1 criteria.1 Other key inclusion criteria comprised measurable disease and an ECOG performance status of 0 to 1. Both treatment-naive and previously treated patients were eligible.
A total of 156 patients were randomly assigned 1:1 to receive oral varegacestat at 1.2 mg once per day or placebo. Patients from both arms were also eligible to receive open-label varegacestat at the same dose following disease progression. Patients were stratified by tumor location (intra- vs extra-abdominal).
Along with the primary end point of PFS by blinded independent central review (BICR), key secondary end points included ORR by BICR, change in estimated tumor volume from baseline at Week 24 by BICR, and change in worst pain intensity (WPI) from baseline at Week 12 as assessed by the GODDESS scale. Patients who progressed on either arm could cross over to an open-label extension receiving varegacestat 1.2 mg once daily.
Baseline characteristics were balanced between arms, with a median age of 42.0 years (range, 18-66) in the varegacestat group vs 39.0 years (range, 20-69) in the placebo group; 67.1% and 62.3% of patients were female, respectively. Extra-abdominal tumor location was reported in 75.9% of patients in the experimental arm vs 63.6% of those in the placebo arm, and 54.4% vs 59.7%, respectively, had received prior systemic therapy.
Prior lines of therapy in the varegacestat group included 0 at 45.6%, 1 at 31.6%, and 2 or more in 22.8%. These respective rates were 40.3%, 28.6%, and 31.2% in the control arm.
Data also showed that the ORR by BICR was 55.7% (95% CI, 44.1%-66.9%) with varegacestat vs 9.1% (95% CI, 3.7%-17.8%) with placebo (P < .0001). Among varegacestat-treated patients, 3.8% achieved a complete response (CR), and 51.9% experienced a partial response (PR); in the placebo arm, respective CR and PR rates were 1.3% and 7.8%.
The median time to response was 8.2 months (range, 2.6-28.0) with varegacestat vs 16.7 months (range, 8.1-30.2) with placebo. Median duration of response was NE in both arms.
The PFS benefit favored varegacestat consistently across all prespecified subgroups analyzed, including by gender, age, tumor location, APC and CTNNB1 mutation status, baseline tumor size, and prior systemic therapy.
Varegacestat also produced a significant reduction in estimated tumor volume at Week 24, at –109.6 cm³ (standard error [SE], 40.64) vs 122.8 cm³ (SE, 42.72) with placebo (difference, –232.4; SE, 57.39; P < .0001). The median best percent change in tumor volume was –83% (range, –100% to 55%) with varegacestat vs 11% (range, –100 to 199%) with placebo.
Patient-reported WPI improved significantly with the experimental treatment, with the mean change from baseline at Week 12 at –2.24 (SE, 0.27) with varegacestat vs 0.18 (SE, 0.27) with placebo (difference, –2.42; SE, 0.37; P < .0001).
Treatment-emergent adverse effects (TEAEs) of any grade occurred in all patients in the varegacestat arm vs 91% in the placebo arm; grade 3 or higher TEAEs were reported in 57% vs 17% of patients, respectively.
Among any-grade TEAEs reported in at least 25% of patients in either arm, the most common with varegacestat included diarrhea (82%), fatigue (44%), rash (43%), nausea (35%), cough (34%), hypophosphatemia (34%), alopecia (33%), dry mouth (30%), hair color changes (25%), and pruritus (25%). Grade 3 or higher TEAEs were uncommon across most categories, with diarrhea representing the most frequent at 10.1%.
Serious AEs occurred in 32% of varegacestat-treated patients vs 9% of placebo-treated patients. No deaths due to AEs were reported.
Dose reductions due to AEs occurred in 80% of varegacestat-treated patients vs 9% of placebo-treated patients, with a median time to first dose reduction of 3.5 months vs 5.6 months. Diarrhea was the most common AE leading to dose reductions (19%). Discontinuation due to AEs was reported in 20% of patients treated with varegacestat vs 7% of those given placebo, with no AE exceeding 2.6%.
Ovarian toxicity, which is a known class effect of gamma-secretase inhibitors, was observed in 56% of premenopausal women in the varegacestat arm vs 5% in the placebo arm. These toxicities resolved in 55% of patients who reported it, and no patients discontinued treatment due to ovarian toxicity.
Median treatment exposure was 20 months with varegacestat vs 11 months with placebo.
