RINGSIDE Phase II Reports Varegacestat Tumor Responses in Progressive Desmoid Tumors

The RINGSIDE phase II trial evaluated varegacestat, an oral gamma-secretase inhibitor, in 42 adults with histologically confirmed, progressive desmoid tumors. Participants were randomized equally to 1.2 mg once daily or intermittent 2-mg or 4-mg regimens, administered for two consecutive days followed by five days off. Safety was the primary endpoint; tumor volume change at week 16, assessed by blinded independent central review, was the secondary endpoint.

Median exposure was 50.5 weeks. Treatment-related adverse events occurred in 41 participants (97.6%), with grade 3 events reported in nine (21.4%). No serious treatment-related adverse events or grade 4–5 events were reported. Median tumor volume changes at week 16 were −51.91%, −15.25%, and −9.50% in the daily, 2-mg intermittent, and 4-mg intermittent arms, respectively. Confirmed objective response rates were 35.7%, 21.4%, and 21.4%.

Twenty-nine participants entered an open-label extension receiving 1.2 mg daily, with median exposure of 102 weeks. The abstract reports a median best tumor volume change of −85.88% and a confirmed response rate increasing to 57.1%, but does not clearly specify the denominator for the latter. The daily dose was selected for phase III. These findings support further evaluation, but the small dose groups, open-label design, and absence of a placebo or active comparator limit conclusions about comparative efficacy and clinical benefit.