Gamma-secretase pill shrinks desmoid tumours in a dose-finding trial

Varegacestat, an oral gamma-secretase inhibitor, shrank desmoid tumours in a small phase 2 dose-finding trial, with the lowest once-daily dose producing the deepest responses [s1]. Desmoid tumours are rare connective-tissue growths that do not spread but can invade locally and cause pain and disability, and effective drug options have been limited [s1]. Gamma-secretase inhibitors act on the Notch signalling pathway, which is thought to help drive these tumours, and varegacestat is taken as a pill [s1]. The RINGSIDE trial was designed to pick a dose rather than to prove benefit against a comparator, and that is the weight its result can carry [s1].

What the trial did

RINGSIDE phase 2 was an open-label, randomised, dose-finding study in adults with histologically confirmed desmoid tumours that were progressing [s1]. Forty-two participants enrolled and were assigned 1:1:1 — 14 per arm — to oral varegacestat at 1.2 mg once daily, 2 mg on an intermittent schedule (once daily for two consecutive days, then five days off), or 4 mg on that same intermittent schedule [s1]. The primary endpoint was safety; the main efficacy measure was change in tumour volume from baseline to week 16, read by a blinded independent central review [s1]. At the end of the randomised phase, participants could enter an open-label extension and receive the dose chosen for the planned phase 3 trial, 1.2 mg once daily [s1][s2].

What it found

Median exposure to varegacestat during the randomised phase was 50.5 weeks (range 3.0 to 76.0) [s1]. Treatment-related adverse events were reported by 41 of the 42 participants (97.6%), of whom 9 (21.4%) had a grade 3 event; no participant had a serious adverse event, and there were no grade 4 or grade 5 events [s1]. That safety picture — frequent but mostly low-grade side-effects — is what the trial was primarily built to measure [s1].

On the efficacy side, the median tumour-volume reduction at week 16 was 51.91% with 1.2 mg once daily, 15.25% with the 2 mg intermittent dose and 9.50% with the 4 mg intermittent dose [s1]. The confirmed objective response rate was 35.7% for the 1.2 mg once-daily arm and 21.4% for each of the two intermittent arms [s1]. The once-daily regimen, despite being the lowest nominal dose, gave both the largest volume reductions and the highest response rate [s1].

Twenty-nine participants (69%) entered the open-label extension and received 1.2 mg once daily, with a median exposure there of 102.0 weeks (range 3.0 to 169.0) [s1]. In that group the median best percentage change in tumour volume was a reduction of 85.88%, and the confirmed objective response rate rose to 57.1% [s1]. Responses deepening with longer treatment is consistent with how slow-growing desmoid tumours tend to respond, though the extension was open-label and not randomised [s1].

How to read it

The central caution is design. RINGSIDE phase 2 had no placebo or active comparator, so the shrinkage cannot be weighed against what untreated or differently treated tumours would have done [s1]. Desmoid tumours can also regress spontaneously, which makes a single-arm readout harder to interpret, and the trial was small — 14 participants per dose arm [s1]. The volume endpoint was read by a blinded independent central review, which guards against biased measurement, but it is a radiological surrogate rather than a direct measure of how patients feel or function [s1]. The headline numbers describe what happened in the people who received the drug, not a demonstrated advantage over an alternative [s1].

The trial met its stated purpose, which was to characterise safety across dose regimens and select a dose for further testing [s1]. On those terms the signal is coherent: the 1.2 mg once-daily dose combined the deepest volume reductions, the highest confirmed response rate and a side-effect profile with no serious, grade 4 or grade 5 events, and it was chosen for the phase 3 programme [s1]. Deeper responses in the extension add to that picture but, being open-label, are supportive rather than confirmatory [s1].

What to watch

The decisive question is whether the randomised phase 3 trial, testing 1.2 mg once daily, shows a benefit against a control group on endpoints that matter to patients — progression-free survival, pain and function — rather than volume change alone [s1][s2]. Durability beyond the roughly two years of extension follow-up, and how tolerability holds over years of continuous dosing, are also open [s1]. This article describes early-phase research and is not medical advice; decisions about treating a desmoid tumour belong with treating clinicians.