Varegacestat Demonstrates Promising Antitumor Activity in Patients With Progressive Desmoid Tumors

Clinical Summary:

• Design/Population: The phase 2 RINGSIDE trial evaluated 3 dosing regimens of varegacestat, an oral gamma-secretase inhibitor, in adult patients with progressing desmoid tumors. The primary end point was safety, with tumor volume reduction and objective response evaluated as measures of antitumor activity. 
• Key Outcomes: All 3 regimens demonstrated antitumor activity, with 1.2 mg of once daily varegacestat producing the greatest tumor volume reduction and highest objective response rate during the randomized phase. Responses deepened with extended treatment, while adverse events were mainly grade 1/2 in nature. 
• Clinical Relevance: These findings support continued evaluation of 1.2 mg of once daily varegacestat as the preferred regimen for patients with progressing desmoid tumors. The observed responses and tolerability provide a rationale for the ongoing phase 3 RINGSIDE trial, although comparative efficacy against established treatments remains unconfirmed. 

Results from the phase 2 RINGSIDE trial demonstrated that varegacestat, an investigational oral gamma-secretase inhibitor, produced tumor volume reductions and objective responses in adult patients with progressive desmoid tumors, with the greatest activity observed using a 1.2 mg once daily regimen. 

“Desmoid tumors are challenging to treat because of their variable presentation and unpredictable disease course,” stated Rashmi Chugh, MD, University of Michigan Rogel Comprehensive Cancer Center, Ann Arbor, Michigan, and coauthors. “Systemic therapies, such as gamma-secretase inhibitors, tyrosine kinase inhibitors, or cytotoxic chemotherapy, are broadly recommended when indicated to shrink tumors and alleviate symptoms.”

In this multicenter, open-label trial, 42 patients with histologically confirmed progressing desmoid tumors were randomized 1:1:1 to receive either 1.2 mg of once daily varegacestat (n = 14), 2 mg of varegacestat intermittently (n = 14), or 4 mg of varegacestat intermittently (n = 14). 

Intermittent dosing consisted of treatment on 2 consecutive days followed by 5 days without treatment. Patients could continue treatment until disease progression, unacceptable toxicity, withdrawal, or entry into the open-label extension.

 The primary end point was safety. The key secondary end point was change in tumor volume at week 16, assessed via MRI and blinded independent central review. Exploratory end points included objective response rate (ORR), duration of response, and additional MRI-based measures of antitumor activity. 

During the randomized phase, median varegacestat exposure was 50.5 weeks across all treatment groups. Among 37 patients evaluable by MRI, median tumor volume decreased by 51.91% at week 16 in patients who received 1.2 mg of once daily varegacestat. Reductions of 15.25% and 9.50% were observed in patients treated with the 2 mg and 4 mg intermittent regimens. 

The reduction in tumor volume from baseline to week 16 was statistically significant in patients treated with 1.2 mg of once daily varegacestat, whereas the changes observed with the intermittent regimens did not reach statistical significance. 

The confirmed ORR was 35.7% in patients treated with 1.2 mg of once daily varegacestat, compared with 21.4% in each intermittent dosing group. Median time to response was 30 weeks in patients who received once daily treatment, 40.3 weeks in patients who received the 2 mg intermittent regimen, and 51 weeks in patients who received the 4 mg intermittent regimen. 

Stable disease was reported in 54.8% of patients across the randomized treatment groups.

Following selection of the 1.2 mg once daily regimen for phase 3 evaluation, 29 patients entered an open-label extension in which all participants received the selected dose, regardless of their initial treatment assignment.

Median cumulative treatment exposure among patients entering the extension was 102 weeks. With longer treatment, the median best tumor volume reduction reached 85.88%, and the confirmed ORR increased to 57.1% across the original randomized population.

The ORR increased to 57.1% among patients initially assigned to once daily treatment, to 50% among those initially assigned to 2 mg intermittent dosing, and to 64.3% among those initially assigned to 4 mg intermittent dosing.

During the extension, 11 additional patients achieved a partial response and 2 achieved a complete response. Median duration of response was not reached.

Treatment-related adverse events were reported in 97.6% of patients during the randomized phase, with grade 3 treatment-related events reported in 21.4% of patients. No treatment-related serious adverse events or grade 4/5 adverse events were reported. The most frequently reported adverse events included diarrhea (81%), nausea (50%), and fatigue (42.9%). 

Ovarian toxicities including amenorrhea and premature menopause were reported in 52.2% of women of childbearing potential. Among those who experienced ovarian toxicities, events resolved in half of patients and remained unresolved at last follow-up in the other half. 

Six patients discontinued treatment due to adverse events during the randomized phase.

“Varegacestat demonstrated clinically meaningful desmoid tumor volume reduction and ORR with a manageable safety profile across dose regimens,” concluded Dr Chugh et al. “The largest responses were seen with the 1.2 mg once daily dose, which was selected for the RINGSIDE phase 3 trial.”

“While the link between the Notch pathway blocked by this gamma-secretase inhibitor and the Wnt/beta-catenin pathway remains a mystery, the clinical data are clearcut, and varegacestat will provide another option for patients with this challenging diagnosis,” added Journal of Clinical Oncology associate editor Robert Maki, MD, PhD, Memorial Sloan Kettering Cancer Center, New York, New York. 

Source:

Chugh R, Singh A, Andelkovic V, et al. RINGSIDE phase II study of varegacestat for treatment of desmoid tumors: A randomized dose-finding clinical trial. J Clin Oncol. Published online: October 8, 2026. doi: 10.1200/jco-26-00725