SUMMIT: Bezuclastinib Outperforms Placebo in Nonadvanced Systemic Mastocytosis

Bezuclastinib has displayed significant benefits on patient-reported symptoms and objective measures of mast cell (MC) burden, as well as demonstrated significant correlation between disease pathology and patient-reported symptom severity, in patients with nonadvanced systemic mastocytosis (NonAdvSM), according to results from the registration-directed part 2 of the phase 2 SUMMIT trial announced by parent company Cogent Biosciences, Inc.1

Presented at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida, SUMMIT was a multicenter, randomized, double-blind, placebo-controlled phase 2 trial investigating bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care medications.2

“Nonadvanced systemic mastocytosis patients currently have very limited treatment options, and the benefit of bezuclastinib demonstrated in the SUMMIT trial across measures of disease pathology and symptomatic improvement is very exciting for this patient population,” Lindsay Rein, MD, associate professor of medicine in the division of hematologic malignancies and cellular therapy at Duke University, said in a statement. “The SUMMIT trial results match my clinical experience using bezuclastinib with NonAdvSM patients, delivering rapid and deep improvement in symptom control and objective measures of disease without tolerability challenges.”1

Part 2 of SUMMIT saw patients randomly assigned in a 2:1 ratio to either 100 mg bezuclastinib or placebo daily, in addition to best supportive care medication. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score. Secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow (BM), mast cell burden, and a ≥30% reduction in MS2D2 total symptom score.2

Ultimately, investigators enrolled 179 patients; of these, 119 received bezuclastinib and 60 received placebo. The median age was 51 years (range, 23-78) and mean baseline MS2D2 total symptom score was 55.6 (standard deviation [SD], 19.8). Additionally, 82% of patients had indolent systemic mastocytosis (ISM), 11% had bone marrow mastocytosis (BMM), and 7% had smoldering systemic mastocytosis (SSM). At baseline, median KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (range, 0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively.2

By week 24, patients receiving bezuclastinib exhibited substantially greater symptom improvement compared to placebo recipients (least-squares mean MS2D2 total symptom score change: -24.3; 95% CI, -27.6 to -21.1, vs -15.4; 95% CI, -19.6 to -11.2; P = .0002). A reduction of serum tryptase ≥50% was achieved by 87.4% of bezuclastinib recipients, versus 0% on placebo (P <.0001). Additionally, significantly more patients receiving bezuclastinib saw ≥50% reductions in KIT p.D816V VAF, serum tryptase, BM MCs (P <.0001), MS2D2 total symptom score (P = .01), and ≥30% reduction in MS2D2 total symptom score (P = .0004).2

Consistent with data presented on July 7, 2025, most treatment emergent adverse events (TEAEs) were of low grade. The most frequent TEAEs reported on bezuclastinib treatment were hair color change (69.5% bezuclastinib vs 5% placebo), altered taste (23.7% bezuclastinib vs 0% placebo), and nausea (22% bezuclastinib vs 13.3% placebo). Serious adverse events occurred in 4.2% of patients receiving bezuclastinib, versus 5% of patients receiving placebo.1

“We are excited to present additional data from the SUMMIT trial that support our conviction that bezuclastinib will be the best-in-class treatment option for patients with nonadvanced systemic mastocytosis,” Andrew Robbins, president and chief executive officer of Cogent Biosciences, said in a statement. “We remain on track to submit our first New Drug Application for bezuclastinib in NonAdvSM with the FDA this month.”1

Cogent Biosciences has announced plans to present data from a 48-week follow-up period at an upcoming scientific meeting in Q1 2026.1

References

1. Rein L, Boggs N, Bose P, et al. Efficacy and Safety Results from the Primary Analysis of the Pivotal SUMMIT Trial: Bezuclastinib in Adults With Non-Advanced Systemic Mastocytosis. Abstract presented at the 67th American Society of Hematology Annual Meeting and Exposition. Orlando, FL. December 6-9, 2025.

2. Waarich C. Cogent Biosciences Presents Full SUMMIT Results of Bezuclastinib in Patients With Nonadvanced Systemic Mastocytosis (NonAdvSM) at the 67th Annual Meeting of the American Society of Hematology (ASH). Cogent Biosciences. December 6, 2025. Accessed December 8, 2025. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-presents-full-summit-results-bezuclastinib