Bezuclastinib Improves TSS in Non-Advanced Systemic Mastocytosis

Non-Advanced Systemic Mastocytosis
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Treatment with bezuclastinib (CGT9486) led to a statistically significant improvement in total symptom score (TSS) compared with placebo in patients with non-advanced systemic mastocytosis, meeting the primary end point of part 2 of the phase 2 SUMMIT trial (NCT05186753).1

Findings announced by Cogent Biosciences demonstrated that patients treated with bezuclastinib experienced a mean change in TSS of 24.3 points at week 24 compared with 15.4 points in patients treated with placebo (P = .0002).

Furthermore, bezuclastinib yielded improvements in all key secondary end points, including a reduction in serum tryptase levels. Bezuclastinib produced a reduction in serum tryptase levels by at least 50% reduction in 87.4% of patients compared with 0% for placebo (P < .0001). Statistically significant improvements were also seen in regard to at least a 50% reduction in KIT D816V variant allele frequency (P < .0001); at least a 50% reduction in TSS (P = .0142); at least a 50% reduction in bone marrow mast cell aggregates (P < .0001); at least a 30% reduction in TSS (P = .0004); and mean change in most severe symptom at baseline (P = .0001).

Based on these findings, Cogent Biosciences intends to submit a new drug application (NDA) to the FDA by the end of 2025. Full data from part 2 of SUMMIT will be presented at an upcoming medical conference.

“We have been eagerly awaiting this day and are thrilled to announce bezuclastinib’s performance in the SUMMIT trial, demonstrating clinically meaningful and statistically significant results across all trial end points,” Andrew Robbins, president and chief executive officer of Cogent Biosciences, stated in a news release. “We are committed to providing bezuclastinib access to the thousands of patients with non-advanced systemic mastocytosis as quickly as possible, including through our recently announced Bezuclastinib Expanded Access Program.”

Bezuclastinib Background and SUMMIT Overview

Bezuclastinib is a TKI designed to inhibit KIT D816V mutations and other KIT exon 17 mutations.

The multi-part, randomized, double-blind, placebo-controlled SUMMIT trial enrolled patients at least 18 years of age who had indolent systemic mastocytosis, bone marrow mastocytosis, or smoldering systemic mastocytosis.2 Patients needed to have moderate-to-severe symptoms, per a minimum TSS of the mastocytosis activity score (MAS) after establishing a stable regimen of at least 2 anti-mediator therapies for 14 days prior to enrollment. An ECOG performance status of 0 to 2 was also required.

In part 2 of the study, patients were randomly assigned to receive bezuclastinib—at the optimal dose selected based on part 1—in combination with best supportive care (BSC); or placebo plus BSC. Bezuclastinib and placebo were administered orally once per day in 28-day cycles. Notably, part 3 of the study will evaluate 2 different formulations of bezuclastinib in combination with best supportive care, and patients from the first 2 parts of the trial were permitted to participate.

Bezuclastinib Safety

Data announced by Cogent Biosciences also showed that 98.3% of treatment-emergent adverse effects (TEAEs) in bezuclastinib arm and 88.3% of TEAEs in placebo arm were low grade.

The most common TEAEs were hair color change (bezuclastinib, 69.5%; placebo, 5.0%), altered taste (23.7%; 0%), nausea (22.0%; 13.3%) and increased alanine and aspartate aminotransferase (ALT/AST) levels (22.0%; 6.6%). Grade 3 or higher elevated ALT/AST levels occurred in 5.9% and 0% of patients, respectively.

Serious AEs were reported in 4.2% of patients in the bezuclastinib arm vs 5.0% of patients in the placebo group. Treatment-related AEs led to treatment discontinuation in 5.9% of patients given bezuclastinib, and all were attributed to ALT/AST elevations. These AEs resolved in all patients. No hepatic AEs occurred, except for transient and manageable lab abnormalities.

References

1. Cogent Biosciences announces positive top-line results achieving statistical significance across all primary and key secondary endpoints from the SUMMIT trial of bezuclastinib in patients with non-advanced systemic mastocytosis. News release. Cogent Biosciences. July 7, 2025. Accessed July 7, 2025. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-positive-top-line-results-achieving
2. (Summit) a study to evaluate the efficacy and safety of CGT9486 versus placebo in patients with indolent or smoldering systemic mastocytosis. ClinicalTrials.gov. Updated January 10, 2025. Accessed July 7, 2025. https://www.clinicaltrials.gov/study/NCT05186753