Notably, both patient populations have no currently approved standard-of-care therapies. This designation was based on data from the registration-directed phase 2 SUMMIT trial (NCT05186753). In the trial, patients with non-advanced systemic mastocytosis who received bezuclastinib experienced statistically significant benefits compared with those who received placebo across all primary and secondary end points.
Top-line data from part 2 of SUMMIT, which were announced on July 8, 2025, showed that patients in the bezuclastinib arm achieved a mean change in total symptom score (TSS) at week 24 of 24.3 points vs 15.4 points among those in the placebo arm (P = .0002).2 Moreover, bezuclastinib yielded a reduction in serum tryptase levels of at least 50% in 87.4% of patients vs 0% of those who received placebo (P < .0001). Furthermore, reductions in KIT D816V variant allele frequency of at least 50% (P < .0001), reductions in TSS of at least 50% (P = .0142), reductions in TSS of at least 30% (P = .0004), reductions in bone marrow mast cell aggregates of at least 50% (P < .0001), and mean changes in most severe symptom at baseline (P = .0001) were all observed to be greater with bezuclastinib compared with placebo.
Additional data are planned to be shared at an upcoming medical meeting.1
“We are excited to announce breakthrough therapy designation for bezuclastinib, which highlights the FDA’s recognition of the unmet need for patients with non-advanced systemic mastocytosis and the potential for bezuclastinib to redefine the treatment paradigm for this disease,” Andrew Robbins, president and chief executive officer of Cogent Biosciences, stated in a news release. “In addition, we recently completed a very productive pre–new drug application [NDA] meeting discussing the results from the SUMMIT pivotal trial and look forward to our continued collaboration with the FDA as we prepare to submit our NDA for non-advanced systemic mastocytosis by the end of 2025. We are excited that this designation supports eligibility for priority review as we prepare for our planned commercial launch.”
What was the design of the SUMMIT trial?
SUMMIT enrolled patients with indolent systemic mastocytosis, bone marrow mastocytosis, or smoldering systemic mastocytosis who had moderate-to-severe symptoms and an ECOG performance status of 0 to 2.3 In part 2, patients received bezuclastinib at the optimal dose selected in part 1 in combination with best supportive care [BSC]; or placebo in combination with BSC. Bezuclastinib and placebo were each administered orally once daily in continuous 28-day cycles.
What was the safety profile of bezuclastinib in the SUMMIT trial?
In total, 98.3% of patients in the bezuclastinib arm experienced low-grade treatment-emergent adverse effects (TEAEs) vs 88.3% of those in the placebo arm.2 The most commonly reported TEAEs in these respective arms 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%). Increased ALT/AST levels were reported to be grade 3 or higher in 5.9% and 0% of patients treated with bezuclastinib and placebo, respectively.
Additionally, 4.2% of patients who received bezuclastinib had serious AEs compared with 5.0% of those who received placebo. Moreover, 5.9% of patients treated with bezuclastinib experienced treatment-related AEs that led to treatment discontinuation; all discontinuations were attributed to elevated ALT/AST levels that eventually resolved in full. Notably, hepatic AEs were not reported in any patients, except for laboratory abnormalities that were deemed transient and manageable.
References
- Cogent Biosciences announces FDA breakthrough therapy designation for bezuclastinib. News release. Cogent Biosciences, Inc. October 20, 2025. Accessed October 20, 2025. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-fda-breakthrough-therapy
- 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 October 20, 2025. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-positive-top-line-results-achieving
- (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 October 20, 2025. https://www.clinicaltrials.gov/study/NCT05186753
