Bezuclastinib Shows Promise in Nonadvanced Systemic Mastocytosis

Treatment with bezuclastinib (CGT0486) led to clinically meaningful symptom improvements and significant reductions in objective markers of disease in patients with nonadvanced systemic mastocytosis, according to results from the phase 2 SUMMIT trial (NCT05186753) shared during the 2025 ASH Annual Meeting.¹

A rapid, durable, statistically significant, and clinically meaningful symptom improvement was reported with bezuclastinib vs placebo, with mean changes in MS2D2 (mastocytosis symptom severity daily diary) total symptom score (TSS) of –24.32 (95% CI, –27.56 to –21.08) vs –15.41 (95% CI, –19.58 to –11.24), respectively, at week 24; the difference between the arms was –8.91 (95% CI, –13.56 to –4.26; P < .001), which met the trial’s primary end point. A significant improvement occurred as early as 6 weeks.

Moreover, a significantly greater proportion of patients who received bezuclastinib achieved reductions of at least 30% and at least 50% in TSS vs placebo. Specifically, 65.4% (95% CI, 56.9%-73.9%) of those who received bezuclastinib at 100 mg experienced a reduction in MS2D2 TSS of at least 30% vs 38.6% (95% CI, 26.2%-50.9%) of those who received placebo (P < .001). Moreover, 34.3% (95% CI, 25.8%-42.8%) of patients who received bezuclastinib achieved a reduction in MS2D2 TSS of at least 50% vs 18.1% (95% CI, 8.4%-27.9%) of those given placebo (P = .01).

Notably, bezuclastinib also significantly reduced serum tryptase vs placebo, with 95.4% of patients reaching a 50% or higher reduction at 24 weeks vs 0% of patients (P < .0001). The drug also led to a significant reduction in bone marrow mast cell burden and abnormal mast cell phenotype vs placebo at 24 weeks, with 88.2% vs 25.5% of patients, respectively, reaching at least a 50% reduction in mast cell burden or clearance of aggregates (P < .0001). Lastly, 97.5% of patients who received bezuclastinib achieved a 50% or greater reduction in KIT p.D816V variant allele frequency (VAF) in blood or undetectable mutation at 24 weeks vs 0% of those given placebo (P < .0001).

“Bezuclastinib represents a promising new treatment with evidence of potential disease modification in patients with nonadvanced systemic mastocytosis. Patients who received bezuclastinib achieved clinically meaningful symptom improvements as measured by the TSS and the mean change in this. This was reported not only in the total score but also reflected across individual symptoms. We saw significant reductions across objective markers of disease, including serum tryptase, bone marrow mast cells, and KIT p.D816V variant allele frequency,” Lindsay A.M. Rein, MD, said in a presentation of the data. “This is really the first demonstration of a significant correlation between reduction in objective markers and measures of disease and improvement in symptoms, which is consistent with the pathogenic link between the neoplastic mast cells and the clinic symptomatology.”

Rein is a hematologic oncologist, associate professor of medicine, and member of the Duke Cancer Institute, in Durham, North Carolina.

What led to the exploration of bezuclastinib in nonadvanced systemic mastocytosis?

It is known that systemic mastocytosis is a disorder of mast cells, and nonadvanced systemic mastocytosis subtypes comprise indolent, smoldering, and bone marrow mastocytosis. “Nonadvanced SM is associated oftentimes with debilitating symptoms, including life-threatening anaphylaxis, as well as various symptoms which significantly impair quality of life,” Rein underscored.

Specifically, these patients can experience neurocognitive symptoms such as difficulty concentrating or remembering, brain fog, cognitive dysfunction, anxiety, or depression; fatigue; cardiovascular symptoms in the form of hypotension, tachycardia, palpitations, or chest tightness; gastrointestinal symptoms such as nausea, abdominal pain, diarrhea, vomiting, bloating, or gastroesophageal reflux disease; and pain.

The oral and selective type I TKI bezuclastinib has activity against KIT p.D816V, which is an activating mutation that is commonly observed in those with systemic mastocytosis, Rein noted. She added that the drug has minimal brain penetration and spares closely related kinases which could prevent off-target effects like bleeding, cognitive impairment, edema, and pleural effusion.

How was bezuclastinib evaluated in the phase 2 SUMMIT trial?

The multicenter, randomized, double-blind, placebo-controlled SUMMIT study enrolled patients with indolent systemic mastocytosis, bone marrow mastocytosis, or smoldering systemic mastocytosis per World Health Organization 2022 classification. Patients had inadequate symptom control defined as moderate to severe symptoms despite receipt of at least 2 antimediator therapies. Best supportive care (BSC) could have been histamine receptor type 1 antagonist, histamine receptor type 2 antagonist, cromolyn, leukotriene receptor antagonists, corticosteroids, omalizumab, and proton pump inhibitors.

The study was comprised of 2 parts: the dose-optimization and -expansion phases. Part 1 data were previously presented. At the meeting, Rein focused on part 2, where patients were randomly assigned 2:1 to receive bezuclastinib at 100 mg once daily plus BSC (n = 119) or placebo plus BSC (n = 60). “[All patients] had the opportunity to roll into an open-label extension,” Rein noted. The primary end point for part 2 was the evaluate the mean change in MS2D2 TSS from baseline to 24 weeks. Key secondary end points included at least 50% reductions in serum tryptase, KIT p.D816V VAF, bone marrow mast cell burden, and MS2D2 TSS as well as at least a 30% reduction in TSS.

The MS2D2 is a comprehensive patient-reported outcome measure of symptom severity spanning nonadvanced systemic mastocytosis; it is comprised of 17 items. The 11 symptoms featured include difficulty concentrating and remembering (neurocognitive domain); tiredness (fatigue domain); itching, flushing, skin redness, and spots (skin domain); and nausea, abdominal pain, headache, and bone pain (other domain). Severity of the symptoms is evaluated on a daily basis and rated from 0 to 10, with 10 graded as the “worst possible.” The TSS is examined as a 14-day average.

“Data from SUMMIT part one² really supported use of this as a fit-for-purpose tool,” Rein said.

With regard to patient characteristics and demographics, Rein noted that the population was representative of a patient population with nonadvanced systemic mastocytosis and moderate to severe symptoms. “I want to point out 2 key differences between the patients who received bezuclastinib vs placebo. First of all, and importantly, this particular study included patients with smoldering systemic mastocytosis. Secondly, this study included patients who had received prior KIT inhibitor therapy, and you’ll see there were slightly more patients [who received this] in [the bezuclastinib group; 14.3% vs 8.3%],” Rein said. “And then, the other notable difference is that patients who received bezuclastinib had a slightly higher score from the total symptom score perspective, as measured again by the MS2D2 [mean, 57.1 vs 52.6]. Those were really the very few differences.”

What did subgroup analyses reveal?

Two key subgroups—those with smoldering systemic mastocytosis (n = 8) and with previous exposure to avapritinib (Ayvakit; n = 11)—were found to derive meaningful improvements in symptoms and objective measures of disease.

Specifically, in those with smoldering systemic mastocytosis, the mean change in symptom severity at 24 weeks from baseline was a MS2D2 TSS of –35.6 (95% CI, –48.1 to –23.1); in those with previous exposure to avapritinib, the mean change was –21.6 (95% CI, –32.6 to –21.6). Moreover, 100%, 75%, and 100% of patients with smoldering systemic mastocytosis experienced a reduction of at least 50% from baseline or reaching other threshold with regard to KIT p.D816V in the whole blood, bone marrow mast cell burden, and serum tryptase; these respective rates were 83%, 63.6%, and 82% in those with prior avapritinib exposure.

“This is important, although a small population of patients. And again, with the large data set that was collected here, the magnitude of symptom burden was able to be correlated with the change in the various disease markers that we’ve discussed, and what we see is that the greater reduction in serum tryptase, bone marrow mast cells, [and] KIT D816V, was significantly correlated with greater reduction in symptom severity, again, as assessed by our MS2D2 TSS,” Rein said. “This is really one of the first correlations that we’ve seen between change in disease markers and symptom severity and supports the idea that there may be some evidence here of disease modification within the context of this disease.”

What was the toxicity profile of bezuclastinib?

Rein noted that the agent had a favorable and manageable safety profile. Treatment-emergent adverse effects (TEAEs) occurred in 98.3% of those who received bezuclastinib (n = 118) vs 88.3% of those given placebo (n = 60). Most were low grade (grade 1, 70%) and reversible with cessation of therapy, but serious TEAEs occurred in 4.2% and 5.0% of patients, respectively. TEAEs led to treatment-related reductions or discontinuation for 11.0% and 5.9%, respectively, of those in the bezuclastinib arm.

The most common TEAEs that occurred at greater frequency in the bezuclastinib arm vs the placebo arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased alanine and aspartate aminotransferase levels (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased alkaline phosphatase (10.2% vs 3.3%). The following adverse effects occurred more frequently in the placebo arm vs the bezuclastinib arm: dizziness, fatigue, arthralgia, and diarrhea.

“We found low rates of cognitive impairment and other disturbances related to the central nervous system,” Rein said, “and the main hepatic events we saw were increased liver transaminases.”

What’s next for bezuclastinib?

Rein concluded by saying that there are plans to submit a new drug application for bezuclastinib in a broad nonadvanced systemic mastocytosis population by the end of the year.

Previously, in October 2025, the FDA granted breakthrough therapy designation to bezuclastinib for use in patients with nonadvanced systemic mastocytosis who previously received avapritinib, and for those with smoldering systemic mastocytosis.³

References

1. Rein L, Boggs N, Rose P, et al. Efficacy and safety results from the primary analysis of the pivotal summit trial: bezuclastinib in adults with non-advanced systemic mastocytosis. Blood. 2025;146(suppl 1):80. doi:10.1182/blood-2025-80
2. Bose P, Oh ST, Modena B, et al. Initial results from Summit: an ongoing, 3-part, multi-center, randomized, double-blind, placebo-controlled phase 2 clinical study of bezuclastinib in adult patients with nonadvanced systemic mastocytosis (NonAdvSM). Blood. 2023;142(suppl 1):77. doi:10.1182/blood-2023-178927
3. Cogent Biosciences announces FDA breakthrough therapy designation for bezuclastinib. News release. Cogent Biosciences, Inc. October 20, 2025. Accessed December 8, 2025. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-fda-breakthrough-therapy