SUMMIT: Bezuclastinib Delivers Durable, Deepening Symptom Relief in NonAdvSM, With Cem Akin, MD

Bezuclastinib, an oral, highly selective type 1 KIT inhibitor, has demonstrated that clinically meaningful symptom improvement not only holds but continues to deepen out to 48 weeks of treatment in patients with nonadvanced systemic mastocytosis (NonAdvSM), with every assessed symptom domain showing progressive gains over the treatment course.1,2

These data were from the pivotal, multicenter, randomized, double-blind, placebo-controlled phase 2 SUMMIT trial and were presented at the American Academy of Allergy, Asthma & Immunology (AAAAI) 2026 Annual Meeting held in Philadelphia, Pennsylvania.1

The trial is evaluating bezuclastinib 100 mg once daily versus placebo in patients with NonAdvSM (n = 179; bezuclastinib, n = 119; placebo, n = 60). To discuss the findings and what they mean for a patient population with limited established options, HCPLive spoke with Cem Akin, MD, Professor of Medicine at the University of Michigan Division of Allergy and Immunology, a leading authority in mast cell disorders and a principal investigator on the trial, during the meeting. Akin also discussed the importance of prioritizing the symptom burden in patients with NonAdvSM, as visualized with SUMMIT trial entry interviews, which were highlighted in the poster he presented at the meeting.2

Across the MS2D2 Total Symptom Score, bezuclastinib produced broad, sustained reductions from a mean baseline score of 8.1. At 48 weeks, mean changes from baseline were observed across all symptom domains: itching (–5.2), flushing (–5.1), skin papules (–5.2), fatigue (–6.0), cognitive concentration (–7.3), memory (–5.7), nausea (–5.5), abdominal pain (–3.3), headache (–4.3), bone pain (–4.0), diarrhea (–5.6), brain fog (–3.0), and dizziness (–3.4) — with all symptoms showing deepening improvement from the 24-week timepoint. In total, 86% of bezuclastinib-treated patients achieved a ≥30% reduction in MS2D2 TSS (81/94), and 56.4% achieved ≥50% reduction (53/94) at 48 weeks.1

“These interviews were conducted before they were enrolled in the trial, and they focused on different domains, like skin, gastrointestinal, neurocognitive domains and there are some sentences taken directly from the patient interview that kind of tells you the impact of these patients are experiencing. And some of them are really very severe. And I think for somebody who is new to the field, it is absolutely eye opening to recognize what the patient's going through,” Akin said.

On biomarker endpoints, 98.9% of patients (88/89) in the bezuclastinib arm achieved ≥50% reduction in serum tryptase at week 48, compared to 96.1% (49/51) among placebo crossover patients — with median serum tryptase of 4.7 ng/mL (range 1.0–128.0) versus 5.8 ng/mL (range 1.1–143.0), respectively. Patients achieving tryptase below 20 ng/mL reached 91.7% (66/72), and 83.3% (70/84) fell below 11.4 ng/mL. KIT p.D816V variant allele fraction in peripheral blood was reduced to a median of 0.04% (range, 0–10.5) in the bezuclastinib arm versus 0.07% (range 0–12.1) in placebo crossovers, with 98.4% (61/62) of the ITT population achieving ≥50% VAF reduction. The tolerability profile remained favorable through 48 weeks, with serious TEAEs occurring in just 1.7% of bezuclastinib-treated patients and discontinuations due to TEAEs in 9.2% (11/119 in the double-blind period).1

Cogent Biosciences submitted a new drug application (NDA) for a broad NonAdvSM indication in December 2025.3

Akin’s disclosures include Blueprint Medicines, Cogent, Telios, GSK, and Novartis.

References

1. Boggs NA, Rein L, Bose P, et al. Expanded Results From the Phase 2 Summit Trial: Bezuclastinib in Adults With Nonadvanced Systemic Mastocytosis. Presented at: AAAAI 2026 Annual Meeting, February 27-March 2, Philadelphia, Pennsylvania. Abstract #519

2. Akin C, Boggs NA, Rein L, et al. Results From the Phase 2 Summit Trial of Bezuclastinib in Adults With Nonadvanced Systemic Mastocytosis (NonAdvSM): Patient Experience of Living With NonAdvSM. Presented at: AAAAI 2026 Annual Meeting, February 27-March 2, Philadelphia, Pennsylvania. Abstract #510

3. Cogent Biosciences announces submission of new drug application for bezuclastinib in nonadvanced systemic mastocytosis. News release. Cogent Biosciences, Inc. December 30, 2025. Accessed January 2, 2025. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-submission-new-drug-application