Efficacy and safety results from the primary analysis of the pivotal SUMMIT trial: bezuclastinib in adults with nonadvanced systemic mastocytosis
1Duke Cancer Institute, Durham, NC, USA; 2Department of Medicine, Uniformed Services University & Walter Reed National Military Medical Center, Bethesda, MD, USA; 3MD Anderson Cancer Center, Huston, TX, USA; 4Modena, La Jolla, CA, USA; 5Antwerp University Hospital (UZA), Edegem, Belgium; 6University Hospital Basel and University of Basel, Basel, Switzerland; 7University of Michigan, Ann Arbor, MI, USA; 8Huntsman Cancer Institute, University of Utah, ARUP Laboratories, Salt Lake City, UT, USA; 9Mayo Clinic Arizona, Phoenix, AZ, USA; 10University Medical Center Groningen, Groningen Research Institute of Asthma and COPD, University of Groningen, Groningen, The Netherlands; 11Guy’s & St Thomas’ Hospitals NHS Foundation Trust, London, UK; 12Universitatsmedizin Mannheim, Mannheim, Germany; 13Ramon y Cajal Hospital, Madrid, Spain; 14Oslo University Hospital, Oslo, Norway; 15Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf (CIO ABCD), Aachen, Germany; 16Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen, Aachen, Germany; 17Washington University School of Medicine, St. Louis, MO, USA; 18University of Alabama at Birmingham, Birmingham, AL, USA; 19Emory University School of Medicine, Atlanta, GA, USA; 20Brigham and Women’s Hospital, Boston, MA, USA; 21CHU de Toulouse, Hopital Larrey, Toulouse, France; 22Erasmus Medical Center, Rotterdam, The Netherlands; 23Allervie, Glenn Dale, MD, USA; 24Instituto de Esudio de Mastocitosis de Castilla-La Mancha, Hospital Virgen del Valle, Toledo, Spain; 25The Ohio State University, Columbus, OH, USA; 26University of Alberta, Edmonton, Alberta, Canada; 27Department of Medicine, Uniformed Services University & Walter Reed National Military Medical Center, Calgary, Alberta, Canada; 28Uniwersyteckie Centrum Kliniczne, Klinika Hematologii I Transplantologii, Gdnask, Poland; 29Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland; 30Azienda Ospedaliero Universitaria Policlinico Rodolico San Marco, Catania, Italy; 31Vanderbilt University Medical Center, Nashville, TN, USA; 32Dartmouth Cancer Center, Lebanon, NH, USA; 33IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant’Orsola, Bolgna, Italy; 34Institut Catala d’Oncologia L’Hospitalet, Barcelona, Spain; 35Azienda Unita Sanitaria Locale della Romagna, Ospedale S.Maria delle Croci, Ravenna, Italy; 36Rush University Medical Center, Chicago, IL, USA; 37AirCare, Plano, TX, USA; 38One of a Kind Medical Research, Paradise Valley, AZ, USA; 39Assistance Publique-Hopitaux de Paris, CEREMAST-Pitie, Paris, France; 40Hospital Universitario Vall d’Hebron, Barcelona, Spain; 41Mayo Clinic Jacksonville, Jacksonville, FL, USA; 42University of Cincinnati, Cincinnati, OH, USA; 43St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; 44Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 45Royal Prince Alfred Hospital, Camperdown, Australia; 46St. James’s Hospital, Dublin, Ireland; 47Cork University Hospital, Cork, Ireland; 48Azienda Ospedaliera Universitaria Careggi, Firenze, Italy; 49Department of Oncology, Hematology, and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 50Cogent Biosciences Inc., Waltham, MA, USA; 51Charite-Universitaetsmedizin Berlin, Berlin, Germany; 52Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Background:
Systemic mastocytosis (SM) is characterized by neoplastic mast cell (MC) infiltration of tissues. Nonadvanced SM (NonAdvSM) is the most prevalent form, associated with debilitating symptoms which significantly impair quality of life. Bezuclastinib is an oral, potent, selective type 1 tyrosine kinase inhibitor with activity against KIT D816V, the mutation found in ~95% of SM patients. Study (NCT05186753) Part 1 informed the recommended dose for Part 2. Here we report primary results from SUMMIT Part 2.
Objectives:
- Explain the therapeutic hypothesis of bezuclastinib, an oral, potent, and selective type 1 tyrosine kinase inhibitor, in nonadvanced systemic mastocytosis. April 2026 | Vol. 2, Suppl 1 | 2026 NCODA International Spring Forum 28 NCODA.org NOHMA | Partner Abstracts A21-A33
- Evaluate the efficacy and safety data of bezuclastinib from the pivotal SUMMIT trial in patients with nonadvanced systemic mastocytosis and recognize how therapeutic targeting of the underlying disease mechanism may improve patient outcomes.
- Understand the relevance of correlating subjective and objective measures of disease burden with emerging targeted therapies such as bezuclastinib.
Methods:
SUMMIT Part 2 is a pivotal trial of bezuclastinib in NonAdvSM patients with inadequate symptom control despite best supportive care (BSC) medications. Patients were randomized 2:1 to 100mg every day (QD) bezuclastinib+ BSC or placebo+BSC. Primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), a fit-for-purpose patient-reported outcome measure of NonAdvSM symptom severity. Key secondary endpoints included the proportion of patients with ≥50% reduction in serum tryptase (ST), KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, MS2D2 TSS, and ≥30% TSS reduction.
Results:
179 patients enrolled in Part 2: n=119 bezuclastinib, n=60 placebo; median age (range) 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8). At baseline, median (range) blood KIT p.D816V VAF, BM MC burden, and ST were 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. At Week 24, bezuclastinib significantly improved symptoms versus (vs) placebo (least squares (LS) mean placebo-adjusted difference in MS2D2 TSS: –8.9 points; P=0.0002). Significantly more patients receiving bezuclastinib vs placebo achieved ≥50% reductions in KIT D816V VAF (P<0.0001), ST (P<0.0001), BM MCs (P<0.0001), TSS (P=0.01), and ≥30% reduction in TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (70% grade 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring more with bezuclastinib were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased alkaline phosphatase (ALP) (10.2% vs 3.3%). All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved.
Conclusions:
At 24 weeks, bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints, showing clinically meaningful improvements in symptoms and disease biomarkers in patients with NonAdvSM; treatment was generally well-tolerated. Results support use of bezuclastinib to reduce SM burden and symptoms in NonAdvSM, and a potentially disease- modifying impact.
Funding: Cogent Biosciences.
Prior Presentations:
Presented at the American Society of Hematology (ASH) Annual Meeting 2025, December 6-9, Orlando, FL.
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