Efficacy and safety results from the primary analysis of the pivotal summit trial: Bezuclastinib in adults with non-advanced systemic mastocytosis
Abstract
Abstract Background: Systemic mastocytosis (SM) comprises a spectrum of subtypes characterized by neoplastic mast cell (MC) infiltration of tissues and release of MC mediators. Non-advanced SM (NonAdvSM), including indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) subtypes, is the most prevalent form of SM. NonAdvSM can be associated with debilitating symptomology which can significantly impair quality of life. The gain-of-function somatic KIT c.2447 C>T (p.D816V) mutation is found in up to 95% of patients with SM. Bezuclastinib (CGT9486) is an oral, potent, and selective type 1 tyrosine kinase inhibitor with activity against KIT D816V. Results from Summit (NCT05186753) Part 1 informed the recommended phase 2 dose (100 mg QD bezuclastinib) for Part 2. We report topline results from the 24-week assessment of Summit Part 2. Methods: Summit is a multi-center, randomized, double-blind, placebo (PBO)-controlled Phase 2 trial of bezuclastinib in patients with NonAdvSM who had inadequate symptom control despite best supportive care (BSC) medications. The primary endpoint was 24-week mean change from baseline in Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS) (range 0–110), which is 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, KIT p.D816V variant allele frequency (VAF), bone marrow (BM) MC burden, and MS2D2 TSS, ≥30% TSS reduction. Patients were randomized 2:1 to receive 100mg QD bezuclastinib + BSC or PBO + BSC. Results: As of May 22, 2025, 179 patients were enrolled in Part 2: 119 were randomized to receive bezuclastinib and 60 to placebo. Patients enrolled were representative of the NonAdvSM population with moderate to severe symptoms. Median age (range) was 51 (23-78) years; 65.9% female; mean (SD) baseline MS2D2 TSS 55.6 (19.8); 82% of patients had ISM, 11% had BMM, and 7% had smoldering SSM. At baseline, median (range) KIT p.D816V VAF in whole blood, BM MC burden, and serum tryptase was 0.25% (0-34%), 10% (1-75%), and 40 (6-692) ng/mL, respectively. Bezuclastinib demonstrated statistically significant superiority to placebo on all primary and key secondary endpoints. At Week 24, bezuclastinib led to significantly greater symptom improvement vs placebo (LS mean [95% CI] MS2D2 TSS change: –24.3 [–27.6 to –21.1] vs –15.4 [–19.6 to –11.2]; placebo-adjusted difference: –8.9 points; P=0.0002). A ≥50% reduction in serum tryptase was achieved in 87.4% of bezuclastinib-treated patients vs 0% on placebo (P<0.0001). Significantly more patients receiving bezuclastinib achieved ≥50% reductions in KIT D816V VAF, serum tryptase, BM MCs (P<0.0001), MS2D2 TSS (P=0.01), and ≥30% reduction in MS2D2 TSS (P=0.0004). Most treatment-emergent adverse events (TEAEs) were low grade (gr; 70% Gr 1) and reversible. The most common TEAEs (≥10%) in any treatment group and occurring in greater frequency in the bezuclastinib arm were hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), increased ALT/AST (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and increased ALP (10.2% vs 3.3%). TEAEs (≥10%) that occurred more often in the placebo group were diarrhea (13% vs 18%), dizziness (10% vs 12%), fatigue (7% vs 12%), and arthralgia (6% vs 15%). ALT/AST elevations ≥Gr 3 were experienced by 5.9% of patients. The only hepatic adverse events (AEs) reported were transient lab abnormalities; none required hospitalization. Treatment-related AEs requiring dose reductions occurred in 11% of patients receiving bezuclastinib. All discontinuations (5.9%) due to treatment-related AEs were due to transaminase elevations; all fully resolved. Conclusions: At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significant improvements in symptom burden and biomarkers of disease vs placebo in patients with NonAdvSM. The treatment was generally well-tolerated and effective across a population that is representative of the real-world NonAdvSM population, including SSM. These results support the use of bezuclastinib to reduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact.
Article Details
Authors (57)
Lindsay Rein
10Duke University School of Medicine, Durham, United States
Nathan Boggs
2Uniformed Services University & Walter Reed National Military Medical Center, Department of Medicine, Bethesda, United States
Prithviraj Bose
5University of Texas MD Anderson Cancer Center, Houston, United States
Brian Modena
4Modena, La Jolla, United States
Vito Sabato
5Department of Immunology, Allergology and Rheumatology, University of Antwerp, and Antwerp University Hospital, Antwerp, Belgium
Karin Hartmann
6Division of Allergy, Department of Dermatology, University Hospital Basel and University of Basel, Basel, Switzerland
Cem Akin
7University of Michigan, Ann Arbor, United States
Tracy George
2ARUP Laboratories, Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States
Cecilia Arana Yi
2Mayo Clinic, Phoenix, United States
Hanneke Oude Elberink
2Department of Allergology, Groningen Research Institute Asthma and COPD, University Medical Center, University of Groningen, Groningen, Netherlands
Deepti Radia
4Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom
Andreas Reiter
Miguel Piris-Villaespesa
20Hospital Universitario Ramón y Cajal, Hematology Department, Madrid, Spain
Ingunn Dybedal
20Department of Hematology and Pharmacology, Oslo University Hospital, Oslo, Norway
Jens Panse
9Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University & Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
Stephen Oh
1Washington University School of Medicine, St. Louis, St. Louis, United States
Pankit Vachhani
25University of Alabama at Birmingham Cancer Center, Birmingham, United States
Anthony Hunter
3Emory University, Winship Cancer Institute, Atlanta, United States
Mariana Castells
1Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States
Cristina Bulai Livideanu
6Département de dermatologie, CEREMAST CHU de Toulouse, Toulouse University Hospital, Toulouse, France
Paul van Daele
18Department of Internal Medicine, and Department of Immunology, Erasmus Medical Center, Rotterdam, Netherlands
Arnold Kirshenbaum
22Allervie, Glenn Dale, United States
Iván Álvarez-Twose
3Red Española de Mastocitosis, Toledo, Spain
Jennifer Vaughn
1The Ohio State University, Hematology, Columbus, United States
Minakshi Taparia
25University of Alberta, Edmonton, Canada
Sonia Cerquozzi
19Department of Medicine, Cumming School of Medicine, University of Calgary, Arthur Child Comprehensive Cancer Centre, Calgary, Canada
Andrzej Mital
10Medical University of Gdansk, Department of Hematology and Transplantology, Gdansk, Poland
Marek Hus
Alessandra Romano
John Fahrenholz
30Vanderbilt University Medical Center, Nashville, United States
Frederick Lansigan
19Dartmouth-Hitchcock Medical Center, Lebanon, United States
Cristina Papayannidis
2IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy
Helena Pomares
1Institut Català d'Oncologia - Hospital Duran i Reynals, Hematology, Hospitalet de Llobregat, Spain
Michela Rondoni
6Hematology Unit, Ravenna Hospital, University of Bologna, Ravenna, Italy
Celalettin Ustun
9Rush University, Chicago, United States
Richard Herrscher
36AirCare, Planto, United States
Michael Manning
37One of a Kind Medical Research, Paradise Valley, United States
Stéphane Barete
22Unit of Dermatology Reference Centre for Mastocytosis (CEREMAST) AP-HP, Pitié-Salpêtrière Hospital, Paris, France
Mar Guilarte
39Hospital Universitario Vall d'Hebron, Barcelona, Spain
Candido Rivera
1Mayo Clinic, Department of Internal Medicine, Rochester, United States
Jonathan Bernstein
41University of Cincinnati, Cincinnati, United States
Peter Vadas
29Department of Medicine, Division of Clinical Immunology and Allergy, St Michael's Hospital, University of Toronto, Toronto, Canada
Chiara Elena
4University of Pavia, Hematology, Pavia, Italy
Derek McCulloch
44Royal Prince Alfred Hospital, Camperdown, Australia
Nina Orfali
45St. James's Hospital, Dublin, Ireland
Clodagh Keohane
46Cork University Hospital, Cork, Ireland
Francesco Mannelli
1SOD Ematologia, Università di Firenze, AOU Careggi, Firenze, Italy
Philippe Schafhausen
3University Medical Center Hamburg-Eppendorf, Department of Oncology and Hematology, Hamburg, Germany
Amanda Pilla
49Cogent Biosciences Inc., Waltham, United States
Jenna Zhang
49Cogent Biosciences Inc., Waltham, United States
Lei Sun
Nisha Shah
49Cogent Biosciences Inc., Waltham, United States
Hina Jolin
49Cogent Biosciences Inc., Waltham, United States
Rachael Easton
1Cogent Biosciences Inc., Waltham, United States
Jessica Sachs
49Cogent Biosciences Inc., Waltham, United States
Frank Siebenhaar
9Institute of Allergology, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Daniel Deangelo
2Dana Farber Cancer Institute, Boston, United States