Efficacy and safety results from the primary analysis of the pivotal summit trial: Bezuclastinib in adults with non-advanced systemic mastocytosis

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.

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Journal
Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-80
Primary Topic
Mast cells and histamine
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article
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article

Efficacy and safety results from the primary analysis of the pivotal summit trial: Bezuclastinib in adults with non-advanced systemic mastocytosis

Jennifer E. Vaughn, Frederick Lansigan, C. Bulaï Livideanu, Stephen T. Oh et al.
Blood
Mast cells and histamine
article

Efficacy and safety results from the primary analysis of the pivotal summit trial: Bezuclastinib in adults with non-advanced systemic mastocytosis

Jennifer E. Vaughn, Frederick Lansigan, C. Bulaï Livideanu, Stephen T. Oh, Rachael Easton, Cecilia Y. Arana Yi, Richard Herrscher, Paul Van Daele, Prithviraj Bose, Tracy I. George, Michela Rondoni, Jens Panse, Alessandra Romano, Anthony Michael Hunter, Andrzej Mital, Deepti H. Radia, Mar Guilarte, Chiara Elena, Francesco Mannelli, Sonia Cerquozzi, Marek Hus, John M. Fahrenholz, Miguel Piris‐Villaespesa, Brian D. Modena, Pankit J. Vachhani, Amanda Pilla, Vito Sabato, Cristina Papayannidis, Helena Pomares, Frank Siebenhaar, Iván Álvarez‐Twöse, Philippe Schafhausen, Mariana Castells, Nina Orfali, Derek McCulloch, Candido E. Rivera, Ingunn Dybedal, Jenna Zhang, Celalettin Üstün, Stéphane Barète, Nathan A. Boggs, Karin Hartmann, Cem Akin, Hanneke Oude Elberink, Minakshi Taparia, Daniel J. DeAngelo, M.A. Manning, Jonathan A. Bernstein, Arnold S. Kirshenbaum, Hina Jolin, Nisha Shah, Andreas Reiter, Peter Vadas, Lindsay Rein, Clodagh Keohane, Lei Sun, Jessica Sachs
article en

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.

BloodVol. 146(Supplement 1)
Dartmouth College (US), Medical University of Lublin (PL), Oslo University Hospital (NO), Brigham and Women's Hospital (US), St. Michael's Hospital (CA), University Medical Center Groningen (NL), The University of Texas MD Anderson Cancer Center (US), Emory University (US), University of Alberta (CA), Universität Hamburg (DE), University of Calgary (CA), University of Mannheim (DE), Guy's and St Thomas' NHS Foundation Trust (GB), Heidelberg University (DE), University of Michigan (US), Royal Prince Alfred Hospital (AU), Walter Reed National Military Medical Center (US), Paradise Valley Community College (US), Huntsman Cancer Institute (US), Erasmus MC (NL), University Hospital Heidelberg (DE), Cork University Hospital (IE), University Hospital of Basel (CH), Major League Baseball (US), University of Alabama at Birmingham (US), University of Chicago Medical Center (US), Clinical Research Institute (US), Düsseldorf University Hospital (DE), ARUP Laboratories (United States) (US), Integrated Oncology (United States) (US), Hospital Virgen del Valle (ES), IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT), Assistance Publique – Hôpitaux de Paris (FR), Górnośląskie Centrum Medyczne (PL), Antwerp University Hospital (BE), La Jolla Alcohol Research (US), Institut Català d'Oncologia (ES), Azienda Unità Sanitaria Locale Della Romagna (IT), Fraunhofer Institute for Translational Medicine and Pharmacology (DE), University Medical Center Hamburg-Eppendorf (DE), Azienda Ospedaliero-Universitaria di Modena (IT), Iscare I.V.F (CZ), Azienda Ospedaliero-Universitaria Careggi (IT), Dana-Farber Cancer Institute (US), Vall d'Hebron Hospital Universitari (ES), Profectus Biosciences (United States) (US), Hôpital Larrey (FR), Policlinico Universitario di Catania (IT), Policlinico San Matteo Fondazione (IT), St. James's Hospital (IE), TOCA at Banner Health (US), Nemours Children's Clinic (US), Azienda Ospedaliero Universitaria Policlinico "G.Rodolico - San Marco" (IT), Hospital Universitario Ramón y Cajal (ES), Heinrich Heine University Düsseldorf (DE), Saint Louis University (US), The Ohio State University (US), University of Cincinnati (US), RWTH Aachen University (DE), Vanderbilt University Medical Center (US)
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