bezuclastinib (PLX9486) / Daiichi Sankyo, Cogent Biosci - LARVOL DELTA

Relationship between KIT inhibition by bezuclastinib and effects on disease burden in mouse models of systemic mastocytosis (ASH 2025) - P2 | "The approval of the first KIT-targeted therapy, avapritinib (AVA),demonstrates proof-of-concept clinical efficacy in these patients, but effects on mast cell burden in bloodand bone marrow are limited...For a functional target engagement readout, Ba/F3-KIT-D816V cells were injectedintravenously into nude mice, and spleen weights and drug exposure (AUC) analyzed after 9 days drugadministration of BEZU (0.1-200 mg/kg), AVA (0.3-100 mg/kg), or the AVA analog, elenestinib (ELE, 1-200mg/kg)... Overall, these analyses suggest that while partial inhibition of KIT achieved clinically mayyield a measurable clinical effect, substantially higher target coverage is likely needed to observesignificant impact on clonal mast cell expansion."

Preclinical • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

The effect of bezuclastinib on the pathobiology of mastocytosis: Changes in BM mast cells, tryptase, and KIT p.D816V variant allele frequency from the pivotal summit trial (ASH 2025) - P2 | "Substantial reductions of KIT p.D816V VAF in some cases to undetectable levels,normalization of serum tryptase, as well as normalization of BM MC percentage and morphology mayrepresent potential reversal of the underlying pathogenesis of SM. The effect of bezuclastinib treatmenton these disease markers and changes in BM MC characteristics will be presented. The impact oftreatment on the WHO criteria which define SM supports the mechanism of action of the targeted KITinhibitor bezuclastinib as a disease-modifying investigational therapeutic in NonAdvSM."

Hematological Malignancies • CD34 • IL2RA • TNFRSF8

Efficacy and safety results from the primary analysis of the pivotal summit trial: Bezuclastinib in adults with non-advanced systemic mastocytosis (ASH 2025) - P2 | "At 24-weeks, bezuclastinib 100 mg QD demonstrated statistically and clinically significantimprovements 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 thereal-world NonAdvSM population, including SSM. These results support the use of bezuclastinib toreduce SM burden and symptoms in pts with NonAdvSM, and a potentially disease-modifying impact."

Clinical • Metastases • Alopecia • Immunology • Musculoskeletal Pain

Cogent Biosciences Announces Positive Top-line Results of APEX Trial of Bezuclastinib in Patients with Advanced Systemic Mastocytosis (AdvSM) (GlobeNewswire) - "Based on these top-line data, Cogent expects to submit a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for bezuclastinib in AdvSM during the first half of 2026. In addition, Cogent plans to present detailed data from the APEX trial at an upcoming scientific meeting in the first half of 2026...Primary endpoint: 57% ORR (CR+CRh+PR+CI) per mIWG-MRT-ECNM (mIWG) criteria: 49% ORR (CR+CRh+PR) per mIWG; At the time of data cut-off, multiple additional patients had achieved unconfirmed response criteria and remain on study awaiting follow-up assessment; Key secondary endpoint: 80% ORR (CR+CRh+PR) per pure pathological response (PPR) criteria; Median time to achieve response was 2.0 months and median duration of response is not yet mature."

FDA filing • P2 data • Hematological Malignancies

Cogent Biosciences Presents Full SUMMIT Results of Bezuclastinib in Patients with NonAdvanced Systemic Mastocytosis (NonAdvSM) at the 67th Annual Meeting of the American Society of Hematology (ASH) (GlobeNewswire) - "Bezuclastinib achieves clear clinical benefit across all symptom domains including significant improvements on 11 individual symptoms plus the most severe symptom at baseline. Bezuclastinib demonstrates that reducing objective measures of disease, including serum tryptase, correlates with improvement in symptom severity; the first time this has been shown in NonAdvSM patients. New 48-week data demonstrate a clear, continued deepening of symptomatic improvement over time. Bezuclastinib demonstrated a favorable safety and tolerability profile supporting chronic use....New Drug Application (NDA) on track for submission in December 2025."

FDA filing • P2 data • Hematological Disorders • Rare Diseases

(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors (clinicaltrials.gov) - P3 | N=442 | Active, not recruiting | Sponsor: Cogent Biosciences, Inc. | Trial primary completion date: Jul 2025 ➔ Sep 2025

Trial primary completion date • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

BEZUCLASTINIB EXPANDED ACCESS PROGRAM (EAP) FOR PATIENTS WITH GASTROINTESTINAL STROMAL TUMORS (GIST) (CTOS 2025) - P, P3 | "Objective: Imatinib is the worldwide standard for first-line therapy of advanced KIT-mutant GIST...High selectivity of bezuclastinib allows it to be combined with sunitinib, which targets mutations in exons 9, 11, 13, and 14... N/A"

Clinical • Stroma • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

Bezuclastinib Expanded Access Program (EAP) for Patients With Systemic Mastocytosis (SM) (MPN 2025) - No abstract available

Clinical

Multiple bezuclastinib abstracts selected for presentation at the 67th Annual Meeting of the American Society of Hematology (ASH); SUMMIT data in NonAdvSM selected for two oral presentations (Cogent Biosciences Press Release) - "'On top of this progress, we recently presented updated preclinical data from our research pipeline that demonstrated potential best-in-class attributes of our pan-KRAS inhibitor and plan to describe for the first time at ASH 2025 our highly potent, highly selective JAK2 V617F mutant-selective inhibitor. Both of these programs are on track for IND in 2026.'"

Clinical data • IND • JAK2V617F • Preclinical • Hematological Malignancies

Safety and Efficacy of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM): Results from Part 1 of the Phase 2 Apex Trial (ASH 2023) - P2 | "Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the trial. Enrollment in Part 1 of the Apex trial is complete. Patients enrolled in Part 1 of the Apex trial are generally representative of the population of patients with AdvSM based on patient characteristics and markers of disease. Part 1 includes a small subset of patients with prior use of TKIs."

Clinical • Metastases • P2 data • Aggressive Systemic Mastocytosis • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Oncology • Rare Diseases • ASXL1 • RUNX1 • SRSF2

634. Myeloproliferative Syndromes: Clinical and Epidemiological: Treatment and Outcomes in MPNs (ASH 2023) - "Hydroxyurea and pegylated interferon are common first line treatments for MPN, each with potential advantages and disadvantages...Novel therapies include hepcidin mimetic rusfertide in PV and the LSD-1 inhibitor bomedemstat in ET. In mastocytosis, the KIT inhibitor bezuclastinib shows efficacy and safety in patients with indolent mastocytosis. In myeloid neoplasms with eosinophilia, a custom NGS panel is used to explore the molecular landscape in patients negative for tyrosine kinase fusion genes, identifying recurrent JAK/STAT mutations associated with response to JAK inhibitors."

Clinical • Cardiovascular • Eosinophilia • Essential Thrombocythemia • Hematological Disorders • Hematological Malignancies • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Polycythemia Vera • Thrombocytosis • Thrombosis

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) (ASH 2023) - P2 | "The Summit trial evaluating safety and efficacy of bezuclastinib enrolled 20 patients in Part 1a. The patients enrolled in Part 1a of the Summit trial are generally representative of the population of patients with moderate to severe nonadvanced systemic mastocytosis based on number of supportive care medications, symptom severity, and disease impact on HRQoL. Initial safety and efficacy results from Part 1a of the 3-part, randomized, double-blind, placebo-controlled Summit trial will be presented."

Clinical • Metastases • P2 data • Rare Diseases

Apex Part 2 Trial in Progress: A Phase 2 Open-Label Clinical Study of Bezuclastinib in Adult Patients with Advanced Systemic Mastocytosis (ASH 2024) - P2 | "In addition, a high-risk SM-AHN sub-study assessing the safety and feasibility of the combination of bezuclastinib 150 mg QD and azacitidine may enroll up to 20 patients who are currently receiving or indicated for azacitidine and have biopsy-proven SM with an associated high- or very high-risk myeloid neoplasm. Patients with SM-AHN from Part 1 or Part 2 who have demonstrated AHN progression may enroll in an additional rollover cohort to receive bezuclastinib with concomitant azacitidine or hydroxyurea."

Clinical • Metastases • P2 data • Tumor mutational burden • Aggressive Systemic Mastocytosis • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Oncology • TMB

Updated Efficacy and Safety Results of Patients Receiving Selected 100mg Bezuclastinib Dose and Participating in the Open-Label Extension of Summit: A Randomized, Double-Blind, Placebo Controlled Phase 2 Clinical Trial of Bezuclastinib in Adult Patients with Nonadvanced Systemic Mastocytosis (ASH 2024) - P2 | "The presentation will report on durability and safety/tolerability data beyond 12 wks for those pts randomized to 100 mg in Part 1 and pts who crossed over from PBO in Part 1 to 100mg in Part 3. Summit Part 2 is actively enrolling."

Clinical • Metastases • P2 data • Alzheimer's Disease • Cognitive Disorders • Fatigue • Gastroesophageal Reflux Disease • Hematological Disorders • Neutropenia • Rare Diseases

Apex Part 1: Updated Assessment of Bezuclastinib (CGT9486), a Selective KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM) (ASH 2024) - P2 | "TKI-naïve patients and those with a history of prior TKI therapy (e.g., avapritinib, midostaurin) or other treatments were permitted in the trial after appropriate washout. Conclusion : In Part 1 of the Apex trial, bezuclastinib is well tolerated and exhibits durable signs of clinical activity, with marked reductions in objective measures of mast cell burden. Based on a composite of safety/tolerability, efficacy, and pharmacokinetics, 150 mg daily has been chosen as the recommended dose."

Clinical • Metastases • Aggressive Systemic Mastocytosis • Alzheimer's Disease • Cognitive Disorders • Fatigue • Hematological Disorders • Hematological Malignancies • Hepatology • Leukemia • Liver Failure • Mast Cell Leukemia • Neutropenia • Oncology • Rare Diseases • Thrombocytopenia

Cogent Biosciences Reports Positive Results from Bezuclastinib PEAK Phase 3 Trial in Gastrointestinal Stromal Tumors (GIST) (GlobeNewswire) - "The combination reached a median progression free survival (mPFS) of 16.5 months compared to sunitinib monotherapy, which reached a mPFS of 9.2 months (HR=0.50, CI: 0.39-0.65; p<0.0001). In addition, the combination of bezuclastinib with sunitinib resulted in a 46% objective response rate (ORR) compared to 26% with sunitinib monotherapy (p<0.0001). Based on these data, Cogent is on track to submit a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for bezuclastinib in GIST in the first half of 2026. Cogent also plans to present detailed results from the PEAK trial at an upcoming scientific conference in the first half of 2026."

FDA filing • P3 data • Gastrointestinal Stromal Tumor

Cogent Biosciences Announces FDA Breakthrough Therapy Designation for Bezuclastinib (GlobeNewswire) - "The Breakthrough Therapy Designation is based on positive results from the registration-directed SUMMIT trial in which bezuclastinib achieved statistical significance across all primary and key secondary endpoints in patients with NonAdvSM, including the consistent benefit observed in populations with high unmet need."

Breakthrough therapy • Hematological Malignancies

…New Drug Application (NDA) filing for NonAdvSM remains on track for year-end 2025 (Cogent Biosciences Press Release)

FDA filing • Hematological Malignancies

Anticipated Upcoming Milestones (Cogent Biosciences Press Release) - "Announce top-line results from PEAK in November 2025. PEAK is a global, randomized Phase 3 clinical trial studying the combination of bezuclastinib and sunitinib versus sunitinib alone in patients with imatinib-resistant GIST; Announce top-line results from APEX in December 2025. APEX is a registration-directed, global, open-label trial in patients with AdvSM."

P2 data • P3 data: top line • Aggressive Systemic Mastocytosis • Gastrointestinal Stromal Tumor

SARC044: A Phase II Trial of Bezuclastinib in Combination With Sunitinib in Patients With GIST (clinicaltrials.gov) - P2 | N=40 | Active, not recruiting | Sponsor: Sarcoma Alliance for Research through Collaboration | Recruiting ➔ Active, not recruiting

Enrollment closed • Monotherapy • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

MODULE 5: Current and Future Management of Systemic Mastocytosis (SM) (ASH 2025) - "This program is supported by educational grants from Blueprint Medicines, Bristol Myers Squibb, GSK, and Incyte Corporation. Rationale for targeting the KIT D816V mutation in patients with SM; mechanism of action of avapritinib Published efficacy and safety findings from the pivotal Phase II PIONEER trial of avapritinib versus placebo for patients with indolent SM whose symptoms were not adequately controlled with standard therapy Outcomes achieved in key studies, such as EXPLORER and PATHFINDER, evaluating avapritinib for advanced SM Selection of patients with various SM subtypes for whom treatment with avapritinib would be appropriate Mechanistic similarities and differences between avapritinib and next-generation KIT D816V inhibitors, such as elenestinib and bezuclastinib; implications for efficacy and tolerability Preliminary safety and efficacy data with elenestinib for patients with indolent SM whose symptoms are not adequately controlled by best supportive care;..."

Myelofibrosis

Bezuclastinib Expanded Access Program (EAP) for Patients with Systemic Mastocytosis (SM) (JADPRO 2025) - "CNS-related adverse events have been observed with Type I engineered TKIs.(Chart: Bezulacnib concentration in brain vs. plasma compared to sunitinib)Nonclinical Data Suggests Optimal Activity Against Mastocytosis May Require Higher Exposure than Clinically Tolerable with Available TherapyI-Cell $D816V$ $KIT$ Assay: Bezulacnib achieved an $IC_{50}$ of $0.4 text{ nM}$, which was measured over 5 days with a maximum drug concentration of $1 text{ nM}$ (a clinically relevant target concentration).An exposure-response model predicted that a sustained exposure of Bezulacnib above $1 text{ nM}$ is required for maximal $D816V$ inhibition.(Table: Drug Exposure Ratio Measured in SM Mouse Model)Drug: Avapritinib; AUC (Total) ng*h/mL: 2100; Cmax (Total) ng/mL: 510Drug: Midostaurin; AUC (Total) ng*h/mL: 11100; Cmax (Total) ng/mL: 2500Drug: Bezulacnib; AUC (Total) ng*h/mL: 77100; Cmax (Total) ng/mL: 6180(Chart: MC Inhibitors in SM Mouse Model)CLINICAL RESULTS FOR INVESTIGATIONAL..."

Clinical • Aggressive Systemic Mastocytosis • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Rare Diseases

(Summit) A Study to Evaluate the Efficacy and Safety of CGT9486 Versus Placebo in Patients With Indolent or Smoldering Systemic Mastocytosis (clinicaltrials.gov) - P2 | N=237 | Active, not recruiting | Sponsor: Cogent Biosciences, Inc. | Trial primary completion date: Sep 2025 ➔ May 2025

Trial primary completion date

Tyrosine Kinase Inhibitors for Gastrointestinal Stromal Tumor After Imatinib Resistance. (PubMed, Pharmaceutics) - "Sunitinib, regorafenib, and ripretinib are currently approved as standard second-, third-, and fourth-line therapies, each demonstrating efficacy against distinct mutational profiles. Avapritinib, notably effective against PDGFRA D842V mutations, represents a milestone for previously untreatable subgroups. Several alternative agents-such as nilotinib, masitinib, sorafenib, dovitinib, pazopanib, and ponatinib-have shown varying degrees of success in refractory cases or specific genotypes. Investigational compounds, including crenolanib, bezuclastinib, famitinib, motesanib, midostaurin, IDRX-42, and olverembatinib, are under development to address resistant or wild-type GISTs...Future strategies include precision medicine approaches such as ctDNA-guided therapy, rational drug combinations, and novel drug delivery systems to optimize bioavailability and reduce toxicity. Ongoing research will be crucial for refining treatment sequencing and expanding therapeutic options,..."

Journal • Review • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • KIT • PDGFRA

Bezuclastinib Expanded Access Program for Patients with Systemic Mastocytosis (SOHO 2025) - P, P2 | "The duration of bezuclastinib treatment through the EAP will be determined by the treating physician but may continue until regulatory approval and commercial availability per indication. The EAP is currently open to receive EAP requests from treating physicians for patients residing in the United States."

Clinical • Aggressive Systemic Mastocytosis • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Oncology