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

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

Second Quarter 2025 Financial Results (Morningstar.com) - "Research and development expenses were $62.2 million for the second quarter of 2025 as compared to $54.3 million for the second quarter of 2024. The increase was primarily due to costs incurred to support our on-going SUMMIT, PEAK and APEX clinical trials and to the continued progression of our early stage, preclinical and discovery programs."

Commercial • Aggressive Systemic Mastocytosis • Gastrointestinal Stromal Tumor

Tyrosine Kinase Inhibitors for the Treatment of Mast Cell Diseases: Review and Update. (PubMed, J Investig Allergol Clin Immunol) - "TKIs represent a major advance in the management of MCDs, with more patients being able to benefit from a treatment that addresses pathophysiology. We review the main TKIs currently available for SM, their indications, and their safety and effectiveness."

Journal • Review • Bone Marrow Transplantation • Transplantation • KIT

Cogent remains on track to provide top-line results (GlobeNewswire) - "...both PEAK, a Phase 3 trial of bezuclastinib in combination with sunitinib in patients with gastrointestinal stromal tumors (GIST), and APEX, a registration-directed trial of bezuclastinib in advanced systemic mastocytosis (AdvSM) patients, during the second half of 2025."

FDA filing • P2 data • P3 data: top line • Gastrointestinal Stromal Tumor • Rare Diseases

Cogent Biosciences Announces Positive Top-line Results Achieving Statistical Significance Across All Primary and Key Secondary Endpoints from the SUMMIT Trial of Bezuclastinib in Patients with Non-Advanced Systemic Mastocytosis (GlobeNewswire) - P2 | N=207 | SUMMIT (NCT05186753) | Sponsor: Cogent Biosciences, Inc | "The SUMMIT trial, which was designed to assess the clinical benefit of bezuclastinib versus placebo, achieved its primary endpoint with a highly statistically significant difference in the mean change in total symptom score (TSS) at 24 weeks (p=0.0002). TSS was assessed by the Mastocytosis Symptom Severity Daily Diary (MS2D2). The bezuclastinib arm had a mean reduction of 24.3 points in TSS at 24 weeks, versus the placebo arm which had a mean reduction of 15.4 points in TSS, resulting in a placebo-adjusted TSS improvement of 8.91 points...Complete analysis of the full SUMMIT Part 2 data are ongoing, and Cogent plans to present detailed results at an upcoming major medical conference later this year...Cogent is on track to submit its first new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for bezuclastinib in NonAdvSM by the end of 2025."

FDA filing • P2 data • Rare Diseases

Cogent Biosciences Secures up to $400 Million in Non-Dilutive Financing (Yahoo Finance) - "Cogent Biosciences, Inc... announced it has secured a debt financing facility of up to $400 million with credit funds managed by SLR Capital Partners, LLC ('SLR')....Cogent remains on track in July to announce top-line results from SUMMIT, a registration-directed, randomized, double-blind, placebo-controlled, global, multicenter, clinical trial of bezuclastinib in patients with NonAdvSM. In the second half of 2025, Cogent is on track to release results from APEX, a registration-directed, global, open-label trial in patients with AdvSM. Finally, before the end of 2025, Cogent expects to release results from PEAK, a global, blinded, randomized Phase 3 clinical trial studying the combination of bezuclastinib and sunitinib versus sunitinib alone in patients with imatinib-resistant GIST....Facility provides additional funding for next steps of the Company’s growth, including the expected launch of bezuclastinib in 2026."

Financing • Launch • P2 data • P3 data • Aggressive Systemic Mastocytosis • Colorectal Gastrointestinal Stromal Tumors • Mast Cell Leukemia

New treatments for systemic mastocytosis in 2025. (PubMed, Curr Opin Allergy Clin Immunol) - "Despite the considerable therapeutic progress in recent years, systemic mastocytosis is an incurable disease. In the last 20 years, the management of systemic mastocytosis has transformed from a one-size-fits-all approach, characterized by nonspecific cytoreductive drugs, to a tailored strategy focused on increasingly precise molecular targets, with the most notable example being the KIT inhibitors. Recently, the FDA and EMA have approved two drugs for treating systemic mastocytosis: avapritinib and midostaurin. Moreover, numerous trials are currently assessing the efficacy of new molecules: most are testing new-generation KIT inhibitors (ripretinib, bezuclastinib, elenestinib, masitinib, nintedanib), others focusing on Bruton's kinase (TL-895), interleukin-6 (sarilumab), sialic acid-binding immunoglobulin-like lectin-8 (lirentelimab), mTOR and CD33, among others. Real-life data are needed to confirm preliminary preclinical results."

Journal • Aggressive Systemic Mastocytosis • CD33 • IL6

SARC044: A phase II trial of bezuclastinib in combination with sunitinib in patients with GIST who progressed on sunitinib monotherapy. (ASCO 2025) - P2, P3 | " SARC044 is a multi-center, open label, single-arm phase II trial enrolling up to 40 adult pts with KIT exon 9 or 11-mutant GIST resistant to imatinib and SUN. 35 evaluable pts achieves 83% power (p<0.05, one-sided) in a one-sample log-rank test to detect a mPFS of 6.5 mo vs 4 mo (historic control). Expected accrual is 12 mo across 4 sites in the United States with ~36 mo to study completion."

Clinical • Combination therapy • Monotherapy • P2 data • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor

(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. | Recruiting ➔ Active, not recruiting

Enrollment closed • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

Expanded Access to Bezuclastinib to be Coadministered With Sunitinib for Patients With Gastrointestinal Stromal Tumors (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Cogent Biosciences, Inc.

New trial • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

Expanded Access to Bezuclastinib for Patients With NonAdvanced Systemic Mastocytosis or Advanced Systemic Mastocytosis (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Cogent Biosciences, Inc.

New trial

Fourth Quarter and Full Year 2024 Financial Results (GlobeNewswire) - "Research and development expenses were $62.0 million for the fourth quarter of 2024 and $232.7 million for the year ended December 31, 2024, as compared to $48.7 million for the fourth quarter of 2023 and $173.8 million for the year ended December 31, 2023. The increase was driven by the development of bezuclastinib, including costs associated with the accelerated completion of enrollment of the SUMMIT and PEAK trials and ongoing cost of the APEX trial, and the continued progression of our research pipeline. R&D expenses include non-cash stock compensation expense of $5.0 million for the fourth quarter of 2024 and $19.0 million for the year ended December 31, 2024, as compared to $4.1 million for the fourth quarter of 2023 and $14.6 million for the year ended December 31, 2023."

Commercial • Aggressive Systemic Mastocytosis • Gastrointestinal Stromal Tumor • Rare Diseases

CGT9486 (Formerly Known as PLX9486) as a Single Agent and in Combination With PLX3397 (Pexidartinib) or Sunitinib in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=51 | Completed | Sponsor: Cogent Biosciences, Inc. | Phase classification: P1b ➔ P1/2

Phase classification • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor

Efficacy and Safety Results of Adult Patients with NonAdvanced Systemic Mastocytosis Receiving Bezuclastinib 100 mg in the Ongoing Summit Trial: A Randomized, Double-Blind, Placebo Controlled Phase 2 Clinical Trial of Bezuclastinib (AAAAI-WAO 2025) - P2 | "TEAEs observed in OLE were comparable to Part 1. Conclusions Favorable safety and clinically meaningful improvements in symptoms were demonstrated with bezu-100 at 12 weeks in Part 1 that continued into OLE."

Clinical • Metastases • P2 data

Cogent Biosciences Announces Bezuclastinib Poster in NonAdvanced Systemic Mastocytosis (NonAdvSM) at the 2025 AAAAI Annual Meeting (GlobeNewswire) - "Cogent Biosciences, Inc...today announced an upcoming poster for bezuclastinib at the 2025 American Academy of Allergy Asthma & Immunology Annual Meeting (AAAAI) being held in San Diego, CA, February 28-March 3, 2025."

P2 data • Rare Diseases

Bezuclastinib With Sunitinib Improves Safety, Efficacy in Patients With GIST (Target Oncol) - P3 | N=442 | Peak (NCT05208047) | Sponsor: Cogent Biosciences, Inc. | "In the randomized, open-label, multicenter trial, the median progression-free survival (PFS) in all patients (n = 42) was 10.2 months (95% CI, 7.4-19.4), with a 2.5 (range, 1-6) median number of prior tyrosine kinase inhibitors (TKI). The median PFS in patients receiving the combination in the second-line following imatinib (Gleevec) was 19.4 months (95% CI, 1.0–not estimable). Notably, 3 of 7 patients treated with 1 prior TKI remain on the treatment beyond 19 months...Looking to responses observed per investigator assessment, treatment with bezuclastinib plus sunitinib resulted in an objective response rate of 27.5% in all patients and 33% in patients with prior imatinib. In all patients, 27.5% had a partial response, 57.5% had stable disease, and 15.0% had progressive disease. Additionally, the disease control rate was 80%."

P3 data • Gastrointestinal Stromal Tumor

Peak part 1 summary: A phase 3, randomized, open-label, multicenter clinical study of bezuclastinib (CGT9486) and sunitinib combination versus sunitinib in patients with gastrointestinal stromal tumors (GIST). (ASCO-GI 2025) - P3 | "Funded by Cogent Biosciences Clinical Trial Registration Number: NCT05208047 Background: After initial response to first line therapy with imatinib, GISTs commonly progress due to secondary resistance mutations in KIT. Data from Peak Part 1 show an encouraging safety and tolerability profile generally consistent with published sunitinib monotherapy experience. ORR in evaluable pts from Part 1 was 20%; ORR in 2nd line pts was 33%. Part 2 of the Peak study is actively enrolling pts globally at the selected dose of bezuclastinib 600 mg QD + sunitinib 37.5 mg QD versus sunitinib 37.5 mg QD."

Clinical • P3 data • Stroma • Gastrointestinal Cancer • Oncology • KIT

Cogent Biosciences Announces Planned 2025 Milestones for Bezuclastinib and Emerging Portfolio of Selective and Potent Targeted Therapeutics (GlobeNewswire) - "Report top-line results in July 2025 from the SUMMIT trial...Report top-line results during the second half of 2025 from the APEX trial...Submit the first bezuclastinib New Drug Application (NDA) by the end of 2025...Report top-line results by the end of 2025 from the pivotal Phase 3 PEAK trial...During Q1 2025, initiate Expanded Access Programs (EAP) in the U.S. for SM and GIST patients to receive investigational bezuclastinib after meeting certain eligibility criteria."

FDA filing • New trial • P2 data • P3 data: top line • Aggressive Systemic Mastocytosis • Gastrointestinal Stromal Tumor

(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=207 | Active, not recruiting | Sponsor: Cogent Biosciences, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed

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

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 • Oncology • 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 Disorders • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Oncology • TMB

Study Spotlight: SARC044 Phase Il bezuclastinib in combination with sunitinib in patients with GIST who progressed on sunitinib monotherapy (CTOS 2024) - No abstract available

Clinical • Combination therapy • Monotherapy • Oncology

SARC044: A PHASE II TRIAL OF BEZUCLASTINIB IN COMBINATION WITH SUNITINIB IN PATIENTS WITH GIST WHO PROGRESSED ON SUNITINIB MONOTHERAPY (CTOS 2024) - P2, P3 | "SARC044 (NCT06208748) investigates bezuclastinib + sunitinib in patients with sunitinib-resistant, KIT-mutant GIST, and incorporates robust correlatives to determine mechanisms of treatment resistance and response. SARC044 is a multi-center, open label, single-arm phase II trial enrolling up to 40 adult patients with KIT exon 9 or 11-mutant GIST resistant to imatinib and sunitinib monotherapy. N/A, No conclusion for this abstract type."

Clinical • Combination therapy • Monotherapy • P2 data • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor

FMC60: Mastocytosis and mast cell activation syndromes: diagnostic and therapeutic progress in 2024. (JDP 2024) - "Therapeutically, there is cladribine (off-label) which retains a place and avapritinib which is a tyrosine kinase inhibitor (TKI) which has obtained European marketing authorization for indolent systemic forms and also advanced forms. Other TKIs, such as elenestinib and bezuclastinib, are in phase 2 trials...Educational objectives The educational objectives are to better understand mast cell pathologies and what to do when faced with a patient with a suspicion or diagnosis of mast cell pathology with a therapeutic proposal. Content of this training Clinical cases, new developments, literature review and sharing of experience."

Dermatology