Ayvakit (avapritinib) / CStone Pharma, Sanofi - LARVOL DELTA

Systemic mastocytosis with associated lymphoid neoplasms (SM-ALN): A distinct subset with indolent clinical course and favorable outcomes (ASH 2025) - "SM management was divided into two categories: (1) Conservative approach, including observation alone in 4 patients (22%) and symptomatic therapies such as antihistamines or leukotriene inhibitors in 7 (39%); and (2) Cytoreductive treatments, comprising avapritinib in 5 patients (28%), cladribine in 1 (6%), and imatinib in 1 (6%). Management of lymphoid neoplasms included intensive regimens such as R-CHOP and hyper-CVAD for high-grade subtypes (e.g., DLBCL and T-ALL), while indolent forms (e.g., CLL and follicular lymphoma) were treated with bendamustine-rituximab or observation depending on disease burden... SM-ALN is a rare but distinct SM subtype characterized by indolent behavior, favorable treatment responses, and prolonged survival. Recognition of this subset is critical to avoid over-treatment and to guide risk-adapted management strategies."

Clinical • Acute Lymphocytic Leukemia • Aggressive Systemic Mastocytosis • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Dermatology • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Indolent Lymphoma • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Pruritus • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma • ASXL1 • CCND3 • CXCR4 • DNMT3A • IDH1 • JAK2 • KIT • MYD88 • NOTCH2 • RUNX1 • SF3B1 • SRSF2 • TET2 • TP53

primary CD34+ derived mast cells provide an excellent platform to assess single agent and combination therapies for mastocytosis (ASH 2025) - "Multiple compounds targeting different receptors have been used to treat mastocytosis including Omalizumab (FcεR1A), Avapritinib (CD117), Budesonide (glucocorticoid receptor) and Salmetrol (β2 adrenergic receptors). Combinations of Avapritinib (dose response) with Omalizumb at 1 nM significantly increased the degranulation with a mean IC 50 value of 85 nM for Avapritinib. This data confirm primary MPB CD34+ cell derived mast cells provide an excellent in vitro platform with an unlimited supply of cells to assess single agent and combinations for mastocytosis and other mast cell diseases."

Combination therapy • Asthma • Cardiovascular • Dermatology • Immunology • Inflammatory Arthritis • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Rosacea • CD34 • CD63 • CORT • IL6 • KIT

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

Improved overall survival in patients with advanced systemic mastocytosis treated with avapritinib versus real-world therapy based on mutation-adjusted risk score (MARS) stratification (ASH 2025) - P=N/A, P1, P2 | "This analysis builds on the earlier work, comparing OS betweenintermediate- and high-risk MARS pts treated with Ava (200 mg/day starting dose) in the PATHFINDER trialand those treated with BAT in real-world (RW) clinical practice.MethodsData from the PATHFINDER trial (median follow-up: 38.0 months) and a RW retrospective chart reviewstudy (NCT04695431) conducted at six global sites, were used to compare OS between pts treated with 1LAva vs 1L Mido, and 2L+ Ava vs 2L+ BAT, which was predominantly Mido and cladribine (Clad)...Common 2L+ BAT agents included Mido (47.5%), Clad (34.4%), and hydroxyurea (8.2%)...After adjustment, OSwas significantly improved in Ava vs BAT pts (HR [95% CI]: 0.31 [0.13, 0.74]; p=0.008).ConclusionsAmong the combined cohort of MARS intermediate- and high-risk AdvSM pts, avapritinib was associatedwith significantly improved OS compared to midostaurin in the 1L setting and BAT in the 2L+ setting,including in the SM-AHN subgroup. This..."

Clinical • Metastases • Real-world • Real-world evidence • Aggressive Systemic Mastocytosis • Hematological Disorders • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Thrombocytopenia • ASXL1 • RUNX1 • SRSF2

Changes in long-term bone health in patients receiving avapritinib for the treatment of indolent systemic mastocytosis in the pioneer study (ASH 2025) - P2 | "Long-term avapritinib therapy (~3 years) led to improvements in BMD. These favorable changes wereobserved regardless of concomitant use of other medications known to increase bone density.Unexpectedly, TRAcP-5b was lower at baseline in patients with ISM from PIONEER compared to healthydonors and an increase in TRAcP-5b was observed while on avapritinib. These results provide an impetusfor pursuing longitudinal follow-up studies assessing changes in BMD and bone dysregulation with KITD816V-targeted therapy in larger cohorts of patients with ISM."

Clinical • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • TRAP

Diagnostic evolution in systemic mastocytosis: Clinical impact of who 2022 criteria on smoldering systemic mastocytosis identification in pioneer (ASH 2025) - P2 | "The PIONEER (NCT03731260) study, which ledto the approval of avapritinib for the treatment of ISM, includes one of the largest, most well-characterized populations of patients with ISM, per WHO 2016 criteria... The expansion of the B-finding definitions from WHO 2016 to WHO 2022 led to considerablymore patients meeting the high MC burden B-finding (4 vs 53 patients) and led to an increase in thenumber of patients with SSM enrolled on PIONEER from 0 to 8. These findings highlight the heterogeneityof ISM.KIT D816V VAF is a disease burden finding distinct from serum tryptase and BM MC. The specific KITD816V VAF threshold that best correlates with prognostic risk has yet to be determined and needs to befurther explored."

Clinical • Hematological Malignancies • Myelodysplastic Syndrome • DNMT3A • KIT • TET2 • TP53

An analysis of clonal dynamics in patients with indolent systemic mastocytosis treated with avapritinib in the pioneer study (ASH 2025) - P2 | "Longer-term avapritinib therapy is associated with favorable clonal dynamics in patients with ISM. Afternearly a year of therapy, there was no emergence of drug-resistance mutations in KIT, nor theappearance of additional pathogenic mutations in other genes commonly implicated in hematologicmalignancies. These data suggest that avapritinib treatment in ISM does not promote the emergence ofclonal hematopoiesis and, in some cases, is associated with regression of abnormal clones.Understanding whether treatment can modify rates of progression to SM with associated hematologicalneoplasms would require larger prospective studies and longer follow-up."

Clinical • Hematological Malignancies • DNMT3A • TET2 • TP53

Avapritinib treatment of patients with advanced systemic mastocytosis: 4-year safety, effect on bone and first-line efficacy results of the pathfinder clinical study (ASH 2025) - P2 | "With a median follow-up of ~4 years, avapritinib showed durable effects including prolonged OS as 1Ltherapy regardless of AdvSM subtype. Improved effects on bone, including BD in the BDlow group andBTM normalization were observed. These results and the well-characterized and favorable benefit-riskprofile, highlight the disease-modifying effects of avapritinib and support its long-term use for AdvSM,particularly as a 1L treatment."

Clinical • Metastases • Hematological Disorders • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Myeloproliferative Neoplasm • Thrombocytopenia • KIT • TRAP

Investigating the clonal and biological underpinnings of systemic mastocytosis with an associated hematological neoplasm (ASH 2025) - "Therefore we hypothesized that the use of Avapritinib in our heterotopic model would leadto potent inhibition of mast cell tumors and a subsequent loss of monocytic proliferative suppression.Indeed treatment with 30mg/kg for 6 days resulted in a rescue of monocytic leukemia growth in theAvapritinib treated group supporting the notion that AHN progression is likely due to the loss of mast-cellderived secreted factors which suppress monocytic leukemia (fold change bilateral vs single: U937vehicle=0.39 p=0.009, U937 Avapritinib=0.92 p=0.75 n=5 per group). RNA-sequencing of tumors, broadcytokine profiling, and phosphoproteomics are underway to identify networks that are responsible forour observed phenotype and may be leveraged as therapy for both CMML and SM-AHN."

Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • IL2RA

Real-world evidence demonstrates superior overall survival and favorable safety of avapritinib over midostaurin in newly diagnosed advanced systemic mastocytosis (ASH 2025) - "In this large, real-world analysis of first-line therapy for AdvSM, avapritinib was associated with astatistically significant and clinically meaningful improvement in overall survival compared tomidostaurin. These findings, coupled with a favorable observed safety profile, support the preferentialuse of avapritinib in the first-line treatment of Advanced Systemic Mastocytosis."

Clinical • HEOR • Metastases • Real-world • Real-world evidence • Aggressive Systemic Mastocytosis • Cerebral Hemorrhage • CNS Disorders • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Musculoskeletal Diseases • Orthopedics • Rheumatology • KIT

Effect of avapritinib on skin lesions in patients with advanced systemic mastocytosis using a novel, artificial intelligence-based technology (ASH 2025) - P2 | "Of the 34 patients withskin assessments, 30 patients were response-evaluable with ORR (95% confidence interval) of 73% (54–88).ConclusionAvapritinib treatment in patients with AdvSM resulted in rapid reductions in affected skin lesion area andimprovement in skin lesion color in the majority of patients that was sustained for more than 1 year. Thevisible and patient-reported improvement in skin symptoms augment observed, sustained efficacy in thiscohort of patients."

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

Avapritinib achieves deep and durable symptom control with a well-tolerated safety profile in ism: Long-term outcomes from pioneer (ASH 2025) - P2 | "Longer follow-up of patients with ISM treated on the PIONEER trial, including some on avapritinib for upto 5 years, demonstrates that prolonged avapritinib therapy continues to be effective and well tolerated. Additional prospective analyses will be needed to determine effects of selective KIT D816V-inhibition onanaphylaxis. These data support a favorable benefit-risk profile of avapritinib as a chronic treatment foradult patients with ISM."

Clinical • Myelodysplastic Syndrome

The efficacy of avapritinib for unresectable or metastatic gastrointestinal stromal tumors with and without PDGFRA D842V mutations: A meta-analysis. (ASCO-GI 2026) - "The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Metastases • Retrospective data • Stroma • Gastrointestinal Cancer • Oncology • PDGFRA

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (SNO 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • CNS Tumor • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • MCL1 • PDGFRA

Consideration of Off-Label Therapies as Appropriate Comparator Therapy in Early Benefit Assessments in Germany Under the ALBVVG Legislation (ISPOR-EU 2025) - "The G-BA decisions regarding the choice of ACT were analyzed with a focus on the reasoning provided in the supporting documents. The selected EBA procedures showed varying outcomes: For dupilumab (eosinophilic esophagitis), an established off-label therapy was considered appropriate based on evidence-based guidelines and extensive clinical experience. For midostaurin (systemic mastocytosis), avapritinib, cladribine, and imatinib were recognized as ACT despite not all being approved for the corresponding indication, acknowledging their established role in treatment algorithms. For lisocabtagene maraleucel (various B-cell lymphomas after prior therapy), off-label use was deemed appropriate, particularly considering the disease severity and limited therapeutic alternatives for these vulnerable patients. Conversely, for talazoparib (metastatic castration-resistant prostate carcinoma), the off-label use of abiraterone acetate with prednisone/prednisolone and enzalutamide was..."

B Cell Lymphoma • Castration-Resistant Prostate Cancer • Eosinophilic Esophagitis • Gastrointestinal Disorder • Genito-urinary Cancer • Hematological Malignancies • Immunology • Lymphoma • Non-Hodgkin’s Lymphoma • Prostate Cancer • Solid Tumor

PATHFINDER: Survival Benefits in Intermediate- and High-Risk Patients with Advanced SM, a Historically Underserved Population (Poster Presentation; Abstract Number 5595) (PRNewswire) - "This analysis included patients with advanced SM who had intermediate- and high-risk prognostic scores at baseline, as determined by the Mutation-Adjusted Risk Score (MARS); In the treatment-naïve setting, PATHFINDER results for AYVAKIT (n=24) were indirectly compared to real-world data for midostaurin (n=43), and statistical methods were used to adjust for baseline demographic differences between the two patient populations; AYVAKIT was associated with improved OS relative to midostaurin (Hazard Ratio [HR]: 0.08; p<0.001) in these patients, who have traditionally had the worst prognosis."

P2 data • Aggressive Systemic Mastocytosis

PATHFINDER: Prolonged Survival, Robust Clinical Responses and Improved Bone Health with a Consistent Safety Profile Over Time in Advanced SM (Oral Presentation; Abstract Number 1022) (PRNewswire) - "In patients with advanced SM receiving first-line AYVAKIT (n=38), the median overall survival (OS) was not reached and the OS rate at 48 months was 79 percent after a median follow-up of more than four years, reflecting sustained clinical benefit; In treatment-naïve patients who were response evaluable (n=30), the overall response rate (ORR) was 87 percent, and the rate of complete remissions with full or partial hematologic recovery (CR/CRh) was 43 percent."

P2 data • Aggressive Systemic Mastocytosis

PIONEER: Durable Symptom Control, Quality-of-Life Benefits and Bone Health Improvements in ISM, with a Multi-Year Safety Profile Similar to the 24-Week Placebo-Controlled Portion of the Trial (Poster Presentations; Abstract Numbers 2024, 5582) (PRNewswire) - "In patients with ISM (N=226), AYVAKIT showed sustained improvements in overall symptoms, all symptom domains (skin, gastrointestinal, neurocognitive) and most severe symptom per the ISM Symptom Assessment Form (ISM-SAF), and in quality of life per the Mastocytosis Quality of Life Questionnaire (MC-QoL). AYVAKIT led to durable benefits in bone health among patients receiving dual-energy X-ray absorptiometry (DXA) scans (n=79), independent of concomitant use of other treatments known to improve bone density. "

P2 data • Hematological Disorders

Investigating neuroimmune-tumor interactions and oncological therapy responses in human brain organoid model of diffuse midline glioma (SNO 2025) - "A high dose of temozolomide, a standard-of-care chemotherapy prescribed for glioblastoma patients, did not show any reduction in tumor infiltration. Our innovative MiCBO-DMG fusion model is a biologically complex, reproducible, and scalable platform for DMG mechanism investigation and therapy screening."

Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor • PDGFRA

Preclinical Efficacy of Brain Penetrant, Single Agent Avapritinib in PDGFRA EcDNA-amplified Glioblastoma (SNO 2025) - "Similar to 5-week treatment, continuous avapritinib therapy improved xenograft survival (log rank p > 0.0001; n≥8/group), increasing median survival by an additional 4 days in males. Our work validates PDGFRA ecDNA as a predictive biomarker for PDGFRA-targeted therapies and justifies the clinical implementation of avapritinib in the treatment of PDGFRA-altered brain tumors."

Preclinical • Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Solid Tumor • PDGFRA

FDA-approved drug repurposing identifies small molecules with antitumor activity and temozolomide sensitization in glioblastoma (SNO 2025) - "Three agents - decitabine, raloxifene, and gefitinib – the targets of which are upregulated in GBM, demonstrated selective toxicity in ≥6 GBM models and collectively covered all 12. As a single agent, avapritinib significantly reduced viability in all GBM lines – especially of interest given its preliminary efficacy in pediatric high-grade glioma...Further in vitro and in vivo experiments are in progress. These findings nominate several drug candidates for rapid clinical evaluation in GBM."

Brain Cancer • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor • PDGFRA

A Non-Interventional Study in Participants With Indolent Systemic Mastocytosis (ISM) in Germany (clinicaltrials.gov) - P=N/A | N=80 | Not yet recruiting | Sponsor: Blueprint Medicines Corporation

New trial • Real-world evidence

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (WFNOS 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • CNS Tumor • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • MCL1 • PDGFRA

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (WFNOS 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • Pediatrics • Solid Tumor • MCL1 • PDGFRA

BGS-2456 Is a Novel Potent Covalent Inhibitor of FLT3 That Highly Discriminates Against KIT and Is Not Toxic Toward Normal Hematopoiesis in Vitro (ASH 2023) - "While there are numerous examples of KIT TKIs that do not inhibit FLT3 (imatinib, avapritinib, dasatinib), to date, all clinically active FLT3 TKIs (quizartinib, gilteritinib, midostaurin, sorafenib) fail to spare KIT inhibition...Compared to FF-10101 and gilteritinib, BGS-2456 exhibited the least amount of hematologic toxicity, facilitating in vitro proliferation and differentiation of normal hematopoietic progenitor cells even at 100x EC50 concentration against Molm14 cells... This is the first description of a potent and exquisitely specific FLT3 inhibitor that spares KIT inhibition and displays no myelosuppression in vitro at >100x EC50 concentration. The potent inhibitory effects of BGS-2456 on both D835Y and F691L mutants support its promise as a best-in-class TKI for the treatment of FLT3-mutant AML. Efforts to molecularly dissect the basis of the high degree of selectivity of BGS-2456 are ongoing."

Preclinical • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Hematological Disorders • Oncology • Sarcoma • ABL1 • CSF1R • FLT3 • PDGFRA