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

Acute Myelocytic Leukemia with Monosomy 7 in a Patient with Indolent Systemic Mastocytosis (ACAAI 2025) - "Case Description A 73-year-old female with cKIT D816V-positive ISM on avapritinib was admitted inpatient due to progressively worsening generalized weakness and epistaxis...Due to her age and inability to tolerate more toxic chemotherapy, the patient was treated with azacitidine and venetoclax instead of cytarabine and anthracycline...Discussion Clinical deterioration is not always due to ISM recrudescence and can instead be due to the rare development of a second malignancy such as AML, especially in the setting of cytogenetic abnormalities (e.g., monosomy 7). A timely diagnosis is possible with regular monitoring of symptoms and laboratories, which may improve clinical outcomes."

Clinical • Acute Myelogenous Leukemia • Anemia • Febrile Neutropenia • Hematological Malignancies • Leukemia

A Rare Case of Telangiectasia Macularis Eruptiva Perstans with Avapritinib Response Despite Negative Systemic Evaluation (ACAAI 2025) - "Over the years, she received multiple therapies including cetirizine, famotidine, UV therapy, omalizumab, cromolyn, and topical ruxolitinib, all without significant benefit. Although the patient did not meet classic WHO criteria for systemic disease, her response to avapritinib, a selective KIT D816V inhibitor, supports an underlying pathologic mast cell process. This underscores the potential role of targeted therapy in cutaneous mastocytosis and suggests that molecular profiling may be a key therapeutic guide in select cases."

Clinical • Ophthalmology • Rare Diseases • KIT

Severe New-Onset Brazil Nut Anaphylaxis Reveals Underlying Indolent Systemic Mastocytosis in a Young Adult (ACAAI 2025) - "He was placed on avapritinib by a local allergist, despite the negative KIT mutation testing, and experienced significant improvement both objectively and symptomatically, with tryptase decreasing from 27 to 10 µg/L and improvement in exercise-induced pruritus. Elevated tryptase levels and confirmatory bone marrow findings established the diagnosis. Patients with ISM require lifelong education, epinephrine access, and avoidance strategies."

Clinical • Dermatology • Food Hypersensitivity • Hypotension • Immunology • Pruritus • Urticaria • CD2 • IL2RA • ISG20 • KIT

Symptom Severity Reduction Observed with Avapritinib in Indolent Systemic Mastocytosis: Analysis of the PIONEER Study (ACAAI 2025) - P2 | "Conclusions Avapritinib-treated patients continued to experience improvements in symptoms and QoL through 3 years. Avapritinib was generally well tolerated with longer-term treatment."

KIT

Association of Hereditary a-Tryptasemia with Indolent Systemic Mastocytosis Characteristics and Avapritinib Response in PIONEER (ACAAI 2025) - P2 | "HαT+ patients had statistically significant higher baseline tryptase values and lower KIT D816V VAF vs HαT- patients. Symptoms and disease biomarker reduction were similar in both groups following avapritinib treatment."

TPSAB1

Lampson B, Zakharyan A, Shimony SO, Shi H, Deangelo D. Analysis of avapritinib clinical trial data generates a highly accurate predictive model for advanced systemic mastocytosis versus indolent systemic mastocytosis based on peripheral blood testing. Blood. 2024;144(suppl 1):107. (PubMed, Blood) - No abstract available

Journal

Investigating neuroimmune-tumor interactions and oncological therapy responses in human brain organoid model of diffuse midline glioma (WFNOS 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

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

Preclinical Efficacy of Brain Penetrant, Single Agent Avapritinib in PDGFRA EcDNA-amplified Glioblastoma (WFNOS 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 • Pediatrics • Solid Tumor • PDGFRA

FDA-approved drug repurposing identifies small molecules with antitumor activity and temozolomide sensitization in glioblastoma (WFNOS 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 • Pediatrics • Solid Tumor • PDGFRA

MARS-R: The Revised Mutation-Adjusted Risk Score for Predicting Overall Survival in Patients with Advanced Systemic Mastocytosis Treated with Midostaurin or Avapritinib (DGHO 2025) - P1, P2 | "MARS-R stratifies AdvSM pts taking ava or mido into 3 risk categories and serves as a tool that may help guide treatment of AdvSM pts."

Clinical • Metastases • Myeloproliferative Neoplasm • ASXL1 • RUNX1 • SETBP1

Overall Survival and Duration of Treatment in Patients with Advanced Systemic Mastocytosis Receiving Avapritinib Versus Midostaurin or Best Available Therapy in a Real-World Setting (DGHO 2025) - P=N/A, P2 | "In 1L IPTW-weighted Cox analyses, OS (hazard ratio [HR] [95% CI]: 0.19 [0.06, 0.57]; P=0.003) and DOT (HR [95% CI]: 0.37 [0.19, 0.70]; P=0.002) were significantly longer in avapritinib- vs midostaurin-treated patients.2L+ BAT patients contributed data on 104 lines of therapy. Common 2L+ agents were midostaurin (46.1%), cladribine (32.6%), and hydroxyurea (7.9%). This study supports the use of avapritinib for AdvSM for patients with prior treatment, demonstrating significant OS and DOT benefits vs 1L midostaurin and 2L+ BAT, respectively."

Clinical • Metastases • Real-world • Real-world evidence • Myeloproliferative Neoplasm

Avapritinib, imatinib and pioglitazone for the treatment of metastatic gastrointestinal stromal tumors (GIST) harboring dual mutations in KIT exons 9/17: a case report (DGHO 2025) - "A relapse occurred in 2018, leading to guideline-based treatment with sunitinib, regorafenib and ripretinib administered intermittently...However, this combination caused angiodysplastic bleeding as a side effect, which was managed through off-label treatment with bevacizumab... In personalized oncology, traditional trials face challenges with small participant numbers and delayed results, highlighting the importance of publishing off-label therapy outcomes as case reports. However, the vast majority of treatments remain unpublished, necessitating the development of new digital AI-supported platforms for collecting real-world data of innovative off-label treatments, thus enabling the development of decision support in personalized oncology for multidisciplinary teams."

Case report • Clinical • Metastases • Stroma • Chronic Myeloid Leukemia • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Hematological Malignancies • Leukemia • Oncology • Sarcoma • HIF1A • KIT

Clonal architecture of multimutated systemic mastocytosis with associated hematologic neoplasm (SM-AHN) with three phenotypic driver mutations (DGHO 2025) - "In patient #1, treatment with avapritinib (median dose 75mg/day due to side effects) for six months resulted in normalization of leukocytosis and monocytosis, serum tryptase levels slightly increased...Because of short duration, treatment with midostaurin in patient #2 cannot be assessed yet. The CFU-GM assays in two patients prove three independent phenotype clones. The CFU-GM assays in two patients prove three independent phenotype clones. Additional somatic mutations were identified in all three phenotype clones suggesting later acquisition of the phenotype mutations. Targeting one clone may confer expansion of other clones, thereby supporting the rationale for dual inhibitory approaches in these patients."

Hematological Malignancies • ASXL1 • JAK2 • SF3B1 • SRSF2 • U2AF1

KIT-targeting drugs in the management of non-advanced and advanced systemic mastocytosis. (PubMed, J Allergy Clin Immunol Pract) - "Here we discuss the diagnosis and treatment of two patients with KIT D816V positive SM, one with AdvSM and one with ISM, both of whom received KIT-targeted therapies. In addition to clinical presentations caused by a combination of mast cell (MC) mediator symptoms and consequences from MC infiltration of different organ systems, the diagnostic work-up included qualitative and quantitative assessment of variably affected key parameters from (i) peripheral blood (e.g., blood counts, serum tryptase and other serum markers, variant allele frequency [VAF] of KIT D816V and additional somatic mutations), (ii) BM MC infiltration, KIT D816V VAF, presence/absence of an AHN/AMN, cytogenetic analysis and (iii) organ infiltration/dysfunction (primarily affecting skin, bone/BM and visceral organs)."

Journal • Aggressive Systemic Mastocytosis • Hematological Disorders • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Oncology

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

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

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

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 • Anemia • Hematological Disorders • Hematological Malignancies • Leukemia • Mast Cell Leukemia • Thrombocytopenia • ASXL1 • RUNX1 • SRSF2

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 • Anemia • 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."

IL2RA

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

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

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