P1, N=10, Completed, Blueprint Medicines Corporation | Recruiting --> Completed | N=20 --> 10 | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Nov 2023 --> Mar 2024

Furthermore, we evaluated the sensitivity of these mutants to three FDA-approved tyrosine kinase inhibitors: imatinib, dasatinib, and avapritinib, which effectively suppressed the constitutive activity of the mutant receptors. Interestingly, K385M was reported in a few cases of brain tumors but not in MGNT. Our results provide valuable insights into the molecular mechanism underlying the activation of PDGFRα by the K385I/L mutations, highlighting their potential as actionable targets in the treatment of myxoid glioneuronal tumors.

P1, N=34, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

P2, N=50, Recruiting, Children's Hospital of Soochow University

No abstract available

Avapritinib and midostaurin can also temper IgE-mediated degranulation...Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM...Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.

Against this background, we solve the crystal structures of avapritinib in complex with wild-type and mutant PDGFRA and stem cell factor receptor (KIT), which provide evidence and understanding of inhibitor binding and lead to the identification of a sub-pocket (Gα-pocket). We utilize this information to design, synthesize and characterize avapritinib derivatives for the determination of key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration.

Moreover, mutations in Kit exon 9 and 11 are actionable, due to their response to imatinib, while mutations in PDGFRA respond to sunitinib and/or avapritinib. This allows the clinician to have an accurate picture of the genetic changes of the tumor over time. In this work, we aimed to discuss the implications of mutational testing in clinical outcomes, the methods to test ctDNA and the future challenges in the establishment of alternatives of personalized medicine.

P1, N=30, Recruiting, Taivex Therapeutics Corporation

P=N/A, N=25, Active, not recruiting, Centre Leon Berard | Recruiting --> Active, not recruiting | N=45 --> 25 | Trial completion date: Apr 2025 --> Dec 2024 | Trial primary completion date: Apr 2023 --> Apr 2024

2 patients did not achieve continuous RUNX1: : RUNX1T1 negative after preemptive therapy with Decitabine (DAC) and donor lymph infusion (DLI), and then was treated with Avapritinib, one's RUNX1: : RUNX1T1 fusion achieved continuously negative after 1 month treatment of Avapritinib, the other's achieved continuous negative after 7 months treatment of Avapritinib. Avapritinib is safe and effective in the prophylactic and preemptive treatment of AML with KIT mutation after allo-HSCT in children, which provides a clinical drug for the prevention of relapse after transplantation.

Key exclusion criteria include a diagnosis of acute myeloid leukemia, history of intracranial hemorrhage or risk of major hemorrhage, prior treatment with avapritinib or decitabine with documented progression in SM or AHN component, respectively, or history of treatment with alternative KIT inhibitor or azacitidine within 4 weeks of study treatment initiation. Patients with platelet count ≥ 25 x 10 9/L and < 75 x 10 9/L, will receive lead-in dosing with decitabine or decitabine/cedazuridine with the ability to add avapritinib if sufficient platelet thresholds are achieved. This study will open at 7 sites in the United States and is anticipated to open in January 2024.

Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ³4 line settings.

Cell viability and live cell imaging studies revealed that the loaded NGs are capable of intracellular drug release by showing similar IC values to those of the free drugs. Furthermore, multi-drug-loaded NGs were capable of overcoming BLU-285 resistance in T1-α-D842V + G680R cells, demonstrating the utility of this carrier system.

Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.

One patient with PDGFRA/KIT amplification developed a spontaneous EGFR gain and a secondary PDGFRA mutation in a cerebellar metastatic lesion that progressed on avapritinib therapy. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in HGG patients.

A gain-of-function KIT D816 V mutation is the primary oncogenic driver found in about 90% of all patients with AdvSM. Midostaurin, an oral multikinase inhibitor with activity against KIT D816V, and avapritinib, an oral selective KIT D816V inhibitor are approved for AdvSM.

"CStone Pharmaceuticals...announced that the AYVAKIT® (avapritinib) companion diagnostic (CDx) kit, known as 'Human platelet-derived growth factor receptor alpha (PDGFRA) Gene D842V Mutation Detection Kit', developed in partnership with Genetron Holdings Limited (Genetron Health) has been approved by the China National Medical Products Administration (NMPA). This CDx kit is the first companion diagnostic product co-developed through the bridging pathway in China to gain regulatory approval following the release of the companion diagnostic guidelines by NMPA. It is used to detect PDGFRA gene mutations in gastrointestinal stromal tumor (GIST) for patients receiving treatment with AYVAKIT."

The proposed approach was effectively employed for determining the stated pharmaceuticals in plasma with a high percentage of recovery ranging from 96.87 to 98.09 and pharmaceutical formulations with a percentage of recovery equal to 102.11 ± 1.05 %. In addition, the study was extended to a pharmacokinetic study of AVP with twenty human volunteers as a step for AVP management in therapeutic cancer centers.

Different KIT mutation types and signaling pathways atlerations were detected in progression samples of KIT-mutant GISTs after avapritinib or ripretinib failure compared with baseline, which may be associated with mechanism of resistance.

"QIAGEN...announced the U.S. Food and Drug Administration (FDA) approval of its therascreen PDGFRA RGQ PCR kit (therascreen PDGFRA kit). This companion diagnostic is intended for use to aid clinicians in identifying patients with gastrointestinal stromal tumors (GIST) who may be eligible for treatment with AYVAKIT® (avapritinib), which is approved in the U.S. for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. The kit is the first platelet-derived growth factor receptor alpha (PDGFRA) assay to receive FDA approval as a companion diagnostic."

We report three patients with AdvSM-AHN on avapritinib who achieved complete remission (CR) of SM and were successfully bridged to allogeneic haematopoietic cell transplant (allo-HCT). Two cases additionally highlight the risk of clonal evolution within the AHN component and requirement for close monitoring while on targeted therapy.

Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM...Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era...Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.

MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.

Although the multi tyrosine kinase inhibitors (TKI) Midostaurin and Avapritinib are approved for the treatment of SM with overall response rates (ORR) of 75% for Avapritinib, the median overall survival ranges from 3.5 years (aggressive SM: ASM) to less than six months (mast cell leukemia: MCL). In conclusion, we demonstrate in preclinical SM models the efficient targeting and killing in vitro and in vivo by CAR T-cells directed against human CD117. Given that CD117 is expressed on healthy hematopoietic stem and progenitor cells (HSPCs) on a substantially lower level, there might be a therapeutic window for anti-CD117 immunotherapy in advanced forms ofmastocytosis. However, as CAR T-cells are highly efficient, collateral damage on healthy HSPCs will likely need to be compensated by subsequent HSC transplantation.

In patients with AdvSM, avapritinib continues to provide robust efficacy with a favorable benefit-risk profile, regardless of prior therapy or disease subtype. Tyrosine kinase inhibitor, c-kit, Systemic mastocytosis

These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers.

P3; CtDNA sequencing efficiently detects KIT/PDGFRA mutations and prognosticates outcomes in patients with TKI-resistant GIST treated with avapritinib. ctDNA analysis can be used to monitor disease progression and provide more personalized treatment.

P2, N=50, Recruiting, The First Affiliated Hospital of Soochow University

The main adverse effect was hematological toxicity, which could generally be tolerated. In summary, avapritinib was effective for MRD treatment in patients with t(8;21) AML with KIT mutations failing to respond to immunotherapy after allo-HSCT.

P2; Trial completion date: Dec 2022 --> Feb 2025 | Trial primary completion date: Dec 2022 --> Feb 2025

In summary, we report that avapritinib is a selective, CNS-penetrant small molecule inhibitor of PDGFRA that shows potent activity in preclinical models and produces promising clinical responses with good tolerability in patients with high-grade glioma. This suggests a promising role for avapritinib therapy in this population with previously dismal outcomes.

Compared to patients receiving placebo plus BSC, avapritinib plus BSC patients experienced significant reductions in ISM disease burden with corresponding improvements in symptoms and measures of patient QoL and health.

P1, N=86, Completed, Blueprint Medicines Corporation | Active, not recruiting --> Completed

Avapritinib was generally well tolerated and showed marked anti-tumor activity in Chinese patients with GIST bearing PDGFRA D842V mutations and notable efficacy as fourth- or later-line monotherapy (ClinicalTrials.gov Identifier: NCT04254939).

PDGFRA-mutant GIST mostly derived from stomach, with a relative indolent behavior. D842V mutation and lose of CD34 expression were adverse prognostic factors. Avapritinib can effectively control advanced patients in a certain period of time.

Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the study. Early data suggest that bezuclastinib is well-tolerated and is associated with encouraging early signs of clinical activity as demonstrated by meaningful reductions in serum tryptase, MC burden, and KIT D816V VAF. Enrollment is currently ongoing. Updated safety and clinical activity as well as initial clinical objective response data will be presented.

Prior treatment included midostaurin while subsequent treatment approaches included individually or sequentially midostaurin, avapritinib, acute myeloid leukemia-like intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Treatment options with a low disease-modifying impact (e.g. interferon-alpha) or solely directed towards the associated hematologic neoplasm (e.g. hydroxyurea, azacytidine) were not considered as 1L- or 2L-treatment...The various prognostic models for AdvSM are of limited value because of high mortality in low- and intermediate-risk patients. Overall, cladribine remains a relevant sequential treatment option for patients with AdvSM.

Three patients were previously treated with other regimes - one patient with midostaurin, one with cladribine and one with azacytidine. This small cohort of patients reflects the clinical heterogeneity of AdvSM and mirrors the PATHFINDER trial outcomes in 'real world 'experience in the UK. Avapritinib as 1st line was tolerated, producing sustained clinical and pathological responses in the majority of this group of non-selected patients with AdvSM with high risk disease. Dose adjustments due to anticipated myelosuppression were made, with 72.2% of patients maintained on 100mg Avapritinib od.

In advanced GIST, treatment is based on tyrosine kinase inhibitors, including imatinib, which has been the standard first-line treatment since the early 2000s, with sunitinib and regorafenib as second- and third-line standards, respectively...Ripretinib has become the validated fourth-line therapy for patients with KIT or PDGFRA non-D842V mutations, and avapritinib has been shown to be effective in patients with D842V mutations who were previously resistant to validated treatments...Specific treatments are available or under evaluation for some rare subgroups, and new therapeutic strategies are likely to further improve the management of advanced GIST in the coming years. This overview summarizes the results of recent trials and the place of these new molecules, as well as the main strategies under development for advanced GIST.

In cases of progressive disease after successive treatment with imatinib, sunitinib, and regorafenib, a fourth-line therapy with ripretinib was recently approved. Approved in 2020, avapritinib is the first effective targeted therapy for advanced stage GIST harboring an imatinib-resistant PDGFRA D842V mutation.