Ayvakit (avapritinib)

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

Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA...However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.

P2, N=500, Recruiting, Children's Hospital of Soochow University | Not yet recruiting --> Recruiting

No abstract available

P2, N=500, Not yet recruiting, Children's Hospital of Soochow University

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.

P2, N=425, Recruiting, Centre Leon Berard

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

The average monthly cost for the treatment of neoplastic diseases was $17,900 with a price of $44,000 for futibatinib (used to treat cholangiocarcinomas with FGFR2 fusions) and minimum of $5100 for binimetinib (melanoma). The average monthly cost for the treatment of non-neoplastic diseases was $6800 with a maximum of $17,000 for belumosudil (graft vs. host disease) and a minimum of $200 for netarsudil eye drops (glaucoma). There is a negative correlation of the cost of the drugs and the incidence of the targeted disease. Many of these agents are or were designated as orphan drugs meaning that there are fewer than 200,000 potential patients in the United States.

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.

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.

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.

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.

As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.

An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib...While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care...Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.

Apart from approved drugs (imatinib, sunitinib, regorafenib, ripretinib, and avapritinib, we evaluated cabozantinib, pazopanib, dasatinib, and sorafenib... Preclinical testing suggests that dose-escalation of or retreatment with imatinib is not effective in exon 11 mutant GIST with secondary mutations. Pazopanib appears highly ineffective against any secondary mutation but shows notable activity in exon 9 mutant GIST. Cabozantinib is the only drug with strong activity against the gatekeeper T670I and the AL D820Y mutation.

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.

If a patient progresses on imatinib, there are additional FDA-approved treatments (sunitinib, regorafenib, ripretinib), which are not currently available for those patients that progress on avapritinib. Our model has the potential to identify which PDGFRA exon 18 mutant GIST patients would benefit from front-line imatinib therapy, while subsequently identifying those that would require avapritinib treatment. Avapritinib was recently approved for first-line treatment for all PDGFRA exon 18 mutant GIST in the United States. Imatinib has been used clinically for over two decades, and is more cost-effective and has a superior safety and tolerability profile compared to avapritinib.

"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."

IDRX-42 showed significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induced volumetric responses, decreased mitotic activity and had antiproliferative effects. In models with KIT exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.

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.

Hypomethylating agents, either decitabine (0.1-0.2mg/kg) or azacytidine (75mg/m2) were administered with intermittent dosing schedule day 1-3, day 8- 9(10), and/or day 15-16(17)...One patient previously received one cycle of idarubicin and cytarabine (IA) without response and other 7 patients were newly diagnosed AML patients...Patient 5 didn't respond after cycle 1, and avapritinib was added on in cycle 2 because of the c-Kit mutation detected, and then achieved CRi... These results imply that the triple regimen of selinexor, venetoclax and hypomethylating agents are potentially highly effective in AML patients, even for those with serious infections or other comorbidities. Based on this preliminary result, we designed a prospective study to further evaluate the efficacy and safety of the triple regimen of selinexor, venetoclax, and azacytidine (SAV regimen) for newly diagnosed patients with AML ineligible forintensive therapy (NCT05736965).

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