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    Home > Active Ingredient News > Drugs Articles > The latest research progress of KIT inhibitors

    The latest research progress of KIT inhibitors

    • Last Update: 2021-08-28
    • Source: Internet
    • Author: User
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    Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, with an incidence rate of 10% to 35%, accounting for <1% of all gastrointestinal malignancies


    Image source: ResearchGate

    KIT is a family of transmembrane type III tyrosine kinase receptors with a molecular weight of approximately 14 000 Da.


    Image source: PNAS

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    Image source: ResearchGate

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    The statistics of listed drugs are as follows

    Forecast based on the sales of some listed drugs : It can be seen that the overall market will stabilize in the next five years, and the growth rate will be limited.


    Forecast based on the sales of some listed drugs

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    Seen from the indications of drugs under research

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    From the perspective of research companies that are researching drugs

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    The statistics of drugs currently under research in the clinical stage are as follows

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    For advanced patients, patients with advanced first-line imatinib therapy have multiple drug resistance mutation sites, and patients with advanced second- and third-line therapy have more complex gene mutations, and it is difficult for drugs with a single target to effectively inhibit tumor cell proliferation.


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    Avapritinib

    In April 2020, NMPA accepted a new drug marketing application for avapritinib for the treatment of GIST
    .
    Avapritinib is a potent, highly selective, research-in-progress oral inhibitor against KIT and PDGFRA gene mutations, jointly developed by CStone Pharmaceuticals and Blueprint Medicines
    .
    In November 2019, the Phase I clinical trial of NAVIGATOR showed that among 43 patients with PDGFRA exon 18 mutation and 111 patients with fourth-line treatment, the efficacy can be assessed: in PDGFRA exon 18 mutation patients, the ORR was 86% (1 patient to be confirmed), the median duration of remission (DOR) has not been reached; in the fourth-line treatment of GIST patients, the ORR reached 22% (1 patient to be confirmed), and the median DOR was 10.
    2 months
    .
    Preliminary data from the China Phase I/II bridging study showed that the safety and pharmacokinetic characteristics data of Chinese patients with advanced GIST are consistent with the data from the NAVIGATOR global study and are well tolerated
    .

    3.
    BLU-263

    3.
    BLU-263

    BLU-263 is a new generation of D816V KIT inhibitor developed by Blueprint Medicines for the potential oral treatment of indolent systemic mastocytosis (ISM)
    .
    In June 2021, at the 26th EHA Annual Conference, the ongoing Phase 1, randomized, double-blind, placebo-controlled single ascending dose (SAD) and multiple ascending dose (MAD) healthy volunteer research data were announced , Showing that the average half-life of BLU-263 administration is 20-28 hours, reaching a steady state on the 7th day, supporting qd administration; after repeated oral administration of 25-100 mg BLU-263 for 10 days, the geometric mean cumulative ratio of the area under the curve is 1.
    6 -1.
    8.
    In June 2021, a randomized, double-blind, placebo-controlled, phase II/III trial evaluated its efficacy and safety in asymptomatic systemic ISM patients.
    The primary endpoint is the recommended dose for ISM patients According to the proportion of responders under (RD), the long-term safety and tolerability of BLU-263 are evaluated based on the number of adverse events and serious adverse events and the average change of ISM-SAF TSS
    .

    4.
    Bezuclastinib (CGT-9486.
    PLX-9486)

    4.
    Bezuclastinib (CGT-9486.
    PLX-9486)

    PLX-9486 is a TYPE I KIT inhibitor developed by Cogent Biosciences.
    It can bind to the active conformation, and can detect the primary mutations on KIT exon 9/11 and the acquired mutations on exon 17/18.
    Sensitive
    .
    A phase 1b/2a study exploring the safety and effectiveness of PLX-9486 (TYPE I) and sunitinib (TYPE II) in the treatment of refractory GIST showed that: PLX-9486 (≤500mg per day) alone In 7 cases, the objective effective rate was 0%, the disease control rate was 14%, the median progression-free survival period was 1.
    74 months, and the median overall survival period was 2.
    96 months; 12 cases of PLX-9486 (1000 mg per day) single drug, the objective effective rate was 8.
    3% , Disease control rate was 50%, median progression-free survival period was 5.
    75 months, median overall survival period was 11.
    34 months; 15 cases of PLX-9486 (500mg or 1000mg per day) combined with sunitinib (25mg or 37.
    5mg per day), objectively The efficiency was 13.
    3%, the disease control rate was 80%, the median progression-free survival was 12.
    1 months, and the median overall survival was 18.
    11 months
    .

    Outlook

    Outlook

    In the past ten years, the application of KIT inhibitors in tumor fields such as GIST has brought new options and directions for patient treatment
    .
    However, there are still quite a few patients whose initial treatment is ineffective or have secondary drug resistance
    .
    In clinical practice, it can be considered in combination with other treatment strategies, including chemotherapy, radiotherapy, various molecular targeted drugs, immunosuppressants, cytokine inhibitors, viral therapies, and tumor vaccines
    .
    It is believed that as the treatment of malignant tumors and the exploration of drug resistance mechanisms continue to deepen, more and more patients will benefit from treatment in the future
    .

    references

    References References

    [1] Bannon AE, Klug LR, Corless CL, et al.
    Using molecular diagnostic testing to personalize the treatment of patients with gastrointestinal stromaltumors[J].
    Expert Review of Molecular Diagnostics, 2017.
    17(5):445.

    [1] Bannon AE, Klug LR, Corless CL, et al.
    Using molecular diagnostic testing to personalize the treatment of patients with gastrointestinal stromaltumors[J].
    Expert Review of Molecular Diagnostics, 2017.
    17(5):445.

    [2] Zhang Yiwen, Pan Zongfu, Ye Qiang, Liu Yujia, Sun Jiao, Li Li, Huang Ping.
    The role and research progress of a new generation of TKI drug Repetinib in gastrointestinal stromal tumors[J].
    Chinese Journal of New Drugs, 2020.
    29(23):2690-2694.

    [2] Zhang Yiwen, Pan Zongfu, Ye Qiang, Liu Yujia, Sun Jiao, Li Li, Huang Ping.
    The role and research progress of a new generation of TKI drug Repetinib in gastrointestinal stromal tumors[J].
    Chinese Journal of New Drugs, 2020.
    29(23):2690-2694.

    [3] Meng Lin.
    The role of KIT gene double mutation in gastrointestinal stromal tumors[J].
    Journal of Clinical and Pathology, 2018.
    38(4):830-836.

    [3] Meng Lin.
    The role of KIT gene double mutation in gastrointestinal stromal tumors[J].
    Journal of Clinical and Pathology, 2018.
    38(4):830-836.

    [4] O Yélamos, Merkel EA, Sholl LM, et al.
    Nonoverlapping Clinical andMutational Patterns in Melanomas from the Female Genital Tract and AtypicalGenital Nevi[J].
    Journal of Investigative Dermatology, 2016:S0022202X16312568.

    [4] O Yélamos, Merkel EA, Sholl LM, et al.
    Nonoverlapping Clinical andMutational Patterns in Melanomas from the Female Genital Tract and AtypicalGenital Nevi[J].
    Journal of Investigative Dermatology, 2016:S0022202X16312568.
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