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    Home > Active Ingredient News > Antitumor Therapy > A breakthrough in the first-line treatment of advanced lung cancer with PFS by heavy vomitinib

    A breakthrough in the first-line treatment of advanced lung cancer with PFS by heavy vomitinib

    • Last Update: 2021-11-14
    • Source: Internet
    • Author: User
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    Foreword This week, Shanghai Ellis announced that China’s original third representative skin growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) Ivesa® (Vormetinib mesylate, hereinafter referred to as "Vormetin") The first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with sensitive EGFR mutations in the national multi-center, randomized controlled, double-blind Phase III clinical study (FURLONG) reached the primary end point, compared with the first-generation EGFR-TKI.
    The progression-free survival (PFS) of the Fetinib (Iressa®) treatment group and the vometinib treatment group were significantly prolonged
    .

    The difference between the two groups has significant statistical significance and clinical significance
    .

    There are still huge unmet clinical needs in the first-line treatment of EGFR-sensitive mutant NSCLC.
    EGFR-TKI has become the standard first-line treatment for advanced EGFR-sensitive mutant NSCLC.
    The first, second, and third-generation EGFR-TKI drugs have been approved by China’s authoritative lung cancer diagnosis and treatment guidelines.
    Recommended
    .

    The "Lung Cancer Clinical Diagnosis and Treatment Guidelines of the Chinese Medical Association Oncology Branch (2021 Edition)" recommended advanced lung cancer targeted therapy1 The third-generation EGFR-TKI can not only act on sensitive mutations, but also overcome the EGFR that appears after the first and second-generation EGFR TKI treatments.
    T790M mutation, and also shows a good effect on the treatment of central nervous system (CNS) metastasis
    .

    The PFS benefit and overall survival (OS) benefit of the third-generation EGFR TKI were better than those of the first-generation drug.
    The median PFS was prolonged by 8.
    7 months (18.
    9 months vs.
    10.
    2 months, HR=0.
    46), and OS was prolonged 6.
    8 months (38.
    6 months vs 31.
    8 months, HR = 0.
    80) 2, 3
    .

    The first-line treatment of the third-generation EGFR-TKI osimertinib (blue line) brings greater survival benefits than the first-generation EGFR-TKI (red line) 2,3 However, one of the metabolites of osimertinib, AZ5104, has a positive effect on EGFR-WT ( Wild-type) has relatively low selectivity and has a strong inhibitory effect with wild-type EGFR (IC 50 33nm).
    Therefore, the incidence of rash and diarrhea caused by osimertinib treatment is still relatively high
    .

    Osimertinib metabolite AZ5104 has relatively low selectivity to EGFR-WT, and the incidence of rash and diarrhea is still relatively high.
    The main researcher of FURLONG, Professor Yuankai Shi of the National Cancer Center/Tumor Hospital of the Chinese Academy of Medical Sciences pointed out that EGFR gene sensitive mutation NSCLC Patients still have unmet needs for first-line treatment; with the release of the specific data of the FURLONG study in the future, the good efficacy and safety of vomitinib in the treatment of advanced lung cancer will be verified again, and it is locally advanced or metastatic NSCLC with sensitive mutations in the EGFR gene.
    Patients provide new options for first-line treatment
    .

    It has excellent efficacy and safety in the treatment of advanced EGFR-mutant NSCLC.
    Vometinib is the third-generation EGFR-TKI drug for the treatment of advanced lung cancer.
    It is a national class 1 innovative drug originally developed in China
    .

    In March of this year, vomitinib was approved in China for the treatment of locally advanced or metastatic NSCLC patients who have experienced disease progression during or after treatment with EGFR-TKI, and confirmed the presence of EGFR T790M mutation-positive adult patients with locally advanced or metastatic NSCLC.
    It is recommended daily The dose is 80mg
    .

    The approved indications were written into the Chinese Guidelines for the Treatment of Stage IV Primary Lung Cancer (2021 Edition)1 and the Chinese Guidelines for the Treatment of Lung Cancer Brain Metastases (2021 Edition)4
    .

    Vometinib mesylate was approved in March this year for the treatment of advanced lung cancer.
    On March 27 this year, "The Lancet Respiratory Medicine" (The Lancet Respiratory Medicine, Impact Factor 25.
    094) published the full text online for the treatment of EGFR T790M by Vometinib.
    Results of Phase Ⅱb Clinical Study in Patients with Mutational Advanced NSCLC (NCT03452592) 5
    .

    The IIb study of vomitinib included patients with an ECOG PS score of 2 (4%) and primary T790M mutation (3%).
    The proportion of patients with L858R mutation (38%) and baseline CNS metastasis (48%) was relatively high.
    ; Patients who have received 1/2/≥3 line system therapy were 74%/17%/6%, respectively
    .

    Professor Yuankai Shi said, “In the case of a relatively high proportion of the L858R population and those who have previously received line 2 and above, and nearly half (48%) of the patients have CNS metastasis at baseline, the objective response rate (ORR) of vometinib remains It reached 74% (163/220, [95% CI 68–80]), the disease control rate (DCR) was as high as 94% (206/220, [95% CI 90–97]), and the median PFS reached 9.
    6 months ( 95% CI 8.
    2–9.
    7), and the efficacy data are encouraging
    .

    "In the phase IIb study, 26% of patients observed adverse events (AE) ≥ grade 3, of which 11% were treatment-related, and each single item ≥ grade 3 treatment-related Adverse events were not higher than 1%
    .

    The incidence of treatment-related diarrhea and skin rash is relatively low, at 5% and 7%, respectively, and both are grade 1 to 2, reflecting the high selectivity of vometinib to EGFR wild-type
    .

    The most common treatment-related adverse reactions of grade ≥3 were mainly aspartate aminotransferase elevation (1%), alanine aminotransferase elevation (1%), and gamma glutamyl transpeptidase elevation (1%).
    No unexpected events were found Special adverse events
    .

    Structural innovation brings better efficacy and safety.
    The unique drug structure of vometinib itself is the basis for its excellent clinical efficacy
    .

    The structure of vomitinib is further innovative than that of osimertinib, introducing a unique trifluoroethoxypyridine structure, which has strong hydrophobicity and is composed of hydrophobic amino acids L792 and M793 in the binding region of EGFR ATP.
    The concave hydrophobic pocket has a higher affinity and can improve the activity of the drug itself
    .

    In addition, vomitinib and its main metabolites have high anti-tumor activity, and both can "into the brain", and their anti-tumor effects are highly selective, laying a safe foundation for clinical application
    .

    Vormetinib and its metabolite AST5902 "double into the brain", and are highly selective.
    Therefore, Vormetinib innovatively introduces the trifluoroethoxypyridine structure to make it have dual anti-tumor activities (prototype and main metabolism).
    The products have high activity), high selectivity (high selectivity for EGFR-WT), better safety (metabolic products do not cause obvious additional safety problems), and better drug distribution (lung The concentration is high, the prototype and metabolites enter the brain)
    .

    About the FURLONG study The FURLONG study is a randomized, double-blind, positive-controlled, multi-center phase III clinical study, which aims to compare vomitinib mesylate (AST2818) and gefitinib in the first-line treatment of locally advanced EGFR-sensitive mutations Or the effectiveness and safety of patients with metastatic non-small cell lung cancer
    .

    The study was carried out in 55 domestic research centers.
    A total of 358 patients with advanced NSCLC with EGFR mutations were enrolled and randomly received first-line treatment with vomitinib 80 mg/d or gefitinib 250 mg/d until the disease progressed or withdrawn due to other reasons.

    .

    The primary endpoint of the study is PFS, and secondary endpoints include ORR, OS, and safety
    .

    According to Ellis, the specific data of the research will be officially announced at the future international academic conference
    .

    It is hoped that the results of the FURLONG study will bring a new breakthrough for the third-generation EGFR-TKI treatment of advanced EGFR-sensitive mutant NSCLC
    .

     References: 1.
    Chinese Medical Doctor Association Oncologist Branch, Chinese Medical Care International Exchange Promotion Association Medical Oncology Branch.
    Chinese Treatment Guidelines for Stage IV Primary Lung Cancer (2021 Edition)[J].
    Chinese Journal of Oncology 2021,43(1): 39-59, DOI:10.
    3760/cma.
    j.
    cn112152-20201009-00884.
    2.
    J.
    -C.
    Soria et al.
    , Osimertinib in Untreated EGFR-Mutated Advanced Non--Small-Cell Lung Cancer; N Engl J Med 2018;378 :113-25.
    DOI: 10.
    1056/NEJMoa17131373.
    SS Ramalingam et al.
    , Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC; N Engl J Med 2020;382:41-50.
    DOI: 10.
    1056/NEJMoa19136624.
    Chinese physician Association of Oncologists Branch, Chinese Medical Care International Exchange Promotion Association of Medical Oncology Branch.
    Chinese treatment guidelines for lung cancer brain metastases (2021 edition) [J].
    Chinese Journal of Oncology, 2021, 43(3):269-281
    .

    DOI:10.
    3760/cma.
    j.
    cn112152-20210104-00009.
    5.
    Yuankai Shi,Xingsheng Hu,Shucai Zhang, et al.
    Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study.
    Lancet Respir Med.
    Published on March 26, 2021.
    DOI: https://doi.
    org/10.
    1016/S2213-2600(20)30455-0
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