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    Home > Biochemistry News > Biotechnology News > Can loratinib break the dilemma of ALK mutant neuroblastoma treatment?

    Can loratinib break the dilemma of ALK mutant neuroblastoma treatment?

    • Last Update: 2022-01-11
    • Source: Internet
    • Author: User
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    Article source: Med

    Author: Ala Lei

    Lolatinib, the third-generation ALK inhibitor, has attracted attention in the field for its excellent performance in the treatment of NSCLC
    .
    In the CROWN study, 78% of patients in the loratinib group had no disease progression at a 12-month follow-up, and 39% in the crizotinib group (HR=0.
    28, P<0.
    001) [1]

    .
    Objectively speaking, this result is indeed commendable.
    The name "CROWN" may also contain the expectations of researchers for it!

    Picture from: N Engl J Med.
    2020; 383(21): 2018-2029.

    Since it is a sharp sword, how can it better reflect its value? Naturally, it is to challenge a problem that others cannot solve
    .
    This time, standing in front of loratinib is neuroblastoma (NB)

    .

    NB and ALK mutations

    NB and ALK mutations

    Neuroblastoma (NB) is the most common extracranial solid tumor in children, accounting for 8%-10% of childhood malignant tumors and 15% of childhood tumor-related deaths.
    The median age of diagnosis is ~2 years

    .
    According to risk factors, NB can be divided into low, medium and high risk groups

    .
    Low- and intermediate-risk patients have a good prognosis, with a 5-year survival rate of more than 90%; high-risk patients account for about half of NB, and may have repeated recurrences.
    The 5-year survival rate is only 40% to 50%, which is a clinical difficulty [2 ]

    .

    Studies have shown that about 6% to 10% of NBs have ALK mutations, making ALK inhibitors a possible treatment strategy
    .
    In NB, 85% of ALK mutations are at these 3 sites-F1174 (~30%), F1245 (~12%), R1275 (~43%) [2]

    .

    Picture from: Cancer (Basel).
    2018; 10(4): 113.

    However, the sensitivity of the first generation ALK inhibitor crizotinib to ALK mutant NB is not ideal
    .
    Preclinical studies have shown that R1275Q, L1198F, and I1170N mutant NB cell lines are sensitive to crizotinib, while F1174L/C/V/I, I1171N, L1196M, L1152P, C1156Y, and G1269A are resistant to crizotinib [3]

    .

    Clinical study of ALK inhibitor in NB

    Clinical study of ALK inhibitor in NB

    At present, there are few clinical research data on the correlation between ALK mutation characteristics and the efficacy of ALK inhibitors in NB
    .
    In 2009, the Children's Oncology Group (COG) initiated the ADVL0912 phase I-II clinical trial to evaluate the use of crizotinib in childhood relapsed/refractory solid tumors and anaplastic large cell lymphoma (ALCL) The efficacy (NCT00939770)

    .

    In May 2013, preliminary data was published in the journal Lancet Oncol.
    Among 11 NB patients with clear ALK mutations, only 1 showed anti-tumor activity (CR) and R1275 mutations; 7 cases showed disease progression (PD) Of the patients, 3 cases have F1174 mutations [4]

    .
    According to the available data, crizotinib monotherapy can be considered for patients with R1275 mutations.
    If F1174 mutations exist, primary drug resistance should be considered.
    Crizotinib combined chemotherapy regimens are also being explored

    .

    As the third-generation ALK inhibitor, loratinib has shown anti-tumor activity against F1174, F1245, and R1275 in preclinical studies
    .
    The clinical trial of loratinib single agent or combination chemotherapy for ALK-positive relapsed/refractory NB is ongoing (NCT03107988)

    .
    Preliminary data was released during ASCO in 2020.
    A total of 33 patients were enrolled, 13 of whom had previously received ALK inhibitor therapy

    .
    Divided into two cohorts, the average age of patients in cohort 1 was 5.
    5 years, and the average age of patients in cohort 2 was 21.
    5 years

    .
    In cohort 1, 1/18 is PR, 3/18 is MR (minor response), 4/18 is SD; in cohort 2, 1/10 is CR, 3/10 is PR, 3/10 is MR, ALK mutation The situation is related to the level of clinical treatment response [5]

    .

    There is also a case report from Cold Spring Harb
    .
    A patient with relapsed and refractory NB who did not respond to crizotinib treatment showed a F1174L mutation and achieved a 13-month CR after adjusting to lauratinib

    .
    In the clinical trial ANBL 1531 conducted by COG, loratinib showed extensive inhibition of ALK mutations in NB patients

    .
    For patients with ALK mutations, COG is considering using loratinib instead of crizotinib [3]

    .

    E map (maximum signal projection, MIP) and F map (SPECT/CT): disease recurrence period; G map (MIP) and H map (SPECT/CT): CR after the use of loratinib
    .
    Picture from: Cold Spring Harb Mol Case Stud.
    2021; 7(4): a006064.

    However, drug resistance after loratinib treatment is also a problem that doctors must face
    .
    In the case of the aforementioned Cold Spring Harbor Laboratory, the patient relapsed 13 months after using loratinib.
    Cell-free DNA sequencing revealed the presence of CD4 and FGFR1 amplification, and NRAS Q61K mutation [3]

    .

    In the study of ALK-positive lung cancer, mutations related to loratinib resistance include: TP53, NRAS, BRCA1/2, APC, MAP3K1, BRAF, etc.
    [6]

    .
    There are fewer cases of NB, and reports have shown that bypass activation (AXL, PIM1, EGFR, ERBB4) may be related to resistance to ALK inhibitors

    .
    How to deal with loratinib resistance is still in the exploratory stage, such as the combined application with CDK4/6 inhibitors or MEK/FGFR inhibitors, and related clinical trials are ongoing

    .

    Overview of loratinib resistance mechanism.
    Picture from: Cancer Discov.
    2018; 8(6): 714-729.

    Summary: According to the ALK mutation characteristics of NB, loratinib has more therapeutic potential than crizotinib
    .
    Because NB is less common, and the development of clinical trials on children's tumors is more difficult than that of adults, there are fewer clinical data

    .
    The use of available anti-tumor drugs for the treatment of childhood tumors requires the joint efforts of many parties

    .
    At the same time, the problem of drug resistance and follow-up treatment after loratinib treatment has also become a new challenge

    .

    references

    1.
    N Engl J Med.
    2020; 383(21): 2018-2029.

    2.
    Cancer (Basel).
    2018; 10(4): 113.

    3.
    Cold Spring Harb Mol Case Stud.
    2021; 7(4): a006064.

    4.
    Lancet Oncol 2013; 14(6): 472-80.

    5.
    https://meetinglibrary.
    asco.
    org/record/185854/abstract

    6.
    Cancer Discov.
    2018; 8(6): 714-729.

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