Method for predicting therapeutic effect or prognosis, therapeutic agent, kit, or biomarker

Abstract

To provide a method for predicting therapeutic effect or prognosis when an EGFR tyrosine kinase inhibitor is administered to a patient with EGFR gene mutation-positive non-small cell lung cancer.SOLUTION: The method includes the steps of: measuring or visualizing expression level of ACTN4 in lung cancer tissue or lung cancer cells of a patient; determining, based on the expression level, whether ACTN4 expression is positive; and, if determined positive, predicting that the EGFR tyrosine kinase inhibitor will have insufficient therapeutic effect on the patient or that prognosis of the patient administered with the EGFR tyrosine kinase inhibitor will be poor.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a therapeutic agent for EGFR gene mutation-positive non-small cell lung cancer, a method for predicting the therapeutic effect or prognosis thereof, a kit, or a biomarker. [Background technology]

[0002] Histologically, lung cancer is broadly divided into two types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Lung cancer is the leading cause of cancer-related death in Japan, with NSCLC accounting for approximately 80% of all cases. NSCLC is composed of a heterogeneous tumor population with a variety of histopathological findings, genetic alterations, and gene expression patterns. However, in clinical practice, these tumors are uniformly treated with chemotherapy or related therapies in combination with surgery.

[0003] The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that plays an important role in signal transduction related to cancer growth and progression. In the treatment of lung cancer, particularly NSCLC, activating mutations in the EGFR gene, such as the deletion mutation in exon 19 (19del) and the point mutation in exon 21 (L858R), have been found to be closely correlated with sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib, and osimertinib (Non-Patent Documents 1-4). These findings are being utilized to select treatments for NSCLC patients. In addition, it has been reported that EGFR-TKIs such as osimertinib and afatinib show promising clinical activity and manageable adverse events even in NSCLC patients with rare EGFR gene mutations other than 19del or L858R (Non-Patent Documents 5-7).

[0004] The Lung Cancer Clinical Practice Guidelines 2023 recommends multiple treatments as first-line drug therapies, including osimertinib, gefitinib + carboplatin + pemetrexed combination therapy, and erlotinib + angiogenesis inhibitor combination therapy. In the Lung Cancer Clinical Practice Guidelines 2023, osimertinib is given the strongest recommendation (strength of recommendation: 1, strength of evidence: A).

[0005] However, even among patients treated with osimertinib, nearly half of them develop resistance to treatment within about one to one and a half years (Non-Patent Document 8).

[0006] Identifying factors that contribute to poor response to EGFR tyrosine kinase inhibitors, including osimertinib, may lead to improved treatment options and may also advance the development of treatments for patients who do not respond well to osimertinib. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] N Engl J Med, 2010; 362: 2380-2388 [Non-patent document 2] Lancet Oncol, 2012; 13: 239-246 [Non-patent document 3] Lancet Oncol, 2015: 16: 141-151 [Non-patent document 4] N Engl J Med, 2017; 376: 629-640 [Non-Patent Document 5] J Clin Oncol. 2020;38(5):488-495. [Non-patent document 6] J Thorac Oncol. 2020 May;15(5):803-815. [Non-Patent Document 7] JAMA Oncol. 2023 Nov 22:e235013. [Non-patent document 8] Soria JC, et al. N Engl J Med. 2018;378(2):113-125. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention has been made in consideration of these problems, and aims to provide a method for predicting the therapeutic effect or prognosis when an EGFR tyrosine kinase inhibitor, including osimertinib, is administered to a patient with EGFR gene mutation-positive non-small cell lung cancer. [Means for solving the problem]

[0009] The method for predicting therapeutic effect or prognosis of the present invention is a method for predicting therapeutic effect or prognosis in a patient with EGFR gene mutation-positive non-small cell lung cancer when an EGFR tyrosine kinase inhibitor is administered to the patient, and is characterized in that it comprises the steps of measuring or visualizing the expression level of ACTN4 (α-actinin-4, an actin-binding protein) in the patient's lung cancer tissue or lung cancer cells, and determining whether or not ACTN4 expression is positive based on the expression level, and if determined to be positive, predicting that the therapeutic effect of the EGFR tyrosine kinase inhibitor on the patient will be insufficient or that the prognosis of the patient administered the EGFR tyrosine kinase inhibitor will be poor. [Effects of the Invention]

[0010] According to the present invention, it is possible to predict the therapeutic effect or prognosis when an EGFR tyrosine kinase inhibitor including osimertinib is administered to a patient with EGFR gene mutation-positive non-small cell lung cancer. [Brief explanation of the drawings]

[0011] [Figure 1] Photographs showing stained tumor tissues, of which (A) is an ACTN4(-) case and (B) is an ACTN4(+) case. [Figure 2]This figure shows that in EGFR gene mutation-positive non-small cell lung cancer, when the tumor has high ACTN4 expression, the effect of EGFR tyrosine kinase inhibitors is poor. (A) shows PFS, and (B) shows OS. DETAILED DESCRIPTION OF THE INVENTION

[0012] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, these embodiments are intended to facilitate understanding of the principles of the present invention, and the scope of the present invention is not limited to the following embodiments. Other embodiments in which a person skilled in the art appropriately replaces the configuration of the following embodiments are also included in the scope of the present invention.

[0013] The present invention relates to a method for predicting the therapeutic effect or prognosis of a patient with EGFR gene mutation-positive non-small cell lung cancer when the patient is administered an EGFR tyrosine kinase inhibitor.

[0014] The epidermal growth factor receptor (EGFR) is a glycoprotein with a molecular weight of 170 kDa present on the cell membrane, and is known to be activated by binding to its ligand, epidermal growth factor (EGF), leading to cell differentiation and proliferation. The amino acid sequence of human EGFR and the nucleotide sequence encoding it can be easily found in databases such as NCBI.

[0015] Examples of EGFR gene mutations in EGFR gene mutation-positive non-small cell lung cancer include, but are not limited to, exon 19 deletion mutation (19del), exon 21 L858R point mutation (L858R), T790M, exon 20 insertion mutation, or combinations thereof. EGFR gene mutations also include rare EGFR gene mutations, specifically, mutations in which glycine at position 719 of the encoded protein is replaced by another amino acid (G719X), mutations in which leucine at position 861 of the encoded protein is replaced by glutamine (L861Q), S768I, D761Y, T854A, G796S, L844V, R776H, L718Q, L861R, S720A, L747S, C797S, E709X, Ins 19, N771F, or 18del. Although many other mutations in the EGFR gene have been reported, the two mutations mentioned above, 19del and L858R, are said to account for more than 80% of cases.

[0016] The present invention is a method for predicting the therapeutic effect or prognosis when an EEGFR tyrosine kinase inhibitor is administered as a single agent.

[0017] Examples of EGFR tyrosine kinase inhibitors (EGFR-TKIs) used as single agents include, but are not limited to, osimertinib, gefitinib, erlotinib, and afatinib.

[0018] The present invention includes the following steps. A step of measuring or visualizing the expression level of ACTN4 in the patient's lung cancer tissue or lung cancer cells determining whether or not ACTN4 expression is positive based on the expression level, and predicting, if determined to be positive, that the therapeutic effect of the EGFR tyrosine kinase inhibitor on the patient will be insufficient or that the prognosis of the patient administered with the EGFR tyrosine kinase inhibitor will be poor;

[0019] The sequence of the ACTN4 gene and the amino acid sequence encoded thereby are well known in the art, and examples thereof include the human ACTN4 sequences shown in Ensembl ID: ENSG00000130402 and ENST00000252699. The human ACTN4 sequence is also registered with NCBI (National Center for Biotechnology Information) under accession numbers: NM_004924 and NP_004915. The locus of the ACTN4 gene is also well known in the art; for example, the human ACTN4 gene is located at bases 43,830,167 to 43,913,010 of chromosome 19.

[0020] Measurement or visualization of the expression level of ACTN4 can be performed, for example, by measuring or visualizing ACTN4 protein by immunostaining (immunohistochemistry: IHC), by measuring or visualizing the copy number of the ACTN4 gene in the genome by in situ hybridization (ISH), or by measuring or visualizing ACTN4 genomic DNA mRNA by qPCR.

[0021] The normal tissues or cells used as a control may be normal tissues or cells from the same individual as the subject, or normal tissues or cells from different individuals. Alternatively, the expression levels of ACTN4 protein may be measured in normal tissues or cells from multiple different individuals, and the average value may be used as a control.

[0022] To determine whether ACTN4 expression is positive, for example, by measuring the expression level of ACTN4, the positive result can be determined by examining the copy number of ACTN4. When ACTN4 is visualized, for example, cells in which ACTN4 is stained circumferentially on the cell membrane are determined to be positive, and cases in which 20% or more, preferably 30% or more, of tumor cells are positive can be determined to be ACTN4-positive.

[0023] Next, the therapeutic agent for EGFR gene mutation-positive non-small cell lung cancer according to the present invention contains an EGFR tyrosine kinase inhibitor as an active ingredient, and is characterized by being used in combination or mixture with other anticancer agents for patients determined to have positive ACTN4 expression in lung cancer tissue or lung cancer cells.

[0024] The EGFR tyrosine kinase inhibitor may be in the form of various pharmaceutically acceptable salts, including hydrohalides such as hydrochloride and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as formate, acetate, malate, fumarate, succinate, citrate, tartrate, oxalate and maleate; amino acid salts such as ornithine, glutamate and aspartate; and alkali metal salts such as sodium salt, potassium salt and lithium salt. Examples include alkaline earth metal salts such as calcium salts and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as dibenzylamine salts, morpholine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, diethylamine salts, triethylamine salts, cyclohexylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, diethanolamine salts, N-benzyl-N-(2-phenylethoxy)amine salts, piperazine salts, tetramethylammonium salts, and tris(hydroxymethyl)aminomethane salts.

[0025] The EGFR tyrosine kinase inhibitor contains a pharmaceutically acceptable carrier and can be administered by various methods, such as various injections such as intravenous injection, intramuscular injection, and subcutaneous injection, or by oral administration or transdermal administration. A pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material (e.g., excipient, diluent, additive, solvent, etc.) involved in transporting a composition from one organ or organ to another.

[0026] The formulation can be prepared by selecting an appropriate formulation (e.g., oral or injectable) depending on the administration method, and by various commonly used methods for preparing formulations. Examples of oral formulations include tablets, powders, granules, capsules, pills, lozenges, solutions, syrups, elixirs, emulsions, and oily or aqueous suspensions. For oral administration, the compound may be in either a free form or a salt form. Aqueous formulations can be prepared by forming an acid adduct with a pharmaceutically acceptable acid or by converting the compound into an alkali metal salt such as sodium. Injectable formulations can also contain stabilizers, preservatives, solubilizing agents, etc. A solution that may contain these additives may be placed in a container and then freeze-dried or otherwise converted into a solid formulation for immediate preparation. Alternatively, a single dose may be placed in a single container, or multiple doses may be placed in a single container.

[0027] Examples of solid preparations include tablets, powders, granules, capsules, pills, and lozenges. These solid preparations may contain pharmaceutically acceptable additives in addition to the compound of the present invention. Examples of additives include fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, and lubricants, which can be selected as needed and mixed to form a formulation.

[0028] Liquid preparations include, for example, solutions, syrups, elixirs, emulsions, and suspensions. Additives include, for example, suspending agents and emulsifying agents, which can be selected as needed and mixed to form the preparation.

[0029] EGFR tyrosine kinase inhibitors can be used to treat cancer in mammals, particularly humans. The dosage and administration interval of the medicament of the present invention can be appropriately selected at the discretion of a physician depending on the site of the disease, the patient's height, weight, sex, and medical history. When the medicament of the present invention is administered to humans, the dosage range is about 0.01 mg / kg to about 500 mg / kg of body weight per day, preferably about 0.1 mg / kg to about 100 mg / kg of body weight per active ingredient. When administered to humans, it is preferably administered once a day or in two to four divided doses, preferably repeated at appropriate intervals. Furthermore, the daily dose may exceed the above amounts if necessary, at the discretion of a physician.

[0030] When used in combination with or mixed with other anticancer drugs for patients determined to have positive ACTN4 expression, examples of the other anticancer drugs include, for example, anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer drugs, anticancer platinum coordination compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, anticancer serine-threonine kinase inhibitors, anticancer phospholipid kinase inhibitors, anticancer monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, other antitumor agents, or pharmaceutically acceptable salts thereof. It is possible to use not only one type of other anticancer drug, but also multiple types. For example, a combination therapy in which cisplatin + pemetrexed is inserted midway through osimertinib is included.

[0031] When used in combination or mixture with other anticancer drugs, the administration period of the other drugs is not limited, and they may be administered to the subject simultaneously or at different times. Furthermore, the other drugs may be used in combination with an EGFR tyrosine kinase inhibitor (EGFR-TKI) as a combined drug. The dosage of the other drugs used in combination can be appropriately selected based on the doses used clinically.

[0032] The kit of the present invention is a kit for diagnosing the therapeutic effect or prognosis of a patient with EGFR gene mutation-positive non-small cell lung cancer when an EGFR tyrosine kinase inhibitor is administered to the patient, and is characterized by comprising: a means for measuring or visualizing the expression level of ACTN4 in the patient's lung cancer tissue or lung cancer cells; and instructions for determining whether ACTN4 expression is positive or not based on the expression level, and, if determined to be positive, determining that the therapeutic effect of the EGFR tyrosine kinase inhibitor on the patient is insufficient or that the prognosis of the patient administered the EGFR tyrosine kinase inhibitor is poor. In the kit of the present invention, the means for measuring or visualizing the expression level of ACTN4 can be, for example, a primer set of a forward primer and a reverse primer for detecting ACTN4, or primers, etc.

[0033] In addition to probes and primers for detecting ACTN4, the kit of the present invention also includes various enzymes, buffer solutions, washing solutions, lysis solutions, etc. Furthermore, the kit may include materials, equipment, etc. for detecting ACTN4, and materials, equipment, etc. for collecting lung cancer tissues or lung cancer cells.

[0034] Furthermore, the kit of the present invention may include a program for determining the results, processing the data, and visualizing them on a computer in order to analyze the therapeutic effect or prognosis prediction for a patient when an EGFR tyrosine kinase inhibitor is administered, as well as a device and system equipped with the computer.

[0035] Furthermore, the biomarker of the present invention is a biomarker for assisting in the diagnosis of the therapeutic effect or prognosis prediction for patients with EGFR gene mutation-positive non-small cell lung cancer when an EGFR tyrosine kinase inhibitor is administered to the patient, and is ACTN4 in the patient's lung cancer tissue or lung cancer cells.

[0036] Conventionally, no biomarker has been established for predicting the therapeutic effect or prognosis of patients with EGFR gene mutation-positive non-small cell lung cancer when an EGFR tyrosine kinase inhibitor is administered to the patient. In contrast, by using the biomarker according to the present invention, when ACTN4 is determined to be positive, it is determined that the therapeutic effect of the EGFR tyrosine kinase inhibitor on the patient is insufficient or that the prognosis of the patient administered with the EGFR tyrosine kinase inhibitor is poor, and treatment can be appropriately performed by using the EGFR tyrosine kinase inhibitor in combination or mixture with other anticancer drugs, enabling accurate early treatment and improved therapeutic effects. [Example]

[0037] (subject) The study included 79 patients who were pathologically diagnosed with EGFR gene mutation-positive non-small cell lung cancer at Nippon Medical School Hospital between August 2018 and October 2021 and received osimertinib (EGFR tyrosine kinase inhibitor) as first-line treatment. Of these, 63 patients for whom tumor tissue samples were available were included.

[0038] (Evaluation items) Immunohistochemical staining of ACTN4 was performed on tumor tissue before the start of osimertinib (EGFR tyrosine kinase inhibitor) administration, and patients were divided into ACTN4-positive (ACTN4(+)) and ACTN4-negative (ACTN4(-)) cases. The therapeutic effect of osimertinib (progression-free survival [PFS] / overall survival [OS]) was compared between ACTN4(+) and ACTN4(-) cases.

[0039] PFS and OS were reported using the Kaplan-Meier method and analyzed using the log-rank test. A P value of less than 0.05 was considered significant. When comparing ACTN4(+) and ACTN4(-) patients, it was necessary to adjust for differences in patient background factors between groups that could affect the evaluation of treatment efficacy. Therefore, statistical adjustments for background factors were performed using two methods: inverse probability weighting (IPTW) using propensity scores and a multivariate Cox regression model using covariates.

[0040] The propensity score for the IPTW method was calculated using age, sex, performance status, smoking history, disease stage, EGFR gene mutation type, and PD-L1 expression. Additionally, the presence or absence of ACTN4 expression and patient background factors (age, sex, performance status, smoking history, disease stage, EGFR gene mutation type, and PD-L1 expression that were significant in univariate analysis) were used as covariates in the multivariate Cox regression model.

[0041] (Criteria for determining ACTN4 positivity) Cells with ACTN4 staining circumferentially around the cell membrane were considered positive, and cases in which 30% or more of the tumor cells were positive were considered ACTN4-positive. ACTN4 evaluation was performed by three independent researchers. Figure 1 shows photographs of stained tumor tissue from an ACTN4(-) case and an ACTN4(+) case.

[0042] A total of 63 patients were enrolled in this study, with 33 being ACTN4 positive and 30 being negative. PD-L1 expression was missing in 7 patients (11% of 63), but all other patient background factors (covariates used for adjustment) were measured.

[0043] (result) Of the 63 patients (median age 73 [34-89] years, 65% female, 83% PS 0-1, 100% adenocarcinoma, 51% EGFR19del / L858R / uncommon, 38% EGFR19del / L858R / uncommon, 11% EGFR19del / L858R / uncommon), 33 (52%) were in the ACTN4(+) group and 30 (48%) were in the ACTN4(-) group (Table 1).

[0044] [Table 1]

[0045] After adjusting for background factors using the IPTW method, median PFS was 12.3 (95% CI, 5.3-15.6) months in the ACTN4(+) group and 16.9 (95% CI, 13.3-22.3) months in the ACTN4(-) group, significantly shorter in the ACTN4(+) group (HR 1.87, 95% CI 1.01-3.48, p=0.035) (Figure 2A). OS was also significantly shorter in the ACTN4X(+) group compared with the ACTN4(-) group (HR 2.76, 95% CI 1.02-7.45, p=0.037) (Figure 2B).

[0046] As shown in Figures 2A and 2B, in EGFR gene mutation-positive non-small cell lung cancer, when the tumor had high ACTN4 expression, the effect of EGFR tyrosine kinase inhibitors was poor (PFS and OS were significantly shorter in ACTN4(+) cases).

[0047] Furthermore, multivariate COX hazard analysis of PFS and OS also demonstrated that ACTN4 expression was an independent predictor of poor response to osimertinib (HR 2.21; 95% CI, 1.08-4.53; p=0.030) (Table 2). Multivariate COX hazard analysis of OS also demonstrated that ACTN4 expression was an independent predictor of poor response to osimertinib (HR 3.29; 95% CI, 1.33-8.17; p=0.010) (Table 3).

[0048] [Table 2]

[0049] [Table 3]

[0050] Furthermore, in EGFR gene mutation-positive non-small cell lung cancer, ACTN4 expression (protein and mRNA) has been found to be a biomarker that can lead to treatment selection and development for patients with EGFR gene mutation-positive non-small cell lung cancer, such as through the use of EGFR tyrosine kinase inhibitor + platinum combination therapy. [Industrial Applicability]

[0051] It can be used to determine the effectiveness of treatment for EGFR gene mutation-positive non-small cell lung cancer.

Claims

1. A method for predicting the therapeutic effect or prognosis of a patient with EGFR gene mutation-positive non-small cell lung cancer when the patient is administered an EGFR tyrosine kinase inhibitor, measuring or visualizing the expression level of ACTN4 in the lung cancer tissue or lung cancer cells of the patient; determining whether or not ACTN4 expression is positive based on the expression level, and if determined to be positive, predicting that the therapeutic effect of the EGFR tyrosine kinase inhibitor on the patient will be insufficient or that the prognosis of the patient administered with the EGFR tyrosine kinase inhibitor will be poor; A method for predicting therapeutic effect or prognosis, comprising:

2. The method for predicting therapeutic effect or prognosis according to claim 1, wherein the EGFR tyrosine kinase inhibitor is osimertinib or a pharmaceutically acceptable salt thereof.

3. The method for predicting therapeutic effect or prognosis according to claim 1, wherein the EGFR gene mutation of the EGFR gene mutation-positive non-small cell lung cancer is exon19del, L858R, T790M, or exon20 insertion mutation, or a combination of these mutations.

4. 2. The method for predicting a therapeutic effect or prognosis according to claim 1, wherein the EGFR gene mutation of the EGFR gene mutation-positive non-small cell lung cancer is G719X, L861Q, S768I, D761Y, T854A, G796S, L844V, R776H, L718Q, L861R, S720A, L747S, C797S, E709X, Ins19, N771F, or 18del, or a duplicate mutation thereof.

5. The method for predicting therapeutic effect or prognosis according to claim 1, characterized in that the measurement or visualization of the expression level is measurement or visualization of ACTN4 protein by immunostaining (immunohistochemistry: IHC), measurement or visualization of the copy number of the ACTN4 gene in the genome by in situ hybridization (ISH), or measurement or visualization of ACTN4 genomic DNA and mRNA by qPCR.

6. In the treatment of EGFR gene mutation-positive non-small cell lung cancer, It contains an EGFR tyrosine kinase inhibitor as an active ingredient. A therapeutic agent for EGFR gene mutation-positive non-small cell lung cancer, characterized by being used in combination or mixture with other anticancer drugs for patients determined to have positive ACTN4 expression in lung cancer tissue or lung cancer cells.

7. The therapeutic agent according to claim 6, wherein the EGFR tyrosine kinase inhibitor is osimertinib or a pharmaceutically acceptable salt thereof.

8. The therapeutic agent according to claim 6, wherein the EGFR gene mutation in the EGFR gene mutation-positive non-small cell lung cancer is exon19del, L858R, T790M, or exon20 insertion mutation, or a combination of these mutations.

9. The therapeutic agent according to claim 6, wherein the EGFR gene mutation in the EGFR gene mutation-positive non-small cell lung cancer is G719X, L861Q, S768I, D761Y, T854A, G796S, L844V, R776H, L718Q, L861R, S720A, L747S, C797S, E709X, Ins19, N771F, or 18del, or a combination thereof.

10. A kit for diagnosing the therapeutic effect or prognosis of a patient with EGFR gene mutation-positive non-small cell lung cancer when an EGFR tyrosine kinase inhibitor is administered to the patient, comprising: a means for measuring or visualizing the expression level of ACTN4 in the lung cancer tissue or lung cancer cells of the patient; instructions for determining whether or not ACTN4 expression is positive based on the expression level, and determining, if determined to be positive, that the therapeutic effect of the EGFR tyrosine kinase inhibitor on the patient is insufficient or that the prognosis of the patient administered with the EGFR tyrosine kinase inhibitor is poor; A kit comprising:

11. The kit according to claim 10, wherein the EGFR tyrosine kinase inhibitor is osimertinib or a pharmaceutically acceptable salt thereof.

12. The kit according to claim 10, wherein the EGFR gene mutation of the EGFR gene mutation-positive non-small cell lung cancer is exon19del, L858R, T790M, or exon20 insertion mutation, or a combination thereof.

13. The kit according to claim 10, wherein the EGFR gene mutation in the EGFR gene mutation-positive non-small cell lung cancer is G719X, L861Q, S768I, D761Y, T854A, G796S, L844V, R776H, L718Q, L861R, S720A, L747S, C797S, E709X, Ins19, N771F, or 18del, or a duplicate mutation thereof.

14. A biomarker for assisting in the diagnosis of a therapeutic effect or prognosis prediction for a patient with EGFR gene mutation-positive non-small cell lung cancer when an EGFR tyrosine kinase inhibitor is administered to the patient, A biomarker characterized by being ACTN4 in the lung cancer tissue or lung cancer cells of the patient.

15. The biomarker of claim 14, wherein the EGFR tyrosine kinase inhibitor is osimertinib or a pharmaceutically acceptable salt thereof.

16. The biomarker according to claim 14, wherein the EGFR gene mutation in the EGFR gene mutation-positive non-small cell lung cancer is exon19del, L858R, T790M, or exon20 insertion mutation, or a combination thereof.

17. The biomarker according to claim 14, wherein the EGFR gene mutation in the EGFR gene mutation-positive non-small cell lung cancer is G719X, L861Q, S768I, D761Y, T854A, G796S, L844V, R776H, L718Q, L861R, S720A, L747S, C797S, E709X, Ins19, N771F, or 18del, or a duplicate mutation thereof.

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