Antitumor pharmaceutical compositions containing azuvudine

Abstract

To provide an anti-tumor pharmaceutical composition comprising azvudine.SOLUTION: The present invention discloses a pharmaceutical composition comprising azvudine and an EGFR / TKI inhibitor. The pharmaceutical composition of the present invention shows a superior synergistic effect in antitumor applications, and can delay the generation of drug resistance and improve the therapeutic effect and safety, thereby achieving the goal of prolonging the survival of patients.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention belongs to the field of medicine, and specifically relates to an antitumor pharmaceutical composition containing azuvudine. [Background technology]

[0002] Deoxycytidine kinase (DCK), an enzyme with broad substrate specificity, can phosphorylate pyrimidine and purine deoxynucleosides. It is a key enzyme in the salvage pathway of deoxynucleoside biosynthesis, maintains normal DNA metabolism, and phosphorylates various antiviral and anticancer nucleoside analogue drugs, which are activated only after phosphorylation, thereby inhibiting tumor growth. Radiotherapy strategies for apoptosis, which have been widely studied over the past decades, have become an important tool in tumor therapy.

[0003] Azuvudine is a broad-spectrum RNA virus inhibitor. It is an artificially synthesized nucleoside analogue of the viral RNA-dependent RNA polymerase (RdRp). It is metabolized intracellularly to a 5'-triphosphate metabolite (azuvudine triphosphate) with antiviral activity. It specifically targets the viral RdRp and inhibits its activity in host cells, thereby blocking the synthesis and replication of RNA strands. In July 2021, azuvudine tablets were approved for sale in China for the treatment of adult HIV-1-infected patients with high viral loads. In July 2022, azuvudine was also approved for the treatment of COVID-19.

[0004] Patent document CN201010506595.X discloses the use of azuvudine to treat tumors such as colon cancer, liver cancer, gastric cancer, esophageal cancer, lung cancer, breast cancer, cervical cancer, leukemia, lymphoma, etc. Azuvudine has been shown to have obvious inhibitory effects on various human cancer cells and animal transplant tumors.

[0005] EGFR (Epidermal Growth Factor Receptor) is a member of the erbB receptor family of transmembrane protein tyrosine kinases. Upon binding to its ligand, such as epidermal growth factor (EGF), EGFR can form homodimers on the cell membrane or heterodimers with other receptors in the family (e.g., erbB2, erbB3, or erbB4). The formation of these dimers allows EGFR to be phosphorylated at key tyrosine residues within the cell, thereby activating multiple downstream signaling pathways within the cell. These intracellular signaling pathways play important roles in cell proliferation, survival, and anti-apoptosis. Dysregulation of the EGFR signaling pathway, including increased expression of the ligand and receptor, amplification and mutation of the EGFR gene, promotes malignant transformation of cells and plays an important role in tumor cell proliferation, invasion, metastasis, and angiogenesis. EGFR has been reported to be overexpressed in many human malignancies, including bladder, brain, head and neck, pancreatic, lung, breast, ovarian, colon, prostate, and kidney cancers, and EGFR overexpression is often associated with poor patient prognosis.

[0006] Lung cancer has the highest incidence rate of any cancer, with approximately 85% of cases being non-small cell lung cancer (NSCLC). According to statistics, in 2020, there were 2.2 million newly diagnosed cases of lung cancer worldwide, and 1.8 million deaths from lung cancer, accounting for approximately 18% of cancer-related deaths. The 5-year survival rate was only 10%-20%. Statistics show that approximately 10%-40% of NSCLC patients in various countries and regions around the world have epidermal growth factor receptor (EGFR) mutations. Therefore, targeting EGFR is an important therapeutic strategy for NSCLC. Clinically, the use of EGFR inhibitors has become the standard first-line treatment for EGFR mutation-positive NSCLC.

[0007] First-generation EGFR inhibitors are reversible competitive inhibitors, with representative drugs being gefitinib and erlotinib. However, 50–60% of patients develop drug resistance after 1–2 years, primarily through the development of the T790M mutation. Second-generation EGFR inhibitors are covalent inhibitors, with afatinib being a representative drug. While more effective than first-generation EGFR inhibitors, they still pose a risk of developing drug resistance due to the T790M mutation. Third-generation EGFR inhibitors, primarily designed to target the T790M drug resistance mutation, include osimertinib. However, drug resistance due to the C797S mutation may develop after approximately one year of use. To address the issue of drug resistance, new EGFR inhibitors are currently being developed worldwide. China has a large population, a high number of smokers, and a higher incidence of lung cancer than other countries, so developing new lung cancer treatments to improve the 5-year survival rate is particularly important for the country.

[0008] Multi-mechanism combination therapy is an important strategy for delaying or avoiding the development of drug resistance to tumor drugs. Based on current treatment strategies for non-small cell lung cancer and advances in EGFR inhibitor research, multi-mechanism combination therapy for non-small cell lung cancer can delay the development of drug resistance, improve efficacy and safety, and thereby achieve the goal of prolonging patient survival. Summary of the Invention

[0009] The present disclosure provides a pharmaceutical combination product of azuvudine and an EGFR inhibitor, and the use of this pharmaceutical composition product in the preparation of a medicament for preventing or treating a tumor disease.

[0010] The pharmaceutical composition of the present invention has the following advantages compared to each individual drug. 1. After combined use, the tumor-suppressing effects of each single agent were improved. 2. The development of drug resistance is delayed, improving efficacy and safety, thereby extending patient survival.

[0011] In order to solve the technical problem of the present invention, the present invention provides: (i) azuvudine or a pharmaceutically acceptable salt, stereoisomer, or isotopic derivative thereof; (ii) an EGFR / TKI inhibitor; and

[0012] In a preferred technical aspect of the present invention, the EGFR / TKI inhibitor is selected from the group consisting of osimertinib, gefitinib, erlotinib, doxitinib, olmutinib, icotinib, pyrotinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, barlitinib, HLX-07, tesevatinib, teliatinib, epertinib succinate, S-222611, flumonertinib, befotertinib, resibertinib, poziotinib and any combination thereof.

[0013] In a preferred technical aspect of the present invention, the EGFR / TKI inhibitor is osimertinib, doxitinib, or a combination thereof.

[0014] In a preferred technical embodiment of the present invention, (i) and (ii) are administered simultaneously, separately, or sequentially, or (i) and (ii) are present in the same dosage form.

[0015] The present invention also provides the above pharmaceutical combination product for treating tumor-related diseases.

[0016] In a preferred technical aspect of the present invention, the tumor-related disease is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, renal cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureter tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, bile duct carcinoma and choriocarcinoma, preferably non-small cell lung cancer.

[0017] In some embodiments, the dose of azuvudine ranges from 1 to 100 mg and the dose of the EGFR / TKI inhibitor ranges from 1 to 100 mg.

[0018] The doses of azuvudine described in this disclosure include 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg , 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, and 100mg.

[0019] The doses of EGFR / TKI inhibitors described in this disclosure may be 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, The dose is selected from 0 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, and 100 mg.

[0020] In some embodiments, the azuvidine may have a dose in the range of 1 to 100 mg and may be administered once daily, twice daily, or three times daily, and the EGFR / TKI inhibitor may have a dose in the range of 1 to 100 mg and may be administered once daily, twice daily, or three times daily.

[0021] In some embodiments, the azuvidine has a dose in the range of 1 to 60 mg and can be administered once daily or twice daily, and the EGFR / TKI inhibitor has a dose in the range of 1 to 60 mg and is administered once daily.

[0022] In some embodiments, the azuvidine has a dose in the range of 1 to 20 mg and can be administered once daily or twice daily, and the EGFR / TKI inhibitor has a dose in the range of 1 to 20 mg and is administered once daily.

[0023] In some embodiments, the azuvidine has a dose in the range of 1 to 10 mg and can be administered once daily or twice daily, and the EGFR / TKI inhibitor has a dose in the range of 1 to 10 mg and is administered once daily.

[0024] In some embodiments, the EGFR / TKI inhibitor is administered at a dose of 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, and the EGFR / TKI inhibitor has a dose selected from 10 mg, 20 mg, 40 mg, 60 mg, and is administered once a day.

[0025] In some embodiments, the azuvidine is administered at a dose selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, and 20 mg and at a frequency of once daily or twice daily; or the azuvidine is administered at a dose selected from 1 mg, 2 mg, 4 mg, and 6 mg and at a frequency of once daily.

[0026] In some embodiments, the EGFR / TKI inhibitor has a dose selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg and is administered once daily or twice daily; and the EGFR / TKI inhibitor has a dose selected from 10 mg, 20 mg, 40 mg, 60 mg and is administered once daily.

[0027] In some embodiments, the EGFR / TKI inhibitor has a dose selected from 1 mg, 2 mg, 4 mg, 6 mg, or 8 mg and is administered once daily or twice daily; and the EGFR / TKI inhibitor has a dose selected from 1 mg, 2.5 mg, 5 mg, or 10 mg and is administered once daily.

[0028] The administration routes of the combinations described in the present invention include oral, parenteral and transdermal administration, preferably oral administration, which includes, but is not limited to, intravenous, subcutaneous and intramuscular injection.

[0029] The present invention also provides a pharmaceutical composition comprising the above-mentioned azuvudine, an EGFR / TKI inhibitor, and one or more pharmaceutically acceptable carriers, excipients, or diluents. The pharmaceutical composition can be in any pharmaceutically acceptable dosage form, such as tablets, capsules, drop pills, granules, solutions, suspensions, syrups, injections (including infusions, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalants, or sprays. The pharmaceutical composition can also be in the same dosage form, such as azuvudine and an EGFR / TKI inhibitor formulated as a combined tablet, combined capsule, combined drop pill, combined granules, combined solutions, combined suspensions, combined syrup, combined injections (including infusions, sterile powders for injection, and concentrated solutions for injection), combined suppositories, combined inhalants, or combined sprays.

[0030] The present invention also provides a method for treating tumor diseases, which comprises administering to a patient an effective amount of the azuvudine and an effective amount of the EGFR / TKI inhibitor.

[0031] The present invention also provides a pharmaceutical kit for use in treating tumor diseases, which contains a pharmaceutical composition of azuvudine and an EGFR / TKI inhibitor as described in the present disclosure.

[0032] In the present invention, the combined administration of azuvudine and an EGFR / TKI inhibitor enhances the efficacy of the drugs for treating tumor diseases.

[0033] The term "combination" as used herein refers to a method of administration in which at least one dose of azuvidine and at least one dose of an EGFR / TKI inhibitor are administered within a specified period of time, and both drugs exhibit pharmacological effects. This period may be within one administration cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or 24 hours, and more preferably within 12 hours. The azuvidine and the EGFR / TKI inhibitor may be administered simultaneously or sequentially. This period includes treatments in which the azuvidine and the EGFR / TKI inhibitor are administered via the same or different routes of administration. [Brief explanation of the drawings]

[0034] [Figure 1] Figure 1 shows the effect of azuvudine (FNC) and osimertinib, alone or in combination, on the tumor volume of human lung cancer NCI-H1975 tumors subcutaneously transplanted into mice. [Figure 2] Figure 2 shows the effect of azuvumab and osimertinib, alone or in combination, on tumor weight in mice. [Figure 3] FIG. 3 shows the effect of azuvudine and doxitinib, either alone or in combination, on the tumor volume of subcutaneously transplanted tumors from human lung cancer NCI-H1975 in mice. [Figure 4] FIG. 4 shows the effect of azuvudine and doxitinib, alone or in combination, on tumor weight in mice. [Figure 5] Figure 5 shows the chemical structures of azuvudine, osimertinib, and doxitinib. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present disclosure will be described in more detail below with reference to examples. The examples of the present disclosure are used only to describe the technical aspects of the present disclosure and are not intended to limit the essence and scope of the present disclosure.

[0036] Experimental materials Experimental animals and breeding environment experimental animals Species: Mouse Strain: BALB / c nude mouse Age and weight: 6-8 weeks, 17.42-23.71g Gender: Female Quantity: 40 mice (excluding mice left over from group allocation) Supplier: Zhejiang Weitong Lihua Laboratory Animal Co., Ltd.

[0037] Rearing environment After arrival, the animals were housed in an experimental environment for 7 days before the start of the experiment. Animals were housed in IVC (independently ventilated system) cages in SPF-grade animal rooms (4 per cage). An animal information card in each cage indicated the number of animals in the cage, sex, strain, date of receipt, medication regimen, experiment number, group, and start date of the experiment. All cages, bedding, and drinking water were sterilized before use. Cages, food, and drinking water were changed twice a week. The housing environment and lighting conditions were as follows: - Temperature: 20~26°C - Humidity: 40~70% - Light cycle: 12 hours light, 12 hours no light (lights on at 8am - lights off at 8pm)

[0038] Cage: Polycarbonate, 325mm x 210mm x 180mm. Corn cob bedding was replaced twice a week. Food: Experimental animals were given free access to food (irradiation sterilized dry pelleted food) throughout the experiment. Drinking water: Experimental animals were given free access to sterile water. Cage Identification: Animal information for each cage indicated the number of animals in the cage, sex, strain, date of receipt, dosing regimen, experiment number, group, and start date of the experiment. Animal identification: Experimental animals were identified by ear tags.

[0039] Example 1 Experimental Objective: To evaluate the antitumor effect of azuvudine and osimertinib in a subcutaneous xenograft animal model of human lung cancer NCI-H1975 (EGFRL858R / T790M) cell line in BALB / c nude female mice.

[0040] NCI-H1975 was cultured in RPMI 1640 medium containing 10% serum at 37°C under sterile, constant temperature conditions of 5% CO2. When the cells in each bottle reached a confluence of 90% or more, the cells were digested, resuspended in PBS, and counted using a cell counter until the cell concentration reached 5x10. 7 The 8th passage cells were subcutaneously inoculated into nude mice, and tumors were grown to 800 mm 3 When the tumor grew to about 2 × 2 × 2 mm, it was removed and 3 The tumors were cut into pieces of 100-120 mm2 each and inoculated into the right back of each mouse. 3 When tumor size reached 100 mg / kg, treatment was initiated in each group using a randomized stratified grouping method based on tumor volume and animal weight. The lung cancer cell line models were randomly divided into four experimental groups, with eight animals in each group. After grouping, treatment was administered continuously for 28 days.

[0041] Tumor volume inhibition rate (TGI TV ): T.G.I. TV (%) = [1-(Ti-T0) / (Vi-V0)] x 100% (Ti: mean tumor volume of the treatment group on day i of administration, T0: mean tumor volume of the treatment group on day 0 of administration, Vi: mean tumor volume of the vehicle control group on day i of administration, V0: mean tumor volume of the vehicle control group on day 0 of administration)

[0042] Tumor weight suppression results (T 重量 / C 重量 ): After the experiment, the surviving animals were euthanized, the tumor tissues were removed, and the tumor weights were weighed. The difference in tumor weight between the groups was calculated, and the tumor weight inhibition results (T 重量 / C 重量 ) was calculated using the following formula: Tumor weight suppression results (T 重量 / C 重量 )%=W Mean治療群 / W Mean溶媒対照群 × 100%, where W refers to tumor weight.

[0043] Tumor volume suppression results Figure 1 shows the tumor volume change curves for tumor-bearing mice in each group, and Table 1 lists the average tumor volumes and statistical significance at different time points. The first administration day was designated Day 0. After 28 days of administration, significant differences in tumor volume were observed in each treatment group, except for G2, compared with the control group. Tumor TGI was as follows: osimertinib + azuvudine (2.5 + 1 mpk) group (94.5%) > osimertinib group (66.4%) > azuvudine (1 mpk) group (35.7%).

[0044] [Table 1]

[0045] Tumor weight suppression results T in tumor-bearing mice in the control and treatment groups 重量 / C 重量 The percentages are shown in Table 2, and the tumor weight change curves of the tumor-bearing mice in each group are shown in Figure 2.

[0046] [Table 2]

[0047] In a mouse model bearing the lung cancer cell line NCI-H1975, statistical analysis of the tumor inhibition rate (TGI) (%) showed that azuvuzine had a dose-dependent effect in inhibiting tumor growth. The combination of azuvuzine and osimertinib enhanced the tumor-inhibitory effects of each drug alone. The dose of the test drug used in this experiment did not cause any obvious toxic side effects in the animals, and was safe.

[0048] Example 2 Objective: To evaluate the antitumor effect of azuvudine and doxitinib in a subcutaneous xenograft animal model of human lung cancer NCI-H1975 (EGFRL858R / T790M) cell line in BALB / c nude female mice.

[0049] NCI-H1975 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Regular passages were performed once a week. When the cells reached 80%-90% saturation and the required number of cells was reached, they were harvested, counted, and inoculated.

[0050] Tumor cell inoculation NCI-H1975 cells 0.1mL (5×10 6 ) was subcutaneously inoculated into the right back of each mouse, and the average tumor volume was approximately 154 mm 3 Dosing began in each group when the

[0051] The experimental endpoint was to investigate whether tumor growth was inhibited, delayed, or cured. Tumor diameters were measured twice a week or every other day with a vernier caliper. Tumor volume was calculated as V = 0.5a × b 2 The calculation was performed using the formula: where a and b represent the long and short diameters of the tumor, respectively.

[0052] The antitumor effect of the compound was evaluated by TGI (%) or the relative tumor growth rate T / C (%). TGI (%) reflects the tumor growth inhibition rate. TGI (%) was calculated using the following formula: TGI (%) = [1 - (mean tumor volume at the end of treatment in a treatment group - mean tumor volume at the start of treatment in that treatment group) / (mean tumor volume at the end of treatment in the vehicle control group - mean tumor volume at the start of treatment in the vehicle control group)] × 100%.

[0053] Relative tumor growth rate T / C (%) is T / C%=T RTV / C RTV ×100% (However, T RTV represents the mean RTV of the treatment group, and C RTV The RTV was calculated using the formula: RTV = V t Relative tumor volume (RTV) was calculated using the formula: / V0, where V0 is the tumor volume measured at the time of group administration (i.e., d0), and V t is the tumor volume at a given measurement, and T RTV and CRTV The data are taken on the same day.

[0054] statistical analysis Statistical analysis included the mean and standard error (SEM) of tumor volume for each group at each time point (see Table 3 for specific data). Because the treatment group showed the greatest therapeutic effect from day 20 after administration to the end of the study, statistical analysis based on this data was used to evaluate differences between groups. Comparisons between two groups were analyzed using a T-test, and comparisons between three or more groups were analyzed using one-way ANOVA. All data analyses were performed using Prism. A p<0.05 was considered significant.

[0055] Table 3 shows the change in tumor volume in each group after administration of the test drug to BALB / c nude mice bearing subcutaneous xenograft tumors of NCI-H1975 cells, and Figure 3 shows the tumor volume change curves for the tumor-bearing mice in each group.

[0056] [Table 3]

[0057] Antitumor drug efficacy evaluation index [Table 4]

[0058] The tumor weight change curves for the tumor-bearing mice in each group are shown in FIG.

[0059] Test results Experiments showed that azuvudine had a dose-dependent effect on tumor growth in a mouse xenograft tumor model of the human lung cancer cell line NCI-H1975. The combination of azuvudine and doxitinib enhanced the tumor-suppressing effects of either drug alone.

[0060] Although specific embodiments of the present invention have been described above, it should be understood by those skilled in the art that these are merely examples and that various changes and modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims. This specification includes the disclosure of the following inventions. [Item 1] (i) Azuvudine or a pharmaceutically acceptable salt, stereoisomer or isotope derivative thereof; (ii) a pharmaceutical combination product comprising an EGFR / TKI inhibitor. [Item 2] The EGFR / TKI inhibitor is osimertinib, gefitinib, erlotinib, doxitinib, olmutinib, icotinib, pyrotinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, varlitinib, HLX-07, tesevatinib, theliatinib, epertinib succinate, or 2. The pharmaceutical combination product according to item 1, wherein the active ingredient is selected from the group consisting of flumonertinib, befotertinib, rezivertinib, poziotinib, and combinations thereof. [Item 3] The pharmaceutical combination product according to Item 1 or 2, wherein the EGFR / TKI inhibitor is osimertinib, doxitinib, or a combination thereof. [Item 4] The pharmaceutical combination product according to any one of Items 1 to 3, wherein (i) and (ii) are administered simultaneously, separately, or sequentially, or wherein (i) and (ii) are present in the same dosage form. [Item 5] The pharmaceutical combination product according to any one of Items 1 to 4, which is used for the treatment of a tumor-related disease. [Item 6] The pharmaceutical combination product according to Item 5, wherein the tumor-related disease is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, renal cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureter tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, bile duct carcinoma, and choriocarcinoma, preferably non-small cell lung cancer.

Claims

1. (i) A pharmaceutical composition comprising azuvudine or a pharmaceutically acceptable salt or stereoisomer thereof, (ii) used in combination with the administration of an EGFR / TKI inhibitor; The EGFR / TKI inhibitors include osimertinib, gefitinib, erlotinib, doxitinib, olmutinib, icotinib, pyrotinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, varlitinib, HLX-07, tesevatinib, theliatinib, epeltinib succinate, and the like. succinate), S-222611, flumonertinib, befotertinib, resivertiniib, poziotinib, and combinations thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the EGFR / TKI inhibitor is selected from the group consisting of osimertinib, doxitinib, and combinations thereof.

3. 2. The pharmaceutical composition of claim 1, wherein (i) and (ii) are administered simultaneously, separately, sequentially, or wherein (i) and (ii) are present in the same dosage form.

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