Anti-tumor pharmaceutical composition comprising azvudine

Abstract

A pharmaceutical composition containing Azvudine and an EGFR / TKI inhibitor. The pharmaceutical composition exhibits relatively good synergistic anti-tumor effects, and is capable of delaying the generation of drug resistance and increasing the curative effects and safety, thereby achieving the purpose of prolonging the survival period of a patient.

Description

Antitumor pharmaceutical composition containing azithromycin Technical Field

[0001] The present disclosure belongs to the field of medicine, and particularly relates to an anti-tumor pharmaceutical composition containing azvudine. Background Art

[0002] Deoxycytidine kinase (DCK) is an enzyme with broad substrate specificity that phosphorylates pyrimidine and purine deoxynucleosides. It is a key enzyme in the salvage pathway of deoxynucleotide biosynthesis, maintaining normal DNA metabolism and phosphorylating a variety of antiviral and anticancer nucleoside analogs. These drugs are activated only upon phosphorylation, thereby inhibiting tumor growth. Over the past few decades, apoptosis has been extensively studied, and radiotherapy strategies targeting apoptosis have become an important approach to tumor treatment.

[0003] Azvudine is a broad-spectrum RNA virus inhibitor. As a synthetic nucleoside analog of viral RNA-dependent RNA polymerase (RdRp), it is metabolized into a 5'-triphosphate metabolite (azvudine triphosphate) with antiviral activity in cells. It can specifically act on the novel coronavirus polymerase (RdRp). Its target is the viral RdRp, which can block the synthesis and replication of RNA chains in host cells by inhibiting the activity of RdRp. In July 2021, azvudine tablets were approved for marketing in my country for the treatment of adult HIV-1-infected patients with high viral loads. In July 2022, azvudine was approved for the treatment of novel coronavirus infection. In addition, studies have found that azvudine has a significant inhibitory effect on a variety of human cancer cells and animal transplanted tumors.

[0004] EGFR (Epidermal Growth Factor Receptor) is a member of the erbB 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, such as erbB2, erbB3, or erbB4. The formation of these dimers leads to phosphorylation of key tyrosine residues within the cell, thereby activating multiple downstream signaling pathways. 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, EGFR gene amplification, and mutation, can promote malignant transformation and play a crucial role in tumor cell proliferation, invasion, metastasis, and angiogenesis. Overexpression of EGFR has been reported in numerous human malignancies, including bladder, brain, head and neck, pancreatic, lung, breast, ovarian, colon, prostate, and kidney cancers. In many cases, overexpression of EGFR is associated with poor prognosis in patients. Lung cancer is one of the most prevalent types of cancer, of which approximately 85% are non-small cell lung cancer (NSCLC). According to statistics, in 2020, there were 2.2 million new cases of lung cancer and 1.8 million deaths from lung cancer worldwide, accounting for approximately 18% of cancer-related deaths, and the 5-year survival rate was only 10%-20%. According to statistics, approximately 10%-40% of NSCLC patients in different countries and regions around the world have epidermal growth factor receptor (EGFR) mutations, and targeting EGFR is an important treatment strategy for non-small cell lung cancer. Clinically, the use of EGFR inhibitors has become the standard first-line treatment for EGFR mutation-positive non-small cell lung cancer.

[0005] First-generation EGFR inhibitors are reversible competitive inhibitors, represented by gefitinib and erlotinib. However, 50-60% of patients develop acquired resistance after 1-2 years, primarily due to the T790M mutation in EGFR. Second-generation EGFR inhibitors, represented by afatinib, are covalent inhibitors. While they are more effective than first-generation EGFR inhibitors, patients can still develop resistance due to the T790M mutation. Third-generation EGFR inhibitors, represented by osimertinib, are primarily designed to target the T790M resistance mutation, but resistance can develop after approximately one year of use due to the C797S mutation. New EGFR inhibitors are currently being developed globally to address the issue of EGFR inhibitor resistance. China, with its large population and numerous smokers, has a higher incidence of lung cancer than other countries. Therefore, developing new lung cancer treatments is crucial for improving the five-year survival rate of lung cancer patients in my country.

[0006] Multi-mechanism combination therapy is an important strategy for delaying or even circumventing the development of tumor drug resistance. Based on current treatment strategies for non-small cell lung cancer and research progress in EGFR inhibitors, multi-mechanism combination therapy for non-small cell lung cancer can delay the development of drug resistance, improve efficacy and safety, and thus achieve the goal of prolonging patient survival.

[0007] Summary of the Invention

[0008] The present disclosure provides a pharmaceutical combination product of azvudine and an EGFR inhibitor, and use of the pharmaceutical combination product in preparing a medicament for preventing or treating tumor diseases.

[0009] Compared with each single drug, the pharmaceutical composition disclosed herein has at least the following advantages:

[0010] 1. The combined use enhanced the tumor-suppressing effect of each drug alone;

[0011] 2. Delay the development of drug resistance, improve efficacy and safety, and thus achieve the goal of prolonging patient survival.

[0012] The present disclosure provides a pharmaceutical combination product comprising:

[0013] (i) Azithromycin or a pharmaceutically acceptable salt, stereoisomer or isotopic derivative thereof;

[0014] (ii) EGFR / TKI inhibitors.

[0015] In an optional technical solution of the present disclosure, the EGFR / TKI inhibitor is selected from any one of osimertinib, gefitinib, erlotinib, dositinib, omotinib, icotinib, pyrotinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, valitinib, HLX-07, tesifatinib, teritinib, ipatinib succinate, S-222611, flumetinib, befortinib, rizitinib, and poziotinib, or any combination thereof.

[0016] In an optional technical solution of the present disclosure, the EGFR / TKI inhibitor is selected from osimertinib, dosimetinib or a combination thereof.

[0017] In an optional technical solution of the present disclosure, (i) and (ii) are administered simultaneously, separately, or sequentially, or (i) and (ii) are present in the same dosage form.

[0018] In addition, the present disclosure also provides the above-mentioned pharmaceutical combination product for treating tumor-related diseases.

[0019] In an optional technical solution of the present disclosure, the tumor-related disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney 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, ureteral tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, bile duct cancer or choriocarcinoma, preferably non-small cell lung cancer.

[0020] In some optional embodiments, the dose of the azvudine is selected from 1-100 mg, and the dose of the EGFR / TKI inhibitor is selected from 1-100 mg.

[0021] The dosage of azivudine described in the present disclosure is 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, 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, 100mg.

[0022] The dosage of the EGFR / TKI inhibitors disclosed herein is 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, 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. , 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75 mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg.

[0023] In some optional embodiments, the dose of the azithromycin is selected from 1-100 mg, and the administration frequency can be once a day, twice a day or three times a day. The dose of the EGFR / TKI inhibitor is selected from 1-100 mg, and the administration frequency can be once a day, twice a day or three times a day.

[0024] In some optional embodiments, the dose of the azvudine is selected from 1-60 mg, and the administration frequency can be once a day or twice a day, and the dose of the EGFR / TKI inhibitor is selected from 1-60 mg, and the administration frequency is once a day.

[0025] In some optional embodiments, the dose of the azvudine is selected from 1-20 mg, and the administration frequency can be once a day or twice a day, and the dose of the EGFR / TKI inhibitor is selected from 1-20 mg, and the administration frequency is once a day.

[0026] In some optional embodiments, the dose of the azvudine is selected from 1-10 mg, and the administration frequency can be once a day or twice a day, and the dose of the EGFR / TKI inhibitor is selected from 1-10 mg, and the administration frequency is once a day.

[0027] In some optional embodiments, the dose of the EGFR / TKI inhibitor is selected from 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 g, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, and the administration frequency is once a day or twice a day. The dose of the EGFR / TKI inhibitor is selected from 10mg, 20mg, 40mg, 60mg, and the administration frequency is once a day.

[0028] In some optional embodiments, the dose of azvudine is 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, 20 mg, and the administration frequency is once a day or twice a day. The dose of azvudine is selected from 1 mg, 2 mg, 4 mg, 6 mg, and the administration frequency is once a day.

[0029] In some optional embodiments, the dosage of the EGFR / TKI inhibitor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and the administration frequency is once a day or twice a day. The dosage of the EGFR / TKI inhibitor is selected from 10 mg, 20 mg, 40 mg, 60 mg, and the administration frequency is once a day.

[0030] In some optional embodiments, the dosage of the EGFR / TKI inhibitor is selected from 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, and the administration frequency is once a day or twice a day. The dosage of the EGFR / TKI inhibitor is selected from 1 mg, 2.5 mg, 5 mg, 10 mg, and the administration frequency is once a day.

[0031] The combined administration route disclosed herein is oral administration, parenteral administration, and transdermal administration. The parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection, and oral administration is preferred.

[0032] The present disclosure also provides a pharmaceutical composition of the above-mentioned azvudine and EGFR / TKI inhibitor and one or more pharmaceutical carriers, excipients, and diluents. The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, it can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalers or sprays; the pharmaceutical composition can also be prepared into the same dosage form, for example, azvudine and EGFR / TKI inhibitors can be formulated into composite tablets, composite capsules, composite pills, composite granules, composite solutions, composite suspensions, composite syrups, composite injections (including injections, sterile powders for injection and concentrated solutions for injection), composite suppositories, composite inhalers or composite sprays.

[0033] The present disclosure also provides a method for treating tumor diseases, comprising administering an effective amount of the above-mentioned azvudine and an effective amount of the above-mentioned EGFR / TKI inhibitor to a patient.

[0034] The present disclosure also provides a pharmaceutical kit for use in treating tumor diseases, wherein the pharmaceutical composition of azvudine and an EGFR / TKI inhibitor according to the present disclosure is packaged.

[0035] The present disclosure administers azvudine in combination with an EGFR / TKI inhibitor, thereby enhancing the effect of the drug in treating tumor diseases.

[0036] As used herein, "combination" refers to a regimen that includes administering at least one dose of azvudine and at least one dose of an EGFR / TKI inhibitor within a timeframe, wherein both agents exhibit a pharmacological effect. The timeframe can be within a single dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours, more preferably within 12 hours. Azvudine and the EGFR / TKI inhibitor can be administered simultaneously or sequentially. This timeframe includes treatments in which azvudine and the EGFR / TKI inhibitor are administered via the same route of administration or via different routes of administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG1 is a graph showing the effects of azvudine, osimertinib, or their combination on the tumor volume of subcutaneous xenografts of human lung cancer NCI-H1975 in mice, wherein FNC represents azvudine;

[0038] FIG2 is a graph showing the effects of azivudine, osimertinib, or their combination on tumor weight in mice;

[0039] FIG3 is a graph showing the effects of azvudine, doxitinib, or both alone or in combination on the tumor volume of subcutaneous xenografts of human lung cancer NCI-H1975 in mice;

[0040] FIG4 is a graph showing the effects of azvudine, doxitinib, or both alone or in combination on tumor weight in mice;

[0041] FIG5 is a diagram showing the chemical structures of azivudine, osimertinib, and dosimetinib. DETAILED DESCRIPTION

[0042] The present disclosure will be explained in more detail below with reference to embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure and are not intended to limit the essence and scope of the present disclosure.

[0043] Experimental Materials

[0044] Experimental animals and breeding environment

[0045] experimental animals

[0046] Species: Mouse

[0047] Strain: BALB / c nude mice

[0048] Age and weight: 6-8 weeks; 17.42-23.71g

[0049] Gender: Female

[0050] Quantity: 40 (excluding the remaining mice in the group)

[0051] Supplier: Zhejiang Weitonglihua Experimental Animal Co., Ltd.

[0052] breeding environment

[0053] Upon arrival, animals were housed in the experimental environment for 7 days before the experiment began. Animals were housed in an SPF-grade animal room using IVC (independent ventilation system) cages (4 animals per cage). Each cage's animal information card indicated the number of animals in the cage, sex, strain, date of receipt, dosing regimen, experiment number, group, and experiment start date. All cages, bedding, and drinking water were sterilized before use. Cages, feed, and drinking water were changed twice weekly. The housing environment and lighting conditions were as follows:

[0054] √ Temperature: 20-26℃

[0055] Humidity: 40-70%

[0056] √ Light cycle: 12 hours of light, 12 hours of no light (lights on 8 am to off 8 pm)

[0057] Cages: Made of polycarbonate, 325mm x 210mm x 180mm. Bedding is corn cobs, changed twice a week.

[0058] Food: The experimental animals had free access to food (irradiation sterilized, dry pelleted food) throughout the experimental period.

[0059] Drinking water: Experimental animals can drink sterile water freely.

[0060] Cage identification: The animal information card for each cage should indicate the number of animals in the cage, sex, strain, receipt date, dosing regimen, experiment number, group and start date of the experiment.

[0061] Animal identification: Experimental animals were identified with ear tags.

[0062] Example 1

[0063] The purpose of the experiment was to evaluate the anti-tumor effect of azvudine combined with osimertinib in the BALB / c nude female mouse model with subcutaneous xenografts of human lung cancer NCI-H1975 (EGFRL858R / T790M) cell line.

[0064] NCI-H1975 cells were cultured in RPMI 1640 medium containing 10% serum at 37°C under sterile conditions with 5% CO2. When the cell confluence in each bottle reached more than 90%, the cells were digested, resuspended in PBS, and counted using a cell counter until the cell concentration reached 5x10 7 Each mouse was injected with 0.1 ml. The 8th generation cells were inoculated subcutaneously in nude mice. 3 Remove the tumor and cut into 2*2*2mm 3 The tumors were inoculated on the right back of each mouse. The average tumor volume after inoculation was 100-120 mm 3 At 4 hr, randomized stratified groups were used based on tumor volume and animal weight to initiate drug administration. Lung cancer cell line models were randomly divided into four experimental groups, with eight animals in each group. Drug administration continued for 28 days after grouping.

[0065] Tumor volume inhibition rate (TGI TV ):

[0066] TGI TV (%)=[1-(Ti-T0) / (Vi-V0)]×100%

[0067] (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 solvent control group on day i of administration, V0: mean tumor volume of the solvent control group on day 0 of administration)

[0068] Tumor weight inhibition results (T weight / C weight ):

[0069] At the end of the experiment, the surviving animals were euthanized and the tumor tissues were removed. The tumor weights were weighed and the differences in tumor weights among the groups were calculated to further calculate the tumor weight inhibition results (T weight / C weight ), the calculation formula is as follows:

[0070] Tumor weight inhibition results (T weight / C weight )%=W Mean治疗组 / W Mean溶剂对照组 × 100%, W refers to tumor weight.

[0071] Tumor volume inhibition results

[0072] The tumor volume change curves for each group of tumor-bearing mice are shown in Figure 1. The average tumor volume and significance statistics at different time points are shown in Table 1. The day of the first administration was designated as Day 0. After 28 days of administration, compared with the control group, the tumor volume of each treatment group, except for G2, showed significant differences. The ranking by tumor TGI was: osimertinib + azvudine (2.5 + 1 mpk) group (94.5%) > osimertinib group (66.4%) > azvudine (1 mpk) group (35.7%).

[0073] Table 1. Effects of the tested drugs on tumor volume in tumor-bearing mice

[0074] Note: a: mean ± standard error;

[0075] b: Statistical comparison of tumor volume between the treatment group and the control group on day 28 of administration, T-test analysis, *p<0.05, **p<0.01, ***P<0.005

[0076] Tumor weight inhibition results

[0077] The Tweight / Cweight percentages of tumor-bearing mice in the control group and the treatment group are shown in Table 2 , and the tumor weight change curves of tumor-bearing mice in each group are shown in Figure 2 .

[0078] Table 2. Tweight / Cweight of tumor weight in mice treated with test drugs

[0079] Note: a: mean ± standard error.

[0080] b: Statistical comparison of tumor weight between the treatment group and the control group at the end of the experiment, T-test analysis, *p<0.05, **p<0.01, ***P<0.005

[0081] Statistical analysis of the tumor inhibition rate (TGI) (%) in a mouse model bearing the lung cancer cell line NCI-H1975 showed that azvudine inhibited tumor growth in a dose-dependent manner. Combining azvudine with osimertinib enhanced the tumor inhibition effect of each drug alone. The doses administered in this experiment did not produce significant toxic side effects in the animals, demonstrating a good safety profile.

[0082] Example 2

[0083] The purpose of the experiment was to evaluate the anti-tumor effect of azovudine combined with doxetinib in the BALB / c nude female mouse model with subcutaneous xenografts of human lung cancer NCI-H1975 (EGFRL858R / T790M) cell line.

[0084] NCI-H1975 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Routine passage was performed weekly. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[0085] Tumor cell inoculation

[0086] 0.1 mL (5 × 10 6 )NCI-H1975 cells were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached approximately 154 mm 3 The group dosing started at 14:00.

[0087] The experimental indicator is to examine whether tumor growth is inhibited, delayed, or cured. Tumor diameter is measured with a vernier caliper twice a week or every other day. The formula for calculating tumor volume is: V = 0.5a × b 2 , a and b represent the long diameter and short diameter of the tumor, respectively.

[0088] The tumor inhibition efficacy of a compound was evaluated using TGI (%) or relative tumor growth rate (T / C) (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) is calculated as follows: TGI (%) = [1 - (mean tumor volume at the end of dosing in a given treatment group - mean tumor volume at the start of dosing in that treatment group) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100%.

[0089] Relative tumor proliferation rate T / C (%): The calculation formula is as follows: T / C% = T RTV / C RTV ×100%(T RTV : Average RTV value of treatment group; C RTV: Average RTV value of negative control group). Relative tumor volume (RTV) was calculated based on the tumor measurement results. The calculation formula is RTV=V t / V0, where V0 is the tumor volume measured at the time of group administration (i.e., d0), V t is the tumor volume at a certain measurement, T RTV with C RTV Get data for the same day.

[0090] Statistical analysis

[0091] Statistical analysis included the mean and standard error (SEM) of tumor volume at each time point for each group (see Table 3 for specific data). The treatment group showed the best therapeutic effect on day 20 after administration at the end of the trial, so statistical analysis was performed based on this data to assess differences between groups. Comparisons between two groups were analyzed using T-tests, and comparisons between three or more groups were analyzed using one-way ANOVA. All data analyses were performed using Prism. p < 0.05 was considered to be significantly different.

[0092] The changes in tumor volume in each group of BALB / c nude mice bearing subcutaneous xenograft tumors of NCI-H1975 cells after treatment with the test drug are shown in Figure 3 . The curves of tumor volume changes in each group of tumor-bearing mice are shown in Figure 3 .

[0093] Table 3. Tumor volume of each group at different time points

[0094] Note:

[0095] a. Mean ± SEM

[0096] b. Days after administration

[0097] Anti-tumor efficacy evaluation indicators

[0098] Table 4. Evaluation of the anti-tumor efficacy of the test drugs in the NCI-H1975 cell xenograft tumor model (calculated based on the tumor volume on day 20 after administration)

[0099] Note:

[0100] a. Mean ± SEM.

[0101] b. TGI (TGI (%) = [1-(T 20 -T0) / (V 20 -V0)]×100) calculation.

[0102] The curves of tumor weight changes in each group of tumor-bearing mice are shown in Figure 4.

[0103] Test results

[0104] Experiments have shown that azithromycin inhibits tumor growth in a mouse model bearing the human lung cancer cell line NCI-H1975 xenograft tumor in a dose-dependent manner. Combining azithromycin with doxitinib enhances the tumor-suppressing effect of each drug alone.

[0105] Although the specific embodiments of the present disclosure have been described above, those skilled in the art will appreciate that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present disclosure. Therefore, the scope of protection of the present disclosure is defined by the appended claims. Industrial Applicability

[0106] The pharmaceutical composition herein exhibits good synergistic effects in anti-tumor effects, and can delay the development of drug resistance, improve efficacy and safety, thereby achieving the goal of prolonging patient survival, and has broad prospects for industrial application.

Claims

1. A pharmaceutical composition comprising: (i) azithromycin or a pharmaceutically acceptable salt, stereoisomer or isotopic derivative thereof; (ii) EGFR / TKI inhibitors.

2. The pharmaceutical composition according to claim 1, wherein The EGFR / TKI inhibitor is selected from any one of osimertinib, gefitinib, erlotinib, dositinib, omotinib, icotinib, pyrotinib, dacomitinib, afatinib, neratinib, lapatinib, ABT-414, valitinib, HLX-07, tesifatinib, tadalafil, ipatinib succinate, S-222611, flumetinib, befortinib, ruzitotinib, and pozitotinib, or any combination thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein The EGFR / TKI inhibitor is selected from osimertinib, dosimetinib or a combination thereof.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein said (i) and (ii) are administered simultaneously, separately, sequentially or said (i) and (ii) are present in the same dosage form.

5. The pharmaceutical composition according to any one of claims 1 to 4, for use in treating tumor-related diseases.

6. The pharmaceutical composition according to claim 5, wherein The tumor-related disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney 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, ureteral tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, bile duct cancer or choriocarcinoma, preferably non-small cell lung cancer.

7. A method for treating a tumor-related disease, comprising the step of administering the pharmaceutical composition of any one of claims 1 to 4 to an individual in need thereof.

8. The method of claim 7, wherein the tumor-related disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney 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, ureteral tumor, bladder tumor, gallbladder cancer, non-small cell lung cancer, bile duct carcinoma or choriocarcinoma.

9. The method according to claim 7, wherein the tumor-related disease is non-small cell lung cancer.