Use of quinazoline compound and third-generation EGFR inhibitor in combined drug for treating non-small cell lung cancer

Abstract

Use of a quinazoline compound and a third-generation epidermal growth factor receptor (EGFR) inhibitor in a combined drug for treating non-small cell lung cancer. The quinazoline compound comprises at least one of a quinazoline derivative represented by formula (I), a salt thereof, a solvate thereof, a hydrate thereof, and a polymorph thereof.

Description

Use of quinazoline compounds and third-generation EGFR inhibitors in combination for the treatment of non-small cell lung cancer Technical Field

[0001] The present invention relates to use of a quinazoline compound and a third-generation EGFR inhibitor in a combined drug for treating non-small cell lung cancer, and belongs to the technical field of biomedicine. Background Art

[0002] Quinazoline derivatives with the ability to cross the blood-brain barrier, molecular formula C 23 H 21 F3N4O2, chemically known as (R)-6-[(3,3-difluoro-1-methylpiperidin-4-yl)oxy]-nitro-(3-ethynyl-2-fluorophenyl)-7-methoxyquinazolin-4-amine (I), is a molecularly targeted anti-tumor drug and a highly selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. It can be used to treat brain metastases of non-small cell lung cancer, meningeal metastases, head and neck squamous cell carcinoma, squamous cell carcinoma, brainstem tumors, primary brain cancer, gliomas, or other cancers. As known to those skilled in the art, a single drug with dose-dependent efficacy can advantageously inhibit cancer cell growth at high doses, but may also produce greater toxic side effects. Therefore, the development of pharmaceutical compositions that can produce synergistic effects, enhance the efficacy of a single drug, minimize the toxic side effects of a second therapeutic agent or the compound (I) described herein, improve efficacy, enhance the ease of administration or use, and / or reduce the overall cost of the compound product or formulation is extremely useful and of great significance. Summary of the Invention

[0003] In view of the defects in the prior art, the purpose of the present invention is to provide a combination of a quinazoline compound and a third-generation EGFR inhibitor in the treatment of non-small cell lung cancer.

[0004] The purpose of the present invention is achieved through the following technical solutions:

[0005] The present invention provides the use of a quinazoline compound in combination with a third-generation EGFR inhibitor in the treatment of non-small cell lung cancer. The quinazoline compound of the present invention has unique properties, such as a non-competitive ATP binding mechanism with EGFR, which potentially overcomes the various resistance mechanisms of various third-generation inhibitors. Therefore, the combination produces a synergistic effect and achieves better results. Furthermore, the dosage must be within a certain range (for humans, the dosage is 80-240 mg / day) to achieve better results. Too high a dosage will cause severe side effects and be intolerable, while too low a dosage will not produce better results.

[0006] As an embodiment of the present invention, the quinazoline compound includes at least one of the quinazoline derivatives shown in Formula I and its salts, solvates, hydrates and polymorphs,

[0007] As one embodiment of the present invention, the quinoline compounds include hydrochlorides, sulfates, maleates, succinates, adipates, glycolates, malates, fumarates, benzenesulfonates, benzoates, hippurates and oxalates, as well as solvates, hydrates and polymorphs of quinazoline derivatives.

[0008] As an embodiment of the present invention, the non-small cell lung cancer includes non-small cell lung cancer meningeal metastasis and non-small cell lung cancer brain metastasis.

[0009] As an embodiment of the present invention, the third-generation EGFR inhibitor is in an oral dosage form.

[0010] As one embodiment of the present invention, the quinazoline compound (I) is in an oral dosage form.

[0011] As an embodiment of the present invention, the dosage ratio of the quinazoline compound (I) to the third-generation EGFR inhibitor is 4:1 to 1:2.

[0012] As one embodiment of the present invention, the third-generation EGFR inhibitor includes a pyrimidine derivative that irreversibly binds to EGFR cysteine ​​797 (C797) to form a covalent bond, and at least one of its salts, solvates, hydrates and polymorphs.

[0013] As one embodiment of the present invention, the third-generation EGFR inhibitor is selected from osimertinib (AZD9291, Osimertinib, Tagrisso), furmonertinib (Furmonertinib, Aifosa), ametinib (Almonertinib, Ami Le), befotertinib (Befotertinib, Semena), oritinib (Oritinib, SH-1028), rizeltinib (BPI-7711), limertinib (ASK120067), lazertinib (Lazertinib, YH25448, LECLAZA) or TY-9591.

[0014] Compared with the prior art, the present invention has the following beneficial effects:

[0015] 1. The combination of the quinazoline derivative (I) and its pharmaceutical salt and the third-generation EGFR inhibitor of the present invention has an unexpected synergistic effect and has better therapeutic effects than single drugs, such as non-small cell lung cancer driven by EGFR L858R or Del19 mutations, non-small cell lung cancer brain metastasis, and non-small cell lung cancer meningeal metastasis;

[0016] 2. The composition of the quinazoline derivative (I) and its pharmaceutical salt and the third-generation EGFR inhibitor described in the present invention can prolong the time required for non-small cell lung cancer cells driven by EGFR L858R or EGFR Del19 mutations to develop drug resistance and prolong the disease progression-free survival. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Other features, objects and advantages of the present invention will become more apparent upon reading the detailed description of non-limiting embodiments with reference to the following drawings:

[0018] Figure 1 shows the efficacy experiment of combined drug administration in the subcutaneous BaF3 EGFR Del19 cancer cell mouse model;

[0019] Figure 2 shows the efficacy experiment of combined drug use in the BaF3 EGFR L858R cancer cell mouse subcutaneous model. DETAILED DESCRIPTION

[0020] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those skilled in the art, several variations and improvements can be made without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0021] Example 1

[0022] Inhibitory Effect of Osimertinib (a third-generation EGFR inhibitor) Combined with the Quinazoline Derivative (I) of the Present Invention on the Growth of Non-Small Cell Lung Cancer BaF3 EGFR Del19 Mouse Xenograft Tumors Non-small Cell Lung Cancer BaF3 EGFR Del19 cells were cultured in suspension in RPMI 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin / amphotericin B, and incubated at 37°C in a 5% CO2 incubator. Routine treatment and passage were performed twice weekly. When cell saturation reached 80%-90% and the required number of cells was reached, the cells were harvested, counted, and 0.1 mL of 0.5×10 6 BaF3 EGFR Del19 cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated into the right back of each NOD SCID mouse (female, 6-8 weeks old, weighing 18-22 g), and the average tumor volume reached approximately 100-150 mm 3 The efficacy experiment was started at 1:00 PM. The anti-tumor effect of the test drug was dynamically observed by measuring tumor diameter. Tumor diameter was measured twice a week with a vernier caliper. The tumor volume was calculated as: V = 0.5a × b 2, a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound is evaluated by TGI (%) or relative tumor proliferation rate T / C (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [(1-(average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the beginning of drug administration)) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the beginning of treatment)] × 100%; where the solvent is 0.5% HPMC with 0.1% tween-80 in water. Relative tumor proliferation rate T / C (%): Calculation formula is as follows: T / C% = T RTV / C RTV ×100%(T RTV : RTV of the treatment group; CRTV: RTV of the negative control group). The relative tumor volume (RTV) was calculated based on the results of tumor measurement. The calculation formula is RTV=V t / V0, where V0 is the average tumor volume measured at the time of group administration (i.e., d0), V t is the average tumor volume at a certain measurement, T RTV with C RTV Data were collected on the same day. Tumor diameter was measured twice a week, and the mice were weighed at each measurement. Grouping and dosing were as follows:

[0023] The osimertinib group was administered by gavage at a dose of 5 mg / kg (5 mg / kg is the equivalent dose of osimertinib approved in humans, 80 mg. Any lower effect is not as good as 5 mg / kg. And too high a dose is intolerable in humans due to its strong toxic side effects), once a day. The quinazoline derivative (I) group described in the present invention was administered by gavage at a dose of 10 mg / kg, twice a day. In the osimertinib-quinazoline derivative (I) combined administration group, osimertinib was administered by gavage at a dose of 5 mg / kg, once a day, and the quinazoline derivative (I) described in the present invention was administered by gavage at a dose of 10 mg / kg, twice a day. The negative control group was gavaged with an aqueous solution of 0.5% hydroxypropyl methylcellulose and 0.1% Tween 80 (0.5% HPMC with 0.1% tween-80) twice a day.

[0024] Example 2

[0025] Efficacy of BaF3 EGFR Del19 tumor cell subcutaneous mouse model

[0026] As shown in Figure 1, in a drug efficacy experiment in a subcutaneous mouse model of BaF3 EGFR Del19 tumor cells, drug administration began on the eighth day after tumor cell implantation. The second group of osimertinib (a third-generation EGFR inhibitor), single-agent, 5 mg / kg, oral, once a day, and the third group of quinazoline derivative (I), single-agent, 10 mg / kg, oral, twice a day, were compared with the first group of control group (a group without drug). Both groups showed good inhibition of tumor growth 18 days after administration, and showed good inhibition of tumor growth compared with the blank group, with statistically significant drug efficacy.

[0027] Table 1

[0028] The fourth group of the pharmaceutical composition of the present invention (the combination group of quinazoline derivative (I) and osimertinib) showed a synergistic effect on the 35th day after administration. Compared with the second and third single-drug groups, the efficacy of the single drug was improved, and there was a statistically significant difference in efficacy. It also prolonged the time required for cancer cells to develop drug resistance.

[0029] Table 2

[0030] Example 3

[0031] Inhibitory effect of the combination of osimertinib (a third-generation EGFR inhibitor) and the quinazoline derivative (I) of the present invention on the growth of non-small cell lung cancer BaF3 EGFR L858R mouse xenograft tumors

[0032] Non-small cell lung cancer BaF3 EGFR L858R cells were cultured in suspension in RPMI 1640 medium supplemented with 10% fetal bovine serum, 1% penicillin / streptomycin / amphotericin B, and incubated at 37°C in a 5% CO2 incubator. Routine treatment and passage were performed twice a week. When cell saturation reached 80%-90% and the required number of cells was reached, the cells were harvested, counted, and 0.2 mL of 1×10 6 BaF3 EGFR L858R cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated into the right back of each NOD SCID mouse (female, 6-8 weeks old, weighing 18-22 g). Efficacy experiments were initiated when the average tumor volume reached approximately 100-150 mm3. Tumor diameter measurement was used to dynamically observe the antitumor effects of the test drug. Tumor diameter was measured twice weekly with a vernier caliper. Tumor volume was calculated using the formula: V = 0.5a × b 2, a and b represent the long diameter and short diameter of the tumor, respectively. The anti-tumor efficacy of the compound is evaluated by TGI (%) or relative tumor proliferation rate T / C (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [(1-(average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the beginning of drug administration)) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the beginning of treatment)] × 100%. Relative tumor proliferation rate T / C (%): Calculation formula is as follows: T / C% = T RTV / C RTV ×100%(T RTV :RTV in treatment group; C RTV : RTV of negative control group). Relative tumor volume (RTV) was calculated based on the results of tumor measurement. The calculation formula is RTV=V t / V0, where V0 is the average tumor volume measured at the time of group administration (i.e., d0), V t is the average tumor volume at a certain measurement, T RTV with C RTV Data were collected on the same day. Tumor diameter was measured twice a week, and the mice were weighed at each measurement. Grouping and dosing were as follows:

[0033] The osimertinib group was administered by gavage at a dose of 5 mg / kg, once a day. The quinazoline derivative (I) group of the present invention was administered by gavage at a dose of 10 mg / kg, twice a day. In the osimertinib-quinazoline derivative (I) combined administration group, osimertinib was administered by gavage at a dose of 5 mg / kg, once a day, and the quinazoline derivative (I) of the present invention was administered by gavage at a dose of 10 mg / kg, twice a day. The negative control group was gavage-administered with an aqueous solution of 0.5% hydroxypropyl methylcellulose and 0.1% Tween 80 (0.5% HPMC with 0.1% tween-80) twice a day.

[0034] Example 4

[0035] Drug efficacy in the subcutaneous mouse model of BaF3 EGFR L858R tumor cells

[0036] As shown in Figure 2, in a drug efficacy experiment in a subcutaneous mouse model of BaF3 EGFR L858R tumor cells, drug administration began on the eighth day after tumor cell implantation. The second group of quinazoline derivatives (I) were administered orally at a dose of 10 mg / kg twice daily, and the third group of osimertinib (a third-generation EGFR inhibitor) were administered orally at a dose of 5 mg / kg once daily. Compared with the first control group (a group without drug), both groups showed good inhibition of tumor growth, with statistically significant drug efficacy.

[0037] Table 3

[0038] The fourth group of the pharmaceutical composition of the present invention (the combination group of quinazoline derivative (I) and osimertinib) showed a synergistic effect on the 60th day after administration. Compared with the second and third single-drug groups, the efficacy of the single drug was improved, and there was a statistically significant difference in efficacy. It also prolonged the time required for cancer cells to develop drug resistance.

[0039] Table 4

[0040] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various variations or modifications within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. Use of a quinazoline compound and a third-generation EGFR inhibitor in a combined drug for the treatment of non-small cell lung cancer.

2. The use according to claim 1, characterized in that The quinazoline compound includes at least one of the quinazoline derivatives shown in Formula I and its salts, solvates, hydrates and polymorphs, 3. The use according to claim 1 or 2, characterized in that The quinazoline compounds include hydrochloride, sulfate, maleate, succinate, adipate, glycolate, malate, fumarate, benzenesulfonate, benzoate, hippurate, oxalate, solvate, hydrate, and polymorph of quinazoline derivatives.

4. The use according to claim 1, characterized in that The third-generation EGFR inhibitors include pyrimidine derivatives that irreversibly bind to EGFR cysteine ​​797 to form a covalent bond, and at least one of their salts, solvates, hydrates, and polymorphs.

5. The use according to claim 1 or 4, characterized in that The third-generation EGFR inhibitor is selected from osimertinib, vumetinib, ametinib, befortinib, arefollowing, razotetinib, rimetinib, lazertinib or TY-9591.

6. The use according to claim 1, characterized in that The third-generation EGFR inhibitors are in oral dosage form.

7. The use according to claim 1, characterized in that The quinazoline compound is in oral dosage form.

8. The use according to claim 1, characterized in that The dosage ratio of the quinazoline compound to the third-generation EGFR inhibitor is 4:1 to 1:

2.

9. The use according to claim 1, characterized in that The non-small cell lung cancer includes non-small cell lung cancer meningeal metastasis and non-small cell lung cancer brain metastasis.

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