Use of quinazoline compound and third-generation EGFR inhibitor in combined drug for treating non-small cell lung cancer
Combining a quinazoline derivative with a third-generation EGFR inhibitor like osimertinib addresses the limitations of drug resistance and efficacy in non-small cell lung cancer treatments by achieving enhanced tumor inhibition and prolonged resistance through dual administration.
Patent Information
- Authority / Receiving Office
- AU · AU
- Patent Type
- Applications
- Current Assignee / Owner
- WEISHANG (SHANGHAI) BIO PHARMA CO LTD
- Filing Date
- 2025-01-14
- Publication Date
- 2026-07-23
AI Technical Summary
Current treatments for non-small cell lung cancer using third-generation EGFR inhibitors like osimertinib often face challenges with drug resistance and limited efficacy over time.
Combining a quinazoline derivative with a third-generation EGFR inhibitor, such as osimertinib, enhances therapeutic efficacy by administering both compounds simultaneously, with the quinazoline derivative given at a higher dose twice daily and osimertinib once daily.
The combination therapy demonstrates a synergistic effect, significantly inhibiting tumor growth and prolonging the development of drug resistance, showing improved efficacy compared to single-agent treatments.
Smart Images
Figure 00000000_0000_ABST
Abstract
Description
The osimertinib group was administered by gavage at 5 mg / kg, once a day. The quinazoline derivative (I) group of the present disclosure was administered by gavage at a dose of 10 mg / kg, twice a day. In the osimertinib-quinazoline derivative (I) of the present disclosure combination administration group, osimertinib was administered by gavage at 5 mg / kg once a day, and the quinazoline derivative (I) of the present disclosure was administered by gavage at a dose of 10 mg / kg twice a day. The negative control group was administered by gavage 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. Example 4 Pharmacodynamics in a subcutaneous mouse model of BaF3 EGFR L858R tumor cells As shown in FIG. 2, in the pharmacodynamic experiment of the subcutaneous mouse model of BaF3 EGFR L858R tumor cells, administration was started on day 8 of tumor cell implantation. The second group, quinazoline derivative (I), single agent, 10 mg / kg, oral, twice a day, and the third group, osimertinib (third-generation EGFR inhibitor), single agent, 5 mg / kg, oral, once a day, both showed good inhibition of tumor growth compared with the first group control group (drug-free group), with statistically significant efficacy. TABLE 3 Group Tumor volume (mm3 ) (day 21 after administration) T / C (%) TGI (%) p-value (vs. control group) Control group 2,252±511 - - - Osimertinib (third-generation EGFR inhibitor), 5 mg / kg, once a day 28±8 1.3 104.8 <0.0001 Quinazoline derivative (I) of the present disclosure group, 10 mg / kg, twice a day 46±13 2.1 104.0 <0.0001 Osimertinib (third-generation EGFR inhibitor), 5 mg / kg, once a day - Quinazoline derivative (I) of the present disclosure, 10 mg / kg, twice a day, combination administration group 18±5 0.8 105.3 <0.0001 The fourth group of the pharmaceutical composition of the present disclosure (quinazoline derivative (I) and osimertinib combination administration group) showed a synergistic effect 5 on day 60 after administration, and improved the efficacy of the single agent compared with the second group and the third group single agent groups, with statistically significant efficacy differences, and prolonged the time required for cancer cells to develop drug resistance. TABLE 4 Group Tumor volume (mm3 ) (day 60 after administration) p-value (vs. combination administration group) Osimertinib (third-generation EGFR inhibitor), 5 mg / kg, once a day 800±405 0.0002 Quinazoline derivative (I) of the present disclosure group, 10 mg / kg, twice a day 974±365 0.0282 Osimertinib (third-generation EGFR inhibitor), 5 mg / kg, once a day -Quinazoline derivative (I) of the present disclosure, 10 mg / kg, twice a day, combined administration group 22±7 - 10 The specific examples of the present disclosure have been described above. It should be understood that the present disclosure is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or alterations within the scope of the claims, which do not affect the substantive content of the present disclosure.
Claims
1. Use of a quinazoline compound and a third-generation EGFR inhibitor in a combination medicament for treating non-small cell lung cancer.
2. The use of claim 1, wherein the quinazoline compound comprises at least one of a quinazoline derivative represented by Formula I, and salts, solvates, hydrates, and polymorphs thereof,3. The use of claim 1 or 2, wherein the quinazoline compound comprises at least one selected from a hydrochloride, sulfate, maleate, succinate, adipate, glycolate, malate, fumarate, benzenesulfonate, benzoate, hippurate, oxalate, solvate, hydrate, and polymorph of the quinazoline derivative.
4. The use of claim 1, wherein the third-generation EGFR inhibitor comprises at least one selected from pyrimidine derivatives that irreversibly bind to EGFR cysteine 797 to form a covalent bond, and salts, solvates, hydrates, and polymorphs thereof.
5. The use of claim 1 or 4, wherein the third-generation EGFR inhibitor is selected from osimertinib, furmonertinib, almonertinib, befotertinib, oritinib, rezivertinib, limertinib, lazertinib, or TY-9591.
6. The use of claim 1, wherein the third-generation EGFR inhibitor is in an oral dosage form.
7. The use of claim 1, wherein the quinazoline compound is in an oral dosage form.
8. The use of claim 1, wherein the dose ratio of the quinazoline compound to the third-generation EGFR inhibitor is from 4:1 to 1:2.
9. The use of claim 1, wherein the non-small cell lung cancer comprises leptomeningeal metastasis of non-small cell lung cancer and brain metastasis of non-small cell lung cancer.