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EP-4736876-A1 - DRUG COMBINATION CONTAINING PD-L1 SMALL MOLECULE INHIBITOR AND USE THEREOF

EP4736876A1EP 4736876 A1EP4736876 A1EP 4736876A1EP-4736876-A1

Abstract

A drug combination containing a PD-L1 small molecule inhibitor and the use thereof. The drug combination comprises a PD-L1 small molecule inhibitor and a chemotherapeutic drug molecule, or a PD-L1 small molecule inhibitor and a COX-2 inhibitor. The drug combination can be used for treating tumors.

Inventors

  • WANG, YUGUANG
  • FENG, ZHENHUA
  • ZHAO, QIANG

Assignees

  • Beijing Maxinovel Pharmaceuticals Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (18)

  1. A drug combination A, comprising a PD-L1 small molecule inhibitor and a chemotherapeutic drug molecule.
  2. The drug combination A according to claim 1, wherein the drug combination A satisfies one or more of the following conditions: (1) The drug combination A has a synergistic effect; (2) The PD-L1 small molecule inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof; (3) The chemotherapeutic drug molecule is one or more of capecitabine, paclitaxel, oxaliplatin, and temozolomide, preferably capecitabine, paclitaxel, or temozolomide; (4) The mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is (0.04 to 50):1, preferably (0.2 to 16):1, more preferably (0.2 to 2):1 or (6 to 16):1, for example, 0.45:1, 0.58:1, 1.2:1, 10:1, or 11:1; (5) The active pharmaceutical ingredients of the drug combination A are the PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule; (6) The PD-L1 small molecule inhibitor is administered via the gastrointestinal tract, injection, respiratory tract, or topical application, such as oral administration; (7) The chemotherapeutic drug molecule is administered via the gastrointestinal tract, injection, respiratory tract, or topical application, such as oral administration or intravenous injection.
  3. The drug combination A according to claim 2, wherein the drug combination A comprises the compound of Formula I and capecitabine, and the mass ratio of the compound of Formula I to capecitabine is preferably (0.2 to 2):1, for example, 0.45:1, 0.58:1, or 1.2:1; Or, the drug combination A comprises the compound of Formula I and paclitaxel, and the mass ratio of the compound of Formula I to paclitaxel is preferably (6 to 16):1, for example, 10:1 or 11:1; Or, the drug combination A comprises the compound of Formula I and temozolomide, and the mass ratio of the compound of Formula I to temozolomide is preferably (6 to 16):1, for example, 6:1, 9.5:1, or 16:1.
  4. A pharmaceutical composition B, comprising a PD-L1 small molecule inhibitor, a chemotherapeutic drug molecule, and a pharmaceutical excipient.
  5. The pharmaceutical composition B according to claim 4, wherein the pharmaceutical composition B satisfies one or more of the following conditions: (1) The pharmaceutical composition B has a synergistic effect; (2) The PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule are as described in claim 2; (3) The content of the PD-L1 small molecule inhibitor is 30 to 500 mg, preferably 40 to 400 mg, for example, 50 mg, 150 mg, or 300 mg; (4) The content of the chemotherapeutic drug molecule is 10 to 650 mg, preferably 30 to 550 mg, for example, 20 mg, 30 mg, 60 mg, 100 mg, 150 mg, or 500 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is (0.04 to 50):1, preferably (0.2 to 16):1, more preferably (0.2 to 2):1 or (6 to 16):1, for example, 0.45:1, 0.58:1, 1.2:1, 10:1, or 11:1; Preferably, when the pharmaceutical composition B comprises the compound of Formula I according to claim 2, capecitabine, and a pharmaceutical excipient, the mass ratio of the compound of Formula I to capecitabine is preferably (0.2 to 2):1, for example, 0.45:1, 0.58:1, or 1.2:1; When the pharmaceutical composition B comprises the compound of Formula I according to claim 2, paclitaxel, and a pharmaceutical excipient, the mass ratio of the compound of Formula I to paclitaxel is preferably (6 to 16):1, for example, 10:1 or 11:1; When the pharmaceutical composition B comprises the compound of Formula I according to claim 2, temozolomide, and a pharmaceutical excipient, the mass ratio of the compound of Formula I to temozolomide is preferably (6 to 16):1, for example, 6:1, 9.5:1, or 16:1; (6) The active pharmaceutical ingredients of the pharmaceutical composition B are the PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule; (7) The dosage form of the pharmaceutical composition B comprises a gastrointestinal dosage form and a parenteral dosage form, preferably a capsule, a tablet, a pill, a granule, a powder, or an oral liquid preparation.
  6. A pharmaceutical composition C, comprising: a first pharmaceutical composition C-1, comprising a PD-L1 small molecule inhibitor and a pharmaceutical excipient; and, a second pharmaceutical composition C-2, comprising a chemotherapeutic drug molecule and a pharmaceutical excipient.
  7. The pharmaceutical composition C according to claim 6, wherein the pharmaceutical composition C satisfies one or more of the following conditions: (1) The pharmaceutical composition C has a synergistic effect; (2) The PD-L1 small molecule inhibitor and the chemotherapeutic drug molecule are as described in claim 2; (3) The content of the PD-L1 small molecule inhibitor is 30 to 500 mg, preferably 40 to 400 mg, for example, 50 mg, 150 mg, or 300 mg; (4) The content of the chemotherapeutic drug molecule is 10 to 650 mg, preferably 30 to 550 mg, for example, 20 mg, 30 mg, 60 mg, 100 mg, 150 mg, or 500 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is (0.04 to 50):1, preferably (0.2 to 16):1, more preferably (0.2 to 2):1 or (6 to 16):1, for example, 0.45:1, 0.58:1, 1.2:1, 10:1, or 11:1; Preferably, when the first pharmaceutical composition C-1 comprises the compound of Formula I according to claim 2 and a pharmaceutical excipient, and the second pharmaceutical composition C-2 comprises capecitabine and a pharmaceutical excipient, then the mass ratio of the compound of Formula I to capecitabine is preferably (0.2 to 2):1, for example, 0.45:1, 0.58:1, or 1.2:1; When the first pharmaceutical composition C-1 comprises the compound of Formula I according to claim 2 and a pharmaceutical excipient, and the second pharmaceutical composition C-2 comprises paclitaxel and a pharmaceutical excipient, then the mass ratio of the compound of Formula I to paclitaxel is preferably (6 to 16):1, for example, 10:1 or 11:1; When the first pharmaceutical composition C-1 comprises the compound of Formula I as described above and a pharmaceutical excipient, and the second pharmaceutical composition C-2 comprises temozolomide and a pharmaceutical excipient, then the mass ratio of the compound of Formula I to temozolomide is preferably (6 to 16):1, for example, 6:1, 9.5:1, or 16:1; (6) The pharmaceutical composition C consists of the first pharmaceutical composition C-1 and the second pharmaceutical composition C-2; The first pharmaceutical composition C-1 consists of the PD-L1 small molecule inhibitor and a pharmaceutical excipient; The second pharmaceutical composition C-2 consists of the chemotherapeutic drug molecule and a pharmaceutical excipient; (7) The first pharmaceutical composition C-1 is presented in an oral dosage form; (8) The second pharmaceutical composition C-2 is presented in an oral dosage form or an injectable dosage form.
  8. A combination kit D, comprising: a first container, comprising the first pharmaceutical composition C-1 according to claim 6 or 7; and, a second container, comprising the second pharmaceutical composition C-2 according to claim 6 or 7.
  9. A drug combination E, comprising a PD-L1 small molecule inhibitor and a COX-2 inhibitor.
  10. The drug combination E according to claim 9, wherein the drug combination E satisfies one or more of the following conditions: (1) The drug combination E has a synergistic effect; (2) The PD-L1 small molecule inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof; (3) The COX-2 inhibitor is nimesulide, meloxicam, celecoxib, or rofecoxib, preferably celecoxib; (4) The mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is (0.1 to 10):1, more preferably (2 to 10):1, for example, 6:1 or 7.5:1; (5) The active pharmaceutical ingredients of the drug combination E are the PD-L1 small molecule inhibitor and the COX-2 inhibitor; (6) The PD-L1 small molecule inhibitor is administered via the gastrointestinal tract, injection, respiratory tract, or topical application, such as oral administration; (7) The COX-2 inhibitor is administered via the gastrointestinal tract, injection, respiratory tract, or topical application, such as oral administration.
  11. A pharmaceutical composition F, comprising a PD-L1 small molecule inhibitor, a COX-2 inhibitor, and a pharmaceutical excipient.
  12. The pharmaceutical composition F according to claim 11, wherein the pharmaceutical composition F satisfies one or more of the following conditions: (1) The pharmaceutical composition F has a synergistic effect; (2) The PD-L1 small molecule inhibitor and the COX-2 inhibitor are as described in claim 10; (3) The content of the PD-L1 small molecule inhibitor is 30 to 500 mg, preferably 40 to 400 mg, for example, 50 mg, 150 mg, or 300 mg; (4) The content of the COX-2 inhibitor is 50 to 250 mg, preferably 100 to 200 mg, for example, 100 mg or 200 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is (0.1 to 10):1, preferably (2 to 10):1, for example, 6:1 or 7.5:1; (6) The active pharmaceutical ingredients of the pharmaceutical composition F are the PD-L1 small molecule inhibitor and the COX-2 inhibitor; (7) The dosage form of the pharmaceutical composition F comprises a gastrointestinal dosage form and a parenteral dosage form, preferably a capsule, a tablet, a pill, a granule, a powder, or an oral liquid preparation.
  13. A pharmaceutical composition G, comprising: a first pharmaceutical composition G-1, comprising a PD-L1 small molecule inhibitor and a pharmaceutical excipient; and, a second pharmaceutical composition G-2, comprising a COX-2 inhibitor and a pharmaceutical excipient.
  14. The pharmaceutical composition G according to claim 13, wherein the pharmaceutical composition G satisfies one or more of the following conditions: (1) The pharmaceutical composition G has a synergistic effect; (2) The PD-L1 small molecule inhibitor and COX-2 inhibitor are as described in claim 10; (3) The content of the PD-L1 small molecule inhibitor is 30 to 500 mg, preferably 40 to 400 mg, for example, 50 mg, 150 mg, or 300 mg; (4) The content of the COX-2 inhibitor is 50 to 250 mg, preferably 100 to 200 mg, for example, 100 mg or 200 mg; (5) The mass ratio of the PD-L1 small molecule inhibitor to the COX-2 inhibitor is (0.1 to 10):1, preferably (2 to 10):1, for example, 6:1 or 7.5:1; (6) The pharmaceutical composition G consists of the first pharmaceutical composition G-1 and the second pharmaceutical composition G-2; The first pharmaceutical composition G-1 consists of the PD-L1 small molecule inhibitor and a pharmaceutical excipient, and the second pharmaceutical composition G-2 consists of the COX-2 inhibitor and a pharmaceutical excipient; (7) The first pharmaceutical composition G-1 is presented in an oral dosage form; (8) The second pharmaceutical composition G-2 is presented in an oral dosage form.
  15. A combination kit H, comprising: a first container, comprising the first pharmaceutical composition G-1 according to claim 13 or 14; and, a second container, comprising the second pharmaceutical composition G-2 according to claim 13 or 14.
  16. Use of the drug combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, the pharmaceutical composition C according to claim 6 or 7, the drug combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 in the manufacture of a medicament for treating tumors; The tumor is preferably one or more of gastric cancer, nasopharyngeal carcinoma, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumors, adrenal tumors, renal cell carcinoma, neuroblastoma, and glioblastoma, more preferably breast cancer, gastric cancer, nasopharyngeal carcinoma, or glioblastoma.
  17. A method of treating tumors, comprising administering a therapeutically effective amount of the drug combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, the pharmaceutical composition C according to claim 6 or 7, the drug combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 to a subject in need thereof.
  18. The method of treating tumors according to claim 17, wherein the method of treating tumors satisfies one or more of the following conditions: (1) The tumor is one or more of gastric cancer, nasopharyngeal carcinoma, lung cancer, colorectal cancer, breast cancer, colon cancer, bladder cancer, cervical cancer, endometrial cancer, pancreatic cancer, prostate cancer, hepatocellular carcinoma, melanoma, head and neck cancer, esophageal cancer, ovarian cancer, bone cancer, central nervous system tumors, adrenal tumors, renal cell carcinoma, neuroblastoma, and glioblastoma, preferably breast cancer, gastric cancer, nasopharyngeal carcinoma, or glioblastoma; (2) The total daily dose of the PD-L1 small molecule inhibitor ranges from 30 to 2400 mg; preferably 500 to 2000 mg; for example, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, or 1900 mg; (3) The administration frequency of the PD-L1 small molecule inhibitor is twice daily, once daily, or once every two days, preferably twice daily; (4) When administering a therapeutically effective amount of the drug combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, or the pharmaceutical composition C according to claim 6 or 7 to a subject in need thereof, and when the chemotherapeutic drug molecule is capecitabine, then the total daily dose ranges from 1000 to 3000 mg/m 2 , preferably 1000 mg/m 2 , 1250 mg/m 2 , 1500 mg/m 2 , 1750 mg/m 2 , 2000 mg/m 2 , 2250 mg/m 2 , 2500 mg/m 2 , 2750 mg/m 2 , or 3000 mg/m 2 , for example, 2000 mg/m 2 or 2500 mg/m 2 ; The administration frequency is once daily or twice daily, preferably twice daily; (5) When administering a therapeutically effective amount of the drug combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, or the pharmaceutical composition C according to claim 6 or 7 to a subject in need thereof, and when the chemotherapeutic drug molecule is paclitaxel, then the total daily dose ranges from 50 to 200 mg/m 2 , preferably 50 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 100 mg/m 2 , 125 mg/m 2 , 135 mg/m 2 , 145 mg/m 2 , 155 mg/m 2 , 165 mg/m 2 , 175 mg/m 2 , 185 mg/m 2 , 195 mg/m 2 , or 200 mg/m 2 , for example, 80 mg/m 2 , 135 mg/m 2 , or 175 mg/m 2 ; The administration frequency is once every two weeks, once every three weeks, or once every four weeks; preferably once every three weeks; (6) When administering a therapeutically effective amount of the drug combination A according to any one of claims 1 to 3, the pharmaceutical composition B according to claim 4 or 5, or the pharmaceutical composition C according to claim 6 or 7 to a subject in need thereof, and when the chemotherapeutic drug molecule is temozolomide, then the total daily dose ranges from 100 to 250 mg/m 2 , preferably 100 mg/m 2 , 125 mg/m 2 , 150 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 225 mg/m 2 , or 250 mg/m 2 , for example, 150 mg/m 2 or 200 mg/m 2 ; The administration frequency is once daily for 5 days, followed by 23 days off, then entering the next cycle; (7) When administering a therapeutically effective amount of the drug combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 to a subject in need thereof, then the total daily dose of the COX-2 inhibitor ranges from 50 to 250 mg, preferably 100 to 200 mg, for example, 100 mg or 200 mg; (8) When administering a therapeutically effective amount of the drug combination E according to claim 9 or 10, the pharmaceutical composition F according to claim 11 or 12, or the pharmaceutical composition G according to claim 13 or 14 to a subject in need thereof, then the administration frequency of the COX-2 inhibitor is once daily or twice daily.

Description

The present application claims priority to Chinese Patent Application No. 202310785638X filed on June 29, 2023 and Chinese Patent Application No. 2023117625926 filed on December 20, 2023. The contents of the Chinese patent application are incorporated herein by reference in their entirety. TECHNICAL FIELD The present disclosure relates to a drug combination comprising a PD-L1 small molecule inhibitor and the use thereof. BACKGROUND Malignant tumors are major diseases that endanger people's life and health. In recent years, with the rapid development of tumor biology and related disciplines, specific antitumor drugs targeting abnormal signaling systems in tumor cells and immunotherapeutic antitumor drugs have become the focus of new drug research and development. Meanwhile, the combination of multiple antitumor drugs for the treatment of tumor diseases is also a hot topic in scientific research. Programmed cell death-1 (PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages. It functions as an intrinsic negative feedback system, thereby preventing T-cell activation, which in turn reduces autoimmunity and promotes self-tolerance. Additionally, PD-1 is known to play a significant role in suppressing antigen-specific T-cell responses in diseases such as cancer and viral infections. The structure of PD-1 consists of an extracellular immunoglobulin variable-like domain, followed by a transmembrane region and an intracellular domain. This intracellular domain contains two phosphorylation sites located within the immunoreceptor tyrosine-based inhibitory motif and the immunoreceptor tyrosine-based switch motif, indicating that PD-1 negatively regulates T-cell receptor-mediated signaling. PD-1 has two ligands, PD-L1 and PD-L2, which differ in their expression patterns. PD-L1 protein is upregulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment and on T cells and B cells following T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on nearly all tumor cells, and this expression further increases after IFN-γ treatment. A large number of studies have confirmed that PD-L1 on the surface of tumor cells in the tumor microenvironment is increased, and at the same time, PD-L1 binds to PD-1 on activated T cells to transmit negative regulatory signals, leading to apoptosis or immune anergy of tumor antigen-specific T cells, thereby inhibiting the immune response and promoting the escape of tumor cells. Although no PD-L1 small molecule inhibitors are currently on the market, several are in clinical research stages. Among them, WO2019128918A1 discloses the structure and preparation method of a PD-L1 small molecule inhibitor, with in vitro and pharmacokinetic studies demonstrating good antitumor activity. Its specific structure is shown in Formula I. SUMMARY The technical problem to be solved by the present disclosure is to overcome the limited variety of antitumor drugs in the prior art and to provide a drug combination comprising a PD-L1 small molecule inhibitor and the use thereof. Compared with the use of PD-L1 small molecule inhibitors alone or other small molecule drugs (e.g., targeted small molecule inhibitors or chemotherapeutic drug molecules), the drug combination of the present disclosure has a synergistic effect, and further has a better effect in treating cancer and prolonging survival time. The present disclosure provides a drug combination A, comprising a PD-L1 small molecule inhibitor and a chemotherapeutic drug molecule. In some embodiments, the drug combination A has a synergistic effect. In the drug combination A, the PD-L1 small molecule inhibitor is preferably a compound of Formula I or a pharmaceutically acceptable salt thereof; In the drug combination A, the chemotherapeutic drug molecule is preferably one or more of capecitabine, paclitaxel, oxaliplatin, and temozolomide, more preferably capecitabine or paclitaxel. In some embodiments, the chemotherapeutic drug molecule is temozolomide. In the drug combination A, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule may be (0.04 to 50):1, preferably (0.2 to 16):1, more preferably (0.2 to 2):1 or (6 to 16):1, for example, 0.45:1, 0.58:1, 1.2:1, 10:1, or 11:1. In some embodiments, the mass ratio of the PD-L1 small molecule inhibitor to the chemotherapeutic drug molecule is 6:1, 9.5:1, or 16:1. In some embodiments, the drug combination A comprises the compound of Formula I as described above and capecitabine. The mass ratio of the compound of Formula I to capecitabine is preferably (0.2 to 2):1, for example, 0.45:1, 0.58:1, or 1.2:1. In some embodiments, the drug combination A comprises the compound of Formula I as described above and paclitaxel. The mass ratio of the compound of Formula I to paclitaxel is preferably (6 to 16):1, for example, 10:1 or 11:1. In some embodiments