WO2023078408A1 - Combinaison pharmaceutique contenant un inhibiteur de la tyrosine kinase du récepteur met et son utilisation - Google Patents

Combinaison pharmaceutique contenant un inhibiteur de la tyrosine kinase du récepteur met et son utilisation Download PDF

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WO2023078408A1
WO2023078408A1 PCT/CN2022/129946 CN2022129946W WO2023078408A1 WO 2023078408 A1 WO2023078408 A1 WO 2023078408A1 CN 2022129946 W CN2022129946 W CN 2022129946W WO 2023078408 A1 WO2023078408 A1 WO 2023078408A1
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cancer
tyrosine kinase
combination
egfr
inhibitor
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PCT/CN2022/129946
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English (en)
Chinese (zh)
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张毅翔
朱淼
李越
李乐平
孙端鸿
周俊
钱莘
吴秋霞
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上海海和药物研究开发股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure relates to a pharmaceutical combination comprising the following combination: (i) a MET receptor tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof and (ii) an EGFR inhibitor or a pharmaceutically acceptable salt thereof.
  • the present disclosure also relates to pharmaceutical preparations, compositions corresponding to the combinations, and methods and uses of using the combinations to treat or prevent cancer.
  • Lung cancer is still one of the most serious public health problems in the world. According to GLOBOCAN 2018 data, lung cancer ranks first among new cancer cases worldwide (accounting for 11.6% of the total), and is the leading cause of cancer-related death (accounting for 18.4% of the total). More than 1.7 million people die from lung cancer each year. In China, the morbidity and mortality of lung cancer rank first among all malignant tumors, and the morbidity and mortality increase with age. The mortality rate approaches the incidence rate in the relatively elderly (>65 years) patient group. Lung cancer survival is highly correlated with tumor stage and type at diagnosis.
  • lung cancer can be roughly divided into two categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which NSCLC accounts for about 80% to 85%.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • the 5-year survival rate of stage I NSCLC in the world is between 47% and 50%, while the 5-year survival rate of stage IV NSCLC is only 2%.
  • the annual cost of lung cancer diagnosis and treatment has caused a heavy burden on my country's national economy and people's death.
  • stage IA-IIIA For early-stage NSCLC patients without distant metastases (mostly stage IA-IIIA), surgery and radiotherapy are the main means; while for advanced patients with multiple distant metastases (mostly stage IIIB-IV), treatment is often based on the general status of the patient.
  • advanced NSCLC patients were further divided into driver gene positive, negative and programmed death receptor-ligand (PD-L1) high expression, and accordingly selected targeted, containing Platinum two-drug chemotherapy or immunotherapy and other regimens are used as first-line and sequential treatment regimens.
  • PD-L1 driver gene positive, negative and programmed death receptor-ligand
  • Epidermal growth factor receptor (Epidermal growth factor receptor; EGFR) has been proven to be a key target for the treatment of lung cancer.
  • EGFR TKI EGFR tyrosine kinase inhibitor
  • Citinib, Erlotinib, etc. have been used as first-line drugs for the treatment of NSCLC internationally.
  • Clinically, the sensitivity of NSCLC patients to EGFR inhibitors is related to specific mutations of EGFR.
  • the currently known sensitive mutations of EGFR inhibitors mainly include exon 19 deletion and L858R mutation.
  • MET gene amplification may be one of the reasons for patients to develop acquired resistance to EGFR inhibitors.
  • MET gene amplification exists in 5-20% of EGFR mutation-positive NSCLC patients with acquired resistance to EGFR inhibitors. Patients with tumors that had MET gene amplification before EGFR inhibitor treatment progressed in a shorter time after EGFR inhibitor treatment.
  • Glumetinib (SCC244) is an oral, ATP-competitive, potent and highly selective mesenchymal-epithelial transforming factor (MET) receptor tyrosine kinase inhibitor, which has a significant inhibitory effect on MET kinase activity.
  • MET mesenchymal-epithelial transforming factor
  • Preclinical research data show that glutetinib can specifically inhibit MET kinase activity and MET signaling pathway, thereby inducing G 1 /S cell cycle arrest and inhibiting the growth of tumor cells.
  • the in vivo antitumor activity of glutatinib was superior to that of capatinib and crizotinib at the same dose.
  • MET activation has been reported to help promote the spread, migration, and invasion of cancer cells, thereby promoting tumor metastasis. Moreover, MET activation also promotes the proliferation of vascular endothelial cells, thereby promoting angiogenesis and sustained tumor growth. Preclinical studies have shown that glutetinib also has significant inhibitory effects on cancer cell proliferation, migration and invasion, and vascular endothelial cell proliferation.
  • the present disclosure provides a drug combination containing a MET receptor tyrosine kinase inhibitor and its application.
  • the drug combination has a better therapeutic effect and higher safety than the single drug of each active ingredient in the combination. .
  • the present disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising: (i) MET tyrosine kinase inhibitor: 6-(1-methyl-1H-pyrazol-4-yl)-1-((6-(1-methyl -1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3yl)sulfonyl)-1H-pyrazolin[4,3-b]pyridine (compound shown in formula (I) , also known as compound SCC244, glutamate), or a pharmaceutically acceptable salt thereof, and (ii) EGFR inhibitor;
  • the EGFR inhibitor can be Osimertinib, Almonertinib , Furmonertinib, Gefitinib, Icotinib, Erlotinib, Afatinib, Dacomitinib, La Lazertinib, Abivertinib, Lapatinib, Amivantamab or their pharmaceutically acceptable salts;
  • the MET tyrosine kinase inhibitor may be in free form (ie not a salt).
  • the EGFR inhibitor can be in free form or in the form of mesylate.
  • the EGFR inhibitor is in the form of a salt; for example a mesylate salt.
  • the MET tyrosine kinase inhibitor is in free form, and the EGFR inhibitor is in mesylate form.
  • the EGFR inhibitor is osimertinib or a pharmaceutically acceptable salt thereof, which is N- ⁇ 2- ⁇ [2-(dimethylamino)ethyl](methyl)amino ⁇ -4 -Methoxy-5- ⁇ [4-(1-methyl-1Hindol-3-yl)pyrimidin-2-yl]amino ⁇ phenyl)prop-2enamide or its mesylate, its free
  • the formal structural formula is as follows:
  • the present disclosure provides a pharmaceutical combination comprising (i) the MET tyrosine kinase inhibitor, and (ii) an EGFR inhibitor: osimertinib or a pharmaceutically acceptable Salt.
  • the EGFR inhibitor is osimertinib, preferably in the form of the mesylate salt.
  • the MET tyrosine kinase inhibitor is in free form, and the EGFR inhibitor is osimertinib mesylate.
  • the MET tyrosine kinase inhibitor in combination with an EGFR inhibitor described herein, such as osimertinib exhibits synergy.
  • said MET tyrosine kinase inhibitor and EGFR inhibitor are in a single preparation or unit dosage form.
  • the single preparation or unit dosage form may comprise: (i) the MET tyrosine kinase inhibitor, and (ii) the EGFR inhibitor, and optionally one or more pharmaceutically acceptable carriers.
  • said MET tyrosine kinase inhibitor and EGFR inhibitor are in separate formulations or unit dosage forms.
  • the separate preparations or unit dosage forms may respectively (i) comprise: the MET receptor tyrosine kinase inhibitor, and optionally one or more pharmaceutically acceptable carriers; and (ii) EGFR inhibitor, and optionally one or more pharmaceutically acceptable carriers.
  • said MET tyrosine kinase inhibitor and/or EGFR inhibitor are administered simultaneously or at different times.
  • the EGFR inhibitor is administered after the compound represented by formula (I).
  • the MET tyrosine kinase inhibitor is in a therapeutically effective amount, for example 200-300 mg in a single dose, for example 200 mg, 250 mg or 300 mg, which amount may be in one or more dosage forms.
  • the EGFR inhibitor is contained in a therapeutically effective amount, for example, 80 mg in a single dose; this amount may be in one or more dosage forms.
  • the content of the MET tyrosine kinase inhibitor is selected from 200-300 mg and the amount is suitable for administration once a day in one or more doses, and the content of the EGFR inhibitor is 80 mg and the amount is suitable for administration once a day.
  • said MET tyrosine kinase inhibitor is preferably in an oral dosage form.
  • the EGFR inhibitor is in an oral dosage form.
  • the present disclosure relates to combinations of the present disclosure for use in the treatment or prevention of cancer. Combinations of the present disclosure are useful for separate, simultaneous or sequential administration to an individual in need thereof for the treatment or prevention of cancer.
  • the present disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising: (i) a MET tyrosine kinase inhibitor: glutetinib, or a pharmaceutically acceptable salt thereof, and (ii) an EGFR inhibitor: azuremetinib Irtinib or a pharmaceutically acceptable salt thereof; the pharmaceutical combination for use in the treatment of cancer in a subject in need thereof.
  • the combinations of the present disclosure are useful for treating subjects with, for example, cancers with EGFR mutations and/or aberrant MET activation (including MET amplification, overexpression, and MET exon 14 skipping mutations, etc.), such as EGFR mutations and/or MET amplifications, especially cancers with abnormalities in both MET and EGFR pathways.
  • cancers with EGFR mutations and/or aberrant MET activation including MET amplification, overexpression, and MET exon 14 skipping mutations, etc.
  • EGFR mutations and/or MET amplifications especially cancers with abnormalities in both MET and EGFR pathways.
  • Suitable cancers include, but are not limited to, lung cancer, gastric cancer, colorectal cancer, esophageal cancer, tongue cancer, glioma, head and neck cancer, kidney cancer, liver cancer, gallbladder cancer, bile duct cancer, endometrial cancer, ovarian cancer, breast cancer cancer, prostate cancer, thyroid cancer, bone cancer, chronic myeloid leukemia (CML), pancreatic cancer, skin cancer, skin or intraocular melanoma, etc.
  • the cancer is lung cancer, especially locally advanced or metastatic NSCLC.
  • the present disclosure relates to a pharmaceutical combination
  • a pharmaceutical combination comprising: (i) a MET tyrosine kinase inhibitor: glutetinib, or a pharmaceutically acceptable salt thereof, and (ii) an EGFR inhibitor such as : osimertinib or a pharmaceutically acceptable salt thereof; the drug combination is used in the treatment of cancer patients in need who are resistant or refractory to currently available therapies, such as EGFR mutations or/and MET Cancers with abnormal activation (including MET amplification, high expression, and MET exon 14 skipping mutations, etc.), such as cancers that are resistant or refractory to EGFR inhibitors or EGFR TKI inhibitors.
  • therapies such as EGFR mutations or/and MET Cancers with abnormal activation (including MET amplification, high expression, and MET exon 14 skipping mutations, etc.), such as cancers that are resistant or refractory to EGFR inhibitors or EGFR TKI inhibitors
  • the present disclosure includes the MET tyrosine kinase inhibitor glutemetinib, or a pharmaceutically acceptable salt thereof, in combination with osimertinib exhibiting synergistic effect.
  • the present disclosure also provides a pharmaceutical composition or pharmaceutical preparation, which comprises the pharmaceutical combination described in any one of the foregoing, and one or more pharmaceutically acceptable carriers (excipients).
  • the present disclosure also provides a pharmaceutical composition or pharmaceutical preparation, comprising (i) the MET tyrosine kinase inhibitor, and (ii) an EGFR inhibitor; and one or more pharmaceutically acceptable carrier (excipient).
  • the present disclosure further relates to a pharmaceutical composition or pharmaceutical formulation for use in the treatment of cancer, said pharmaceutical composition or pharmaceutical formulation comprising (i) said MET tyrosine kinase inhibitor, and (ii) EGFR inhibitors such as osimertinib, and optionally one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition or pharmaceutical preparation comprises (i) the MET tyrosine kinase inhibitor and (ii) EGFR inhibitor: osimertinib or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.
  • the present disclosure relates to (i) a pharmaceutical composition comprising the MET receptor tyrosine kinase inhibitor glutetinib or a pharmaceutically acceptable salt thereof, and (ii) as a separate pharmaceutical composition A pharmaceutical composition comprising osimertinib administered to a subject in need thereof.
  • the present disclosure relates to combinations of the present disclosure for the preparation of a pharmaceutical composition or medicament (eg, a pharmaceutical formulation) for the treatment or prevention of cancer in an individual in need thereof.
  • a pharmaceutical composition or medicament eg, a pharmaceutical formulation
  • the present disclosure relates to the use of the combination of the present disclosure for the treatment or prevention of diseases mediated by EGFR tyrosine kinase activity and/or MET tyrosine kinase activity, especially cancer.
  • the present disclosure relates to the use of the combination of the present disclosure in the preparation of a medicament for treating or preventing EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediated diseases, the combination being any of the aforementioned combinations.
  • the present disclosure relates to the use of the combination of the present disclosure in the production of a medicament or pharmaceutical product for treating diseases mediated by EGFR tyrosine kinase activity and/or MET tyrosine kinase activity, especially cancer, wherein the present disclosure
  • the disclosed combination comprises (i) a MET receptor tyrosine kinase inhibitor such as glutetinib or a pharmaceutically acceptable salt thereof and (ii) an EGFR inhibitor such as osimertinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure relates to the use of the combination of the present disclosure in the preparation of a medicament for treating or preventing cancer.
  • the present disclosure relates to the use of a therapeutically effective amount of a combination of the present disclosure in the manufacture of a medicament for treating or preventing cancer in an individual in need thereof.
  • the MET tyrosine kinase inhibitor and the EGFR inhibitor are in a single preparation or unit dosage form.
  • the MET tyrosine kinase inhibitor and the EGFR inhibitor are in separate preparations or unit dosage forms.
  • the MET tyrosine kinase inhibitor and/or the EGFR inhibitor are administered at the same time or at different times.
  • the MET receptor tyrosine kinase inhibitor and the EGFR inhibitor can be administered separately, simultaneously or sequentially; preferably, the EGFR inhibitor inhibits MET receptor tyrosine kinase administered after the dose.
  • said cancer is resistant or refractory to treatment with an EGFR inhibitor.
  • the cancer is a cancer that is resistant or refractory to treatment with an EGFR inhibitor, such as a cancer with EGFR mutation and/or abnormal activation of MET, or a cancer with both c-MET and EGFR pathways. Unusual cancer.
  • the MET tyrosine kinase inhibitor is in the form of a dosage unit of 200-300 mg, such as 200 mg, 250 mg or 300 mg, preferably an oral dosage form.
  • the content of the MET tyrosine kinase inhibitor is selected from 200-300 mg and the amount is suitable for administration once a day in one or more doses, and the content of the EGFR inhibitor is 80 mg and the amount is suitable for administration once a day.
  • said combination is administered within a specified time, and wherein said combination is administered for a period of time.
  • the cancer is lung cancer, gastric cancer, colorectal cancer, esophageal cancer, tongue cancer, glioma, head and neck cancer, kidney cancer, liver cancer, gallbladder cancer, bile duct cancer, endometrial cancer, ovarian cancer Cancer, breast cancer, prostate cancer, thyroid cancer, bone cancer, CML, pancreatic cancer, skin cancer, skin or intraocular melanoma, preferably lung cancer, more preferably NSCLC.
  • the present disclosure relates to a method of treating or preventing an individual suffering from cancer comprising administering to the individual in need thereof an effective amount of a combination of the present disclosure.
  • the present disclosure relates to methods of treating diseases, especially cancer, mediated by EGFR tyrosine kinase activity and/or MET tyrosine kinase activity, using the following combinations: (i) MET receptor tyrosine kinase inhibitors such as Glumetinib or a pharmaceutically acceptable salt thereof and (ii) EGFR inhibitors such as osimertinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure further provides a method for treating cancer resistant or refractory to EGFR inhibitor therapy by administering a therapeutically effective amount of a MET receptor tyrosine kinase inhibitor such as glutetinib or a pharmaceutically acceptable salt thereof. Methods.
  • the present disclosure provides a method for treating cancer that is resistant or refractory to previous treatment with an EGFR inhibitor, the method comprising administering to a subject in need thereof a therapeutically effective amount of MET Receptor tyrosine kinase inhibitors such as glutetinib or a pharmaceutically acceptable salt thereof and EGFR inhibitors such as osimertinib or a pharmaceutically acceptable salt thereof.
  • MET Receptor tyrosine kinase inhibitors such as glutetinib or a pharmaceutically acceptable salt thereof
  • EGFR inhibitors such as osimertinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating cancer in a subject by administering to the subject in need of such treatment a therapeutically effective amount or dose of a MET receptor tyrosine kinase inhibitory
  • a MET receptor tyrosine kinase inhibitory A combination of an agent such as glutetinib or a pharmaceutically acceptable salt thereof and an EGFR inhibitor such as osimertinib.
  • the present disclosure provides a method of treating cancer by administering to a subject in need of such treatment an amount of a MET receptor tyrosine kinase inhibitor such as glutetinib or A pharmaceutically acceptable salt thereof and an EGFR inhibitor such as osimertinib, or a pharmaceutically acceptable salt thereof, which is therapeutically effective in combination for said treatment.
  • a MET receptor tyrosine kinase inhibitor such as glutetinib or A pharmaceutically acceptable salt thereof
  • an EGFR inhibitor such as osimertinib, or a pharmaceutically acceptable salt thereof
  • the present disclosure relates to a method of treating a disease, especially cancer, mediated by EGFR tyrosine kinase activity and/or MET tyrosine kinase activity, said method comprising administering to a subject in need such as a warm-blooded animal, especially Humans are administered an effective amount of a combination or combination product comprising (i) a MET receptor tyrosine kinase inhibitor such as glutetinib or a pharmaceutically acceptable salt thereof, and (ii) an EGFR inhibitor such as Osimertinib or a pharmaceutically acceptable salt thereof.
  • a MET receptor tyrosine kinase inhibitor such as glutetinib or a pharmaceutically acceptable salt thereof
  • an EGFR inhibitor such as Osimertinib or a pharmaceutically acceptable salt thereof.
  • Examples of types of cancer that may be treated with combinations of the present disclosure include, but are not limited to, lung cancer, gastric cancer, colorectal cancer, esophageal cancer, tongue cancer, glioma, head and neck cancer, kidney cancer, liver cancer, gallbladder cancer, bile duct cancer, uterine Endometrial cancer, ovarian cancer, breast cancer, prostate cancer, thyroid cancer, bone cancer, CML, pancreatic cancer, skin cancer, skin or intraocular melanoma, etc.
  • the cancer is a solid tumor.
  • cancers treatable with the combinations of the present disclosure include, but are not limited to, lung cancer, gastric cancer, esophageal cancer, tongue cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, skin cancer, skin or intraocular melanoma.
  • the cancer is a cancer with EGFR mutation and/or abnormal activation of MET (including MET amplification, high expression, and MET exon 14 skipping mutation, etc.), including but not limited to, lung cancer, gastric cancer, colorectal cancer, etc. carcinoma, glioma, head and neck squamous cell carcinoma, kidney cancer, liver cancer, endometrial cancer, ovarian cancer, breast cancer, thyroid cancer, and prostate cancer.
  • MET including MET amplification, high expression, and MET exon 14 skipping mutation, etc.
  • lung cancer gastric cancer, colorectal cancer, etc. carcinoma, glioma, head and neck squamous cell carcinoma, kidney cancer, liver cancer, endometrial cancer, ovarian cancer, breast cancer, thyroid cancer, and prostate cancer.
  • the cancer is lung cancer, such as locally advanced or metastatic NSCLC.
  • the present disclosure provides a pharmaceutical combination comprising a MET receptor tyrosine kinase inhibitor such as glutetinib or a pharmaceutically acceptable salt thereof and an EGFR inhibitor for the manufacture of a pharmaceutical preparation for the treatment of cancer or Use of medicines.
  • a MET receptor tyrosine kinase inhibitor such as glutetinib or a pharmaceutically acceptable salt thereof
  • an EGFR inhibitor for the manufacture of a pharmaceutical preparation for the treatment of cancer or Use of medicines.
  • the present disclosure further provides a pharmaceutical combination comprising the MET receptor tyrosine kinase inhibitor glutemetinib or a pharmaceutically acceptable salt thereof and an EGFR inhibitor for the manufacture of a pharmaceutical preparation for the treatment of cancer or use of a medicament, the cancer is a cancer that is resistant or refractory to treatment with an EGFR inhibitor or an EGFR TKI inhibitor.
  • the present disclosure further provides the use of a MET receptor tyrosine kinase inhibitor such as glutetinib or a pharmaceutically acceptable salt thereof for the treatment of cancer resistant or refractory to treatment with an EGFR inhibitor .
  • a MET receptor tyrosine kinase inhibitor such as glutetinib or a pharmaceutically acceptable salt thereof for the treatment of cancer resistant or refractory to treatment with an EGFR inhibitor .
  • said combination is administered within a specified period of time, and wherein said combination is administered over a period of time.
  • the MET receptor tyrosine kinase inhibitor glutemetinib is administered at a dose of 200-300 mg, eg 200 mg, 250 mg or 300 mg. In another embodiment, osimertinib is administered at a dose of 80 mg and glutetinib is administered at a dose of 200 mg-300 mg.
  • glutetinib and osimertinib are in a single formulation or unit dosage form. In another embodiment, glutetinib and the EGFR inhibitor, such as osimertinib, are in separate formulations or unit dosage forms.
  • glutetinib and/or an EGFR inhibitor such as osimertinib are administered at substantially the same time. In another embodiment, glutetinib and/or an EGFR inhibitor such as osimertinib are administered at different times. In another embodiment, glutetinib is administered to the subject prior to administration of the EGFR inhibitor, such as osimertinib. In another embodiment, osimertinib is administered to the subject prior to administration of the MET receptor tyrosine kinase inhibitor glutemetinib.
  • glutetinib or a pharmaceutically acceptable salt thereof is in the form of a dosage unit of 200-300 mg, such as 200 mg, 250 mg or 300 mg, preferably an oral dosage form.
  • the daily dose of glutetinib or a pharmaceutically acceptable salt thereof is 200-300 mg, such as 200 mg, 250 mg or 300 mg.
  • the content of glutetinib or a pharmaceutically acceptable salt thereof is selected from 200-300 mg and the amount is suitable for administration once a day in one or more doses
  • the EGFR inhibitor Oxy The content of tinib is 80 mg and this amount is suitable for administration once a day, and the combined medication period is 21 days.
  • the present disclosure relates to a pharmaceutical product or a commercial package comprising a pharmaceutical combination product according to the present disclosure, in particular together with instructions for its simultaneous, separate or sequential use (especially in combination) for the treatment of EGFR tyrosine Indication that acid kinase activity and/or MET tyrosine kinase activity mediates disease, especially cancer.
  • the present disclosure relates to a kit of parts comprising a pharmaceutical combination, pharmaceutical composition or pharmaceutical preparation according to the present disclosure and instructions for the simultaneous, separate or sequential administration of each pharmaceutical combination, preferably the pharmaceutical combination (active dose) is a pharmaceutical dosage unit form.
  • pharmaceutical combination refers to a fixed combination in one dosage unit form, or a non-fixed combination or a kit of parts for combined administration, wherein two or more therapeutic agents may be administered simultaneously independently or in combination The administration is separated within time intervals, especially if these time intervals allow the combination partners to exhibit cooperation, eg synergy.
  • combination therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure.
  • Said “administration” encompasses the co-administration of the therapeutic agents in a substantially simultaneous manner, such as in a single capsule with fixed ratios of active ingredients or in multiple or separate containers of each active ingredient (e.g., capsules and/or intravenous internal preparations).
  • administering also encompasses using each type of therapeutic agent in a sequential manner at about the same time or at different times.
  • EGFR inhibitor refers to a compound that inhibits, reduces, reduces or reduces at least one activity of the epidermal growth factor receptor (EGFR).
  • EGFR inhibitors include, but are not limited to, [6,7-bis(2-methoxyethoxy)-4-quinazolin-4-yl]-(3-ethynylphenyl)amine (OSI-774 ), CI-1033, AG-1478, CGP-59326, PKI-166, EKB-569, AG490 (a tyrosine phosphorylation inhibitor (tyrphostin)), ARRY-334543, BIBW-2992, EKB-569, ZD6474, BMS-599626, MDX-447 and osimertinib, amitinib, fumetinib, gefitinib, icotinib, erlotinib, afatinib, dacomitinib, laratini
  • MET inhibitor refers to a compound which targets, reduces or inhibits at least one activity of MET tyrosine kinase.
  • the "MET tyrosine kinase inhibitor” used herein includes the five-membered heterocyclic pyridine compounds represented by the general formula I described in WO2014201857 patent and their pharmaceutically acceptable salts or pharmaceutically acceptable solvates, Compound 27 (also known as SCC244) disclosed therein and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof are preferred.
  • SCC244 pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof
  • said glutetinib is in the form of its salt.
  • the term "pharmaceutically acceptable” means, within the scope of sound medical judgment, suitable for use in contact with the tissues of warm-blooded animals (eg, mammals or humans) without undue toxicity, irritation of allergic reactions and Other problematic complications, those compounds, antibodies, materials, compositions and/or dosage forms commensurate with a reasonable benefit/risk ratio.
  • fixed combination refers to a single carrier or vehicle or dosage form formulated to deliver to a patient an amount of two therapeutic agents that is effective for the treatment of cancer It is said that combination therapy is effective.
  • a single vehicle is designed to deliver an amount of each agent together with any pharmaceutically acceptable carriers or excipients.
  • the vehicle is a tablet, capsule, pill or patch. In other embodiments, the vehicle is a solution or suspension.
  • Entities as used herein are administered to a patient simultaneously, concurrently or sequentially, but without specific time limitation, wherein such administration provides therapeutically effective levels of both compounds in a warm-blooded animal in need thereof.
  • the latter also applies to cocktail therapy, eg the administration of three or more active ingredients.
  • unit dosage form as used herein is used herein to mean the simultaneous administration of two agents together, in one dosage form, to the patient to be treated.
  • the unit dosage form is a single formulation.
  • unit dosage forms include one or more vehicles such that each vehicle includes an effective amount of at least one such agent in association with pharmaceutically acceptable carriers and excipients.
  • the unit dosage form is one or more tablets, capsules, pills, or patches that are administered to the patient at the same time.
  • Oral dosage form as used herein includes unit dosage forms prescribed or intended for oral administration.
  • Dosage unit refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined quantity of active substance calculated to produce the desired therapeutic effect, together with a suitable pharmaceutically acceptable dose. acceptable excipients.
  • combined administration is intended to encompass the administration of selected active agents to a single patient, and is intended to include therapeutic regimens in which the active agents are not necessarily administered by the same route of administration or at the same time.
  • Continuous administration refers to daily administration.
  • the drug may be administered one or more times per day, for example, the drug may be administered at a frequency of once a day, twice a day, or three times a day, preferably once a day.
  • each treatment cycle (or prophylactic cycle) of administering the combination of the present disclosure is 14 to 28 days, preferably each cycle is two weeks (i.e., 14 days), three weeks (i.e., 21 days) or four weeks (i.e., 28 days).
  • Each active agent of the combination of the present disclosure can be administered on the same day or on different days of the cycle, that is to say, the active agents of the pharmaceutical combination of the present disclosure are administered separately, simultaneously or sequentially (or referred to as sequentially) within the cycle
  • treating as used herein is used herein to mean alleviating, reducing or alleviating at least one symptom of a disease in a subject.
  • treating also refers to controlling, delaying the onset of a disease (ie the period preceding the clinical manifestation of a disease or symptoms of a disease) and/or reducing the risk of developing or worsening symptoms of a disease.
  • an “effective amount” or “therapeutically effective amount” of a combination of therapeutic agents as the term is used herein is an amount sufficient to provide an observable improvement in clinically observable signs and symptoms relative to baseline of the condition being treated with the combination.
  • combined therapeutically effective or “combined therapeutic effect” as used herein means that the therapeutic agents may be administered separately (staggered in time sequence) at such time intervals that they are preferred in the warm-blooded animal to be treated, especially humans. ways, especially sequence-specific ways). Still showing a (preferably synergistic) interaction (combination therapeutic effect). Whether this is the case can be determined inter alia by following blood levels, showing that both compounds are present in the blood of the person to be treated at least during a certain time interval.
  • Subject refers to both mammals and non-mammals.
  • Mammal refers to any member of the class Mammalia, which includes, but is not limited to: humans; non-human primates, cattle, horses, sheep, pigs, rabbits, dogs, and cats, etc.
  • “Individual” is not limited to a specific age or gender.
  • the individual or patient is a human.
  • the term “about” or “approximately” generally means within 20%, more preferably within 10%, and still most preferably within 5% of a given value or range. Alternatively, particularly in biological systems, the term “about” means within about a log (ie, an order of magnitude), preferably within a factor of 2, of a given value.
  • pharmaceutically acceptable salt includes, but is not limited to, an acid addition salt or a base addition salt of a compound.
  • Compound SCC244 can form various salts with various inorganic and organic acids.
  • Acids useful in the preparation of pharmaceutically acceptable acid addition salts of the MET receptor tyrosine kinase inhibitor glutetinib of the present disclosure are those that form non-toxic acid addition salts (i.e., those containing a pharmaceutically acceptable anion).
  • Salts such as hydrochloride, sulfate or phosphate, propionate, fumarate, malonate, methanesulfonate, acetate, benzoate, bromide, chloride, citrate, fumarate salt, hydrobromide, iodate, lactate, maleate, mandelate, nitrate, oxalate, salicylate, succinate and tartrate, benzenesulfonic acid, 4- toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2- or 3-toluenesulfonic acid, methylsulfuric acid, ethylsulfuric acid).
  • Preferred inorganic salts with respect to acidic moieties are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium.
  • Preferred organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzyl-ethylenediamine and like salt.
  • salts of acidic moieties may include, for example, those formed with procaine, quinine, and N-methylglusoamine, plus those formed with basic amino acids such as glycine, ornithine, histidine, phenyl Salts of glycine, lysine and arginine.
  • Particularly preferred salts are the sodium or potassium salts of the disclosed compounds.
  • preferred inorganic salts are those formed with acidic compounds, especially inorganic acids, such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates or similar salts.
  • Preferred organic salts of this type may include, for example, with formic acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, palmitic acid, cholic acid, pamoic acid, mucic acid, D-glutamic acid , D-camphoric acid, glutaric acid, glycolic acid, phthalic acid, tartaric acid, lauric acid, stearic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sorbic acid, uric acid (puric ), benzoic acid, cinnamic acid, and salts of similar organic acids.
  • Especially preferred salts of this type are the hydrochlorides
  • references to compounds suitable for use in combination therapies of the present disclosure include the free base of the MET receptor tyrosine kinase inhibitor glutetinib and the MET receptor tyrosine kinase inhibitor glutetinib. All pharmaceutically acceptable salts of Metinib.
  • ком ⁇ онент of agents refers to a combination of two types of agents: (i) the MET receptor tyrosine kinase inhibitor glutetinib or its pharmaceutically acceptable Accepted salts and (ii) EGFR inhibitors such as osimertinib or a pharmaceutically acceptable salt thereof.
  • combination therapies comprising a MET receptor tyrosine kinase inhibitor (eg, glutemetinib) inhibitor and an EGFR inhibitor (eg, osimertinib).
  • Administration of the combination of glutetinib and osimertinib includes administration of the combination in a single formulation or unit dosage form, simultaneous but separate administration of the individual agents of the combination, or sequential administration of the combination by any suitable route single drug. Dosing of the individual agents of the combination may require more frequent administration of one of the one or more agents than the other one or more agents of the combination.
  • a packaged drug product may include one or more dosage forms containing a combination of agents, and one or more dosage forms containing a combination of agents but not one or more of the combinations.
  • Cancer refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new growth foci at other sites.
  • Cancer includes, but is not limited to: solid tumors and hematological malignancies, preferably solid tumors, more preferably advanced solid tumors, including cancers of the skin, tissues, organs, bones, cartilage, and the like.
  • cancer examples include, but are not limited to, lung cancer, gastric cancer, colorectal cancer, esophageal cancer, tongue cancer, glioma, head and neck cancer, kidney cancer, liver cancer, gallbladder cancer, bile duct cancer, endometrial cancer, ovarian cancer, Breast cancer, prostate cancer, thyroid cancer, bone cancer, CML, pancreatic cancer, skin cancer, skin or intraocular melanoma, etc.
  • the cancer described herein is lung cancer; more preferably, locally advanced or metastatic NSCLC.
  • “Cancer” as used herein also includes:
  • administration refers to the physical introduction of each of the active agents of the combinations of the present disclosure into an individual using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration for each active agent in the combinations of the present disclosure include oral, intravenous (eg, infusion, drip or injection), intramuscular, subcutaneous, intraperitoneal, spinal, topical or other parenteral routes of administration.
  • parenteral administration refers to modes of administration other than gastrointestinal and topical administration, usually intravenously, and includes, without limitation, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrathecal , intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intra-articular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, and in vivo electroporation.
  • each active agent in the combination of the present disclosure can be formulated into capsules, tablets, injections (including infusion or injection solutions), syrups, sprays, lozenges, liposomes or suppositories and the like.
  • synergy refers to a therapeutic combination that is more effective than the additive effects of two or more individual active agents. Synergy can be calculated using a suitable method, for example, the determination of a synergistic interaction between compound SCC244, or a pharmaceutically acceptable salt thereof, and one or more other active agents, such as osimertinib, can be based on determinations from assays described herein get the result in. For example, in vivo anti-tumor drug efficacy experiments can be used to perform pairwise comparisons between all groups through the Conover test in order to obtain the statistical difference index p between the groups.
  • TGI tumor inhibition rate
  • a synergistic effect may be obtained when the active agents are: (1) co-formulated and administered or delivered simultaneously in a combined unit dosage form of two or more active ingredients; (2) delivered separately or sequentially (or sequentially) or as separate The formulations are delivered simultaneously; or (3) administered by some other regimen.
  • Optimal dosages of the combination of agents used to treat a disease can be determined empirically for each individual using known methods and will depend on a variety of factors including, but not limited to, the degree of disease progression; the individual's age, weight, general health , sex, and diet; time and route of administration; and other medications the individual is taking. Optimal dosages can be established using routine testing and procedures well known in the art.
  • unit dosage forms containing combinations of agents as described herein will contain amounts of each agent of the combination that would normally be administered when the agents are administered alone.
  • Dosage frequency may vary depending upon the compound used and the particular condition to be treated or prevented. In general, it is preferred to use the smallest dose sufficient to provide effective treatment. Patients can generally be monitored for therapeutic effectiveness using assays appropriate for the condition being treated or prevented, which assays will be familiar to those skilled in the art.
  • Dosage forms can be prepared by a variety of conventional mixing, comminuting, and manufacturing techniques apparent to those skilled in pharmaceutical formulation chemistry.
  • Oral dosage forms containing the combination of agents or individual agents of the combination of agents may be in the form of microtablets enclosed within a capsule, eg, a gelatin capsule.
  • a capsule eg, a gelatin capsule.
  • gelatin capsules as employed in pharmaceutical formulations may be used, such as the hard gelatin capsules known as CAPSUGEL available from Pfizer.
  • oral dosage forms useful herein contain the combination of agents or individual agents of the combination of agents in the form of granules.
  • Such granules may be compressed into tablets present in the core element of a coated dosage form, such as a taste-masked, squeeze-coated, or enteric-coated dosage form, or may be contained in a capsule, osmotic pump dosage form, or other dosage form middle.
  • Administration of the combination therapies of the present disclosure can produce not only beneficial effects, such as synergistic therapeutic effects with respect to reducing symptoms, delaying the progression of symptoms, or suppressing symptoms, but also other unexpected beneficial effects, such as the activity of drugs used in combinations of the present disclosure alone. Fewer side effects, improved quality of life, or reduced morbidity compared to monotherapy with one of the components.
  • Another benefit may be that lower doses of the active ingredients of the disclosed combinations may be used, eg, the required doses are not only often smaller, but may be applied less frequently, which may reduce the incidence or severity of side effects. This is consistent with the wishes and requirements of the patients to be treated.
  • An object of the present disclosure is to provide a pharmaceutical combination comprising certain amounts, which can effectively target or prevent cancers in combination therapy, such as EGFR mutation and/or abnormal activation of MET (including MET amplification, high expression and MET Exon 14 skipping mutations, etc.)
  • the MET receptor tyrosine kinase inhibitor glutemetinib and the EGFR inhibitor such as osimertinib may be administered together, sequentially or separately in one combined unit dosage form or in two separate unit dosage forms.
  • the unit dosage form can also be a fixed combination.
  • the pharmaceutical composition for separate administration (or non-fixed dose) of the two compounds or for administration in a fixed combination may be prepared in a manner known per se, and are those suitable for enteral (e.g. oral or rectal) and parenteral administration to mammals (warm-blooded animals) including humans, said pharmaceutical compositions comprising alone a therapeutically effective amount of at least one pharmacologically active combination partner (for example, as indicated above), or in combination with one or more pharmaceutically acceptable carriers or diluents, especially suitable for enteral or parenteral application.
  • the pharmaceutical combinations provided herein can be formulated by a variety of methods apparent to those skilled in the art of pharmaceutical formulation.
  • the MET receptor tyrosine kinase inhibitor glutemetinib and the EGFR inhibitor osimertinib can be formulated into the same pharmaceutical composition or into separate pharmaceutical compositions for separate administration.
  • Suitable formulations include, for example, tablets, capsules, squeeze-coated formulations, intravenous solutions or suspensions and other ready-to-administer formulations.
  • One or both combination partners may be administered in pharmaceutical formulations comprising one or more pharmaceutically acceptable carriers.
  • carrier refers to a diluent, adjuvant, excipient or vehicle with which a compound is administered.
  • Such pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions.
  • Suitable pharmaceutical formulations may contain, for example, from about 0.1% to about 99.9%, preferably from about 1% to about 60%, of one or more active ingredients.
  • Pharmaceutical preparations for combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by conventional mixing, granulating, sugar-coating, dissolving or freeze-drying processes. It is to be understood that the unit content of the combination partners contained in the individual doses of each dosage form need not itself constitute an effective amount, since the necessary effective amount can be achieved by administering multiple dosage units.
  • a therapeutically effective amount of each of the combination partners of the disclosed pharmaceutical combination may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • amounts of each combination partner of a combination of the present disclosure combined in a therapeutically effective amount for treating cancer may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • a method of treating a disease according to the present disclosure may comprise: (i) administering a first agent, a MET inhibitor, in free or pharmaceutically acceptable salt form and (ii) in a combined therapeutically effective amount, preferably in a synergistically effective amount,
  • the second agent EGFR inhibitor in free or pharmaceutically acceptable salt form is administered simultaneously or sequentially in any order, for example in daily doses or intermittent doses corresponding to the amounts described herein.
  • the individual combination partners of the combinations of the present disclosure may be administered separately at different times during the course of treatment or administered simultaneously in separate or single combinations.
  • the term administration also covers the use of prodrugs of the combination partner which are converted in vivo into the combination partner itself.
  • the present disclosure should therefore be understood to include all such regimens of simultaneous or alternating treatment and the term "administration" should be interpreted accordingly.
  • Effective dosages of each of the combination partners employed in the combinations of the present disclosure may vary depending upon the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, the severity of the condition being treated. Accordingly, the dosage regimen for the combinations of the present disclosure is selected based on a variety of factors, including the mode of administration and the renal and hepatic function of the patient. A clinician or physician of ordinary skill can readily determine and prescribe the effective amount of the single active ingredient required to alleviate, combat or control the progression of the condition.
  • Combinations of the present disclosure may be in the form of pharmaceutical compositions or pharmaceutical formulations.
  • the active agents contained in the combinations of the present disclosure may be in the form of a pharmaceutical dosage unit, eg a single pharmaceutical dosage unit.
  • the combination of the present disclosure can be any dosage form (for example, unit dosage form) known to those skilled in the art, such as sugar-coated tablet, tablet, capsule, granule, powder, suppository, solution, suspension, injection (injection solution) or injection suspension). They are prepared in a manner known per se, for example by conventional mixing, granulating, sugar-coating, dissolving or lyophilization processes.
  • each agent contained in an individual dose of each dosage form need not itself constitute an effective amount, since the necessary effective amount can be achieved by administering a plurality of dosage units.
  • Unit dosage forms containing the combinations of the present disclosure may contain the active agents in amounts normally administered when the active agents are administered alone.
  • kits of parts may take the form of a kit of parts, in the sense that each active agent may be administered independently or using different fixed combinations with different amounts of the active agents, ie administered simultaneously or at different points in time. Subsequently, the active agents included in the kit of parts can be administered simultaneously or chronologically interleaved, ie at different time points with respect to any active ingredient of the kit of parts and the time intervals between administrations can be equal or unequal.
  • Therapeutically effective amounts may be administered simultaneously or sequentially in any order, either separately or as Fixed combination application.
  • the active agents of the disclosed combinations may be administered separately at different times during the course of treatment or simultaneously in separate or single combinations.
  • Combinations of the present disclosure may be administered to individuals who have been treated with one or more prior therapies but have subsequently relapsed or metastasized.
  • Each active agent in the combinations of the present disclosure may be administered to an individual in need thereof in one or more doses.
  • Each cycle of administration of the combination of the present disclosure is 21 days (3 weeks).
  • Combinations of the present disclosure may be administered for at least one cycle, eg, 2-12 or more treatment cycles.
  • the "PO” or “po” means oral administration;
  • the "QD” or “qd” means once a day;
  • the "BID” means twice a day.
  • Glumetinib, or a pharmaceutically acceptable salt thereof the MET receptor tyrosine kinase inhibitor used in the methods described herein can be administered once daily.
  • the daily dose of glutetinib or a pharmaceutically acceptable salt thereof (calculated as a free compound) is 200-300 mg, such as 200 mg, 250 mg, 300 mg; oral dosage form is preferred.
  • the initial dose of glutetinib or a pharmaceutically acceptable salt thereof is 200 mg or 300 mg, for example administered with an initial dose of 200 mg QD or 300 mg QD.
  • glutetinib or a pharmaceutically acceptable salt thereof is administered continuously in each cycle, with a daily dose of 200 mg, 250 mg or 300 mg, preferably once a day.
  • glutetinib or a pharmaceutically acceptable salt thereof is administered orally to the subject.
  • the EGFR inhibitor osimertinib used in the methods described herein can be administered once daily.
  • the daily (total) dose of osimertinib or a pharmaceutically acceptable salt thereof is 80 mg.
  • osimertinib or a pharmaceutically acceptable salt thereof is administered to the subject orally.
  • glutetinib is administered in combination with an EGFR inhibitor at a daily dose of about 200-300 mg, such as a daily dose of 200 mg, 250 mg, 300 mg.
  • glutetinib is administered at a daily dose of 200 or 300 mg in combination with osimertinib at a daily dose of 80 mg.
  • glutetinib is administered at a dose of 200 mg in combination with osimertinib at a dose of 80 mg.
  • the antitumor activity of glutecitinib combined with the EGFR inhibitor osimertinib was evaluated in a patient-derived xenograft (PDX) model of lung cancer harboring EGFR mutations and MET amplification.
  • PDX patient-derived xenograft
  • the combination of glutemetinib and osimertinib showed stronger antitumor activity, and the TGI of the combination group was greater than that of each single drug group
  • the sum of TGI, the combination of two drugs can significantly inhibit tumor growth, and the combination group has a very significant difference compared with the single drug, indicating that the combination of glutetinib and osimertinib has synergistic anti-tumor activity .
  • the pharmaceutical composition or combination provided herein i.e. the MET receptor tyrosine kinase inhibitor glutemetinib or a pharmaceutically acceptable salt thereof and the EGFR inhibitor such as osimertinib
  • glutemetinib may be in the advanced stage of carrying MET changes Relevant clinical studies in cancer patients; for example, for advanced NSCLC patients with EGFR-sensitive and MET-altered patients who failed EGFR TKI treatment, glutemetinib combined with osimertinib was used to evaluate the safety and effectiveness of combined therapy.
  • Such studies can prove the synergistic effect of the active ingredients of the combination of the present disclosure, and those skilled in the art can determine the beneficial effect of the combination of the present disclosure on cancer through these studies.
  • Such studies may be particularly suitable for comparing the effects of monotherapy with the active ingredients and combinations of the present disclosure, eg, in patients who have failed single agents and the combination of the two agents is still effective.
  • Efficacy of treatment can be determined by efficacy evaluation every 6 weeks.
  • the reagents and raw materials used in the present invention are all commercially available.
  • Combinations of the present disclosure have beneficial therapeutic properties, such as synergistic interactions, strong in vitro or in vivo antiproliferative activity, and/or strong in vitro or in vivo antitumor responses, making them particularly suitable for the treatment of cancer.
  • Figure 1 shows the combination of glutetinib and osimertinib in patients with EGFR mutations and MET amplification. Effect on tumor volume in a lung cancer PDX model (PO QD 27 days).
  • Figure 2 shows the efficacy of the combination of glutetinib and osimertinib in patients with EGFR mutations and MET amplification. Effect on body weight of mice in PDX model of lung cancer (PO QD 27 days).
  • Tumor volume was assessed twice weekly once tumors were palpable. Tumor volumes were determined by digital caliper measurements, and tumor volumes were measured twice a week throughout the experiment, along with body weights of the animals.
  • Body weight change BWC (%) response compared to the percentage of body weight change at the beginning of treatment, the calculation formula is: BWC (%) (BW n -BW 0 )/(BW 0 ) ⁇ 100%, BW n , BW 0 are expressed as Body weight at present and at the beginning of treatment.
  • T/C and TGI are indicators that reflect tumor (tumor volume) response to treatment.
  • T/C (%) reflects the relative tumor proliferation rate, that is, the percentage of tumor treatment/control (T/C) value, which is calculated by the following formula:
  • T/C (%) (T RTV /C RTV ) ⁇ 100%
  • T RTV , C RTV represent the average relative tumor volume (RTV) of the treatment group and the vehicle control group on the treatment day, respectively).
  • the average tumor volume, Vt is the average tumor volume at a certain measurement
  • T RTV and C RTV take the data of the same day.
  • TGI (%) reflects tumor growth inhibition rate.
  • the calculation formula of TGI(%) is:
  • TGI (%) (1-T/C) x 100%.
  • T and C are the relative tumor volume (RTV) of the treatment group and the control group at a specific time point, respectively).
  • the Tukey HSD test was used for pairwise comparisons between all groups, or the Dunnett's t test was used for pairwise comparisons between each treatment group and the control group.
  • the Kruskal Wallis test will be used to test whether the medians of all groups are equal. If the p-value of the Kruskal Wallis test is less than 0.05, the Conover test will be used for pairwise comparisons between all groups or between each treatment group and the control group, and corresponding p-value corrections will be made according to the number of groups in the multiple test .
  • the significance level was set at p ⁇ 0.05 to report significance compared to the control group, ie p ⁇ 0.05 was considered statistically significant, and p ⁇ 0.01 indicated a highly significant statistical difference.
  • mice BALB/c nude mice, female, 6-8 weeks old, weighing 15-20 g (at the time of cell inoculation). Sourced from Beijing Ankai Yibo Biotechnology Co., Ltd. The test animals were fed adaptively in the test site for 3-7 days before the test day.
  • Glumetinib combined with osimertinib in Drug efficacy study in lung cancer LU0858 xenograft tumor model
  • Tumor tissues from tumor-bearing mice of lung cancer xenograft tumor model LU0858 (carrying EGFR gene mutation (L858R) and highly amplified MET gene (copy number 13.75)) were harvested, cut into tumor pieces with a diameter of 2-3 mm, and placed in a sterile Inoculated subcutaneously at the right anterior shoulder blade of BALB/c nude mice under the same conditions to establish a mouse subcutaneous xenograft tumor model.
  • the tumor-bearing mice were randomly divided into 6 groups (8 mice in each group) according to the size of the tumor and administered.
  • mice were randomly divided into 6 groups, 8 mice in each group, and administered orally orally orally every day for a total of 27 days. Before and during dosing, all animals were weighed and tumor volumes were measured with calipers.
  • T/C value and tumor inhibition rate TGI
  • TGI tumor inhibition rate
  • the vehicle control of osimertinib is 40% PEG, 5% Tween 80, 5% DMSO, 50% ddH 2 O; the vehicle control of glutatinib is 43% propylene glycol, 53% polyoxyethylene ether castor sesame oil.
  • Glumetinib combined with osimertinib in The antitumor efficacy in the xenograft model of lung cancer LU0858 female BALB/c nude mice is shown in Figure 1, Figure 2 and Table 2, and the research dosage schemes of each group 1-6 in the above charts are shown in Table 1 1-6 Group.
  • Figure 1 shows the application of glutatinib and osimertinib alone or in combination
  • Fig. 2 has shown the mouse body weight change situation of each treatment group
  • Table 2 has shown each treatment group at the beginning of administration The mean tumor volume on day, and the mean tumor volume after 27 days of administration, the index T/C, TGI and p value of tumor response to treatment.
  • the test product Gumitinib monotherapy (5mg/kg, 10mg/kg) inhibited tumor growth in a dose-dependent manner, and significantly inhibited tumor growth compared with the blank vehicle group (p ⁇ 0.001)
  • the corresponding T/C values were 10.5% and 4.0% respectively; the corresponding relative tumor inhibition rates TGI were 89.5% and 96.0% respectively.
  • tumor shrinkage was observed in the 10mg/kg glutetinib administration group, and 1/8 (one tumor in 8 tumors) had complete tumor regression, and osimertinib 30mg/kg single drug did not show a significant effect.
  • T/C 106.4%
  • TGI -6.4%
  • the TGI of the combined administration group is greater than the sum of the TGIs of the single drug groups, such as glutatinib (10mg/kg)+osimertinib (30mg/kg) in the combination group (TGI: 100%)>( Metinib (10mg/kg) (TGI: 96.0%) + Osimertinib (30mg/kg) (TGI: -6.4%)), combined group Glumetinib (5mg/kg) + Osimertinib (30mg/kg)(TGI:99.8%)>(glumetinib (10mg/kg)(TGI:89.5%)+osimertinib (30mg/kg)(TGI:-6.4%)). It shows that the combined drugs have a synergistic effect on inhibiting tumor growth.
  • the combination of glutemetinib and osimertinib showed a stronger antitumor effect than any single drug, and the combination group had a very significant difference compared with the single drug, and the combination
  • the TGI of the drug group is greater than the sum of the TGI of each single drug group, and can synergistically inhibit the growth of lung cancer tumor models with EGFR mutation and MET amplification.
  • the combination of glutemetinib and osimertinib can overcome the drug resistance induced by MET amplification in PDX models of lung cancer, suggesting that it is possible to use glutemetinib and osimertinib in clinically targeting lung cancer patients with EGFR activating mutations and MET amplification.
  • Combination therapy with sigtinib especially in lung cancer patients with NSCLC.
  • the two-drug combination administration of glutatinib (5, 10mg/kg) and osimertinib (30mg/kg) respectively has a
  • the animal model of lung cancer LU0858 has the effect of synergistically inhibiting tumor growth.
  • the TGI of the combined drug group is greater than the sum of the TGI of each single drug group, and there is a very significant difference between the combined drug group and the single drug group.
  • tumor-bearing mice tolerated the test article well at the test dose.
  • Osimertinib was commercially available and was purchased from Bider Pharmaceuticals; Gumetinib tablets were provided by Shanghai Haihe Pharmaceutical Research and Development Co., Ltd., and its preparation method was as follows: the aforementioned solid dispersion Powder or granules are mixed with pharmaceutical additives to make solid preparations.
  • Phase Ib dose escalation phase and dose expansion study
  • Phase II adjucacy confirmation phase
  • Phase Ib study is to explore the safety and tolerability of glutemetinib combined with osimertinib. Once the safe recommended dose of glutemetinib combined with osimertinib is determined, such as MTD (maximum tolerated dose) or RP2D (phase II recommended dose), that is, to carry out phase II studies.
  • MTD maximum tolerated dose
  • RP2D phase II recommended dose
  • the aim was to evaluate the clinical efficacy of the combination of glutatinib and osimertinib in patients with advanced solid tumors and the drug-drug interaction potential of the combination
  • the patients enrolled in this study are patients with advanced or recurrent metastatic non-small cell lung cancer who have failed EGFR inhibitor therapy and MET amplification; especially patients with EGFR mutations and acquired resistance to previous first-, second- or third-generation EGFR TKI therapy Patients with locally advanced or metastatic NSCLC with MET amplification.
  • the experimental drugs were glutetinib and osimertinib, and the treatment plan was combination therapy.
  • the starting dose is 200mg, administered orally once a day (QD), and 21 days is a cycle.
  • the starting dose is 250 mg, administered orally once a day (QD), 21 days as a cycle.
  • the starting dose is 300 mg, administered orally once a day (QD), 21 days as a cycle.
  • the initial dose is 80 mg, administered orally once a day (BID), and 21 days is a cycle.

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Abstract

L'invention concerne une combinaison pharmaceutique contenant un inhibiteur de tyrosine kinase du récepteur MET et son utilisation. Spécifiquement, la combinaison pharmaceutique comprend : (I) un inhibiteur de tyrosine kinase du récepteur MET 6-(1-methyl-1H-pyrazol-4-yl)-1-((6-(1-méthyl-1H-pyrazol-4-yl)imidazole[1,2-a]pyridin-3yl)sulfonyl)-1H-pyrazoline[4,3-b]pyridine ou un sel pharmaceutiquement acceptable de celui-ci, et un inhibiteur de mutant EGFR ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également un procédé de traitement ou de prévention de cancers à l'aide de la combinaison et l'utilisation de la combinaison. La combinaison a des caractéristiques thérapeutiques bénéfiques telles qu'une interaction synergique, une activité anti-proliférative in vitro ou in vivo élevée et/ou des réactions anti-tumorales in vitro ou in vivo, ce qui est particulièrement approprié pour le traitement de cancers.
PCT/CN2022/129946 2021-11-05 2022-11-04 Combinaison pharmaceutique contenant un inhibiteur de la tyrosine kinase du récepteur met et son utilisation WO2023078408A1 (fr)

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CHINA GENETIC RESOURCES OFFICE FOR HUMAN SCIENCES APPROVAL: "China's Human Genetic Resources Administrative Licensing Items in 2019, Results of the Seventeenth Approval", GOVERNMENT SERVICE PLATFORM OF THE MINISTRY OF SCIENCE AND TECHNOLOGY, 8 November 2019 (2019-11-08), XP009546318 *
MA YUCHI, SUN GUANGQIANG, CHEN DANQI, PENG XIA, CHEN YUE-LEI, SU YI, JI YINCHUN, LIANG JIN, WANG XIN, CHEN LIN, DING JIAN, XIONG B: "Design and Optimization of a Series of 1-Sulfonylpyrazolo[4,3- b ]pyridines as Selective c-Met Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 58, no. 5, 12 March 2015 (2015-03-12), US , pages 2513 - 2529, XP093064248, ISSN: 0022-2623, DOI: 10.1021/jm502018y *

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