WO2023011415A1 - Egfr抑制剂的药物组合及其应用 - Google Patents

Egfr抑制剂的药物组合及其应用 Download PDF

Info

Publication number
WO2023011415A1
WO2023011415A1 PCT/CN2022/109462 CN2022109462W WO2023011415A1 WO 2023011415 A1 WO2023011415 A1 WO 2023011415A1 CN 2022109462 W CN2022109462 W CN 2022109462W WO 2023011415 A1 WO2023011415 A1 WO 2023011415A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
befutinib
icotinib
Prior art date
Application number
PCT/CN2022/109462
Other languages
English (en)
French (fr)
Inventor
汪洋
袁晓玢
竟香艳
刘莉嘉
王世华
孟晓晨
沈佳楠
张丹丹
金向宇
程红科
丁列明
Original Assignee
贝达药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 贝达药业股份有限公司 filed Critical 贝达药业股份有限公司
Priority to CN202280051854.5A priority Critical patent/CN117729922A/zh
Publication of WO2023011415A1 publication Critical patent/WO2023011415A1/zh

Links

Images

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an oral pharmaceutical composition, in particular to a pharmaceutical combination comprising befutinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof and an application thereof.
  • Epidermal growth factor receptor belongs to a family of proteins involved in cell proliferation. EGFR overexpression is present in at least 70% of human cancers, such as non-small cell lung cancer (NSCLC), breast cancer, glioma and prostate cancer. Therefore, EGFR-TK is widely regarded as a target for the design and development of therapies that can specifically bind and inhibit the activity of tyrosine kinases and their signal transduction pathways in cancer cells, and thus serve as diagnostic or therapeutic agents.
  • EGFR tyrosine kinase inhibitors are effective clinical therapies for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC).
  • NSCLC EGFR-mutated advanced non-small cell lung cancer
  • EGFR-TKIs are more effective than traditional chemotherapy drugs and can improve the quality of life of patients.
  • NCCN National Comprehensive Cancer Network
  • Representative drugs of the first-generation EGFR-TKI mainly include gefitinib, erlotinib and domestic drug icotinib, but patients will develop acquired drug resistance to varying degrees after 1 to 2 years of treatment.
  • Afatinib and dacomitinib are second-generation EGFR-TKIs, belonging to a drug that irreversibly binds to human epidermal growth factor receptor 2 (HER2) of EGFR to inhibit EGFR-TK activation.
  • HER2 human epidermal growth factor receptor 2
  • almost all patients who benefited from first- or second-generation EGFR-TKIs eventually develop clinical resistance, and approximately 50% are due to acquired EGFR T790M mutations.
  • the third-generation EGFR-TKIs were designed for T790M mutation positive, mainly including osimertinib, amitinib, and befutinib. Similar to patients treated with first- or second-generation EGFR-TKIs, patients treated with third-generation EGFR-TKIs will eventually develop drug resistance.
  • the present invention provides a drug comprising befutinib or its pharmaceutically acceptable salt, solvate (such as hydrate), prodrug and icotinib or its pharmaceutically acceptable salt, solvate (such as hydrate) ), the pharmaceutical composition of the prodrug.
  • Befutinib The structure of Befutinib is as follows:
  • the pharmaceutical composition further includes at least one pharmaceutically acceptable excipient.
  • the weight ratio of befutinib or its pharmaceutically acceptable salt to icotinib or its pharmaceutically acceptable salt is selected from 20:1 ⁇ 1:20, 1:3 ⁇ 1:20, 1:5-1:20, 1:3-1:10, 1:3-1:6 or 1:5; the weight ratio is preferably the ratio of the average daily dose.
  • the befutinib or a pharmaceutically acceptable salt thereof is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four Administration is once daily, once every five days, once every six days, once every week, once every two weeks or once every three weeks.
  • the befutinib or a pharmaceutically acceptable salt thereof is administered at a dose of 10 to 35 mg each time; preferably, the befutinib or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg each time
  • the dose is calculated as Befutinib.
  • the icotinib or a pharmaceutically acceptable salt thereof is administered three times a day, twice a day, once a day, once every two days, once every three days, once every four Administration is once daily, once every five days, once every six days, once every week, once every two weeks or once every three weeks.
  • the dose of icotinib or a pharmaceutically acceptable salt thereof is 100-150 mg per administration; preferably, the icotinib or a pharmaceutically acceptable salt thereof is 125 mg per administration dosage.
  • the dosage of befutinib or a pharmaceutically acceptable salt thereof is 50-100 mg/day, and the dosage is calculated as Beifutinib.
  • the dosage of befutinib or a pharmaceutically acceptable salt thereof is 75 mg/day, and the dosage is calculated as Beifutinib.
  • the dosage of the befutinib or the pharmaceutically acceptable salt thereof is 25 mg/time, 3 times a day, and the dosage is calculated as Beifutinib.
  • the dosage of icotinib or a pharmaceutically acceptable salt thereof is 375 mg/day.
  • the dose of icotinib or a pharmaceutically acceptable salt thereof is 125 mg/time, 3 times a day.
  • the befotinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof are used simultaneously.
  • the pharmaceutically acceptable salt of befutinib is in the form of mesylate.
  • the pharmaceutically acceptable salt of icotinib is in the form of hydrochloride.
  • the pharmaceutical composition is a fixed combination; optionally the fixed combination is in the form of a solid pharmaceutical composition; optionally, befutinib or its pharmaceutical composition in the fixed combination
  • the pharmaceutical composition is a fixed combination; optionally the fixed combination is in the form of a solid pharmaceutical composition; optionally, befutinib or its pharmaceutical composition in the fixed combination
  • befutinib or its pharmaceutical composition in the fixed combination
  • the above acceptable salt and icotinib or its pharmaceutically acceptable salt exist in the same solid pharmaceutical composition.
  • the pharmaceutical composition is a non-fixed combination; optionally, each of befotinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof in the non-fixed combination in the form of a solid pharmaceutical composition; optionally, each of befutinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof in the non-fixed combination is in the form of a solid pharmaceutical composition, and
  • the solid pharmaceutical composition of befutinib or its pharmaceutically acceptable salt and the solid pharmaceutical composition of icotinib or its pharmaceutically acceptable salt are present in the same medicine bag; optionally, the non-fixed combination Befutinib or its pharmaceutically acceptable salt and icotinib or its pharmaceutically acceptable salt are each in the form of a solid pharmaceutical composition, and the solid pharmaceutical composition of Beifutinib or its pharmaceutically acceptable salt
  • the solid pharmaceutical composition of Icotinib or its pharmaceutically acceptable salt does not exist in the same pouch.
  • the befotinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof may be administered to the patient simultaneously, separately and/or sequentially.
  • the pharmaceutical composition is an oral formulation.
  • the pharmaceutical composition is a tablet or capsule.
  • the present invention relates to a kit comprising the pharmaceutical composition.
  • the present invention relates to an application comprising befutinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament.
  • the present invention relates to the application of a composition comprising befutinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof in the preparation of medicines.
  • the pharmaceutical composition is used for non-small cell lung cancer with EGFR sensitive mutation.
  • the pharmaceutical composition is used for the EGFR sensitive mutation is exon 19 deletion or exon 21 L858R mutation.
  • the pharmaceutical composition is used for sensitive mutations of EGFR without exon 19 deletion and exon 21 L858R co-mutation.
  • the pharmaceutical composition is used for non-small cell lung cancer with EGFR T790M and EGFR C797S mutations.
  • the EGFR C797S mutation is in trans.
  • the present invention relates to a method of treating non-small cell lung cancer in a patient, comprising administering a combination of befotinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof.
  • the patient has not received prior treatment with an EGFR inhibitor.
  • befutinib or a pharmaceutically acceptable salt thereof is administered to the patient at the maximum tolerated dose of the patient.
  • icotinib or a pharmaceutically acceptable salt thereof is administered to the patient at the maximum tolerated dose of the patient.
  • the patient is administered with befutinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof in combination.
  • administration of befotinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof to the patient is the same as administration of icotinib or a pharmaceutically acceptable salt thereof Saline patients experienced longer progression-free survival than those with salt.
  • administration of befotinib or a pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof to the patient is the same as administration of icotinib or a pharmaceutically acceptable salt thereof Saline patients experienced a progression-free survival of at least greater than 4 months.
  • the progression-free survival is significantly different.
  • the combination of icotinib and befutinib has a synergistic effect, which can produce better curative effect (for example, in terms of prolonging PFS) and / or fewer side effects.
  • tumor regression may refer to a reduction in the maximum size of a tumor.
  • administration of a drug combination according to the invention, or a solvate (e.g., hydrate) or salt thereof results in a reduction in tumor size relative to baseline (i.e., size prior to initiation of treatment), or even eradication or Tumors are partially eradicated.
  • the methods of tumor regression provided herein can be characterized as methods of reducing tumor size relative to baseline.
  • tumor is a malignant tumor and is used interchangeably with “cancer”.
  • Befutinib or its solvate (e.g., hydrate) or pharmaceutically acceptable salt can be administered before, during or after Icotinib or its pharmaceutically acceptable administration .
  • befutinib or a solvate (e.g., hydrate) or salt thereof and icotinib can be separated by about one week, about 6 days, about 5 days, about 4 days, about 3 days, About 2 days interval, about 24 hours interval, about 23 hours interval, about 22 hours interval, about 21 hours interval, about 20 hours interval, about 19 hours interval, about 18 hours interval, about 17 hours interval, about 16 hours interval, Approximately 15 hour intervals, approximately 14 hour intervals, approximately 13 hour intervals, approximately 12 hour intervals, approximately 11 hour intervals, approximately 10 hour intervals, approximately 9 hour intervals, approximately 8 hour intervals, approximately 7 hour intervals, approximately 6 hour intervals, About 5-hour intervals, about 4-hour intervals, about 3-hour intervals, about 2-hour intervals, about 1-hour interval
  • befutinib or a solvate (e.g., hydrate) or pharmaceutically acceptable salt thereof and icotinib or a pharmaceutically acceptable salt thereof are administered to the subject simultaneously or substantially simultaneously By.
  • befotinib or a solvate (eg, hydrate) or pharmaceutically acceptable salt thereof and icotinib may be administered as part of one formulation.
  • the therapeutically effective amount of befutinib or its solvate (for example, hydrate) or pharmaceutically acceptable salt and icotinib or its pharmaceutically acceptable combination for the method disclosed in the present invention is when An amount that, when administered at specified time intervals, results in achieving one or more therapeutic benchmarks (eg, slowing or stopping tumor growth, causing tumor regression, cessation of symptoms, etc.).
  • the combinations used in the methods disclosed herein can be administered to the subject one or more times. In those embodiments where the compounds are administered multiple times, they may be administered at set intervals, for example daily, every other day, weekly or monthly. Alternatively, they may be administered at irregular intervals, eg, as needed based on symptoms, patient health, and the like.
  • a therapeutically effective amount of the combination can be administered once, for 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 10 days or at least 15 days.
  • the status of the cancer or regression of the tumor is detected during or after treatment, for example monitored by a FES-PET scan of the subject.
  • the dose of the combination administered to the subject may be increased or decreased.
  • the therapeutically effective amount will not exceed the maximum tolerated dose that causes 50% or more of the subjects to experience nausea or other adverse effects that prevent further administration.
  • the therapeutically effective amount for a subject may vary depending on various factors, including the type and degree of symptoms, sex, age, body weight or general health of the subject, mode of administration and type of salt or solvate, effects on the drug, Variations in sensitivity, specific types of disease, etc.
  • the therapeutically effective amount of befotinib or a solvate (e.g., hydrate) or pharmaceutically acceptable salt thereof is the therapeutically effective amount when administered alone.
  • icotinib or a solvate (e.g., hydrate) or pharmaceutically acceptable salt thereof is from about 30% to about 30% of the therapeutically effective amount when administered alone.
  • befutinib or its solvate (for example, hydrate) or pharmaceutically acceptable salt and icotinib or its solvate (for example, hydrate) or pharmaceutically acceptable salt can be administered once or dividedly. Subjects were given multiple times. In those embodiments where the compound is administered multiple times, the drug may be administered at set intervals, eg, daily, every other day, weekly or monthly. Alternatively, the drug may be administered at irregular intervals, eg, as needed based on symptoms, patient health, and the like.
  • kits comprises an effective amount of one or more pharmaceutical preparations or combinations of the present invention in unit dosage form.
  • kits may contain sterile containers for therapeutic or prophylactic compositions; such containers may be boxes, ampoules, bottles, vials, tubes, bags, blister packs, or other suitable containers known in the art. container form. Such containers may be made of plastic, glass, laminated paper, foil, or other materials suitable for holding medications.
  • the kit includes instructions for administering the pharmaceutical formulation or combination of the invention to an individual. The instructions usually include methods for treating or preventing diseases using the pharmaceutical preparations or combination drugs of the present invention.
  • befutinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof and icotinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof are combined with Administration of separate formulations.
  • the formulations may be of the same type.
  • both formulations may be designed for oral administration (eg, tablets or capsules).
  • befutinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof and icotinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof can be Made into different types of preparations.
  • one compound may be formulated for oral administration while another compound is formulated for injection.
  • befutinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof and icotinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof are used as Administered as part of a single preparation.
  • befutinib or a solvate (e.g., hydrate) or a pharmaceutically acceptable salt thereof and icotinib or a solvate (e.g., hydrate) or a pharmaceutically acceptable salt thereof are formulated for use in In a single tablet for oral administration or in a single dose for capsules.
  • the present invention provides a drug comprising befutinib or a solvate thereof (eg, hydrate) or a pharmaceutically acceptable salt thereof and icotinib or a solvate thereof (eg, hydrate) or a pharmaceutical Combination preparations of the above acceptable salts.
  • administration of the compound in a single formulation improves patient compliance.
  • the therapeutically effective amount of each compound when used in combination may be lower than the therapeutically effective amount of each compound when administered alone.
  • compositions comprising befutinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof and icotinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof
  • Both formulations may further comprise one or more pharmaceutical excipients, carriers, adjuvants and/or preservatives.
  • the salt can be formulated according to any available conventional method.
  • preferred dosage forms include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, lozenges, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops Potions, pastes, lotions, etc.
  • compositions generally used as raw materials for pharmaceutical preparations can also be prepared by mixing them according to conventional methods.
  • compositions include, for example, (1) oils such as soybean oil, tallow, and synthetic glycerides; (2) hydrocarbons such as liquid paraffin, squalane, and paraffin wax; (3) ester oils such as octyldecane Dialkyl myristic acid (octyldodecyl myristic acid) and isopropyl myristic acid (isopropyl myristic acid); (4) higher alcohols, such as cetostearyl alcohol and behenyl alcohol ); (5) silicone resin; (6) silicone oil; (7) surface active agent, such as polyoxyethylene fatty acid ester, sorbitan fatty acid ester (sorbitan fatty acid ester), glycerin fatty acid ester, polyoxyethylene Sorbitan fatty acid ester (polyoxyethylene sorbitan fatty acid ester), solid polyoxyethylene castor oil and polyoxyethylene polyoxypropylene block copolymer (solid polyoxyethylene castor oil and polyoxyethylenepolyoxypropylene block cop
  • Additives used in the above formulations may include, for example, 1) lactose, cornstarch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, and silicon dioxide as diluents; 2) polyvinyl alcohol, polyvinyl ether, formazan cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block copolymer (polypropylene glycol-poly oxyethylene-block co-polymer), meglumine, calcium citrate, dextrin, pectin, etc.
  • binders binders
  • starch agar, rubber powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, Calcium citrate, dextrin, pectin, carboxymethylcellulose/calcium, etc. as disintegrants
  • any coloring agent whose addition is pharmaceutically acceptable is suitable for adding as a coloring agent
  • cocoa powder, menthol, flavoring agent, peppermint oil, cinnamon powder are used as flavoring agents
  • Oxidizing agents such as ascorbic acid or tocopherol ( ⁇ -tophenol).
  • the salts of can be used as any one or more of the active compounds of the present invention and a physiologically acceptable carrier (also known as a pharmaceutically acceptable carrier or solution or diluent) to prepare a pharmaceutical composition.
  • physiologically acceptable carrier also known as a pharmaceutically acceptable carrier or solution or diluent
  • These carriers and solutions include pharmaceutically acceptable salts and solvates of the compounds used in the methods of this invention, as well as pharmaceutically acceptable salts and solvates comprising two or more of these compounds, pharmaceutically acceptable salts of these compounds, and pharmaceutically acceptable mixture of solvates.
  • compositions are prepared according to accepted pharmaceutical methods, for example, according to Remington's "Pharmaceutical Sciences", 17th edition, edited by Alfonso R. Gattuso, Mark Publishing Company (1985) (Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Eaton, Pa. (1985)), which is hereby incorporated by reference.
  • pharmaceutically acceptable carrier refers to a carrier that does not cause allergic or other adverse reactions in the patient to which it is administered and that is compatible with the other ingredients in the formulation.
  • Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers appropriately selected with regard to the intended form of administration and in accordance with conventional pharmaceutical practice.
  • solid carriers/diluents include, but are not limited to, gums, starches (e.g., corn starch, pregelatinized starch), sugars (e.g., lactose, mannitol, sucrose, dextrose), cellulosic materials (e.g., crystalline cellulose), Acrylates (such as polymethylacrylate), calcium carbonate, magnesium oxide, talc or mixtures thereof.
  • Pharmaceutically acceptable carriers may further contain minor amounts of auxiliary substances that increase the shelf-life or effectiveness of the therapeutic agent, such as wetting or emulsifying agents, preservatives or buffering agents.
  • Befutinib or its solvate (for example, hydrate) or pharmaceutically acceptable salt and icotinib or its solvate (for example, hydrate) or pharmaceutically acceptable salt can be converted into by conventional methods Free form of salt.
  • the term "salt" used in the present invention is not limited as long as the salt is formed with befutinib and/or icotinib and is pharmacologically acceptable; preferred examples of the salt include hydrohalide salts (such as hydrochloric acid salt, hydrobromide, hydroiodide, etc.), inorganic acid salts (such as sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.), organic carboxylates (such as ethyl salt, maleate, tartrate, fumarate, citrate, etc.), organic sulfonates (such as methanesulfonate, ethanesulfonate, benzenesulfonate, to
  • Befutinib or its solvate (for example, hydrate) or pharmaceutically acceptable salt and Icotinib or its solvate (for example, hydrate) or isomers of pharmaceutically acceptable salt can be purified into individual isomers using conventional separation methods, including, for example, recrystallization, optical resolution such as diastereomeric salts method, enzymatic fractionation, various chromatographic methods (for example, thin-layer chromatography, column chromatography, glass chromatography, etc.).
  • single isomer here includes not only an isomer with a purity of 100%, but also an isomer containing other than the target isomer which also exists through conventional purification operations.
  • Befutinib or its solvates (e.g., hydrates) or pharmaceutically acceptable salts and Icotinib or its solvates (e.g., hydrates) or pharmaceutically acceptable salts sometimes exist as crystalline polymorphs , and all crystalline polymorphs thereof are included in the present invention.
  • the bulk polymorphs are sometimes single, sometimes mixed, and both are included in the present invention.
  • befutinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof and icotinib or a solvate (eg, hydrate) or a pharmaceutically acceptable salt thereof It may be in prodrug form, meaning it must undergo some alteration (eg, oxidation or hydrolysis) to obtain its active form.
  • befutinib or its solvate (for example, hydrate) or a pharmaceutically acceptable salt and icotinib or its solvate (for example, hydrate) or a pharmaceutically acceptable salt can be obtained by mixing the parent
  • a prodrug is a compound produced by changing its active form.
  • Figure 1 shows the changes in tumor volume over time with different dosages.
  • Figure 2 shows the changes in animal body weight over time with different dosages.
  • the “amount of befutinib or a pharmaceutically acceptable salt thereof” described in the present invention is calculated by "befutinib", for example, “the amount of befutinib or a pharmaceutically acceptable salt thereof"
  • the dosage is 25mg/time/day” means that the dosage based on Befutinib is 25mg/time/day, if it is converted into the pharmaceutically acceptable salt of Befutinib, it is 25mg/M Befutinib *M Befutinib pharmaceutically acceptable salt , wherein, M Beifutinib represents the molecular weight of Beifutinib 567.26, and M Beifutinib pharmaceutically acceptable salt represents the value of Beifutinib pharmaceutically acceptable salt
  • the molecular weight, taking befutinib mesylate as an example, is 29.233 mg/time/day.
  • the "dosage of Icotinib or its pharmaceutically acceptable salt” in the present invention is calculated as "Icotinib Hydrochloride", for example, "Icotinib or its pharmaceutically acceptable salt
  • the dosage is 125mg/time/day” means that the dosage of icotinib hydrochloride is 125mg/time/day, if converted into icotinib, it is 125mg/M icotinib hydrochloride *M icotinib Ni , wherein, M icotinib hydrochloride represents the molecular weight of icotinib hydrochloride 427.88, and M icotinib represents the molecular weight of icotinib hydrochloride 391.42, which is 114.35 mg/time/day after conversion.
  • the pharmaceutical composition comprising befutinib mesylate is composed of 29.233 mg of befutinib mesylate (based on 25 mg of befutinib), 60.000 mg of mannitol (200 SD), 62.767mg of microcrystalline cellulose (PH112), 4.800mg of sodium starch glycolate (DST), 1.600mg of colloidal silicon dioxide and 1.600mg of sodium stearyl fumarate, and choose No. 2 hypromellose Empty capsule shells are filled.
  • the prescription is shown in Table 1:
  • the capsules comprising the above components are prepared by the following preparation method:
  • Premixing Add about half of the amount of mannitol into the hopper of the mixer first, then add befutinib mesylate and the remaining mannitol in turn for premixing, the mixing time is 10min, and the speed is set at 10rpm .
  • Capsule filling according to the theoretical loading capacity of the product, No. 2 hypromellose hollow capsules (I) are used for capsule filling.
  • Example 2 the stability of the preparation sample obtained by the prescription process under high temperature, high humidity and light was studied. This product was placed under the condition of high humidity 75% for 30 days, and the sample had obvious hygroscopic phenomenon. None of the test indicators changed significantly; the product was placed under the conditions of high temperature 40°C, high temperature 60°C and light 4500Lx for 30 days, except for the increasing trend of moisture, other test indicators did not change significantly. The detailed results are shown in Table 2:
  • Example 1 Taking the capsule prepared in Example 1 as an example, multiple batches of samples were prepared for comparative study on dissolution.
  • the dissolution medium selected was 0.1N hydrochloric acid, the method was paddle method plus a settling basket at 50 rpm, and the volume of the dissolution medium was 900ml. The results showed that the dissolution behavior of multiple batches of samples was relatively consistent.
  • Human non-small cell lung cancer HCC827 cell line (ATCC, CRL-2868) was cultured in a single layer in vitro, and the culture condition was RPMI-1640 medium, in which 10% fetal bovine serum and 1% double antibody (penicillin, streptomycin) were added , 37°C, 5% CO 2 incubator. Routine digestion with trypsin-EDTA was performed twice a week for passaging. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
  • HCC827 cells 0.2 mL (1 ⁇ 10 7 cells + Matrigel, volume ratio 1:1) of HCC827 cells were subcutaneously inoculated on the right back of each mouse, and when the average tumor volume reached about 172 mm 3 , they were randomly divided into groups according to the tumor volume, and Administration:
  • PO oral
  • QD stands for once a day
  • TID stands for three times a day.
  • Tumor diameters were measured twice a week with vernier calipers.
  • V 0 is the average tumor volume measured by the solvent control group during group administration
  • V i is the average tumor volume of the solvent control group during a certain measurement
  • T 0 is the average tumor volume measured by the drug administration group during group administration
  • T i is the average tumor volume of the administration group at a certain measurement.
  • c.p value is the comparative analysis of the tumor volume of the treatment group and the solvent control group.
  • This study is a clinical study to evaluate the safety and efficacy of Befotinib Mesylate Capsules combined with Icotinib Hydrochloride Tablets as first-line treatment in previously untreated patients with locally advanced or metastatic NSCLC with sensitive EGFR mutations and PK features.
  • Befutinib mesylate capsules specification: 25mg (calculated as Befutinib)/capsule.
  • Dosage Take orally, on an empty stomach or with food. 25mg/time, TID, 1 capsule each time, 28 days/cycle.
  • Icotinib Hydrochloride Tablets 125mg (calculated as Icotinib Hydrochloride)/tablet. Dosage: Take orally, on an empty stomach or with food. 125mg/time, TID, 1 tablet each time, 28 days/period, taken with Befutinib Mesylate Capsules at the same time.
  • PK blood collection point according to the order of enrollment and the first 10 subjects with the consent of the patient, within 30 minutes before the first administration of Day1 and C1D15, 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h after administration PK blood samples were collected intensively, and PK blood samples were collected sparsely for other subjects within 30 minutes before the first administration of C1D15 and 1-4 hours after administration. All subjects collected trough concentration (C min ) points within 30 minutes before the first administration of C2D1 (Day29) and C3D1 (Day57).
  • Evaluation was performed every 8 weeks according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), and the drug was administered until disease progression (PD), meeting withdrawal criteria or study termination criteria.
  • RECIST v1.1 Solid Tumors Version 1.1
  • the research endpoints of this project include safety endpoints, efficacy endpoints and PK endpoints.
  • safety endpoints ECOG physical fitness score, laboratory tests, electrocardiogram, vital signs, physical examination and AE, etc.
  • Efficacy endpoints objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), intracranial objective response rate (iORR), intracranial disease control rate (iDCR), Intracranial progression-free survival (iPFS), overall survival (OS).
  • PK endpoints area under the plasma concentration-time curve (AUC), time to peak (T max ), peak concentration (C max ) of befotinib and its major metabolites and icotinib.
  • the total diameter of the target lesions in this patient was 61.8mm, and the percentage change of the total diameter of the target lesions relative to the baseline was -41.1%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR .
  • the total diameter of the target lesions was 61.5 mm, and the percentage change of the total diameter of the target lesions relative to the baseline was -41.4%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR.
  • the total diameter of the target lesions was 61.5 mm, and the percentage change of the total diameter of the target lesions relative to the baseline was -41.4%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR.
  • the total diameter of the target lesions was 61.6 mm, and the percentage change of the total diameter of the target lesions relative to the baseline was -41.3%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR.
  • the total diameter of the target lesions was 61.7 mm, and the percentage change of the total diameter of the target lesions relative to the baseline was -41.2%. All non-target lesions existed, and there were no new lesions. The overall curative effect was evaluated as PR.
  • the first overall curative effect evaluation result of this patient was PR
  • the overall best curative effect was PR
  • the best change in the sum of target lesion diameters relative to the baseline was -41.4%.
  • the patient developed grade AE1 hypoalbuminemia, which was judged by the investigator to be related to befotinib but not to icotinib, and recovered on the 60th day.
  • grade AE1 proteinuria occurred, and the investigator judged that it was related to the study drug, and recovered on the 60th day.
  • a grade AE1 sinus tachycardia occurred, which was judged by the investigator to be unrelated to the study drug, and recovered on the 31st day.
  • AE1 grade atrial fibrillation occurred, the investigator judged that it was not related to the study drug, and recovered on the 31st day.
  • Case 2 is a male, 64 years old, with a height of 157cm, a weight of 55.4kg, and an ECOG score of 0.
  • EGFR-positive lung adenocarcinoma bone biopsy
  • TxNxM1c stage IVB
  • the sum of target lesion diameters at baseline was 44 mm.
  • the patient was screened and met the inclusion and exclusion criteria, and was enrolled on the 12th day, and began to take the study drug Befotinib 25mg TID and Icotinib 125mg TID.
  • the total diameter of the target lesions was 44mm, the percentage change of the total diameter of the target lesions relative to the baseline was 0.0%, non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as SD.
  • the total diameter of target lesions in this patient was 30.0 mm, and the percentage change of the total diameter of target lesions relative to the baseline was -31.8%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR.
  • the total diameter of target lesions in this patient was 24.0mm, and the percentage change of the total diameter of target lesions relative to the baseline was -45.5%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR.
  • the total diameter of target lesions in this patient was 19.0 mm, and the percentage change of the total diameter of target lesions relative to the baseline was -56.8%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR.
  • the total diameter of the target lesions was 19.0 mm, and the percentage change of the total diameter of the target lesions relative to the baseline was -56.8%. All non-target lesions existed, and there were no new lesions. The overall curative effect was evaluated as PR.
  • the first overall curative effect evaluation result of this patient was PR
  • the overall best curative effect was PR
  • the best change of the sum of target lesion diameters from the baseline was -56.8%.
  • the patient developed grade AE1 hypercholesterolemia, which was judged by the investigator to be unrelated to the study drug, and recovered on the 23rd day.
  • grade AE rash occurred, which was judged by the investigator to be related to the study drug, and it recovered on the 37th day after being given Claritan (10mg QD) combined with drug treatment; the grade 1 rash occurred again on the 43rd day, and the rash AE was aggravated on the 52nd day To grade 2, Claritan (10mg QD) combined with drug therapy was resumed on day 76.
  • grade AE1 anemia occurred, which was judged by the investigator to be related to befotinib but not to icotinib, and recovered spontaneously on the 63rd day.
  • Case 3 patient female, 58 years old, height 155cm, weight 53.7kg, ECOG score 0. Entered the study on day 0, and was diagnosed as EGFR-positive (exon 19 del) lung adenocarcinoma, stage IVB (T4N3M1c) untreated patients. There was a history of meningioma, liver cyst, chest pain, and venous thrombosis in the lower extremities, but no smoking history or family history.
  • the researcher took the right hilar and right upper lobe as target lesions, bilateral supraclavicular fossa, right hilar and mediastinum, retroperitoneal and mesenteric vessel lymph node metastasis, multiple lung metastases , right pleural effusion, generalized bone metastases, and right frontal lobe metastases were regarded as non-target lesions.
  • the sum of target lesion diameters at baseline was 70.6 mm.
  • the patient was screened and met the inclusion and exclusion criteria, and was enrolled on the 8th day, and began to take the study drug Befotinib 25mg TID and Icotinib 125mg TID.
  • the total diameter of the target lesions was 39.0mm, and the percentage change of the total diameter of the target lesions relative to the baseline was -44.8%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR ; Intracranial non-target lesions are present, there are no new lesions, and the intracranial efficacy evaluation is non-CR/non-PD.
  • the total diameter of target lesions in this patient was 36.7 mm, and the percentage change of the total diameter of target lesions relative to the baseline was -48.0%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR; intracranial non-target The condition of the lesion was existing, and there was no new lesion, and the intracranial efficacy evaluation was non-CR/non-PD.
  • the total diameter of the target lesions was 36.5 mm, and the percentage change of the total diameter of the target lesions relative to the baseline was -48.3%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR; intracranial non-target The condition of the lesion was existing, and there was no new lesion, and the intracranial efficacy evaluation was non-CR/non-PD.
  • the total diameter of target lesions in this patient was 36.3 mm, and the percentage change of the total diameter of target lesions relative to the baseline was -48.6%.
  • Non-target lesions were all present, and there were no new lesions.
  • the overall curative effect was evaluated as PR; intracranial non-target The condition of the lesion was existing, and there was no new lesion, and the intracranial efficacy evaluation was non-CR/non-PD.
  • the total diameter of the target lesions was 36.3 mm, and the percentage change of the total diameter of the target lesions relative to the baseline was -48.6%. All non-target lesions existed, and there were no new lesions.
  • the overall curative effect was evaluated as PR; intracranial non-target The condition of the lesion was existing, and there was no new lesion, and the intracranial efficacy evaluation was non-CR/non-PD.
  • the patient's first overall curative effect evaluation result was PR, and the overall best curative effect was PR, and the best change in the sum of the overall target lesion diameters relative to the baseline was -48.6%; the first intracranial curative effect evaluation result was non-CR/non-PD, and the best intracranial curative effect is non-CR/non-PD.
  • the patient developed grade 1 hypoalbuminemia, which was judged by the investigator to be unrelated to the study drug, and recovered on the 22nd day; Futinib-related, not icotinib-related, recovered spontaneously on day 177.
  • toothache AE2 grade occurred, and the investigator judged that it was related to befotinib and not related to icotinib, and was given metronidazole tablets (0.4g TID) combined with drug treatment and recovered on the 82nd day; on the 132nd day, Toothache AE2 grade occurred again, and the investigator judged that it was related to befotinib and not related to icotinib, and he was given metronidazole tablets (0.4g TID) combined with drug treatment and recovered on the 135th day.

Abstract

本发明涉及一种药物组合物，所述药物组合物包含贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐，以及其在治疗EGFR介导的疾病中的应用。

Description

EGFR抑制剂的药物组合及其应用 技术领域
本发明涉及口服药物组合物，具体涉及一种包含贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐的药物组合及其应用。
背景技术
表皮生长因子受体(EGFR)属于参与细胞增殖的蛋白质家族。EGFR过度表达存在于至少70％的人类癌症中，例如非小细胞肺癌(NSCLC)、乳腺癌、神经胶质瘤和***癌。因此，EGFR-TK被广泛认为是可特异性结合和抑制酪氨酸激酶活性及其在癌细胞中的信号转导途径的疗法的设计和开发的靶标，因此可作为诊断或治疗剂。
EGFR酪氨酸激酶抑制剂(TKIs)是针对EGFR突变晚期非小细胞肺癌(NSCLC)患者的有效临床疗法。在EGFR基因突变的患者中，多项研究均显示EGFR-TKI的疗效优于传统的化疗药物，而且可以提高患者的生活质量。基于EGFR-TKI药物的疗效，美国国立综合癌症网(NCCN)指南推荐EGFR-TKI可用于EGFR基因突变的NSCLC患者的一线治疗。
第一代EGFR-TKI的代表药物主要包括吉非替尼、厄洛替尼和国产药埃克替尼，但患者在通过1～2年的治疗后会出现不同程度的获得性耐药。阿法替尼和达克替尼为第二代EGFR-TKI，属于一种与EGFR的人类表皮生长因子受体2(HER2)不可逆结合以抑制EGFR-TK激活的药物。然而，几乎所有受益于第一代或第二代EGFR-TKI的患者最终发展成临床耐药，约50％是由于获得性EGFR T790M突变。因此，针对T790M突变阳性设计了第三代EGFR-TKI，主要包括奥希替尼、阿美替尼和贝福替尼等。与使用第一代或第二代EGFR-TKI治疗的患者相似，使用第三代EGFR-TKI治疗的患者也最终会形成耐药。
在埃克替尼的一项随机对照III期Convince研究中，以培美曲塞/顺铂一线化疗后培美曲塞维持治疗为阳性对照，比较两种治疗在EGFR突变晚期非小细胞肺腺癌患者中的疗效。296例患者接受随机，埃克替尼组和化疗组分为148例和137例。疗效方面，独立疗效评估委员会(IRC)评估的埃克替尼组中位PFS为11.2月，显著优于化疗组的7.9月。
然而，针对埃克替尼和贝福替尼的联合在既往未经治疗的EGFR敏感突变的非小细胞肺癌患者尚未有研究。并且，目前尚未有不同代系的EGFR-TKI联合治疗的产品上市， 仍有迫切需求。
发明内容
本发明提供一种包含贝福替尼或其药学上可接受的盐、溶剂化物(例如水合物)、前体药物和埃克替尼或其药学上可接受的盐、溶剂化物(例如水合物)、前体药物的药物组合物。
其中贝福替尼的结构如下：
Figure PCTCN2022109462-appb-000001
在一些实施方式中，所述药物组合物还包括至少一种药学上可接受的辅料。
在一些实施方式中，所述贝福替尼或其药学上可接受的盐与埃克替尼或其药学上可接受的盐的重量比例选自20:1～1:20、1:3～1:20、1:5～1:20、1:3～1:10、1:3～1:6或1:5；该重量比例优选为平均日剂量之比。
在一些实施方式中，所述贝福替尼或其药学上可接受的盐每一天施用三次、每一天施用两次、每一天施用一次、每两天施用一次、每三天施用一次、每四天施用一次、每五天施用一次、每六天施用一次、每一周施用一次、每两周施用一次或每三周施用一次。
在一些实施方式中，所述贝福替尼或其药学上可接受的盐每一次施用10～35mg的剂量；优选地，所述贝福替尼或其药学上可接受的盐每一次施用25mg的剂量，以贝福替尼计。
在一些实施方式中，所述埃克替尼或其药学上可接受的盐每一天施用三次、每一天施用两次、每一天施用一次、每两天施用一次、每三天施用一次、每四天施用一次、每五天施用一次、每六天施用一次、每一周施用一次、每两周施用一次或每三周施用一次。
在一些实施方式中，所述埃克替尼或其药学上可接受的盐每一次施用100～150mg的剂量；优选地，所述埃克替尼或其药学上可接受的盐每一次施用125mg的剂量。
在一些实施方式中，所述贝福替尼或其药学上可接受的盐的用量为50-100mg/天，其用量以贝福替尼计。
在一些实施方式中，所述贝福替尼或其药学上可接受的盐的用量为75mg/天，其用量以贝福替尼计。
在一些实施方式中，所述贝福替尼或其药学上可接受的盐的用量为25mg/次，每天3 次，其用量以贝福替尼计。
在一些实施方式中，所述埃克替尼或其药学上可接受的盐的用量为375mg/天。
在一些实施方式中，所述埃克替尼或其药学上可接受的盐的用量为125mg/次，每天3次。
在一些实施方式中，所述贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐同时使用。
在一些实施方式中，所述贝福替尼药学上可接受的盐以甲磺酸盐的形式存在。
在一些实施方式中，所述埃克替尼药学上可接受的盐以盐酸盐的形式存在。
在一些实施方式中，其特征在于，所述药物组合物是固定组合；任选地所述固定组合呈固体药物组合物形式；任选地，所述固定组合中的贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐存在于同一固体药物组合物。
在一些实施方式中，所述药物组合物是非固定组合；任选地，所述非固定组合中的贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐各自呈固体药物组合物形式；任选地，所述非固定组合中的贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐各自呈固体药物组合物形式，且贝福替尼或其药学上可接受的盐的固体药物组合物和埃克替尼或其可药用盐的固体药物组合物存在于同一个药袋；任选地，所述非固定组合中的贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐各自呈固体药物组合物形式，且贝福替尼或其药学上可接受的盐的固体药物组合物和埃克替尼或其可药用盐的固体药物组合物不存在于同一个药袋。
在一些实施方式中，所述贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐可被同时地、分别地和/或依次地给患者施用。
在一些实施方式中，所述药物组合物为口服制剂。
在一些实施方式中，所述药物组合物为片剂或胶囊剂。
一方面，本发明涉及一种药盒，其包含所述的药物组合物。
一方面，本发明涉及一种包含贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐在制备药物中的应用。
一方面，本发明涉及一种包含贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐的组合物在制备药物中的应用。
在一些实施方式中，所述药物组合物用于EGFR敏感突变的非小细胞肺癌。
在一些实施方式中，所述药物组合物用于EGFR敏感突变为19外显子缺失或21外显子L858R突变。
在一些实施方式中，所述药物组合物用于EGFR敏感突变为不含19外显子缺失与21外显子L858R共突变。
在一些实施方式中，所述药物组合物用于EGFR T790M和EGFR C797S突变的非小细胞肺癌。
在一些实施方式中，所述EGFR C797S突变为反式。
一方面，本发明涉及治疗患者非小细胞肺癌的方法，包含施用贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐的组合。
在一些实施方式中，所述患者未接受过使用EGFR抑制剂的在先治疗。
在一些实施方式中，将贝福替尼或其药学上可接受的盐以患者最大耐受剂量的剂量给药于所述患者。
在一些实施方式中，将埃克替尼或其药学上可接受的盐以患者最大耐受剂量的剂量给药于所述患者。
在一些实施方式中，用贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐联合给药于所述患者。
在一些实施方式中，用贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐给药于所述患者与用埃克替尼或其药学上可接受的盐患者相比，经历更长的无进展生存期。
在一些实施方式中，用贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐给药于所述患者与用埃克替尼或其药学上可接受的盐患者相比，经历的无进展生存期至少大于4个月。
在一些实施方式中，所述无进展生存期有显著性差异。
本发明中，埃克替尼和贝福替尼的联合具有协同增效作用，可以产生比埃克替尼单药、贝福替尼单药更优的疗效(例如，在延长PFS方面)和/或更少的副作用。
本发明所用的“肿瘤消退”或“消退”可指减小肿瘤的最大尺寸。在某些实施方式中，施用如本发明所述的联合药物或其溶剂化物(例如水合物)或盐可导致肿瘤尺寸相对于基线(即，在治疗开始之前的尺寸)减小，甚至根除或部分根除肿瘤。因此，在某些实施方式中，本发明提供的肿瘤消退方法可以以此特征被视为相对于基线减小肿瘤大小的方法。
如本发明所用，“肿瘤”是恶性肿瘤，并且与“癌症”互换使用。
术语“联合用药”意指贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐可以在埃克替尼或其药学上可接受的给药之前、期间或之后给药。例如，贝福替尼或其溶剂化物(例如，水合物)或其盐和埃克替尼可以在约一周间隔、约6天间隔、约5天间隔、约4天间隔、约3天间隔、约2天间隔、约24小时间隔、约23小时间隔、约22小时间隔、约21小时间隔、约20小时间隔、约19小时间隔、约18小时间隔、约17小时间隔、约16小时间隔、约15小时间隔、约14小时间隔、约13小时间隔、约12小时间隔、约11小时间隔、约10小时间隔、约9小时间隔、约8小时间隔、约7小时间隔、约6小时间隔、约5小时间隔、约4小时间隔、约3小时间隔、约2小时间隔、约1小时间隔、约55分钟间隔、约50分钟间隔、约45分钟间隔、约40分钟间隔、约35分钟间隔、约30分钟间隔、约25分钟间隔、约20分钟间隔、约15分钟间隔、约10分钟间隔、约5分钟间隔或约5分钟间隔内给药。在其它实施方式中，贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其药学上可接受的被同时或基本上同时给药予受试者。在这些实施方式中，贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼可以作为一个制剂的一部分被施用。
用于本发明公开的方法的治疗有效量的贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其药学上可接受的的联合用药是当在特定的时间间隔被施用时能够导致实现一个或多个治疗基准(例如，减缓或停止肿瘤生长，导致肿瘤消退、症状停止等)的量。用于本发明公开的方法中的联合用药可以一次或多次施用于受试者。在其中化合物被多次施用的那些实施方式中，它们可以以设定的间隔施用，例如每天、每隔一天、每周或每月。或者，它们可以以不规则的间隔施用，例如基于症状、患者健康情况等根据需要施用。治疗有效量的联合用药可以一次给药，连续给药1天、至少2天、至少3天、至少4天、至少5天、至少6天、至少7天、至少10天或至少15天。任选地，在治疗期间或之后检测癌症的状态或肿瘤的消退，例如通过受试者的FES-PET扫描进行监测。根据癌症的状态或检测到的肿瘤的消退，可以增加或减少向受试者施用的联合用药的剂量。
理想的情况下，治疗有效量不超过使50％或更多的治疗对象经历恶心或其它阻止进一步给药的毒副反应的最大耐受剂量。对受试者的治疗有效量可根据各种因素而变化，包括症状的种类和程度、性别、年龄、体重或受试者的一般健康状况、给药方式和盐或溶剂化物类型、对药物的敏感性的变化、疾病的具体类型等。
在一些实施方式中，当作为联合用药的一部分给药时，治疗有效量的贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐是单独给药时治疗有效量的约30％至约 200％、约40％至约200％、约50％至约200％、约60％至约200％、约70％至约200％、约80％至约200％、约90％至约200％、约100％至约200％、30％至约150％、约40％至约150％、约50％至约150％、约60％至约150％、约70％至约150％、约80％至约150％、约90％至约150％、约100％至约150％、约30％至约120％、约40％至约120％、约50％至约120％、约60％至约120％、约70％至约120％、约80％至约120％、约90％至约120％、约100％至约120％、30％至约110％、约40％至约110％、约50％至约110％、约60％至约110％、约70％至约110％、约80％至约110％、约90％至约110％，或约100％至约110％。在一些实施方式中，当作为联合用药的一部分给药时，埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐为单独给药时治疗有效量的约30％至约200％、约40％至约200％、约50％至约200％、约60％至约200％、约70％至约200％、约80％至约200％、约90％至约200％、约100％至约200％、30％至约150％、约40％至约150％、约50％至约150％、约60％至约150％、约70％至约150％、约80％至约150％、约90％至约150％、约100％至约150％、约30％至约120％、约40％至约120％、约50％至约120％、约60％至约120％、约70％至约120％、约80％至约120％、约90％至约120％、约100％至约120％、30％至约110％、约40％至约110％、约50％至约110％、约60％至约110％、约70％至约110％、约80％至约110％、约90％至约110％，或约100％至110％。
贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐的联合用药可一次或分多次给予受试者。在那些化合物被多次给药的实施方式中，药物可以以设定的间隔给药，例如每天、每隔一天、每周或每月。或者，药物可以以不规则的间隔给药，例如基于症状、患者健康等根据需要给药。
术语“药盒”包括有效量的一种或多种单位剂型的本发明的药物制剂或联合用药物。在一些实施方案中,药盒可含有治疗或预防性组合物的无菌容器；这样的容器可以是盒、安瓿、瓶、小瓶、管、袋、泡罩包装或本领域已知的其它合适的容器形式。这种容器可以由塑料、玻璃、层压纸、金属箔或其他适合于保持药物的材料制成。此外，药盒还包括将本发明的药物制剂或联合用药物给予个体的说明书。说明书中通常包含使用本发明的药物制剂或联合用药物来治疗或预防疾病的方法。
在一些实施方式中，贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐以分开的制剂给药。在这些实施方式中的某些中，制剂可以是相同类型的。例如，两种制剂都可以设计为用于口服给药(例如，片剂或胶囊剂)。在其它实施方式中，贝福替尼或其溶剂化物(例如，水合物)或药学上 可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐可以被制成不同类型的制剂。例如，一种化合物可以是设计用于口服给药的制剂，而另一种化合物是设计用于注射的制剂。
在其它实施方式中，贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐作为单一制剂的一部分给药。例如，贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐被配制在用于口服给药的单个片剂中或用于胶囊的单次量中。在某些实施方式中，本发明提供了包含贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐的组合制剂。在某些实施方式中，以单一制剂给予化合物改善了患者的依从性。
每种化合物的治疗有效量在联合使用时可以低于单独给药时的每种化合物的治疗有效量。
在一些实施方式中，包含贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐两者的制剂可进一步包含一种或多种药物赋形剂、载体、佐剂和/或防腐剂。
用于本发明的方法中的贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐可被配制成单位剂型，其指适于作为用于接受治疗的受试者的单位剂量的物理上离散的单位，其中每个单位含有经计算可产生预期的治疗效果的预定量的活性物质，任选地与合适的药物载体组合。单位剂型可以是单次日剂量或多次日剂量中的一种(例如，每日约1至4次或更多次)。当使用多次日剂量时，单位剂型对于每个剂量可以是相同的或不同的。
用于本发明公开的方法中的贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐可以根据任何可用的常规方法配制。优选的剂型实例包括片剂、粉末、精细颗粒、颗粒、包衣片剂、胶囊、糖浆、锭剂、吸入剂、栓剂、注射剂、软膏、眼用软膏、滴眼剂、滴鼻剂、滴耳剂、糊剂、洗剂等。在制剂中，可以使用通常使用的添加剂，例如稀释剂、粘合剂、崩解剂、润滑剂、着色剂、调味剂，以及如果需要，可以使用稳定剂、乳化剂、吸收促进剂、表面活性剂、pH调节剂、防腐剂、抗氧化剂等。另外，也可以按照常规方法将通常用作药物制剂原料的组合物混合进行配制。这些组合物的实例包括，例如，(1)油如大豆油、牛油和合成甘油酯；(2)烃，例如液体石蜡、角鲨烷和固体石蜡；(3)酯油，如辛基十二烷基肉豆蔻酸(octyldodecyl  myristic acid)和异丙基肉豆蔻酸(isopropyl myristic acid)；(4)高级醇，例如十六醇十八醇混合物(cetostearyl alcohol)和二十二醇(behenyl alcohol)；(5)硅树脂；(6)硅油；(7)表面活性剂，例如聚氧乙烯脂肪酸酯、脱水山梨糖醇脂肪酸酯(sorbitan fatty acid ester)、甘油脂肪酸酯、聚氧乙烯脱水山梨糖醇脂肪酸酯(polyoxyethylene sorbitan fatty acid ester)、固体聚氧乙烯蓖麻油和聚氧乙烯聚氧丙烯嵌段共聚物(solid polyoxyethylene castor oil and polyoxyethylenepolyoxypropylene block co-polymer)；(8)水溶性高分子，例如羟乙基纤维素、聚丙烯酸、羧乙烯基聚合物(carboxyvinyl polymer)、聚乙二醇、聚乙烯吡咯烷酮和甲基纤维素；(9)低级醇，例如乙醇和异丙醇；(10)多价醇，例如甘油、丙二醇、二丙二醇和山梨醇；(11)糖，例如葡萄糖和蔗糖；(12)无机粉末如无水硅酸、硅酸铝镁和硅酸铝；(13)纯净水等。用于上述制剂的添加剂可包括，例如，1)乳糖、玉米淀粉、蔗糖、葡萄糖、甘露醇、山梨醇、结晶纤维素和二氧化硅作为稀释剂；2)聚乙烯醇、聚乙烯醚、甲基纤维素、乙基纤维素、***胶、黄芪胶、明胶、虫胶、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚丙二醇-聚氧乙烯嵌段共聚物(polypropylene glycol-poly oxyethylene-block co-polymer)、葡甲胺、柠檬酸钙、糊精、果胶等作为粘合剂；3)淀粉、琼脂、胶粉、结晶纤维素、碳酸钙、碳酸氢钠、柠檬酸钙、糊精、果胶、羧甲基纤维素/钙等作为崩解剂；4)硬脂酸镁、滑石粉、聚乙二醇、二氧化硅、浓缩植物油等作为润滑剂；5)其加入是药学上可接受的任何着色剂都适合作为着色剂添加；6)可可粉、薄荷脑、芳香剂、薄荷油、肉桂粉作为调味剂；7)其加入是药学上可接受的抗氧化剂，如抗坏血酸或生育酚(α-tophenol)。
用于本发明公开的方法中的贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐可以作为本发明所述的活性化合物中的任何一种或多种和生理学可接受的载体(也称为药学可接受的载体或溶液或稀释剂)配制成药物组合物。这些载体和溶液包括本发明方法中所用化合物的药学上可接受的盐和溶剂合物，以及包含两种或多种这些化合物、这些化合物的药学上可接受的盐和这些化合物的药学上可接受的溶剂化物的混合物。这些组合物是按照可接受的制药方法制备的，例如按照雷明顿的《药学科学》，第17版，阿方索·R·加图索编辑，马克出版公司(1985)(Remington’s Pharmaceutical Sciences,17th edition,ed.Alfonso R.Gennaro,Mack Publishing Company,Eaton,Pa.(1985))中所述的方法制备，其在此通过引用并入。
术语“药学上可接受的载体”是指在不引起被给药的患者过敏反应或其它不良反应并且与制剂中的其它成分相容的载体。药学上可接受的载体包括，例如，根据预期的给药形式适当选择的并且与常规的药学实践一致的药物稀释剂、赋形剂或载体。例如，固体载 体/稀释剂包括但不限于树胶、淀粉(例如玉米淀粉、预胶化淀粉)、糖(例如乳糖、甘露醇、蔗糖、右旋糖)、纤维素材料(例如结晶纤维素)、丙烯酸酯(例如聚丙烯酸甲酯(polymethylacrylate))、碳酸钙、氧化镁、滑石粉或其混合物。药学上可接受的载体可以进一步包含少量增加治疗剂的保存期限或有效性的辅助物质，例如润湿剂或乳化剂、防腐剂或缓冲剂。
贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐为可以通过常规方法转化成盐的游离形式。本发明所用的术语“盐”不受限制，只要所述盐与贝福替尼和/或埃克替尼形成并且是药理学可接受的；盐的优选实例包括氢卤酸盐(例如盐酸盐、氢溴酸盐、氢碘酸盐等)、无机酸盐(例如硫酸盐、硝酸盐、高氯酸盐、磷酸盐、碳酸盐、碳酸氢盐等)、有机羧酸盐(例如乙酸盐、马来酸盐、酒石酸盐、富马酸盐、柠檬酸盐等)、有机磺酸盐(例如甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、樟脑磺酸盐等)、氨基酸盐(例如天冬氨酸盐、谷氨酸盐等)、季铵盐、碱金属盐(例如钠盐、钾盐等)、碱土金属盐(镁盐、钙盐等)等。此外，优选盐酸盐、硫酸盐、甲磺酸盐、乙酸盐等作为本发明化合物的“药理学上可接受的盐”。
贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐的异构体(例如，几何异构体、光学异构体、旋转异构体、互变异构体等)可以使用一般的分离方法纯化化为单一异构体，包括例如重结晶、光学拆分如非对映体盐法、酶分级分离法、各种色谱法(例如，薄层色谱法、柱色谱法、玻璃色谱法等)。术语“单一异构体”在此不仅包括纯度为100％的异构体，而且包括含有目标异构体以外的通过常规纯化操作也存在的异构体。贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐有时存在结晶多晶型物，并且其所有结晶多晶型物都包括在本发明中。结体多晶型物有时是单一的，有时是混合的，并且两者都包括在本发明中。
在某些实施方式中，贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐可以为前体药物形式，意味着其必须经历一些改变(例如，氧化或水解)以获得其活性形式。或者，贝福替尼或其溶剂化物(例如，水合物)或药学上可接受的盐和埃克替尼或其溶剂化物(例如，水合物)或药学上可接受的盐可以是通过将母体前药改变为其活性形式而产生的化合物。
附图说明
图1为不同给药量随着时间延长的肿瘤体积变化。
图2为不同给药量随着时间延长的动物体重变化。
具体实施方式
下面通过给出的各实施例和实验例对本发明作出进一步说明，但所述实施例和实验例并不能对本发明要求保护的范围构成任何限制。在本发明的具体实施例中，除非特别说明，所述技术或方法为本领域的常规技术或方法。
除非特别说明，本发明所述“贝福替尼或其药学上可接受的盐的用量”均以“贝福替尼计”，例如，“贝福替尼或其药学上可接受的盐的用量为25mg/次/天”是指以贝福替尼计的用量为25mg/次/天，若折算为贝福替尼药学上可接受的盐，则为25mg/M 贝福替尼*M 贝福替尼 药学上可接受的盐，其中，M 贝福替尼表示贝福替尼的分子量567.26，M 贝福替尼药学上可接受的盐表示贝福替尼药学上可接受的盐的分子量，以贝福替尼甲磺酸盐为例，则为29.233mg/次/天。
除非特别说明，本发明所述“埃克替尼或其药学上可接受的盐的用量”均以“盐酸埃克替尼计”，例如，“埃克替尼或其药学上可接受的盐的用量为125mg/次/天”是指以盐酸埃克替尼计的用量为125mg/次/天，若折算为埃克替尼，则为125mg/M 盐酸埃克替尼*M 埃克替尼，其中，M 盐酸埃克替尼表示盐酸埃克替尼的分子量427.88，M 埃克替尼表示埃克替尼的分子量391.42，经换算为114.35mg/次/天。
实施例1甲磺酸贝福替尼胶囊的处方
包含贝福替尼甲磺酸盐的药物组合物，其药物组成为，包含29.233mg的贝福替尼甲磺酸盐(以贝福替尼25mg计)、60.000mg的甘露醇(200SD)、62.767mg的微晶纤维素(PH112)、4.800mg的羧甲淀粉钠(DST)、1.600mg的胶态二氧化硅以及1.600mg的硬脂富马酸钠，并选用2号羟丙甲纤维素空心胶囊壳进行灌装。处方如表1所示：
表1
Figure PCTCN2022109462-appb-000002
包含上述组分的胶囊剂，利用下述制备方法制备：
(1)配料：分别称取原辅料。
(2)预混：将约一半量的甘露醇先加入混合机料斗内，然后依次加入贝福替尼甲磺酸盐和剩下的甘露醇进行预混，混合时间为10min，转速设置为10rpm。
(3)过筛：将预混后物料将上述预混物料过筛一遍。
(4)混合：将过筛后物料用混合机进行混合，转速设置为10rpm，混合时间为20min。
(5)胶囊填充：根据产品理论装量，使用2号羟丙甲纤维素空心胶囊(I)进行胶囊装填。
实施例2甲磺酸贝福替尼胶囊的稳定性
以实施例1制备的胶囊为例研究了该处方工艺所得制剂样品在高温、高湿以及光照下的稳定性，本品在高湿75％条件下放置30天，样品有明显吸湿现象，其他各项检测指标均无明显变化；本品在高温40℃、高温60℃和光照4500Lx条件下放置30天，除水分有增长趋势，其他各项检测指标均无明显变化。详细结果如表2所示：
表2
Figure PCTCN2022109462-appb-000003
实施例3甲磺酸贝福替尼胶囊的溶出曲线
以实施例1制备的胶囊为例制备了多批次样品进行溶出对比研究，选用的溶出介质为0.1N盐酸，方法为桨法加沉降篮50rpm，溶出介质体积为900ml。结果显示多批次样品溶出行为均较为一致。
实施例A体内药效学研究
人非小细胞肺癌HCC827细胞皮下异种移植肿瘤BALB/c裸小鼠模型的体内药效学研究
1.细胞培养和肿瘤组织准备
人非小细胞肺癌HCC827细胞系(ATCC，CRL-2868)体外单层培养，培养条件为RPMI-1640培养基，培养基中加10％胎牛血清、1％双抗(青霉素，链霉素)，37℃，5％CO 2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。将0.2mL(1×10 7个+Matrigel，体积比为1：1)HCC827细胞皮下接种于每只小鼠的右后背，肿瘤平均体积达到约172mm 3时，根据肿瘤体积进行随机分组，并给药：
表3实验动物分组及给药方案
Figure PCTCN2022109462-appb-000004
注:PO代表口服；QD代表每日1次；TID代表每日3次。
2.肿瘤测量和实验指标
每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为:V＝0.5a×b 2,a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率△T/△C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
相对肿瘤增殖率△T/△C(％)：计算公式如下：△T/△C(％)＝(T i-T 0)/(V i-V 0)x 100。其中V 0是分组给药时溶剂对照组测量所得平均肿瘤体积，V i为某一次测量时的溶剂对照组平均肿瘤体积；T 0是分组给药时给药组测量所得平均肿瘤体积，T i为某一次测量时给药组的平均肿瘤体积。
3.实验结果
实验结果如图1和图2所示；给药35天时结果如表4所示。
表4给药第35天的药效数据
Figure PCTCN2022109462-appb-000005
Figure PCTCN2022109462-appb-000006
注：
a.肿瘤体积为平均值±SEM，n＝9。
b.肿瘤生长抑制由△T/△C(△T/△C TGI(％)＝(T 35-T 0)/(V 35-V 0)×100)和TGI(TGI(％)＝[1-(T 35-T 0)/(V 35-V 0)]×100)计算。
c.p值为治疗组与溶剂对照组肿瘤体积的比较分析。
实验结论：本发明甲磺酸贝福替尼联合盐酸埃克替尼相比单药具有显著的抑瘤作用，且小鼠各个剂量组的体重平稳，无明显不耐受现象。
实施例B贝福替尼联合埃克替尼在既往未经治疗的EGFR敏感突变局部晚期或转移性非小细胞肺癌患者中临床研究
本研究是一项临床研究，在既往未经治疗的EGFR敏感突变局部晚期或转移性NSCLC患者中，评估甲磺酸贝福替尼胶囊联合盐酸埃克替尼片作为一线治疗的安全性、疗效和PK特征。
研究药物：
甲磺酸贝福替尼胶囊，规格：25mg(以贝福替尼计)/粒。用法用量：口服，空腹或与食物同服。25mg/次，TID，每次1粒，28天/周期。
盐酸埃克替尼片，规格：125mg(以盐酸埃克替尼计)/片。用法用量：口服，空腹或与食物同服。125mg/次，TID，每次1片，28天/周期，与甲磺酸贝福替尼胶囊同时服用。
PK采血点：按入组先后顺序并经患者同意的前10例受试者在Day1及C1D15首次给药前30min内、给药后0.5h、1h、2h、3h、4h、5h、6h、8h密集采集PK血样，其余受试者在C1D15首次给药前30min内、给药后1-4h稀疏采集PK血样。所有受试者均在C2D1(Day29)及C3D1(Day57)首次给药前30min内采集谷浓度(C min)点。
每8周一次按照实体瘤疗效评价标准第1.1版(RECIST v1.1)进行评估，用药直至疾病进展(PD)、满足退出标准或研究终止标准。
本项目的研究终点包括安全性终点、疗效终点和PK终点。其中，安全性终点：ECOG体能评分、实验室检查、心电图、生命体征、体格检查和AE等。疗效终点：客观缓解率(ORR)、缓解持续时间(DOR)、疾病控制率(DCR)、无进展生存期(PFS)、颅内客观缓解率(iORR)、颅内疾病控制率(iDCR)、颅内无进展生存期(iPFS)、总生存期(OS)。 PK终点：贝福替尼及其主要代谢物和埃克替尼的血药浓度-时间曲线下面积(AUC)、达峰时间(T max)、达峰浓度(C max)等。
病例1
基线情况
病例1患者，女，64周岁，身高166cm，体重55.4kg，ECOG评分0分。于第0天进入此研究，经检测确认为EGFR阳性(19外显子del)的肺腺癌、IVA期(T4N2M1a)初治患者。无既往病史和现病史、吸烟史、家族史。第1天经影像学检查，研究者将左上肺、右上肺病灶作为靶病灶，双肺多发转移瘤、纵膈***及左肺门***转移、左侧胸腔积液作为非靶病灶，无脑转移病灶。基线靶病灶直径总和为105.0mm。该患者经筛选符合入排标准，于第4天入组，开始服用研究药物贝福替尼25mg TID、埃克替尼125mg TID。
疗效情况
经研究者评估，C3D1访视期，该患者靶病灶直径总和为61.8mm，靶病灶直径总和相对基线变化百分比为-41.1％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR。C5D1访视期，该患者靶病灶直径总和为61.5mm，靶病灶直径总和相对基线变化百分比为-41.4％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR。C7D1访视期，该患者靶病灶直径总和为61.5mm，靶病灶直径总和相对基线变化百分比为-41.4％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR。C9D1访视期，该患者靶病灶直径总和为61.6mm，靶病灶直径总和相对基线变化百分比为-41.3％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR。C11D1访视期，该患者靶病灶直径总和为61.7mm，靶病灶直径总和相对基线变化百分比为-41.2％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR。
该患者首次整体疗效评估结果为PR，整体最佳疗效为PR，靶病灶直径总和相对基线最佳变化为-41.4％。
安全性情况
第18天，该患者发生低白蛋白血症AE1级，研究者判为与贝福替尼有关、与埃克替尼无关，于第60天恢复。第18天，发生蛋白尿AE1级，研究者判为与研究药物有关，于第60天恢复。第18天，发生窦性心动过速AE1级，研究者判为与研究药物无关，于第31天恢复。第21天，发生房颤AE1级，研究者判为与研究药物无关，于第31天恢复。
以上AE均未经合并用药治疗/研究药物剂量调整，自行恢复。
病例2
基线情况
病例2患者，男，64周岁，身高157cm，体重55.4kg，ECOG评分0分。于第0天进入此研究，经检测确认为EGFR阳性(21外显子L858R突变)的肺腺癌(骨穿刺活检)、IVB期(TxNxM1c)初治患者。存在肺大泡现病史、吸烟史，无家族史。于第2天影像学检查，肺部未见原发病灶以及***转移，研究者则将T3椎体旁软组织肿块转移病灶作为靶病灶，全身多发骨转移作为非靶病灶，无脑转移病灶。基线靶病灶直径总和为44mm。该患者经筛选符合入排标准，于第12天入组，开始服用研究药物贝福替尼25mg TID、埃克替尼125mg TID。
疗效情况
经研究者评估，C3D1访视期，该患者靶病灶直径总和为44mm，靶病灶直径总和相对基线变化百分比为0.0％，非靶病灶情况均为存在，无新病灶，整体疗效评估为SD。C5D1访视期，该患者靶病灶直径总和为30.0mm，靶病灶直径总和相对基线变化百分比为-31.8％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR。C7D1访视期，该患者靶病灶直径总和为24.0mm，靶病灶直径总和相对基线变化百分比为-45.5％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR。C9D1访视期，该患者靶病灶直径总和为19.0mm，靶病灶直径总和相对基线变化百分比为-56.8％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR。C11D1访视期，该患者靶病灶直径总和为19.0mm，靶病灶直径总和相对基线变化百分比为-56.8％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR。
该患者首次整体疗效评估结果为PR，整体最佳疗效为PR，靶病灶直径总和相对基线最佳变化为-56.8％。
安全性情况
第1天，该患者发生高胆固醇血症AE1级，研究者判为与研究药物无关，于第23天恢复。第12天，发生皮疹AE1级，研究者判为与研究药物有关，予以开瑞坦(10mg QD)合并药物治疗后于第37天恢复；第43天再次发生皮疹1级，第52天皮疹AE加重至2级，予以开瑞坦(10mg QD)合并药物治疗后于第76天恢复。第37天，发生贫血AE1级，研究者判为与贝福替尼有关、与埃克替尼无关，于第63天自行恢复。
以上AE均未经研究药物剂量调整。
病例3
基线情况
病例3患者，女，58周岁，身高155cm，体重53.7kg，ECOG评分0分。于第0天进入此研究，经检测确认为EGFR阳性(19外显子del)的肺腺癌、IVB期(T4N3M1c)初治患者。存在脑膜瘤、肝囊肿、胸痛、下肢静脉血栓现病史，无吸烟史、家族史。第2天经影像学检查，研究者将右肺门旁、右肺上叶作为靶病灶，双侧锁骨上窝、右肺门及纵膈、腹膜后及肠系膜血管旁***转移、双肺多发转移、右侧胸腔积液、全身广发骨转移、右额叶转移作为非靶病灶。基线靶病灶直径总和为70.6mm。该患者经筛选符合入排标准，于第8天入组，开始服用研究药物贝福替尼25mg TID、埃克替尼125mg TID。
疗效情况
经研究者评估，C3D1访视期，该患者靶病灶直径总和为39.0mm，靶病灶直径总和相对基线变化百分比为-44.8％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR；颅内非靶病灶情况为存在，无新病灶，颅内疗效评估为非CR/非PD。C5D1访视期，该患者靶病灶直径总和为36.7mm，靶病灶直径总和相对基线变化百分比为-48.0％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR；颅内非靶病灶情况为存在，无新病灶，颅内疗效评估为非CR/非PD。C7D1访视期，该患者靶病灶直径总和为36.5mm，靶病灶直径总和相对基线变化百分比为-48.3％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR；颅内非靶病灶情况为存在，无新病灶，颅内疗效评估为非CR/非PD。C9D1访视期，该患者靶病灶直径总和为36.3mm，靶病灶直径总和相对基线变化百分比为-48.6％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR；颅内非靶病灶情况为存在，无新病灶，颅内疗效评估为非CR/非PD。C11D1访视期，该患者靶病灶直径总和为36.3mm，靶病灶直径总和相对基线变化百分比为-48.6％，非靶病灶情况均为存在，无新病灶，整体疗效评估为PR；颅内非靶病灶情况为存在，无新病灶，颅内疗效评估为非CR/非PD。
该患者首次整体疗效评估结果为PR，整体最佳疗效为PR，整体靶病灶直径总和相对基线最佳变化为-48.6％；首次颅内疗效评估结果为非CR/非PD，颅内最佳疗效为非CR/非PD。
安全性情况
第2天，该患者发生低白蛋白血症1级，研究者判为与研究药物无关，于第22天恢 复；第38天，再次发生低白蛋白血症1级，研究者判为与贝福替尼有关、与埃克替尼无关，于第177天自行恢复。第79天，发生牙痛AE2级，研究者判为与贝福替尼有关、与埃克替尼无关，予以甲硝唑片(0.4g TID)合并药物治疗于第82天恢复；第132天，再次发生牙痛AE2级，研究者判为与贝福替尼有关、与埃克替尼无关，予以甲硝唑片(0.4g TID)合并药物治疗于第135天恢复。第132天，发生口腔溃疡AE2级，研究者判为与研究药物无关，予以口炎清颗粒(10g TID)合并药物治疗于第135天恢复。第177天，发生体重AE2级，研究者判为与研究药物无关，至专利申请时未恢复。
以上AE均未经研究药物剂量调整。
综上3例患者的疗效和安全性分析可得，在EGFR敏感突变阳性的晚期NSCLC初治患者中，经贝福替尼联合埃克替尼治疗后，肿瘤病灶得到明显、稳定地缩小，最佳缓解深度均在-40％以上。AE大多为1-2级可自行恢复，或合并药物治疗转归良好，且无须调整研究药物剂量，安全性可控。
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。

Claims (34)

  1. 一种药物组合物，其特征在于，包含贝福替尼或其药学上可接受的盐、溶剂化物(例如水合物)、前体药物和埃克替尼或其药学上可接受的盐、溶剂化物(例如水合物)、前体药物，所述贝福替尼的结构为
    Figure PCTCN2022109462-appb-100001
  2. 根据权利要求1所述的药物组合物，其特征在于，还包括至少一种药学上可接受的辅料。
  3. 根据权利要求1-2任一项所述的药物组合物，其特征在于，贝福替尼或其药学上可接受的盐与埃克替尼或其药学上可接受的盐的重量比例选自20:1～1:20、1:3～1:20、1:5～1:20、1:3～1:10、1:3～1:6或1:5；该重量比例优选为平均日剂量之比。
  4. 根据权利要求1-3任一项所述药的物组合物，其特征在于，所述贝福替尼或其药学上可接受的盐每一天施用三次、每一天施用两次、每一天施用一次、每两天施用一次、每三天施用一次、每四天施用一次、每五天施用一次、每六天施用一次、每一周施用一次、每两周施用一次或每三周施用一次。
  5. 根据权利要求1-4任一项所述的药物组合物，其特征在于，所述贝福替尼或其药学上可接受的盐每一次施用10～35mg的剂量；优选地，所述贝福替尼或其药学上可接受的盐每一次施用25mg的剂量，以贝福替尼计。
  6. 根据权利要求1-5任一项所述的药物组合物，其特征在于：所述埃克替尼或其药学上可接受的盐每一天施用三次、每一天施用两次、每一天施用一次、每两天施用一次、每三天施用一次、每四天施用一次、每五天施用一次、每六天施用一次、每一周施用一次、每两周施用一次或每三周施用一次。
  7. 根据权利要求1-6任一项所述的药物组合物，其特征在于，所述埃克替尼或其药学上可接受的盐每一次施用100～150mg的剂量；优选地，所述埃克替尼或其药学上可接受的盐每一次施用125mg的剂量。
  8. 根据权利要求1-7任一项所述的药物组合物，其特征在于，所述贝福替尼或其药学上可接受的盐的用量为50-100mg/天，其用量以贝福替尼计。
  9. 根据权利要求1-8任一项所述的药物组合物，其特征在于，所述贝福替尼或其药 学上可接受的盐的用量为75mg/天，其用量以贝福替尼计。
  10. 根据权利要求1-9任一项所述的药物组合物，其特征在于，所述贝福替尼或其药学上可接受的盐的用量为25mg/次，每天3次，其用量以贝福替尼计。
  11. 根据权利要求1-10任一项所述的药物组合物，其特征在于，所述埃克替尼或其药学上可接受的盐的用量为375mg/天。
  12. 根据权利要求1-11任一项所述的药物组合物，其特征在于，所述埃克替尼或其药学上可接受的盐的用量为125mg/次，每天3次。
  13. 根据权利要求1-12任一项所述的药物组合物，其特征在于，所述贝福替尼或其药学上可接受的盐和埃克替尼或其药学上可接受的盐同时使用。
  14. 根据权利要求1-13任一项所述的药物组合物，其特征在于，所述贝福替尼药学上可接受的盐以甲磺酸盐的形式存在。
  15. 根据权利要求1-14任一项所述的药物组合物，其特征在于，所述埃克替尼药学上可接受的盐以盐酸盐的形式存在。
  16. 根据权利要求1-15任一项所述的药物组合物，其特征在于，所述药物组合物是固定组合；任选地所述固定组合呈固体药物组合物形式；任选地，所述固定组合中的贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐存在于同一固体药物组合物。
  17. 根据权利要求1-16任一项所述的药物组合物，其特征在于，所述药物组合物是非固定组合；任选地，所述非固定组合中的贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐各自呈固体药物组合物形式；任选地，所述非固定组合中的贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐各自呈固体药物组合物形式，且贝福替尼或其药学上可接受的盐的固体药物组合物和埃克替尼或其可药用盐的固体药物组合物存在于同一个药袋；任选地，所述非固定组合中的贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐各自呈固体药物组合物形式，且贝福替尼或其药学上可接受的盐的固体药物组合物和埃克替尼或其可药用盐的固体药物组合物不存在于同一个药袋。
  18. 根据权利要求1-17任一项所述的药物组合物，其特征在于，所述贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐可被同时地、分别地和/或依次地给患者施用。
  19. 根据权利要求1-18任一项所述的药物组合物，其特征在于，所述药物组合物为口服制剂。
  20. 根据权利要求1-19任一项所述的药物组合物，其特征在于，所述药物组合物为片剂或胶囊剂。
  21. 一种药盒，其包含权利要求1-19任一项所述的药物组合物。
  22. 权利要求1-20中任一项所述的药物组合物在制备药物中的应用。
  23. 根据权利要求22所述的应用，其特征在于，所述药物组合物用于治疗EGFR敏感突变的非小细胞肺癌。
  24. 根据权利要求22或23所述的应用，其特征在于，所述药物组合物用于EGFR敏感突变为19外显子缺失或21外显子L858R突变。
  25. 根据权利要求22或23所述的应用，其特征在于，所述药物组合物用于EGFR敏感突变为不含19外显子缺失与21外显子L858R共突变。
  26. 一种治疗非小细胞肺癌的方法，包含向患者施用权利要求1-20中任一项所述的药物组合物。
  27. 根据权利要求26所述的方法，其特征在于，所述患者未接受过化疗或未使用EGFR抑制剂的在先治疗。
  28. 根据权利要求26或27所述的方法，其特征在于，所述非小细胞肺癌为EGFR敏感突变的非小细胞肺癌。
  29. 根据权利要求26-28任一项所述的方法，其特征在于，所述非小细胞肺癌是晚期的、转移的、不可切除的、难治的或复发的化疗耐药性癌症。
  30. 根据权利要求26-28任一项所述的方法，其特征在于，所述患者是先前化疗后失败的非小细胞患者。
  31. 根据权利要求26-28任一项所述的方法，其特征在于，所述患者是先前治疗后进展的转移性非小细胞患者。
  32. 根据权利要求26-31任一项所述的方法，其特征在于，所述贝福替尼或其药学上可接受的盐和埃克替尼或其可药用盐可被同时地、分别地和/或依次地给患者施用。
  33. 根据权利要求26-31任一项所述的方法，其特征在于，所述EGFR敏感突变的非小细胞肺癌为19外显子缺失或21外显子L858R突变。
  34. 根据权利要求26-31任一项所述的方法，其特征在于，所述EGFR敏感突变的非小细胞肺癌为不含19外显子缺失与21外显子L858R共突变。
PCT/CN2022/109462 2021-08-02 2022-08-01 Egfr抑制剂的药物组合及其应用 WO2023011415A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280051854.5A CN117729922A (zh) 2021-08-02 2022-08-01 Egfr抑制剂的药物组合及其应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNPCT/CN2021/110128 2021-08-02
CN2021110128 2021-08-02

Publications (1)

Publication Number Publication Date
WO2023011415A1 true WO2023011415A1 (zh) 2023-02-09

Family

ID=85154379

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/109462 WO2023011415A1 (zh) 2021-08-02 2022-08-01 Egfr抑制剂的药物组合及其应用

Country Status (2)

Country Link
CN (1) CN117729922A (zh)
WO (1) WO2023011415A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103784453A (zh) * 2014-01-15 2014-05-14 青岛市肿瘤医院 ***疾病的药物组合物及其制备方法
CN105085489A (zh) * 2014-11-05 2015-11-25 上海页岩科技有限公司 嘧啶或吡啶类化合物、其制备方法和医药用途
CN106478605A (zh) * 2015-09-02 2017-03-08 上海页岩科技有限公司 嘧啶类化合物、其制备方法和医药用途
CN110016017A (zh) * 2019-05-16 2019-07-16 益方生物科技（上海）有限公司 一类嘧啶化合物的盐、多晶型物及其药物组合物、制备方法和应用
CN112119074A (zh) * 2018-05-15 2020-12-22 益方生物科技（上海）有限公司 Egfr抑制剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103784453A (zh) * 2014-01-15 2014-05-14 青岛市肿瘤医院 ***疾病的药物组合物及其制备方法
CN105085489A (zh) * 2014-11-05 2015-11-25 上海页岩科技有限公司 嘧啶或吡啶类化合物、其制备方法和医药用途
CN106478605A (zh) * 2015-09-02 2017-03-08 上海页岩科技有限公司 嘧啶类化合物、其制备方法和医药用途
CN112119074A (zh) * 2018-05-15 2020-12-22 益方生物科技（上海）有限公司 Egfr抑制剂
CN110016017A (zh) * 2019-05-16 2019-07-16 益方生物科技（上海）有限公司 一类嘧啶化合物的盐、多晶型物及其药物组合物、制备方法和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU QIANFEI 。, LIN HU BAIHUA: "Research Progress in Treatment of EGFR-Mutated Advanced ", LINCHUANG HELI YONGYAOZAZI = CHINESE JOURNAL OF CLINICAL RATIONAL DRUG USE, SHIJIE ZHISHI CHUBANSHE, CHINA, vol. 13, no. 6, 30 June 2020 (2020-06-30), CHINA , pages 194 - 196, XP093032497, ISSN: 1674-3296 *

Also Published As

Publication number Publication date
CN117729922A (zh) 2024-03-19

Similar Documents

Publication Publication Date Title
JP6871978B2 (ja) イブルチニブ併用療法
ES2620644T3 (es) Combinaciones de compuestos inhibidores de AKT y agentes quimioterapéuticos, y métodos de uso
AU2015360095B2 (en) Quinoline derivative against non-small cell lung cancer
PT1948180E (pt) Tratamento de combinação de cancro compreendendo inibidores de egfr/her2
JP2017522281A (ja) キノリン誘導体による軟部組織肉腫の治療方法と用途、及び軟部組織肉腫治療するための薬用組成物
AU2018308871A1 (en) Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
TWI762784B (zh) Cdk4/6抑制劑與egfr抑制劑聯合在製備治療腫瘤疾病的藥物中的用途
KR20200083532A (ko) 적어도 1종의 스플라이세오솜 조정제, 및 bcl2 억제제, bcl2/bclxl 억제제 및 bclxl 억제제로부터 선택된 적어도 1종의 억제제를 포함하는 조합물 및 사용 방법
KR20140022053A (ko) Akt 및 mek 억제제 화합물의 조합물, 및 사용 방법
WO2019057141A1 (zh) 阿帕替尼和c-Met抑制剂联合在制备***的药物中的用途
KR20220003560A (ko) 유잉 육종의 치료를 위한 퀴놀린 화합물 또는 그의 약제학적으로 허용 가능한 염
CN110840892A (zh) 酪氨酸激酶抑制剂与cdk4/6抑制剂联合在制备预防或***疾病的药物中的用途
CN103263416A (zh) 一种吡啶胺化合物在制备适于口服给药的治疗肺癌的药物中的应用
WO2023011415A1 (zh) Egfr抑制剂的药物组合及其应用
CN113329749A (zh) 用于治疗葡萄膜黑色素瘤的联合疗法
TW202345841A (zh) 藥物組合物、其用途及癌症的治療方法
US20210145834A1 (en) Combination of poziotinib with cytotoxic agent and/or other molecularly targeted agent and use thereof
TW200306185A (en) Combinations comprising EPOTHILONES and anti-metabolites
JP7357386B2 (ja) 化合物又はその薬学的に許容される塩、二量体又は三量体のがん治療用医薬品の調製における応用
CN117177752A (zh) 用于治疗mpnst的化合物和组合物
CN113274394B (zh) 一种治疗酪氨酸激酶抑制剂耐药的非小细胞肺癌的药物组合物
WO2024017316A1 (zh) 药物组合产品以及组合疗法
WO2022199656A1 (zh) 药物组合、包含其的试剂盒及其用途
CN1852738A (zh) 使用伊马替尼和米哚妥林治疗胃肠道基质肿瘤
CN111757737B (zh) 用于治疗三阴性乳腺癌的喹啉衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22852127

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE