WO2024046405A1 - Utilisation d'inhibiteur de kinase egfr - Google Patents

Utilisation d'inhibiteur de kinase egfr Download PDF

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Publication number
WO2024046405A1
WO2024046405A1 PCT/CN2023/116001 CN2023116001W WO2024046405A1 WO 2024046405 A1 WO2024046405 A1 WO 2024046405A1 CN 2023116001 W CN2023116001 W CN 2023116001W WO 2024046405 A1 WO2024046405 A1 WO 2024046405A1
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Prior art keywords
egfr
treatment
advanced
tki
formula
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PCT/CN2023/116001
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English (en)
Chinese (zh)
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关冬梅
徐亚男
张八生
房良华
郑善松
田敏
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齐鲁制药有限公司
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Publication of WO2024046405A1 publication Critical patent/WO2024046405A1/fr

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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
    • A61K31/495—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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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 disclosure relates to the field of biomedicine, specifically the use of a compound represented by formula (I) and its pharmaceutically acceptable salts in advanced or metastatic NSCLC.
  • Lung cancer is currently the most common malignant tumor with the highest fatality rate in the world.
  • the number of global lung cancer cases was about 2.2 million (accounting for 11.4% of the total new cancer cases), and the global number of lung cancer deaths was about 1.8 million.
  • the Global Cancer Observatory predicts that new lung cancer cases and deaths will continue to rise, with approximately 2.5 million new lung cancer cases and 2.1 million deaths by 2025.
  • the number of lung cancer deaths is as high as 715,000, with a mortality rate of 23.8%. Regardless of tumor incidence or mortality, lung cancer occupies the first place, seriously threatening people's health.
  • non-small cell lung cancer accounts for approximately 85%.
  • Non-squamous cell NSCLC accounts for approximately 60% of NSCLC, of which lung adenocarcinoma is the most common type, accounting for approximately 40% of NSCLC.
  • lung adenocarcinoma approximately 10% of Caucasian patients and up to 50% of Asian patients carry EGFR-sensitizing mutations, mainly including deletions in EGFR exon 19 and L858R mutations in exon 21.
  • EGFR-TKIs After first-generation (gefitinib and erlotinib) and second-generation (afatinib) EGFR-TKIs are used to treat patients with advanced NSCLC harboring EGFR activating mutations, the ORR is significantly higher (60-70%), with an average The PFS range is 9 to 15 months. However, most patients will develop EGFR-dependent resistance soon after taking the drug. Among them, the most common resistance mutation is the T790M mutation.
  • the T790M mutation is also known as the "gatekeeper mutation.” In addition to affecting the binding of EGFR-TKI to the ATP kinase pocket, the T790M mutation can also mediate drug resistance by reducing the effectiveness of competitive inhibitors.
  • the third generation EGFR-TKI has good efficacy against T790M mutation, but acquired resistance inevitably occurs.
  • patients treated with first-line osimertinib about 10-15% show EGFR-dependent resistance; among patients treated with second-line therapy, about 20% show EGFR-dependent resistance.
  • EGFR-dependent resistance mechanisms include: C797X mutation (C797X mutation has become the most common osimertinib resistance mechanism), EGFR exon 20 mutations, G796X, L792X, L718Q mutations and other EGFR tertiary mutations (G719X, G724S and S768I) etc.
  • EGFR-independent resistance mechanisms include: acquired amplification (MET amplification, HER2 amplification, PIK3CA amplification), acquired oncogenic fusion (FGFR3 fusion, NTRK fusion, RET fusion, ALK fusion, BRAF fusion), acquired MAPK-PI3K mutations, acquired cell cycle gene alterations, histological and phenotypic switches, and unknown mutations.
  • acquired amplification MET amplification, HER2 amplification, PIK3CA amplification
  • acquired oncogenic fusion FGFR3 fusion, NTRK fusion, RET fusion, ALK fusion, BRAF fusion
  • MAPK-PI3K mutations acquired cell cycle gene alterations, histological and phenotypic switches, and unknown mutations.
  • C797S mutation When osimertinib is used as first-line treatment, the frequency of C797S mutation is 7%, which is the second resistance mechanism after MET amplification; when patients who progressed after second-line treatment with osimertinib were tested, it was found that C797S Mutation frequency ranks first among drug resistance mechanisms, accounting for 14%.
  • EGFR C797S The mutation occurs in exon 20, where the cysteine at codon 797 within the ATP-binding site is replaced by serine, resulting in the loss of the covalent bond between osimertinib and mutant EGFR.
  • the C797S mutation also confers cross-resistance to other irreversible third-generation TKIs by preventing their binding to the EGFR active site. Recent findings indicate that 6% of patients have a C797S single mutation without T790M, and 2% of patients have two coexisting C797S clones (one cis and one trans) containing T790M.
  • NSCLC patients with EGFR-dependent mutations such as C797S who progress after treatment need more effective treatment.
  • Patent WO2021208918A1 discloses a small molecule EGFR inhibitor targeting the C797S mutation. Its structure is shown in formula (I), and its chemical name is N-(6-((5-bromo-2-((6-isopropyl) -8-Methoxy-3-methyl-3,4,5,6-tetrahydrobenzo[b]pyrazolo[4,3-d]aza-9-yl)amino)-pyrimidine-4 -yl)amino)-quinoxalin-5-yl)methanesulfonamide.
  • This small molecule inhibitor has good kinase inhibitory activity and cell anti-proliferation activity. At the same time, the molecule has demonstrated good anti-tumor activity and tolerance in mouse models, and is expected to be developed into a clinical drug.
  • the present disclosure provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in advanced or metastatic NSCLC.
  • the present disclosure provides a method of treating advanced or metastatic NSCLC, characterized by administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • the advanced or metastatic NSCLC described in the above treatment methods refers to advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI.
  • the EGFR-TKI treatment described in the above treatment methods refers to first-generation, second-generation or third-generation EGFR-TKI.
  • the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above treatment methods is an advanced NSCLC that progresses after EGFR-TKI treatment and carries the EGFR C797S mutation.
  • the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above treatment methods is advanced NSCLC that progresses after standard treatment and has no other additional driver gene mutations.
  • the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above treatment method is an advanced NSCLC that carries the EGFR T790M mutation after EGFR-TKI treatment.
  • the advanced or metastatic NSCLC described in the above treatment methods refers to advanced or metastatic NSCLC that progresses without EGFR-TKI treatment.
  • the advanced or metastatic NSCLC that has not progressed after EGFR-TKI treatment described in the above treatment methods is localized NSCLC carrying an EGFR mutation-sensitive mutation (19del or 21L858R) that has not been treated with EGFR-TKI. Progression of inoperable or recurrent metastatic NSCLC.
  • the advanced or metastatic NSCLC described in the above treatment methods is after treatment with EGFR-TKI and carries EGFR L792X and/or EGFR G796X and/or EGFR L718Q and/or EGFR 20 exon. Mutated advanced NSCLC.
  • the advanced or metastatic NSCLC described in the above treatment method is an advanced or metastatic NSCLC carrying a rare mutation of EGFR after treatment with EGFR-TKI.
  • the advanced or metastatic NSCLC described in the above treatment method is an advanced or metastatic NSCLC carrying EGFR L861Q, EGFR G719X, and EGFR S768I mutations after treatment with EGFR-TKI.
  • the advanced or metastatic NSCLC described in the above treatment methods is the advanced or metastatic NSCLC that carries the EGFR L861Q mutation after treatment with EGFR-TKI.
  • the advanced or metastatic NSCLC described in the above treatment methods is NSCLC with brain metastasis.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 5 mg to 400 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 5 mg to 300 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 10 mg-300 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 10 mg-240 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 20 mg-200 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 20 mg-160 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 40 mg-160 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 80 mg-160 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 100 mg- 200mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 120 mg-160 mg.
  • the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt in the above treatment method is 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 120 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is 160 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day in the above treatment method.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice a day in the above treatment method.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above treatment method is suitable for oral administration.
  • the pharmaceutically acceptable salt of the compound of formula (I) in the above treatment method is the hydrochloride.
  • the pharmaceutically acceptable salt of the compound of formula (I) in the above treatment method is a hydrochloride salt.
  • the present disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of advanced or metastatic NSCLC.
  • the advanced or metastatic NSCLC described in the above uses refers to advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI.
  • the EGFR-TKI treatment described in the above uses refers to anti-tumor treatment of first-, second- or third-generation EGFR-TKI.
  • the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above uses is an advanced NSCLC that progresses after EGFR-TKI treatment and carries the EGFR C797S mutation.
  • the advanced or metastatic NSCLC that progresses after EGFR-TKI treatment described in the above uses is advanced NSCLC that progresses after standard treatment and has no other additional driver gene mutations.
  • the advanced or metastatic NSCLC that progresses after treatment with EGFR-TKI described in the above uses is an advanced NSCLC that carries the EGFR T790M mutation after treatment with EGFR-TKI.
  • the advanced or metastatic NSCLC described in the above uses refers to advanced or metastatic NSCLC that has not progressed after EGFR-TKI treatment.
  • the advanced or metastatic NSCLC that has not progressed after EGFR-TKI treatment as described in the above uses is locally advanced and carries an EGFR mutation-sensitive mutation (19del or 21L858R) that has not been treated with EGFR-TKI. Inoperable or recurrent metastatic NSCLC.
  • the advanced or metastatic NSCLC described in the above uses is after treatment with EGFR-TKI and carries EGFR L792X and/or EGFR G796X and/or EGFR L718Q and/or EGFR exon 20 mutations. of advanced NSCLC.
  • the advanced or metastatic NSCLC described in the above uses is an advanced or metastatic NSCLC carrying a rare mutation of EGFR after treatment with EGFR-TKI.
  • the advanced or metastatic NSCLC described in the above uses is an advanced or metastatic NSCLC carrying EGFR L861Q, EGFR G719X, and EGFR S768I mutations after EGFR-TKI treatment.
  • the advanced or metastatic NSCLC described in the above uses is an advanced or metastatic NSCLC carrying the EGFR L861Q mutation after treatment with EGFR-TKI.
  • the advanced or metastatic NSCLC in the above uses is NSCLC with brain metastasis.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 5 mg to 400 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 5 mg to 300 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 10 mg to 300 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 10 mg to 240 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 20 mg to 200 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 20 mg to 160 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 40 mg to 160 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 80 mg to 160 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 100 mg to 200 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 120 mg to 160 mg.
  • the daily dosage of the compound of formula (I) or its pharmaceutically acceptable salt for the above-mentioned uses is 80 mg, 100 mg, 120 mg, 140 mg, or 160 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above-mentioned uses is 120 mg.
  • the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the above-mentioned uses is 160 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day for the above-mentioned uses.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily for the above-mentioned uses.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is suitable for oral administration in the above-mentioned uses.
  • the pharmaceutically acceptable salt of the compound of formula (I) in the above-mentioned uses is the hydrochloride.
  • the pharmaceutically acceptable salt of the compound of formula (I) for the above-mentioned uses is a hydrochloride salt.
  • the compound of formula (I) provided by the present disclosure has better safety and tolerability.
  • the compound of formula (I) provided by the present disclosure has a good curative effect on advanced or metastatic NSCLC that progresses after EGFR-TKI treatment. It is effective for advanced NSCLC carrying EGFR C797S mutation, advanced NSCLC carrying EGFR T790M mutation, and advanced NSCLC carrying EGFR TKI.
  • NSCLC with mutation-sensitive mutations (19del or 21L858R) all have good curative effects; especially late-stage NSCLC carrying EGFR C797S mutations, such as 19del/T790M/C797S mutations, have good curative effects; in addition, NSCLC with rare NSCLC with mutated genes such as L861Q mutation also have better efficacy.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present disclosure prepared from compounds having specific substituents discovered in the present disclosure and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable salts of the present disclosure can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • terapéuticaally effective amount refers to a sufficient amount of a compound or pharmaceutically acceptable salt of the present disclosure to treat a disorder with a reasonable effect/risk ratio suitable for any medical treatment and/or prevention.
  • total daily dosage of pharmaceutically acceptable salts and compositions of the compound represented by Formula I of the present disclosure must be determined by the attending physician within the scope of reliable medical judgment.
  • the specific therapeutically effective dosage level will be determined by a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; The patient's age, weight, general health, sex, and diet; the timing, route of administration, and excretion rate of the specific compound employed; the duration of treatment; medications used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical field. For example, this The practice in the field is to start dosages of compounds at levels lower than those required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained.
  • administering means physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration include oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalational, vaginal, intraocular, topical (e.g., via catheter or stent), subcutaneous, intrafatal, intraarticular, intraperitoneal and intrathecal, etc.
  • administering means delivering to a subject via the oral route.
  • subject includes any human or non-human animal.
  • non-human animals includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
  • the subject is a human.
  • the terms "subject” and “patient” and “subject” are used interchangeably in certain contexts in this disclosure, and in certain embodiments of the disclosure, the "subject” is a human.
  • the EGFR-TKI refers to an epidermal growth factor receptor tyrosine kinase inhibitor, which currently includes first-, second- or third-generation epidermal growth factor receptor tyrosine kinase inhibitors.
  • the EGFR mutation-mediated tumors or cancers refer to cancer driver mutations (driver mutations) of EGFR that can be detected in these tumors or cancer patients, including but not limited to Del19 mutation, L858R mutation, T790M mutation , 20 exon insertion mutations (Exon 20 ins), C797S and other mutations.
  • the Del19 mutation refers to the mutation caused by the deletion of the amino acid in exon 19
  • L858R refers to the missense mutation of the base that causes the 858th amino acid to change from L to R
  • T790M refers to the change of the base in the gene.
  • the missense mutation at the base causes amino acid 790 to change from T to M;
  • Exon 20 ins insertion mutation refers to the in-frame duplication/insertion mutation that occurs in exon 20 of EGFR;
  • C797S mutation is Refers to the mutation of the cysteine residue at position 797 to serine.
  • the EGFR mutations include not only the above-mentioned single mutants of EGFR, but also compound mutants of T790M, Del19, L858R, Exon 20 ins, C797S and other sites freely combined, including but not limited to L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation, Del19/C797S double mutation, L858R/C797S double mutation, etc.
  • Standard treatment in this disclosure refers to the treatment recommended by the Chinese Society of Clinical Oncology (CSCO) or the National Comprehensive Cancer Network (NCCN) non-small cell lung cancer treatment guidelines.
  • CSCO Chinese Society of Clinical Oncology
  • NCCN National Comprehensive Cancer Network
  • the medicament contains a compound represented by formula (I) as an active substance; in certain embodiments, the medicament contains a salt of a compound represented by formula (I); in others
  • the medicament optionally includes a pharmaceutically acceptable carrier, and Compound I or a pharmaceutically acceptable salt thereof can be formulated in various pharmaceutically acceptable pharmaceutical compositions, including oral forms (e.g., tablets). capsules, powders, granules, pills, pastes, powders), injectable forms (e.g. subcutaneous, intravenous, intramuscular and intraperitoneal injections), infusions, topical forms (e.g.
  • nasal sprays such as transdermal preparations, ointments, etc.
  • suppositories such as rectal and vaginal suppositories.
  • These different pharmaceutically acceptable pharmaceutical compositions can be manufactured using known techniques commonly used in the pharmaceutical industry, using pharmaceutically acceptable carriers commonly used in the pharmaceutical industry.
  • pharmaceutically acceptable carrier refers to a carrier generally accepted in the art for delivering biologically active agents to animals, particularly mammals.
  • the medium of the substance includes, for example, adjuvants, excipients or excipients, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, Suspending agents, sweeteners, flavorings, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants.
  • adjuvants such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, Suspending agents, sweeteners, flavorings, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants.
  • the formulation of pharmaceutically acceptable carriers depends on a number of factors within the purview of one of ordinary skill in the art.
  • compositions containing the agent include both aqueous and non-aqueous media and a variety of solid and semi-solid dosage forms.
  • Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients are well known to those of ordinary skill in the art to be included in the formulation for a variety of reasons (e.g., to stabilize the active agent, binders, etc.) .
  • the unit dosage (for example, but not limited to, the daily unit dosage) of the compound of formula (I) or its pharmaceutically acceptable salt is calculated based on the free form of the compound of formula I. Although the value between any two numerical values is not listed one by one, it shall be regarded as To clarify, for example, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5 mg to 300 mg, including but not limited to 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 240 mg, 300 mg, etc.
  • the compound of formula (I) may refer to the free base form of the compound represented by formula (I); it may also refer to the pharmaceutically acceptable salt of the compound represented by formula (I) form, such as hydrochloride, preferably monohydrochloride; it can also refer to the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compound represented by formula (I) or Its pharmaceutically acceptable salts are formulated in various pharmaceutically acceptable pharmaceutical compositions, such as oral tablets, capsules, powders, granules, dropping pills, pastes, powders, etc. These different pharmaceutically acceptable pharmaceutical compositions can be manufactured using known techniques commonly used in the pharmaceutical industry, using pharmaceutically acceptable carriers commonly used in the pharmaceutical industry.
  • Tumor progression refers to the evaluation of tumor efficacy of subjects according to RECIST 1.0 or RECIST 1.1, and the evaluation result is disease progression.
  • Advanced tumors generally refer to solid tumors that have metastasized to distant sites.
  • lung cancer is divided into stages I, II, III, and IV.
  • Lung cancer patients in stages IIIb and IV are usually defined as late-stage lung cancer.
  • Metastatic lung cancer refers to malignant tumors in any location that metastasize to the lungs through various metastasis methods.
  • No other additional driver gene mutations described in this disclosure means that the mutation is not a currently known clear mutation (such as EGFR, MET mutation, etc.), and the mutation type is unknown.
  • the "EGFR rare mutation types" mentioned in this disclosure refer to mutation types such as L861Q, G719X, S768I, etc.
  • Example 1 Phase I clinical study to evaluate the safety, tolerability, pharmacokinetics and efficacy of the compound of formula (I) in patients with advanced or metastatic NSCLC that progressed after EGFR-TKI treatment
  • Phase Ia NSCLC subjects who have progressed after standard EGFR-TKI treatment, or are intolerant to standard treatment or refuse to accept standard treatment;
  • EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor
  • NSCLC non-small cell lung cancer
  • Dose escalation phase Tumor samples from sites of disease progression during or after the last TKI treatment should be provided for new genetic testing. If it cannot be provided, you can communicate with the sponsor and negotiate for inclusion.
  • Cohort 1 Tumor samples from the site of disease progression during or after the last TKI treatment must be provided for central laboratory genetic testing.
  • Cohort 2 and Cohort 3 Tumor samples from the site of disease progression during or after the last TKI treatment must be provided for genetic testing. If there are test results that meet the above requirements before enrollment, re-testing is not required.
  • Cohort 4 Tumor samples during or after disease progression after the last treatment must be provided (if there has been no previous treatment, tumor samples are required to be provided during the screening period) for genetic testing (EGFR mutation). If there are test results that meet the above requirements before enrollment, re-testing is not required.
  • the international normalized ratio of prothrombin time and partial thromboplastin time are ⁇ 1.5 times the upper limit of normal (ULN);
  • AST Aspartate Aminotransferase
  • ALT Alanine Aminotransferase
  • ALT and AST ⁇ 5 ⁇ ULN in subjects with liver metastasis
  • total bilirubin ⁇ 1.5 ⁇ ULN; except for subjects with Gilbert syndrome, who can be enrolled if their conjugated bilirubin is within the normal range;
  • Serum creatinine ⁇ 1.5 ⁇ ULN, or creatinine clearance ⁇ 50mL/min (calculated according to the Cockcroft-Gault formula).
  • Subjects including females and males agree to take effective contraceptive measures from the time of signing the informed consent form to 6 months after the last use of study drugs. Women of childbearing potential must have a negative serum pregnancy test within 7 days before starting treatment.
  • Severe respiratory diseases such as interstitial lung disease, radiation pneumonitis, drug-induced pneumonia, etc. (Those who have been stable for 3 months or more after recovery are allowed to be included);
  • CNS central nervous system
  • Subjects with brain metastases who have been treated and are clinically stable can participate in the study, provided they demonstrate radiological stability (defined as 2 brain images acquired after treatment of brain metastases using the same imaging modality) . These imaging scans should be at least 4 weeks apart and not demonstrate intracranial progression.
  • neurological symptoms induced by brain metastases or their treatment must return to baseline levels or resolve. All steroid treatment given as part of this treatment must be completed ⁇ 3 days before study treatment administration.
  • the 12-lead ECG shows that the mean QT interval (QTcF) is >450ms (males) or >470ms (females);
  • HIV human immunodeficiency virus
  • HBV DNA Hepatitis B virus surface antigen
  • HBV DNA viral deoxyribonucleic acid
  • Oral compound of formula (I) (provided by Qilu Pharmaceutical Co., Ltd.), once daily (QD), 10mg-240mg, every 21 days as a cycle.
  • the subject After the subject starts receiving treatment, there will be one treatment cycle every 3 weeks (the first treatment cycle of Phase Ia starts from C1D1) until disease progression occurs (unless the investigator believes that there is sustained clinical benefit, until the study is discontinued) drug), intolerable toxicity, voluntary withdrawal, loss to follow-up, initiation of other anti-tumor treatments, death or the investigator's judgment that the treatment needs to be terminated, whichever occurs first.
  • the anti-tumor efficacy will be evaluated every 6 weeks ( ⁇ 7 days) in the first year, and then every 12 weeks ( ⁇ 7 days) or as clinically necessary.
  • the clinical safety of study treatments should be evaluated according to NCI CTCAE version 5.0 throughout the study period. Subjects' AEs need to be assessed at each clinical visit.
  • the eCRF should record the start and end time of the AE, severity classification, correlation with the study drug and its therapeutic impact on the study drug, the presence or absence of concomitant treatments, and outcome status, etc.
  • Subjects in remission (CR or PR) need to be re-evaluated 4 weeks (+7 days) after the first evaluation of CR or PR for efficacy confirmation.
  • radiographic evaluation results (including screening studies) will need to be collected for center review and will be detailed in a separate radiology charter.
  • Safety parameters AE, SAE, abnormal laboratory results, ECG changes and vital signs, etc.;
  • ORR blindded independent center imaging evaluation based on RECIST v1.1 for NSCLC patients carrying EGFR-C797S mutation.
  • Safety parameters AE, SAE, abnormal laboratory results, ECG changes and vital signs, etc.;
  • the other 6 SAE cases may be related to underlying diseases and may/definitely not be related to the study drug.
  • the overall safety information is shown in Table 3. From the safety assessment results, it can be concluded that the compound of formula (I) is safe and well tolerated.
  • the gene mutation types of subjects with PR efficacy are 19del/T790M/C797S mutation
  • the gene mutation types of subjects with SD efficacy include L858R mutation, 19del mutation, 19del/C797S mutation, and 19del/T790M/C797S.
  • L861Q mutation 19del/T790M/C797S mutation, L858R/C797S mutation, 19del/T790M mutation.
  • the gene mutation type is 19del/T790M/C797S mutation
  • the subjects whose curative effect is SD have gene mutation types including 19del/T790M/C797S mutation, 19del/C797S mutation, and 19del/T790M/C797S.

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Abstract

L'invention concerne l'utilisation d'un composé représenté par la formule (I) ou d'un sel pharmaceutiquement acceptable de celui-ci dans le traitement du NSCLC avancé ou métastatique.
PCT/CN2023/116001 2022-09-01 2023-08-31 Utilisation d'inhibiteur de kinase egfr WO2024046405A1 (fr)

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WO2020216371A1 (fr) * 2019-04-26 2020-10-29 江苏先声药业有限公司 Inhibiteur d'egfr et son utilisation
WO2021190417A1 (fr) * 2020-03-23 2021-09-30 齐鲁制药有限公司 Nouvel inhibiteur aminopyrimidine d'egfr
WO2021208918A1 (fr) * 2020-04-14 2021-10-21 齐鲁制药有限公司 Composés tricycliques servant d'inhibiteurs d'egfr
WO2023061434A1 (fr) * 2021-10-14 2023-04-20 齐鲁制药有限公司 Utilisation d'un composé tricyclique
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WO2020216371A1 (fr) * 2019-04-26 2020-10-29 江苏先声药业有限公司 Inhibiteur d'egfr et son utilisation
WO2021190417A1 (fr) * 2020-03-23 2021-09-30 齐鲁制药有限公司 Nouvel inhibiteur aminopyrimidine d'egfr
WO2021208918A1 (fr) * 2020-04-14 2021-10-21 齐鲁制药有限公司 Composés tricycliques servant d'inhibiteurs d'egfr
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