WO2024093681A1 - 英菲格拉替尼在治疗胃癌和腺癌中的用途 - Google Patents

英菲格拉替尼在治疗胃癌和腺癌中的用途 Download PDF

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WO2024093681A1
WO2024093681A1 PCT/CN2023/125264 CN2023125264W WO2024093681A1 WO 2024093681 A1 WO2024093681 A1 WO 2024093681A1 CN 2023125264 W CN2023125264 W CN 2023125264W WO 2024093681 A1 WO2024093681 A1 WO 2024093681A1
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fgfr2
use according
fgfr3
gastric cancer
infigratinib
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PCT/CN2023/125264
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English (en)
French (fr)
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吕承
孙乔
牧磊
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Qed医药股份有限公司
吕承
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Publication of WO2024093681A1 publication Critical patent/WO2024093681A1/zh

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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
    • A61K31/505—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer

Definitions

  • the present invention relates to the field of cancer treatment, and in particular to the treatment of gastric cancer or gastroesophageal junction adenocarcinoma, especially the treatment of locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma.
  • Gastric cancer refers to a malignant tumor originating from the epithelial cells of the gastric mucosa, and pathology is the gold standard for the diagnosis of this disease.
  • WHO pathological classification gastric cancer includes gastric adenocarcinoma, adenosquamous carcinoma, carcinoma with lymphoid stromal carcinoma (medullary carcinoma), hepatoid adenocarcinoma, squamous cell carcinoma and undifferentiated carcinoma, among which gastric adenocarcinoma is the most common.
  • the WHO classification and Lauren classification are often used for histological classification, including intestinal type, diffuse type, mixed type, and unclassified type; according to the degree of differentiation of the gland, it can be divided into well-differentiated, moderately differentiated and poorly differentiated (high grade, intermediate grade and low grade).
  • Gastroesophageal junction adenocarcinoma refers to adenocarcinoma whose tumor center is located within 5 cm above and below the anatomical esophagogastric junction.
  • the commonly used classification is the Siewert classification (2022 National Health Commission's "Guidelines for the Diagnosis and Treatment of Gastric Cancer").
  • Gastric cancer is the fifth most common malignant tumor in the world and the fourth leading cause of death from malignant tumors. According to Globocan 2020 Today data, there were 1,089,103 new cases worldwide in 2020, and the number of deaths in the same year was 768,793. The incidence of GC varies in different geographical regions: the highest incidence is in East Asia and Eastern Europe, while the incidence in North America and Northern Europe is generally low, comparable to the rate in Africa. Gastric cancer is a highly prevalent malignant tumor of the digestive tract in my country. According to Globocan 2020 data, the number of new cases of gastric cancer in China ranks second among common malignant tumors each year, with approximately 457,000 new cases; the number of deaths ranks third, at 399,000.
  • Gastric cancer is prone to metastasis, and its common metastatic pathways include direct invasion, lymph node metastasis, and hematogenous metastasis.
  • Direct invasion refers to the primary tumor penetrating the serosal layer of the gastric wall and reaching the surrounding adjacent tissues or organs such as the omentum, liver, pancreas, or colon.
  • Lymph node metastasis refers to the invasion of the tumor along the lymphatic vascular system.
  • Hematogenous metastasis refers to the tumor cells entering the blood circulation and spreading to other parts of the body along the systemic circulation. When encountering a suitable site for proliferation, the tumor cells stay and proliferate to form metastatic foci.
  • Common metastatic organs include the liver, lungs, bones, etc.
  • gastric cancer has a special metastatic mode - peritoneal implantation metastasis: after gastric tumor cells infiltrate the gastric wall and penetrate the serosal layer, the tumor cells fall off and implant in the serosal layer of the peritoneum or other organs, and form metastatic foci. Implantation in the rectum and bladder is a sign of advanced gastric cancer. Metastatic cancer in the anterior rectal fossa can be found by rectal examination. Female gastric cancer patients may develop ovarian metastatic tumors.
  • surgical resection is the main treatment for gastric cancer and is currently the only way to cure gastric cancer.
  • systemic treatment is the main treatment, including chemotherapy, radiotherapy, palliative surgery and other supportive treatments.
  • systemic treatment should be considered for these patients with inoperable local progression or metastasis (stage IV), which has a great significance in improving survival and quality of life compared with the best supportive care.
  • the first-line treatment for these patients is mainly trastuzumab (HER-positive patients) and chemotherapy, tumor immunotherapy;
  • the second-line treatment is mainly chemotherapy and anti-angiogenic drugs (anti-VEGFR); for the treatment of patients in the third line and above, there is currently no recognized treatment plan, and the guidelines of various countries have not clearly stipulated it.
  • the present invention provides a use of Infigratinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing gastric cancer or gastroesophageal junction adenocarcinoma.
  • the present invention provides the use of infigratinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR1 gene fusion, translocation, or another genetic alteration. In some embodiments, wherein the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR2 gene fusion, translocation, or another genetic alteration. In some embodiments, wherein the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR3 gene fusion, translocation, or another genetic alteration. In some embodiments, wherein the gastric cancer or gastroesophageal junction adenocarcinoma has a gene fusion, translocation, or another genetic alteration of any or all of FGFR1, FGFR2, and FGFR3.
  • the FGFR2 gene fusion comprises a FGFR2 gene fusion partner selected from the group consisting of: 10Q26.13, AFF1, AFF4, AHCYL1, ALDH1L2, ARFIP1, BICC1, C10orf118, C7, CCDC147, CCDC6, CELF2, CREB5, CREM, DNAJC12, HOOK1, KCTD1, KIAA1217, KIAA1598, KIFC3, MGEA5, NOL4, NRAP, OPTN, PARK2, PAWR, PCMI, PHLDB2, PPHLN1, RASAL2, SFMBT2, SLMAP, SLMAP2, SORBS1, STK26, STK3, TACC3, TBC1D1, TFEC, TRA2B, UBQLN1, VCL, WAC, ZMYM4, and combinations thereof.
  • FGFR2 gene fusion partner selected from the group consisting of: 10Q26.13, AFF1, AFF4, AHCYL1, ALDH1L2, ARFIP1, BICC
  • the gastric cancer or gastroesophageal junction adenocarcinoma has FGFR1, FGFR2 and/or FGFR3 mutations.
  • the FGFR1, FGFR2 and/or FGFR3 mutations are selected from FGFR1G818R, FGFR1K656E, FGFR1N546K, FGFR1R445W, FGFR1T141R, FGFR2A315T, FGFR2C382R, FGFR2D336N, FGFR2D471N, FGFR2E565A ⁇ FGFR2I547V ⁇ FGFR2K641R ⁇ FGFR2K659E ⁇ FGFR2K659M ⁇ FGFR2L617V ⁇ FGFR2N549H ⁇ FGFR2N549K ⁇ FGFR2N549S ⁇ FGFR2N549Y ⁇ FGFR2N550K ⁇ FGFR2P253R ⁇ FGFR2S252W ⁇
  • the gastric cancer or gastroesophageal junction adenocarcinoma has gene amplification of FGFR1, FGFR2 and/or FGFR3.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has FGFR2 gene amplification
  • the FGFR2 gene amplification is determined by fluorescence in situ hybridization detection method (FISH method) or next generation sequencing detection method (NGS method).
  • the gastric cancer or gastroesophageal junction adenocarcinoma is a gastric cancer or gastroesophageal junction adenocarcinoma that has previously received systemic treatment or has no standard treatment options.
  • the drug is used for patients who have progressed after previously receiving another therapy. In some embodiments, the drug is used for patients who have no standard treatment options.
  • the gastric cancer or gastroesophageal junction adenocarcinoma is of an unresectable type.
  • the gastric cancer or gastroesophageal junction adenocarcinoma is unresectable due to tumor reasons or due to physical condition, such as severe invasion of the primary tumor, inability to be separated from the surrounding normal tissue or surrounding large blood vessels, or regional lymph node metastasis is fixed, fused into a mass, or the metastatic lymph nodes are not within the surgical clearance range, or the patient's general condition is poor (e.g., severe hypoproteinemia and anemia), malnutrition, and severe underlying diseases.
  • the unresectable type of gastric cancer or gastroesophageal junction adenocarcinoma is characterized by the presence of peritoneal metastasis, distant metastasis, or local progression.
  • the peritoneal metastasis is determined by a positive result of peritoneal cytology diagnosis (discovery of malignant tumor cells), and the local progression is characterized by N3 or N4 lymph node infiltration or lymph node invasion/encirclement of major vascular structures.
  • the patient has previously received prior treatment for the gastric cancer or gastroesophageal junction adenocarcinoma.
  • the prior treatment includes surgery, radiotherapy, neoadjuvant therapy, adjuvant therapy, and first-line, second-line, third-line or fourth-line treatment, preferably, the first-line, second-line, third-line or fourth-line treatment includes chemotherapy, immunotherapy, targeted therapy, anti-angiogenic drugs, cell therapy (e.g., cell therapy targeting Claudin 18.2), and combination regimens thereof.
  • the drug is selected from cisplatin, oxaliplatin, 5-fluorouracil, capecitabine, S-1, paclitaxel, albumin-paclitaxel, docetaxel, irinotecan, anthracyclines, trastuzumab, ramucirumab, pembrolizumab, nivolumab, apatinib, trifluridine, tipracic acid, trifluridine tipiracil, epirubicin, leucovorin, and combination regimens or modified regimens thereof.
  • the patient has previously received a receptor tyrosine kinase inhibitor.
  • the receptor tyrosine kinase inhibitor is a selective non-covalent binding inhibitor of FGFR1, FGFR2 and/or FGFR3.
  • the selective non-covalent binding inhibitor of FGFR1, FGFR2 and/or FGFR3 is selected from pemitinib, rogaratinib, derazantinib, Debio 1347, AZD4547 (ABSK091), ABSK012, ABSK061, ABSK121, ABSK011, and combinations thereof.
  • the receptor tyrosine kinase inhibitor is a selective non-covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4.
  • the selective non-covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4 is selected from Erdafitinib, LY2874455, PRN 1371, ASP5878, and combinations thereof.
  • the receptor tyrosine kinase inhibitor is a selective covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4.
  • the selective covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4 is TAS120.
  • the receptor tyrosine kinase inhibitor is a non-selective tyrosine kinase inhibitor.
  • the non-selective tyrosine kinase inhibitor is selected from ponatinib, dovitinib, levatanib, ACTB-1003, Ki8751, lucitinib, masitinib,netinib, nintedanib, orentinib, PD089828, and combinations thereof.
  • the patient has previously received another selective FGFR inhibitor.
  • the other selective FGFR inhibitor is selected from pemitinib, rogatinib, delazentinib, AZD4547, Debio1347, ASP5878, erdatinib, LY2874455, PRN1371, TAS120, ABSK012, ABSK061, ABSK121, ABSK011, and combinations thereof.
  • the other selective FGFR inhibitor is a selective covalently bound FGFR inhibitor.
  • the selective covalently bound FGFR inhibitor is TAS120.
  • the other selective FGFR inhibitor is a selective non-covalently bound FGFR inhibitor.
  • the selective non-covalently bound FGFR inhibitor is pemitinib, rogatinib, delazentinib, AZD4547, erdatinib, ABSK012, ABSK061, ABSK121, ABSK011, and combinations thereof.
  • the drug is used together with surgery, radiotherapy, neoadjuvant therapy, adjuvant therapy, chemotherapy, immunotherapy, targeted therapy, anti-angiogenic drugs, cell therapy (e.g., cell therapy targeting Claudin18.2), and combinations thereof.
  • surgery radiotherapy, neoadjuvant therapy, adjuvant therapy, chemotherapy, immunotherapy, targeted therapy, anti-angiogenic drugs, cell therapy (e.g., cell therapy targeting Claudin18.2), and combinations thereof.
  • the combination drug is selected from cisplatin, oxaliplatin, 5-fluorouracil, capecitabine, S-1, taxanes, albumin-paclitaxel, docetaxel, irinotecan, anthracyclines, trastuzumab, pembrolizumab, apatinib, and combinations thereof.
  • the combination drug is a receptor tyrosine kinase inhibitor.
  • the combination drug is a selective non-covalent binding inhibitor of FGFR1, FGFR2 and/or FGFR3.
  • the selective non-covalent binding inhibitor of FGFR1, FGFR2 and/or FGFR3 is selected from pemitinib, rogatinib, delazentinib, Debio1347, AZD4547, ABSK012, ABSK061, ABSK121, ABSK011, and combinations thereof.
  • the combination drug is a selective non-covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4.
  • the selective non-covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4 is selected from erdafitinib, LY2874455, PRN 1371, ASP5878, and combinations thereof.
  • the combination drug is a selective covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4.
  • the selective covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4 is TAS120.
  • the combination drug is a non-selective tyrosine kinase inhibitor.
  • the non-selective tyrosine kinase inhibitor is selected from ponatinib, dovitinib, levatanib, ACTB-1003, Ki8751, lucitinib, masitinib,netinib, nintedanib, orentinib, PD089828, and combinations thereof.
  • the combination drug is another selective FGFR inhibitor.
  • the other selective FGFR inhibitor is selected from pemitinib, rogatinib, delazentinib, AZD4547, Debio1347, ASP5878, erdatinib, LY2874455, PRN1371, TAS120, ABSK012, ABSK061, ABSK121, ABSK011, and combinations thereof.
  • the other selective FGFR inhibitor is a selective covalent binding FGFR inhibitor.
  • the selective covalent binding FGFR inhibitor is TAS120.
  • the other selective FGFR inhibitor is a selective non-covalent binding FGFR inhibitor.
  • the selective non-covalent binding FGFR inhibitor is pemitinib, rogatinib, delazentinib, AZD4547, erdatinib, ABSK012, ABSK061, ABSK121, ABSK011, and combinations thereof.
  • the drug is provided in a 100 mg unit dose and/or a 25 mg unit dose.
  • the drug is administered orally once a day.
  • the drug is administered in a 28-day cycle, wherein about 125 mg of infigratinib or a pharmaceutically acceptable salt thereof is orally administered to the patient once a day for 3 consecutive weeks and is not administered in the next week.
  • Figure 1 shows the treatment plan for gastric cancer patients based on the TNM staging standard.
  • TNM staging standard published by AJCC (American Joint Committee on Cancer) (the latest version of the TNM staging standard is the AJCC 8th edition (2017)).
  • Figure 2 is a waterfall plot of the maximum percent change (confirmed) in the sum of target lesion diameters from baseline, where PD indicates progressive disease, SD indicates stable disease, PR indicates partial response, and ⁇ indicates new lesions.
  • the data cutoff date included 21 patients in the full analysis set, of whom 2 subjects failed to complete any post-baseline tumor assessments.
  • Figure 3 is a computed tomography image of a patient with a maximum tumor regression of 78.5% from baseline. This patient had baseline scans (A and B) and a 78.5% tumor regression at week 33 (C and D).
  • the present invention provides the use of infigratinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and/or preventing gastric cancer or gastroesophageal junction adenocarcinoma, particularly locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma.
  • compositions and kits are described as having, including, or comprising particular components, or where processes and methods are described as having, including, or comprising particular steps, it is also contemplated that the compositions and kits of the invention consist essentially of, or consist of, the recited components, and that the processes and methods according to the invention consist essentially of, or consist of, the recited processing steps.
  • an element or component is referred to as being included in and/or selected from a list of recited elements or components, it should be understood that the element or component may be any one of the recited elements or components, or the element or component may be selected from two or more of the recited elements or components.
  • variables or parameters are disclosed in groups or ranges.
  • this specification is intended to include each and every single subcombination of members of such groups and ranges.
  • integers in the range of 0 to 40 are particularly intended to disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 and 40 separately
  • integers in the range of 1 to 20 are particularly intended to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 separately.
  • compositions designated as percentages are by weight unless otherwise indicated.
  • a variable is not accompanied by a definition, the preceding definition of the variable controls.
  • composition or “pharmaceutical preparation” refers to the combination of an active agent with an inert or active carrier, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or corresponding agencies in countries outside the U.S. or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • pharmaceutically acceptable salt refers to any salt of an acidic or basic group that may be present in a compound of the invention (eg, infigratinib) that is compatible with pharmaceutical administration.
  • salts of compounds can be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid.
  • Other acids such as oxalic acid, while not pharmaceutically acceptable in themselves, can be used to prepare salts that can be used as intermediates for obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.
  • Examples of the base include, but are not limited to, alkali metal (eg, sodium and potassium) hydroxides, alkaline earth metal (eg, magnesium and calcium) hydroxides, ammonia, and compounds of the formula NW 4 + (wherein W is a C 1-4 alkyl group), and the like.
  • alkali metal eg, sodium and potassium
  • alkaline earth metal eg, magnesium and calcium
  • W is a C 1-4 alkyl group
  • salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, gluconate, glucarate, dodecylsulfate, ethanesulfonate, fumarate, fluoroheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmitate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
  • salts include anions of the compounds of the present invention complexed with suitable cations such as Na + , K + , Ca2+ , NH4 + , and NW4 + (wherein W can be a C1-4 alkyl), etc.
  • salts of the compounds of the invention are pharmaceutically acceptable.
  • salts of acids and bases that are non-pharmaceutically acceptable may also be useful, for example, in the preparation or purification of pharmaceutically acceptable compounds.
  • pharmaceutically acceptable excipients refer to substances that facilitate administration of the active agent to a subject and/or absorption by the subject and that can be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient.
  • pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions such as phosphate buffered saline solutions, emulsions (e.g., such as oil/water or water/oil emulsions), lactated Ringer's solution, physiological sucrose, physiological glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, saline solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, straight-chain starch or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants, etc.
  • Such preparations can be sterilized and mixed with adjuvants as needed, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, colorants, and/or aromatic substances, etc., which do not react toxically with the compounds of the present invention.
  • adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, colorants, and/or aromatic substances, etc.
  • AUC refers to the area under the time/plasma concentration curve after administration of a pharmaceutical composition.
  • AUC 0-infinity represents the area under the plasma concentration versus time curve from time 0 to infinity;
  • AUC 0-t represents the area under the plasma concentration versus time curve from time 0 to time t. It should be understood that AUC values can be determined by methods known in the art.
  • Subjects contemplated for administration include, but are not limited to, humans (i.e., males or females of any age, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly)) and/or non-human animals, such as mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • Cmax refers to the maximum concentration of the therapeutic agent (eg, infigratinib) in the blood (eg, plasma) following administration of the pharmaceutical composition.
  • tmax refers to the time (in hours) at which Cmax is achieved following administration of a pharmaceutical composition comprising a therapeutic agent (eg, infigratinib).
  • solid dosage form means one or more doses of a drug in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewables.
  • administration means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration or subcutaneous administration, or implantation of a sustained-release device, such as a micro-osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal).
  • Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, ventricular and intracranial.
  • compositions described herein are administered simultaneously, before, or after administration of one or more additional therapies (e.g., anticancer agents, chemotherapeutic agents, or treatment of neurodegenerative diseases).
  • additional therapies e.g., anticancer agents, chemotherapeutic agents, or treatment of neurodegenerative diseases.
  • Infigratinib or a pharmaceutically acceptable salt thereof may be administered alone or may be co-administered to a patient.
  • Co-administration is intended to include simultaneous or sequential administration of the compounds alone or in combination (more than one compound or agent).
  • the preparation may also be combined with other active substances as desired (e.g., to reduce metabolic degradation).
  • treatment refers to any type of intervention or procedure performed on a subject or the administration of an active agent to a subject with the purpose of reversing, alleviating, ameliorating, inhibiting or slowing the onset, progression, development, severity or recurrence of symptoms, complications, conditions or biochemical markers associated with a disease.
  • prevention refers to any type of intervention or procedure performed on a subject or the administration of an active agent to a subject with the intent to guard against or prevent the development of a disease or condition or at least prevent it from fully developing (e.g., reducing the symptoms or severity of the disease or condition), such as the occurrence of side effects.
  • systemic therapy refers to systemic therapy, as distinguished from local therapy (such as local radiotherapy or local chemotherapy pump implantation). Further, when describing a patient who has previously received at least two lines of systemic therapy, "at least two lines of systemic therapy” generally refers to first-line therapy + second-line therapy, or first-line therapy + third-line therapy (when second-line therapy is not appropriate), and so on, until the methods in the standard treatment guidelines have been exhausted.
  • an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response (e.g., to treat and/or prevent locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma).
  • a desired biological response e.g., to treat and/or prevent locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma.
  • the effective amount of a compound of the present invention may vary according to factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health status, and condition of the subject.
  • Infigratinib is a selective and ATP-competitive pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, also known as 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1- ⁇ 6-[4-(4-ethyl-1-piperazin-1-yl)phenylamino]-pyrimidinyl-4-yl ⁇ -1-methylurea.
  • FGFR pan-fibroblast growth factor receptor
  • Infigratinib selectively inhibits the kinase activity of FGFR1, FGFR2 and FGFR3.
  • infigratinib including Example 1 provided herein
  • several crystalline and amorphous forms of infigratinib including the anhydrous crystalline monophosphate described herein
  • methods for preparing the forms including Example 2 provided herein are described in U.S. Patent 9,067,896, which is incorporated herein by reference in its entirety.
  • infigratinib or a pharmaceutically acceptable salt thereof for treating and/or preventing locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma in a patient in need thereof.
  • the pharmaceutically acceptable salt of infigratinib is a monophosphate.
  • the monophosphate salt of infigratinib may also be referred to as BGJ398.
  • the monophosphate of infigratinib is an anhydrous crystalline monophosphate.
  • the anhydrous crystalline monophosphate has an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak in 2 ⁇ at about 15.0° or 15.0° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern of the anhydrous crystalline monophosphate also includes one or more characteristic peaks in 2 ⁇ , the characteristic peaks being selected from the peaks at about 13.7° ⁇ 0.2°, about 16.8° ⁇ 0.2°, about 21.3° ⁇ 0.2°, and about 22.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the anhydrous crystalline monophosphate also includes one or more characteristic peaks in 2 ⁇ , the characteristic peaks being selected from the peaks at about 9.2°, about 9.6°, about 18.7°, about 20.0°, about 22.9°, and about 27.2°.
  • the anhydrous crystalline monophosphate has an XRPD pattern comprising at least three characteristic peaks in 2 ⁇ selected from peaks at about 13.7°, about 15°, about 16.8°, about 21.3°, and about 22.4°.
  • the X-ray powder diffraction pattern of the anhydrous crystalline monophosphate may contain one, two, three, four, five, six, seven, eight, nine, ten, or eleven characteristic peaks in 2 ⁇ selected from peaks at about 9.2°, about 9.6°, about 13.7°, about 15°, about 16.8°, about 18.7°, about 20.0°, about 21.3°, and about 22.4°, about 22.9°, and about 27.2°.
  • compositions of infigratinib and methods for preparing the same are described in U.S. Patent Publication No. 2017/0007602, which is incorporated herein by reference in its entirety.
  • a pharmaceutical composition for treating and/or preventing locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma in a patient in need thereof comprising infigratinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition taught by the present invention comprises:
  • a filler selected from the group consisting of cellulose, lactose, mannitol, and combinations thereof;
  • the weight percentages are based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises about 30% to about 45% by weight of infigratinib in its free base form or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises from about 2% to about 4% hydroxypropyl methylcellulose. In a specific embodiment, the pharmaceutical composition comprises from about 2% to about 4% cross-linked polyvinyl pyrrolidone.
  • the pharmaceutical composition further comprises:
  • the one or more fillers are selected from microcrystalline cellulose, lactose and/or mannitol.
  • the one or more lubricants in the pharmaceutical composition are present in an amount of about 0.2 wt % to about 2 wt % based on the total weight of the pharmaceutical composition.
  • the one or more lubricants is magnesium stearate.
  • the one or more glidants are present in the pharmaceutical formulation in an amount of about 0.1 wt % to about 0.5 wt % based on the total weight of the pharmaceutical composition.
  • the one or more glidants are colloidal silicon dioxide (colloidal silicon oxide).
  • the amount of Infigratinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 25 mg to about 150 mg, about 50 mg to about 150 mg, about 75 mg to about 150 mg, about 100 mg to about 150 mg, about 125 mg to about 150 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 25 mg to about 50 mg, about 50 mg to about 125 mg, about 50 mg to about 100 mg, about 50 mg to about 75 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, or about 100 mg to about 125 mg.
  • the amount of Infigratinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 100 mg to about 150 mg of Infigratinib or a pharmaceutically acceptable salt thereof.
  • the amount of Infigratinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg. In some embodiments, the amount of Infigratinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 125 mg. In some embodiments, the amount of Infigratinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 100 mg. In some embodiments, the amount of Infigratinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is about 25 mg.
  • a pharmaceutical composition for treating and/or preventing locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma in a patient in need thereof comprising about 125 mg of infigratinib or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a pharmaceutically acceptable salt of Infigratinib.
  • the pharmaceutically acceptable salt of Infigratinib is a monophosphate.
  • the pharmaceutically acceptable salt of Infigratinib is an anhydrous monophosphate.
  • the pharmaceutically acceptable salt of Infigratinib is a polymorphic anhydrous monophosphate, characterized by an X-ray powder diffraction (XRPD) peak (2 ⁇ ) at 15.0° ⁇ 0.2° (and may include other XRPD peaks of this form as described herein).
  • XRPD X-ray powder diffraction
  • compositions provided herein can be administered by a variety of routes, including but not limited to oral (enteral) administration, parenteral (by injection), rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC), intravenous (IV), intramuscular (IM) administration, and intranasal administration.
  • oral enteral
  • parenteral by injection
  • rectal transdermal administration
  • intradermal administration intrathecal administration
  • SC subcutaneous
  • IV intravenous
  • IM intramuscular
  • intranasal administration intranasal administration.
  • the pharmaceutical compositions disclosed herein are administered orally.
  • Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, e.g., for the rest of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood, e.g., within a therapeutic window over an extended period of time.
  • unit dosage form refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material, which is calculated to be combined with a suitable pharmaceutical excipient to produce a desired therapeutic effect.
  • Typical unit dosage forms include pre-filled pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
  • the pharmaceutical compositions provided herein are administered to a patient in a solid dosage form.
  • the solid dosage form is a capsule.
  • the compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents.
  • compositions suitable for administration to humans relate primarily to pharmaceutical compositions suitable for administration to humans, the skilled artisan will appreciate that such compositions are generally suitable for administration to animals of all kinds. Modifications to pharmaceutical compositions suitable for administration to humans so that the compositions are suitable for administration to a variety of animals are well known, and an ordinary skilled veterinary pharmacologist can design and/or perform such modifications using ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st edition, Lippincott Williams & Wilkins, 2005.
  • the target indication of the present invention is locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma.
  • Advanced gastric cancer refers to cancer tissue that invades the muscularis basement or deeper, regardless of whether there is lymph node metastasis.
  • Gastroesophageal junction adenocarcinoma is also called gastroesophageal junction adenocarcinoma, which means that the center of the tumor is located within 5 cm above and below the anatomical gastroesophageal junction, and the commonly used classification is the Siewert classification.
  • the disease staging of patients with locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma usually adopts the TNM staging criteria published by AJCC (American Joint Committee on Cancer).
  • the latest version of the TNM staging criteria is the AJCC 8th edition (2017), as shown below.
  • T primary tumor
  • N regional lymph nodes
  • M distant metastasis
  • Figure 1 shows the treatment options for gastric cancer patients based on the TNM staging criteria.
  • Gastric cancer patients are considered to be unresectable if they have peritoneal metastasis (including positive peritoneal cytology diagnosis results - malignant tumor cells are found), distant metastasis or local progression (N3 or N4 lymph node infiltration or lymph node invasion/encirclement of major vascular structures except the spleen).
  • peritoneal metastasis including positive peritoneal cytology diagnosis results - malignant tumor cells are found
  • distant metastasis or local progression N3 or N4 lymph node infiltration or lymph node invasion/encirclement of major vascular structures except the spleen).
  • patients with gastric cancer who are not resectable by surgery mainly fall into the following two categories: 1 Unresectable due to tumor reasons, including severe external invasion of the primary tumor, which cannot be separated from the surrounding normal tissue or has surrounded large blood vessels; regional lymph node metastasis is fixed, fused into a mass, or metastatic lymph nodes are not within the scope of surgical clearance; distant tumor metastasis or abdominal implantation (including positive peritoneal lavage fluid cytology), etc. 2 Unresectable or refused surgery due to surgical contraindications, including poor systemic condition (such as severe hypoproteinemia and anemia), malnutrition, and may not tolerate surgery, and those with severe underlying diseases who cannot tolerate surgery.
  • 1 Unresectable due to tumor reasons including severe external invasion of the primary tumor, which cannot be separated from the surrounding normal tissue or has surrounded large blood vessels
  • regional lymph node metastasis is fixed, fused into a mass, or metastatic lymph nodes are not within the scope of surgical clearance
  • distant tumor metastasis or abdominal implantation
  • the fibroblast growth factor FGF (fibroblast growth factor) and its receptor FGFR (fibroblast growth factor receptor) cascade involves multiple intracellular signal transduction pathways, which can regulate cell proliferation, tumor growth, angiogenesis and spread.
  • FGFR consists of 5 different subtypes, including FGFR1, FGFR2, FGFR3, FGFR4, and 1 FGFRL15 without intracellular region.
  • FGFR1-4 membrane tyrosine kinase receptors
  • FGFR In tumor cells, FGFR participates in multiple steps of tumor occurrence and development as an oncogene, by inducing mitogenic and survival signals, promoting tumor cell invasion and metastasis, promoting epithelial-mesenchymal transition, promoting angiogenesis and participating in tumor recurrence and drug resistance.
  • mitogenic and survival signals In tumor cells, FGFR signaling is dysregulated, it leads to the occurrence, development, proliferation and metastasis of cancer.
  • Erdafitinib JNJ-42756493, Erdafitinib trade name Balversa: The FDA approved it in April 2019 for the treatment of patients with locally advanced or metastatic urothelial carcinoma with FGFR2/FGFR3 alterations after platinum-based chemotherapy.
  • Common adverse reactions to Erdafitinib include hyperphosphatemia, fatigue, dry mouth, adverse eye reactions (dry eyes, keratitis, retinal pigment epithelial detachment, corneal erosion, etc.), adverse nail reactions, constipation, anorexia, etc. 14.9% of patients stopped treatment due to adverse reactions.
  • adverse eye reactions which often occur during Erdafitinib treatment, accounting for about 28%, and most of them are grade 3 adverse reactions.
  • Pemigatinib (trade name Pemazyre): The FDA approved it in April 2020 for the treatment of locally advanced, recurrent, or metastatic cholangiocarcinoma that is unresectable and with FGFR2 fusion or rearrangement, after at least one line of systemic treatment has failed.
  • Common adverse reactions include hyperphosphatemia, stomatitis, arthralgia, stomatitis, hyponatremia, etc. About 19% of patients stopped treatment due to adverse reactions.
  • China's NMPA approved the same indication.
  • Futibatinib/TAS-120 A covalent irreversible FGFR1-4 inhibitor, also known as a pan-FGFR inhibitor.
  • the FDA has granted Futibatinib Breakthrough Therapy designation for the treatment of previously treated locally advanced or metastatic cholangiocarcinoma with FGFR2 gene fusion or rearrangement.
  • a Phase III study, the FOENIX-CCA3 trial, is currently underway to compare Futibatinib with cisplatin plus gemcitabine as first-line treatment for patients with advanced metastatic intrahepatic cholangiocarcinoma with FGFR2 gene rearrangement (NCT04093362).
  • the selective FGFR inhibitors under development include: Rogaratinib (BAY163877), Derazantinib (ARQ), LY2874455, Debio1347 (CH5183284), E7090, PRN1371, ABSK091 (AZD4547), ABSK061, Alofanib (RPT), and CPL304110.
  • FGFR1-3 is an important driver gene target for tumors, and many studies are currently underway. The indications are mostly concentrated in cholangiocarcinoma and urothelial carcinoma.
  • Gastric cancer has strong heterogeneity and complex treatment. No drugs have been successfully developed for adult patients with locally advanced or recurrent/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ). Based on LB1001-201 data, it has a good response in terminal patients with FGFR2 gene amplification and may become a potential therapeutic drug.
  • GC recurrent/metastatic gastric cancer
  • GEJ gastroesophageal junction adenocarcinoma
  • FGFR2 gene amplification can be confirmed by FISH testing or NGS testing.
  • the FGFR2 gene amplification confirmation test is performed on the formalin-fixed paraffin-embedded (FFPE) tumor tissue section sample of the subject using the fluorescence in situ hybridization (FISH) method.
  • FFPE formalin-fixed paraffin-embedded
  • FISH fluorescence in situ hybridization
  • the following FISH detection interpretation method for FGFR2 gene amplification was formulated: Count 30 tumor cells under the microscope and calculate the F The ratio of the GFR2 signal to the chromosome 10 counting signal (CSP10) is judged as positive if the FGFR2/CSP10 ratio is ⁇ 2.2, or the FGFR2 signal is distributed in clusters; if the FGFR2/CSP10 ratio is ⁇ 1.8, it is judged as negative; if 1.8 ⁇ FGFR2/CSP10 ratio ⁇ 2.2, the count of 20 tumor cells is expanded, and when the FGFR2/CSP10 ratio is ⁇ 2.0, the result is judged as positive, and when the FGFR2/CSP10 ratio is ⁇ 2.0, the result is judged as negative.
  • the NGS detection method is used to perform FGFR2 gene amplification confirmatory detection on the subject's formalin-fixed paraffin-embedded (FFPE) tumor tissue section sample.
  • FFPE formalin-fixed paraffin-embedded
  • NGS next-generation sequencing
  • the technical methods include methodologically validated target genome capture panel sequencing or whole exome sequencing (Whole Exome Sequencing, WES).
  • gastric cancer or gastroesophageal junction adenocarcinoma particularly locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma
  • the gastric cancer or gastroesophageal junction adenocarcinoma is advanced or metastatic.
  • the patient has the gastric cancer or gastroesophageal junction adenocarcinoma progression after previously administering another therapy.
  • a method for treating and/or preventing locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma in a patient in need thereof comprising: administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof.
  • the patient has progression of the gastric cancer or gastroesophageal junction adenocarcinoma after prior administration of another therapy.
  • the prior administration of another therapy is a therapy for treating the gastric cancer or gastroesophageal junction adenocarcinoma.
  • the prior administration of another therapy is administration of a chemotherapeutic agent.
  • the prior administration of a chemotherapeutic agent is a regimen containing gemcitabine.
  • the gemcitabine-containing regimen comprises gemcitabine.
  • the gemcitabine-containing regimen comprises gemcitabine and cisplatin.
  • the prior administration of another therapy is administration of another chemotherapeutic agent selected from the group consisting of 5-fluorouracil, gemcitabine, cisplatin, capecitabine, oxaliplatin, and combinations thereof.
  • the prior administration of another therapy is administration of a receptor tyrosine kinase inhibitor.
  • the receptor tyrosine kinase inhibitor is a selective non-covalent binding inhibitor of FGFR1, FGFR2 and/or FGFR3.
  • the selective non-covalent binding inhibitor of FGFR1, FGFR2 and/or FGFR3 is selected from pemitinib, rogatinib, delazentinib, Debio 1347, AZD4547, ABSK012, ABSK061, ABSK121, ABSK011, and combinations thereof.
  • the receptor tyrosine kinase inhibitor is a selective non-covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4.
  • the selective non-covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4 is selected from erdafitinib, LY2874455, PRN 1371, ASP5878, and combinations thereof.
  • the receptor tyrosine kinase inhibitor is a selective covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4.
  • the selective covalent binding inhibitor of FGFR1, FGFR2, FGFR3 and/or FGFR4 is TAS120.
  • the receptor tyrosine kinase inhibitor is a non-selective tyrosine kinase inhibitor.
  • the non-selective tyrosine kinase inhibitor is selected from ponatinib, dovitinib, levatanib, ACTB-1003, Ki8751, lucitinib, masitinib,netinib, nintedanib, orentinib, PD089828, and combinations thereof.
  • the prior administration of another therapy is the administration of another selective FGFR inhibitor.
  • another selective FGFR inhibitor is selected from pemitinib, rogatinib, delazentinib, AZD4547, Debio1347, ASP5878, erdatinib, LY2874455, PRN1371, TAS120, ABSK012, ABSK061, ABSK121, ABSK011, and combinations thereof.
  • another selective FGFR inhibitor is a selective covalent binding inhibitor.
  • the selective covalent binding inhibitor is TAS120.
  • another selective FGFR inhibitor is a selective non-covalent binding inhibitor.
  • the selective non-covalent binding inhibitor is pemitinib, rogatinib, delazentinib, AZD4547, erdatinib, ABSK012, ABSK061, ABSK121, ABSK011, and combinations thereof.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR1 gene fusion, translocation, or another genetic alteration.
  • the FGFR1 gene fusion comprises a FGFR1 gene fusion partner selected from the group consisting of: BAG4, ERLIN2, NTM, FGFR1OP2, TACC3, and TRP.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR2 gene fusion, translocation, or another genetic alteration.
  • the FGFR2 gene fusion comprises a FGFR2 gene fusion partner selected from the following: 10Q26.13, AFF1, AFF3, AFF4, AHCYL1, ALDH1L2, ARFIP1, BAG4, BAIAP2L1, BICC1, C10orf118, C10orf68, C7, CASC15, CASP7, CCDC147, CCDC6, CELF2, CIT, COL14A1, CREB5, CREM, DNAJC12, ERLIN2, HOOK1, INA, KCTD1, KIAA1217, KIAA1 598, KIAA1967, KIFC3, MGEA5, NCALD, NOL4, NPM1, NRAP, OFD1, OPTN, PARK2, PAWR, PCMI, PDHX, PHLDB2, PPAPDC1A,
  • the FGFR2 gene fusion comprises a FGFR2 gene fusion partner selected from the group consisting of: 10Q26.13, AFF1, AFF4, AHCYL1, ALDH1L2, ARFIP1, BICC1, C10orf118, C7, CCDC147, CCDC6, CELF2, CREB5, CREM, DNAJC12, HOOK1, KCTD1, KIAA1217, KIAA1598, KIFC3, MGEA5, NOL4, NRAP, OPTN, PARK2, PAWR, PCMI, PHLDB2, PPHLN1, RASAL2, SFMBT2, SLMAP, SLMAP2, SORBS1, STK26, STK3, TACC3, TBC1D1, TFEC, TRA2B, UBQLN1, VCL, WAC, ZMYM4, and combinations thereof.
  • FGFR2 gene fusion partner selected from the group consisting of: 10Q26.13, AFF1, AFF4, AHCYL1, ALDH1L2, ARFIP1, BICC
  • the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR3 gene fusion, translocation or another genetic alteration.
  • the FGFR3 gene fusion comprises a FGFR2 gene fusion partner selected from the group consisting of BAIAP2L1, JAKMIP1, TACC3, TNIP2, WHSC1, and combinations thereof.
  • the FGFR3 gene fusion comprises a FGFR3 gene fusion partner, wherein the FGFR gene fusion partner is TACC3.
  • the patient undergoes molecular prescreening, such as using second-generation sequencing, circulating tumor DNA analysis, or fluorescent in situ hybridization assays to determine whether the gastric cancer or gastroesophageal junction adenocarcinoma has FGFR1, FGFR2, or FGFR3 gene fusions, translocations, or another genetic alteration.
  • molecular prescreening occurs prior to administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof. In some embodiments, molecular prescreening occurs prior to prior administration of another therapy.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has FGFR1, FGFR2 and/or FGFR3 mutations.
  • the FGFR1, FGFR2 and/or FGFR3 mutations are selected from FGFR1G818R, FGFR1K656E, FGFR1N546K, FGFR1R445W, FGFR1T141R, FGFR2A315T, FGFR2C382R, FGFR2D336N, FGFR2D471N, FGFR2E565A, FG FR2I547V, FGFR2K641R, FGFR2K659E, FGFR2K659M, FGFR2L617V, FGFR2N549H, FGFR2N549K, FGFR2N549S, FGFR2N549Y, FGFR2N550K, FGFR2P
  • the FGFR1, FGFR2 and/or FGFR3 mutations are selected from FGFR1N546K, FGFR1K656E, FGFR2S252W, FGFR2P253R, FGFR2A315T, FGFR2Y375C, FGFR2C382R, FGFR2N549K, FGFR2K659E, FGFR3R248C, FGFR3S249C, FGFR3G370C, FGFR3S371C, FGFR3Y373C, FGFR3G380R, FGFR3K650E, FGFR3K650M, and combinations thereof.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR1 gene fusion and a FGFR1 mutation. In a specific embodiment, the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR1 gene fusion and a FGFR2 mutation. In a specific embodiment, the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR1 gene fusion and a FGFR3 mutation.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR2 gene fusion and a FGFR1 mutation. In a specific embodiment, the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR2 gene fusion and a FGFR2 mutation. In a specific embodiment, the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR2 gene fusion and a FGFR3 mutation.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR3 gene fusion and a FGFR1 mutation. In a specific embodiment, the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR3 gene fusion and a FGFR2 mutation. In a specific embodiment, the gastric cancer or gastroesophageal junction adenocarcinoma has a FGFR3 gene fusion and a FGFR3 mutation.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has gene amplification of FGFR1, FGFR2 and/or FGFR3.
  • the gastric cancer or gastroesophageal junction adenocarcinoma has FGFR2 gene amplification, and the FGFR2 gene amplification is determined by FISH detection or NGS detection.
  • administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises administering about 125 mg of infigratinib or a pharmaceutically acceptable salt thereof.
  • an effective amount of infigratinib or a pharmaceutically acceptable salt thereof is administered to the patient once daily.
  • an effective amount of infigratinib or a pharmaceutically acceptable salt thereof is orally administered to a patient.
  • administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises orally administering about 25 mg of infigratinib or a pharmaceutically acceptable salt thereof once a day.
  • administering an effective amount of Infigratinib or a pharmaceutically acceptable salt thereof comprises orally administering about 50 mg of Infigratinib or a pharmaceutically acceptable salt thereof once a day.
  • administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises orally administering about 75 mg of infigratinib or a pharmaceutically acceptable salt thereof once a day.
  • administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises orally administering about 100 mg of infigratinib or a pharmaceutically acceptable salt thereof once a day.
  • administering an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises orally administering about 125 mg of infigratinib or a pharmaceutically acceptable salt thereof once a day.
  • administration of an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises a 28-day cycle, wherein about 25 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the patient once a day for 3 consecutive weeks (21 days), and subsequently infigratinib is not administered within 1 week (7 days).
  • administration of an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises a 28-day cycle, wherein about 50 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the patient once a day for 3 consecutive weeks (21 days), and subsequently infigratinib is not administered within 1 week (7 days).
  • administration of an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises a 28-day cycle, wherein approximately 75 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the patient once a day for 3 consecutive weeks (21 days), and subsequently infigratinib is not administered within 1 week (7 days).
  • administration of an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises a 28-day cycle, wherein about 100 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the patient once a day for 3 consecutive weeks (21 days), and subsequently infigratinib is not administered within 1 week (7 days).
  • administration of an effective amount of infigratinib or a pharmaceutically acceptable salt thereof comprises a 28-day cycle, wherein approximately 125 mg of infigratinib or a pharmaceutically acceptable salt thereof is administered to the patient once a day for 3 consecutive weeks (21 days), and subsequently infigratinib is not administered within 1 week (7 days).
  • an effective amount of infigratinib or a pharmaceutically acceptable salt thereof is administered to a patient for two, three, four, five, six, seven, eight, nine, ten, eleven or twelve consecutive 28-day cycles.
  • about 125 mg of Infigratinib or a pharmaceutically acceptable salt thereof is provided in a unit dose. In some embodiments, about 125 mg of Infigratinib or a pharmaceutically acceptable salt thereof is provided in a 100 mg unit dose and a 25 mg unit dose. In some embodiments, about 125 mg of Infigratinib or a pharmaceutically acceptable salt thereof is provided in a 75 mg unit dose and a 50 mg unit dose.
  • infigratinib or a pharmaceutically acceptable salt thereof is provided in a 75 mg unit dose and a 25 mg unit dose. In some embodiments, about 100 mg of infigratinib or a pharmaceutically acceptable salt thereof is provided in two 50 mg unit doses.
  • infigratinib or a pharmaceutically acceptable salt thereof is provided in a 50 mg unit dose and a 25 mg unit dose.
  • infigratinib or a pharmaceutically acceptable salt thereof is provided in two 25 mg unit doses.
  • the method further comprises administering an effective amount of Infigratinib or a pharmaceutically acceptable salt thereof to a patient in need thereof who is in a fasting state.
  • an effective amount of Infigratinib or a pharmaceutically acceptable salt thereof should be administered to a patient in need thereof at least 1 hour before the patient eats.
  • an effective amount of Infigratinib or a pharmaceutically acceptable salt thereof should be administered to a patient in need thereof at least 2 hours after the patient eats.
  • the gastric cancer or gastroesophageal junction adenocarcinoma is confirmed by histology or cytology. In some embodiments, the gastric cancer or gastroesophageal junction adenocarcinoma is confirmed by histology. In some embodiments, the gastric cancer or gastroesophageal junction adenocarcinoma is confirmed by cytology.
  • the method comprises administering an effective amount of a pharmaceutically acceptable salt of Infigratinib to a patient in need thereof.
  • the pharmaceutically acceptable salt of Infigratinib is a monophosphate.
  • the pharmaceutically acceptable salt of Infigratinib is an anhydrous monophosphate.
  • the pharmaceutically acceptable salt of Infigratinib is a polymorphic anhydrous monophosphate, characterized by an X-ray powder diffraction (XRPD) peak (2 ⁇ ) at 15.0° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • a method for treating and/or preventing locally advanced or recurrent/metastatic gastric cancer or gastroesophageal junction adenocarcinoma in a patient in need thereof comprising: administering any one of the pharmaceutical compositions disclosed herein, wherein the patient has progression of the gastric cancer or gastroesophageal junction adenocarcinoma after prior administration of another therapy.
  • Step A Synthesis of N-4-(4-ethyl-piperazin-1-yl)-phenyl)-N'-methyl-pyrimidine-4,6-diamine
  • This material was prepared by a modified procedure disclosed in the literature (J. Appl. Chem. 1955, 5, 358): To a suspension of commercially available 4,6-dichloropyrimidine (20 g, 131.6 mmol, 1.0 equiv.) in isopropanol (60 mL) was added ethanol (40.1 mL, 328.9 mmol, 2.5 equiv.) containing 33% methylamine at a rate such that the internal temperature did not rise above 50 ° C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour. Then, water (50 mL) was added and the resulting suspension was cooled to 5 ° C. in an ice bath.
  • Step E 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-4-(4-ethyl-piperazin-1-yl)-benzene Synthesis of amino-pyrimidin-4-yl ⁇ -1-methyl-urea
  • the title compound was prepared by adding 2,6-dichloro-3,5-dimethoxyphenyl-isocyanate (1.25 eq) to a toluene solution of N-4-(4-ethyl-piperazin-1-yl)-phenyl)-N'-methyl-pyrimidine-4,6-diamine (2.39 g, 7.7 mmol , 1 eq) and stirring the reaction mixture at reflux for 1.5 h.
  • Example 2 Synthesis of the monophosphate salt form A (BGJ398) of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-4-(4-ethyl-piperazin-1-yl)-phenylamino-pyrimidin-4-yl ⁇ -1-methyl-urea
  • Example 3 Manufacturing process of 25 mg, 100 mg and 125 mg doses of infigratinib pharmaceutical preparations
  • Cellulose MK-GR, lactose (ground), infigratinib, cellulose HPM603 and cross-linked polyvinyl pyrrolidone (PVP-XL) are added sequentially to a vertical wet high shear granulator (e.g., TK Fiedler (bottom drive, 65L) with a granulator filling volume of about 45-50%, and then the five components are mixed for about 5 minutes at an impeller setting of 60-270 rpm, preferably 150 rpm; and a chopper setting of 600-3000 rpm, preferably 1500 rpm to obtain a dry blend.
  • TK Fiedler bottom drive, 65L
  • Purified water is added as granulation liquid at a rate of about 385 g/min over 7 minutes (up to about 2.7 kg of water is added) at a spray setting pressure of 1.5 bar (impeller setting is 60-270 rpm, preferably 150 rpm; and chopper setting is 600-3000 rpm, preferably 1500 rpm).
  • the resulting granulation mixture is kneaded for about 3 minutes (impeller setting is 60-270 rpm, preferably 150 rpm; and chopper setting is 600-3000 rpm, preferably 1500 rpm).
  • the kneaded granulation mass is sieved through a 3.0 mm sieve using a Comil at 90-600 rpm. This procedure is optional and can be omitted, but it is preferably performed.
  • the granules are dried in a fluid bed dryer (eg Glatt GPCG 15/30 or equivalent) with an inlet air temperature of 55-65°C, preferably 60°C, a product temperature of about 30-40°C and an inlet air volume of 300-1200 m3 /h to reach a drying endpoint of ⁇ 2.2%.
  • a fluid bed dryer eg Glatt GPCG 15/30 or equivalent
  • the dried granules are sieved through 800-1000 ⁇ m.
  • the resulting dried and sieved granules are also referred to herein as internal phase.
  • the external phase excipients PVP XL and Aerosil 200 are sieved through a 900-1000 ⁇ m sieve at about 50-150 rpm in a Comil and then combined with the internal phase by mixing at 4-25 rpm, preferably 17 rpm for about 5 minutes (33-66% powder fill) in a suitable container (e.g., box mixer turbula or equivalent).
  • a suitable container e.g., box mixer turbula or equivalent.
  • the solids are lubricated by adding sieved magnesium stearate at 500 rpm as an additional external phase excipient to obtain a final blend ready for capsule filling by blending in a diffusion mixer (tumbler) or box blender (e.g., Bohle PM400, Turbula, or equivalent) at about 17 rpm for about 3 minutes.
  • a diffusion mixer tumbler
  • box blender e.g., Bohle PM400, Turbula, or equivalent
  • the encapsulation machine e.g. & Karg GKF 330, Bosch GKF 1500, Zanasi 12E, Zanasi 40E
  • the final blend was filled into 0, 1 or 3 size hard gelatin capsules (HGC) with an encapsulation rate of 10,000 to 100,000 capsules/hour without pre-compression.
  • the weight of the capsules was controlled and the capsules were dusted.
  • the a -salt factor is 1.175. If the content is ⁇ 99.5%, the amount of drug substance must be adjusted. Compensation is made accordingly by adjusting the lactose content.
  • the a -salt factor is 1.175. If the content is ⁇ 99.5%, the amount of drug substance must be adjusted. Compensation is made accordingly by adjusting the lactose content.
  • the a -salt factor is 1.175. If the content is ⁇ 99.5%, the amount of drug substance must be adjusted. Compensation is made accordingly by adjusting the lactose content.
  • infigratinib has been shown to be a potent ATP-competitive inhibitor of recombinant human FGFR1, FGFR2, and FGFR3, with IC50 values of 1.1nM, 1.0nM, and 2.0nM, respectively (Study RD-2018-00444).
  • the IC50 values for FGFR4, VEGFR2/KDR, LYN(1-512), and KIT were 0.061 ⁇ M (61nM), 0.21 ⁇ M (210nM), 0.3 ⁇ M (300nM), and 0.81 ⁇ M (810nM), respectively.
  • the IC50 values for inhibition of all other kinases were >1 ⁇ M or 10 ⁇ M.
  • the biochemical kinase data support infigratinib as a potent and selective FGFR1-3 inhibitor.
  • infigratinib Inhibition of Target Kinase Phosphorylation in Cell Assays: To confirm that inhibition of enzyme activity by infigratinib translates into inhibition of the corresponding target kinases in cells, the ability of infigratinib to inhibit phosphorylation of wild-type FGFR1 and FGFR2 and constitutively active mutant FGFR3 was evaluated in human embryonic kidney (HEK) 293 cells (Studies RD-2005-01708, RD-2005-01709, RD-2005-01712, RD-2005-01668). Infigratinib inhibited tyrosine phosphorylation of FGFR1 and FGFR2 in HEK293 cells with IC 50 values of 4.6 nM and 4.3 nM, respectively.
  • HEK human embryonic kidney
  • Infigratinib inhibited tyrosine phosphorylation of EFGFR3K650E and FGFR3S249C in HEK293 cells with IC 50 values of 5.6 nM and 4.8 nM, respectively. Compared with the inhibitory effect of infigratinib on FGFR1-3 tyrosine phosphorylation, its inhibitory effect on FGFR4 tyrosine phosphorylation was several orders of magnitude lower ( IC50 value was 164 nM).
  • Infigratinib selectively inhibited the proliferation of human cancer cell lines carrying FGFR genetic alterations and/or protein overexpression, but not in cancer cell lines in which FGFR1-3 were not expressed or altered (Studies RD-2006-01656, RD-2006-01990, RD-2006-01719, RD-2007-01092, RD-2009-00471).
  • the ability of infigratinib to inhibit FGFR downstream signaling was analyzed in sensitive cancer cell lines by monitoring (FGFR substrate 2 (FRS2) tyrosine phosphorylation and ERK/MAPK activation) (Study RD-2006-01812).
  • Infigratinib abolished FRS2 tyrosine phosphorylation at infigratinib concentrations required to inhibit cell proliferation. Inhibition of pFRS2 also inhibited the RAS-MAPK pathway, as assessed by pERK/pMAPK.
  • the metabolites BHS697 and CQM157 have similar activity to that of infigratinib in terms of binding and pharmacological activity; and similar to infigratinib, they are also more potent against FGFR1-3 than FGFR4 (Studies QED003-01-s-00001, QED008-01-s-00001, QED016-01-s-00001, RD-2007-01094, RD-2005-01708, RD-2005-01709, RD-2005-01712, RD-2005-01668).
  • Acetyl-CQM157 binds to the same receptor as infigratinib (Study QED020-01-s-00001).
  • infigratinib The antitumor efficacy of infigratinib was investigated in FGFR-driven human brain, gastric, breast, and liver cancer PDX models.
  • Table 4 Summary of brain, stomach, breast, and liver PDX models induced by FGFR treatment with infigratinib (30 mg/kg)
  • FGFR fibroblast growth factor receptor
  • PDX patient-derived xenograft
  • TGI tumor growth inhibition
  • TGI% [1-( Ti - T0 )/( Ci - C0 )] ⁇ 100; Ti and Ci were the average tumor volumes of the treatment group and the control group on the last day of treatment, respectively; T0 and C0 were the average tumor volumes of the treatment group and the control group on day 0, respectively.
  • glioma model contains FGFR3-TACC3 fusion with FGFR3 kinase domain deletion (KD del) and consistent FGFR1 amplification (amp).
  • infigratinib was examined in HEK293 cells (Study 0870331). In the concentration range of 1-10 ⁇ M, infigratinib was observed to produce a concentration-dependent inhibition of hERG currents, with inhibition rates ranging from 28.1% to 93.8%.
  • the calculated IC 50 value of infigratinib for inhibiting hERG currents was 2.0 ⁇ M (1.1 ⁇ g/mL), which is approximately 104 times the human exposure.
  • C max is 330.3 ng/mL (0.3303 ⁇ g/mL).
  • the unbound plasma C max is expected to be 0.0106 ⁇ g/mL, thus providing a 104-fold exposure ratio (1.1 ⁇ g/mL/0.0106 ⁇ g/mL) at the recommended clinical dose of 125 mg QD infigratinib. Therefore, at clinically relevant exposures, infigratinib is unlikely to cause QT prolongation (Study QEDT-NCA, BGJ398-872). Cardiovascular adverse reactions were also evaluated in awake telemetered dogs or cuffed dogs after a single dose (Study 0870300) or 2 weeks of administration (Study 0770101).
  • Example 7 Phase IIa clinical trial of Infigratinib (BGJ398)
  • the ongoing study LB1001-201 is a multicenter, open-label, single-arm Phase IIa clinical trial evaluating oral infigratinib for the treatment of locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with FGFR2 gene amplification.
  • the key information of the study is as follows:
  • This study was designed to evaluate the efficacy of the targeted, selective, pan-FGFR inhibitor BGJ398 in patients with locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with FGFR2 gene amplification by estimating the objective response rate.
  • ORR objective response rate
  • ECG electrocortical electroencephalogram
  • 6Disease can be measured by RECIST v1.1;
  • the FGFR2 gene amplification test (FISH method) is positive.
  • -ORR The proportion of subjects with confirmed response as CR or PR; the tumor response status was assessed by the investigator or an independent review committee according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) (time frame: every 8 weeks for the first 33 weeks; every 12 weeks thereafter);
  • -DOR the time interval from the first evaluation of CR or PR to the first evaluation of PD or death from any cause (the percentage of subjects with DOR ⁇ 6 months, ⁇ 9 months and ⁇ 12 months will be reported). (Time range: every 8 weeks for the first 33 weeks; every 12 weeks thereafter);
  • -DCR proportion of subjects confirmed as CR (complete response) or PR (partial response) or SD (progressive disease) (RECIST v1.1) (time frame: every 8 weeks for the first 33 weeks; every 12 weeks thereafter);
  • -BOR best response recorded from the start of treatment to disease progression/relapse. For patients assessed as CR, CR must be confirmed at least 4 weeks from the date of assessment, and for patients assessed as PR, PR must be confirmed at least 4 weeks from the date of assessment;
  • time from the first treatment date to the date of disease progression or death from any cause determined by the investigator time frame: every 8 weeks for the first 33 weeks; every 12 weeks thereafter;
  • time from the first treatment date to the date of death time range: first 33 weeks, once every 8 weeks; then once every 12 weeks);
  • -PK parameters including C max , AUC , CL / F , t 1 / 2 , accumulation factor , etc. will be analyzed using a non - compartmental model .
  • the FGFR2 gene amplification was confirmed by fluorescence in situ hybridization (FISH) on formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from the subjects.
  • FISH fluorescence in situ hybridization
  • FFPE formalin-fixed paraffin-embedded
  • Eligible subjects received oral infigratinib (125 mg, QD; 28 days as a dosing cycle, continuous administration for 3 weeks, 1 week off) until intolerable toxicity, disease progression, withdrawal of informed consent, death, loss to follow-up, or start of new anti-tumor treatment (whichever occurred first).
  • tumor assessments will be performed on subjects by CT/MRI at W9, W17, W25, W33 and every 12 weeks thereafter (time window: ⁇ 7 days).
  • Safety assessment Assessments will be performed once in cycle 1 (W2/W3/W4), cycle 2/3 (W1/W3), cycle 4 (W1) and every cycle thereafter, including laboratory tests, 12-lead electrocardiogram, etc. Blood samples will be collected for PK analysis.
  • PK parameters include: single administration: Cmax, Tmax, t1/2, AUC0-t, AUCinf, CL/F, Vz/F, MRT, etc.; multiple administration: Cmax,ss, Tmax,ss, t1/2,ss, Cav,ss, AUC0-t,ss, CLss/F, Vss/F, Rac, Cmin, metabolite: ratio (metabolite/prototype drug), etc.; safety evaluation will be evaluated during the screening phase and visits throughout the treatment period: including adverse events (AEs and SAEs), clinical laboratory tests (blood sampling for clinical laboratory parameters), pregnancy tests, vital signs, physical examinations and electrocardiograms (ECG), left ventricular ejection fraction (LVEF) and ophthalmic evaluations, etc.
  • adverse events AEs and SAEs
  • clinical laboratory tests blood sampling for clinical laboratory parameters
  • pregnancy tests vital signs
  • vital signs vital signs
  • ECG electrocardiograms
  • LVEF left ventricular ejection fraction
  • ophthalmic evaluations etc
  • ORR Objective response rate
  • DCR disease control rate
  • Percentages are based on the number of subjects in each group in the full analysis set.
  • the top five metastatic sites were lymph node metastasis (71.4%), peritoneal metastasis (42.9%), liver metastasis (28.6%), bone metastasis (19.0%), and lung metastasis (19.00%).
  • the median mPFS was 3.3 months (95% CI: 2.3, 4.5), and the median OS was 8.0 months (95% CI: 4.1, NE), see Table 7.
  • ORR confirmed CR + confirmed PR.
  • uORR CR + PR, whether confirmed or not.
  • DCR confirmed CR + confirmed PR + SD.
  • Percentages are based on the number of subjects in each group in the full analysis set.
  • OS was defined as the time from the first treatment to death.
  • the minimum and maximum values represent censored observations.
  • NE means the value is not estimable.
  • Drug-related AEs and serious (Grade 3) drug-related AEs are shown in Tables 8 and 9; there were no cases of drug-induced liver injury (DILI).
  • Table 8 Summary of infigratinib-related CTCAE grade ⁇ 3 TEAEs by SOC and PT
  • TEAEs in Tables 8 and 9 were defined as any adverse event that occurred newly or worsened after the first dose of infigratinib and within 30 days after the last dose (adverse reactions before the first dose or pre-existing conditions), or any adverse reaction related to infigratinib treatment after the first dose.
  • Subjects who experienced adverse reactions multiple times in the same preferred term were counted only once in that preferred term.
  • Subjects who experienced adverse reactions multiple times in the same system organ class were counted only once within that system organ class.
  • System organ classes are listed in descending order of overall frequency, and preferred terms are listed in descending order of overall frequency within system organ class. Percentages are based on the number of subjects in each group of subjects in the safety analysis set.
  • ⁇ Infigratinib monotherapy can bring meaningful clinical benefits to patients with locally advanced or metastatic GC or EGJ with FGFR2 gene amplification;
  • ⁇ Infigratinib monotherapy was generally well tolerated in patients with GC or EGJ who had previously received at least two lines of systemic therapy, and adverse reactions were manageable and usually reversible.

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Abstract

提供了英菲格拉替尼或其药学上可接受的盐在制备用于治疗和/或预防胃癌或胃食管交界部腺癌，尤其是局部进展期或复发/转移性胃癌或胃食管交界部腺癌的药物中的用途。

Description

英菲格拉替尼在治疗胃癌和腺癌中的用途 技术领域
本发明涉及癌症治疗领域，具体涉及胃癌或胃食管交界部腺癌的治疗，尤其是局部进展期或复发/转移性胃癌或胃食管交界部腺癌的治疗。
背景技术
胃癌(Gastric cancer,GC)是指来源于胃粘膜上皮细胞的恶性肿瘤，病理学为该疾病诊断的金标准。根据2010年的WHO病理分型，胃癌包括胃腺癌、腺鳞癌、伴淋巴样间质癌(髓样癌)、肝样腺癌、鳞状细胞癌及未分化癌等类型，其中最常见为胃腺癌。组织学分型常使用WHO分型和Lauren分型，包括肠型、弥漫型、混合型、以及未分型；根据腺体的分化程度，可以分为高分化、中分化和低分化(高级别、中级别和低级别)。胃食管交接部腺癌(Gastro-Esophageal Junction,GEJ)是指肿瘤中心位于解剖学上食管胃交界部上、下各5cm这段范围内的腺癌，常用分型为Siewert分型(2022年卫健委《胃癌诊疗指南》)。
胃癌(Gastric cancer,GC)是全球第五大常见恶性肿瘤，也是恶性肿瘤第四大死亡原因。根据Globocan 2020 Today数据，2020年全球新发病例1,089,103例，同年死亡病例数为768,793例。GC发病率因不同地理区域而异：东亚及东欧地区发病率最高，而北美和北欧的发病率普遍较低，与非洲的比率相当。胃癌是我国高发的消化道系统恶性肿瘤，根据Globocan2020年数据，中国每年胃癌新发病例数居常见恶性肿瘤的第2位，新发病例约为45.7万人；死亡例居第三位，为39.9万人。
胃癌易发生转移，其常见的转移途径包括：直接侵犯、淋巴结转移和血行转移。直接侵犯是指原发肿瘤侵透胃壁浆膜层、达到周围邻近组织或器官如网膜、肝、胰腺或结肠等。淋巴结转移是指肿瘤沿淋巴脉管系统进行侵袭。血行转移指肿瘤细胞进入血液循环，并随着体循环向身体其他部位播散，遇到适合增殖的部位，肿瘤细胞停留、增殖，形成转移灶。常见的转移器官有肝、肺、骨骼等。另外，胃癌还有一种特殊的转移方式-腹膜种植转移：胃部肿瘤细胞浸润胃壁、穿透浆膜层后，肿瘤细胞脱落、种植在腹膜或其他脏器的浆膜层，并形成转移灶。直肠、膀胱处的种植是胃癌进展期的征象。直肠前凹的转移癌，直肠指检可以发现。女性胃癌患者可发生卵巢转移性肿瘤。
对于初步诊断的患者，手术切除是胃癌的主要治疗手段，也是目前治愈胃癌的唯一方法。对于术后复发、或初步诊断时已伴有远处转移的患者，则以系统性治疗为主要治疗手段，包括化疗、放疗、姑息性手术以及其他支持性治疗。
对于无手术根治机会或转移性胃癌患者，目前应采取以全身药物治疗为主的综合治疗。欧洲ESMO(2016)指南指出：对于这部分不可手术的局部进展或者转移的(IV期)的患者应考虑系统性治疗(化疗)，其与最佳支持治疗相比，具有很好改善生存，改善生活质量的意义。目前对于这部分患者一线治疗以曲妥珠单抗(HER表达阳性患者)以及化疗、肿瘤免疫治疗为主；二线治疗以化疗及抗血管生成药物(抗VEGFR)为主；对于三线及以上患者的治疗，目前没有公认的治疗方案，各国指南未有明确规定。三线及以上患者的免疫治疗中，帕博利珠单抗(pembrolizumab)的ORR达到13.3％，mPFS为2.0个月，mOS(median Overall Survival，中位生存期)为5.6个月，仍然存在未被满足的巨大需求。中国指南对于三线及以上患者的治疗推荐，除化疗和免疫治疗，增加了阿帕替尼治疗的推荐。阿帕替尼的三期研究结果，mPFS为2.6个月(95％CI,2.0-2.9)，mOS为6.5个月(95％CI,4.8-7.6)。中国胃癌CSCO(2021)指南指出“晚期胃癌整体预后不佳，传统化疗药物进入瓶颈期，靶向药物选择有限，免疫治疗单药疗效不佳。精准医学时代，面临胃癌的高度异质性、晚期胃癌药物精准治疗的困境和新型抗肿瘤药物挖掘，应积极鼓励患者参加临床研究”。
在中国，约30％的胃癌患者为伴有远处转移的进展期胃癌，该类患者行姑息手术及化疗治疗的5年生存率不足10％。而侵犯邻近脏器的局部进展期胃癌患者的5年生存率为13％～34％。最近，研究表明许多国家GEJ的发病率迅速上升。35％-40％的GC/GEJ患者确诊时已处于进展期、转移性或无法手术的阶段。进展期GC/GEJ的5年总生存率约为5-20％。
因此，本领域对于开发对胃癌或胃食管交接部腺癌具有显著临床效果的治疗方案具有迫切需求。
发明内容
在一个方面，本发明提供了英菲格拉替尼(Infigratinib)或其药学上可接受的盐在制备用于治疗和/或预防胃癌或胃食管交界部腺癌的药物中的用途。
在一些实施方案中，本发明提供了英菲格拉替尼或其药学上可接受的盐在制备用于治疗和/或预防局部进展期或复发/转移性胃癌或胃食管交界部腺癌的药物中的用途。
在一些实施方案中，其中所述胃癌或胃食管交界部腺癌具有FGFR1基因融合、易位或另一种遗传改变。在一些实施方案中，其中所述胃癌或胃食管交界部腺癌具有FGFR2基因融合、易位或另一种遗传改变。在一些实施方案中，其中所述胃癌或胃食管交界部腺癌具有FGFR3基因融合、易位或另一种遗传改变。在一些实施方案中，其中所述胃癌或胃食管交界部腺癌具有FGFR1、FGFR2、FGFR3中任一或全部的基因融合、易位或另一种遗传改变。
在具体实施方案中，其中所述FGFR2基因融合包含选自以下的FGFR2基因融合配偶体：10Q26.13、AFF1、AFF4、AHCYL1、ALDH1L2、ARFIP1、BICC1、C10orf118、C7、CCDC147、CCDC6、CELF2、CREB5、CREM、DNAJC12、HOOK1、KCTD1、KIAA1217、KIAA1598、KIFC3、MGEA5、NOL4、NRAP、OPTN、PARK2、PAWR、PCMI、PHLDB2、PPHLN1、RASAL2、SFMBT2、SLMAP、SLMAP2、SORBS1、STK26、STK3、TACC3、TBC1D1、TFEC、TRA2B、UBQLN1、VCL、WAC、ZMYM4，及其组合。
在一些实施方案中，其中所述胃癌或胃食管交界部腺癌具有FGFR1、FGFR2和/或FGFR3突变。在具体实施方案中，其中所述FGFR1、FGFR2和/或FGFR3突变选自FGFR1G818R、FGFR1K656E、FGFR1N546K、FGFR1R445W、FGFR1T141R、FGFR2A315T、FGFR2C382R、FGFR2D336N、FGFR2D471N、FGFR2E565A、FGFR2I547V、FGFR2K641R、FGFR2K659E、FGFR2K659M、FGFR2L617V、FGFR2N549H、FGFR2N549K、FGFR2N549S、FGFR2N549Y、FGFR2N550K、FGFR2P253R、FGFR2S252W、FGFR2V395D、FGFR2V564F、FGFR2Y375C、FGFR3A391E、FGFR3D785Y、FGFR3E627K、FGFR3G370C、FGFR3G380R、FGFR3K650E、FGFR3K650M、FGFR3K650N、FGFR3K650T、FGFR3K652E、FGFR3N540S、FGFR3R248C、FGFR3R399C、FGFR3S131L、FGFR3S249C、FGFR3S371C、FGFR3V555M、FGFR3V677I、FGFR3Y373C、FGFR4D425N、FGFR4R183S、FGFR4R394Q、FGFR4R610H、FGFR4V510L，及其组合。
在一些实施方案中，其中所述胃癌或胃食管交界部腺癌具有FGFR1、FGFR2和/或FGFR3的基因扩增。在一些实施方案中，其中所述胃癌或胃食管交界部腺癌具有FGFR2基因扩增，优选地，所述FGFR2基因扩增通过荧光原位杂交检测法(FISH法)或下一代测序检测法(NGS法)确定。
在一些实施方案中，其中所述胃癌或胃食管交界部腺癌为先前接受过系统性治疗或无标准治疗可选的胃癌或胃食管交界部腺癌。在一些实施方案中，其中所述药物用于先前接受过另一种疗法后具有进展的患者。在一些实施方案中，其中所述药物用于无标准治疗可选的患者。
在一些实施方案中，其中所述胃癌或胃食管交界部腺癌为不可切除类型。在具体实施方案中，其中所述胃癌或胃食管交界部腺癌因肿瘤原因不可切除或因身体状况不可切除，如原发肿瘤外侵严重、与周围正常组织无法分离或已包绕大血管，或者区域淋巴结转移固定、融合成团，或转移淋巴结不在手术可清扫范围内，或者患者全身情况差(例如严重的低蛋白血症和贫血)、营养不良、合并严重基础疾病。在具体实施方案中，其中所述不可切除类型的胃癌或胃食管交界部腺癌特征在于存在腹膜转移、远隔转移或局部进展。在具体实施方案中，其中所述腹膜转移由腹膜细胞学诊断阳性结果(发现恶性肿瘤细胞)确定，所述局部进展特征为N3或N4淋巴结浸润或淋巴结侵犯/包绕主要血管结构。
在一些实施方案中，其中所述患者先前接受过所述胃癌或胃食管交界部腺癌的既往治疗。在具体实施方案中，其中所述既往治疗包括手术、放疗、新辅助治疗、辅助治疗以及一线、二线、三线或四线治疗，优选地，其中所述一线、二线、三线或四线治疗包括化疗、免疫治疗、靶向治疗、抗血管生成药物、细胞治疗(例如靶向Claudin 18.2的细胞治疗)，及其联合方案。在具体实施方案中，所述药物选自顺铂、奥沙利铂、5-氟尿嘧啶、卡培他滨、替吉奥、紫杉醇、白蛋白紫杉醇、多西他赛、伊立替康、蒽环类、曲妥珠单抗、雷莫芦单抗、帕博利珠单抗、纳武利尤单抗、阿帕替尼、三氟吡啶、替普拉西酯、曲氟尿苷替匹嘧啶、表阿霉素、亚叶酸钙，及其联合方案或改良方案。
在一些实施方案中，其中所述患者先前接受过受体酪氨酸激酶抑制剂。
在具体实施方案中，其中所述受体酪氨酸激酶抑制剂是FGFR1、FGFR2和/或FGFR3的选择性非共价结合抑制剂。在具体实施方案中，其中所述FGFR1、FGFR2和/或FGFR3的选择性非共价结合抑制剂选自佩米替尼、罗加替尼(Rogaratinib)、德拉赞替尼(Derazantinib)、Debio1347、AZD4547(ABSK091)、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。
在具体实施方案中，其中所述受体酪氨酸激酶抑制剂是FGFR1、FGFR2、FGFR3和/或FGFR4的选择性非共价结合抑制剂。在具体实施方案中，其中所述FGFR1、FGFR2、FGFR3和/或FGFR4的选择性非共价结合抑制剂选自厄达替尼(Erdafitinib)、LY2874455、PRN 1371、ASP5878，及其组合。
在具体实施方案中，其中所述受体酪氨酸激酶抑制剂是FGFR1、FGFR2、FGFR3和/或FGFR4的选择性共价结合抑制剂。在具体实施方案中，其中所述FGFR1、FGFR2、FGFR3和/或FGFR4的选择性共价结合抑制剂是TAS120。
在具体实施方案中，其中所述受体酪氨酸激酶抑制剂是非选择性酪氨酸激酶抑制剂。在具体实施方案中，其中所述非选择性酪氨酸激酶抑制剂选自帕纳替尼、多韦替尼、levatanib、ACTB-1003、Ki8751、lucitinib、马赛替尼、木利替尼、尼达尼布、奥伦替尼、PD089828，及其组合。
在一些实施方案中，其中所述患者先前接受过另一种选择性FGFR抑制剂。
在具体实施方案中，其中所述另一种选择性FGFR抑制剂选自佩米替尼、罗加替尼、德拉赞替尼、AZD4547、Debio1347、ASP5878、厄达替尼、LY2874455、PRN1371、TAS120、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。在具体实施方案中，其中所述另一种选择性FGFR抑制剂是选择性共价结合FGFR抑制剂。在具体实施方案中，其中所述选择性共价结合FGFR抑制剂是TAS120。在具体实施方案中，其中所述另一种选择性FGFR抑制剂是选择性非共价结合FGFR抑制剂。在具体实施方案中，其中所述选择性非共价结合FGFR抑制剂是佩米替尼、罗加替尼、德拉赞替尼、AZD4547、厄达替尼、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。
在一些实施方案中，所述药物与手术、放疗、新辅助治疗、辅助治疗、化疗、免疫治疗、靶向治疗、抗血管生成药物、细胞治疗(例如靶向Claudin18.2的细胞治疗)，及其联合方案一起使用。
在具体实施方案中，所述联用药物选自顺铂、奥沙利铂、5-氟尿嘧啶、卡培他滨、替吉奥、紫杉醇类、白蛋白紫杉醇、多西他赛、伊利替康、蒽环类、曲妥珠单抗、帕博利珠单抗、阿帕替尼，及其组合。
在具体实施方案中，所述联用药物为受体酪氨酸激酶抑制剂。
在具体实施方案中，所述联用药物是FGFR1、FGFR2和/或FGFR3的选择性非共价结合抑制剂。在具体实施方案中，其中所述FGFR1、FGFR2和/或FGFR3的选择性非共价结合抑制剂选自佩米替尼、罗加替尼、德拉赞替尼、Debio1347、AZD4547、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。
在具体实施方案中，所述联用药物是FGFR1、FGFR2、FGFR3和/或FGFR4的选择性非共价结合抑制剂。在具体实施方案中，其中所述FGFR1、FGFR2、FGFR3和/或FGFR4的选择性非共价结合抑制剂选自厄达替尼、LY2874455、PRN 1371、ASP5878，及其组合。
在具体实施方案中，所述联用药物是FGFR1、FGFR2、FGFR3和/或FGFR4的选择性共价结合抑制剂。在具体实施方案中，其中所述FGFR1、FGFR2、FGFR3和/或FGFR4的选择性共价结合抑制剂是TAS120。
在具体实施方案中，所述联用药物是非选择性酪氨酸激酶抑制剂。在具体实施方案中，其中所述非选择性酪氨酸激酶抑制剂选自帕纳替尼、多韦替尼、levatanib、ACTB-1003、Ki8751、lucitinib、马赛替尼、木利替尼、尼达尼布、奥伦替尼、PD089828，及其组合。
在一些实施方案中，所述联用药物是另一种选择性FGFR抑制剂。在具体实施方案中，其中所述另一种选择性FGFR抑制剂选自佩米替尼、罗加替尼、德拉赞替尼、AZD4547、Debio1347、ASP5878、厄达替尼、LY2874455、PRN1371、TAS120、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。在具体实施方案中，其中所述另一种选择性FGFR抑制剂是选择性共价结合FGFR抑制剂。在具体实施方案中，其中所述选择性共价结合FGFR抑制剂是TAS120。在具体实施方案中，其中所述另一种选择性FGFR抑制剂是选择性非共价结合FGFR抑制剂。在具体实施方案中，其中所述选择性非共价结合FGFR抑制剂是佩米替尼、罗加替尼、德拉赞替尼、AZD4547、厄达替尼、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。
在一些实施方案中，其中所述药物以100mg单位剂量和/或25mg单位剂量提供。
在一些实施方案中，其中所述药物每天一次口服给药。
在一些实施方案中，其中所述药物以28天周期给药，其中连续3周内每天一次向所述患者口服给药约125mg的英菲格拉替尼或其药学上可接受的盐，并且在下1周内不给药。
附图说明
图1是依据TNM分期标准，对胃癌患者的治疗方案，相关术语的定义详见AJCC(American Joint Committee on Cancer，美国癌症联合委员会)发布的TNM分期标准(最新一版TNM分期标准为AJCC第8版(2017))。
图2是目标病灶直径总和与基线相比最大百分比变化(经确认)的瀑布图，其中PD表示疾病进展，SD表示疾病稳定，PR表示部分缓解，☆表示新病灶。数据截止日期包括完整分析集中的21名患者，其中2名受试者未能完成任何基线后肿瘤评估。
图3是一名具有自基线的最大肿瘤消退为78.5％的患者的计算机断层扫描图。该患者基线扫描图为A和B，第33周时具有78.5％肿瘤消退，见图C和D。
具体实施方式
如本文一般描述，本发明提供了英菲格拉替尼或其药学上可接受的盐在制备用于治疗和/或预防胃癌或胃食管交界部腺癌，尤其局部进展期或复发/转移性胃癌或胃食管交界部腺癌的药物中的用途。
定义
为了有利于理解本发明，以下定义了许多术语和短语。
除非另有定义，否则本文使用的所有技术术语和科学术语都具有与本发明所属领域的普通技术人员通常理解的相同的含义。本文使用的缩写具有其在化学和生物领域内的常规含义。本文所阐述的化学结构和式根据化学领域中已知的化学价的标准规则来构建。
在整个说明书中，在组合物和试剂盒被描述为具有、包括、或包含特定组分的情况下，或者在过程和方法被描述为具有、包括、或包含特定步骤的情况下，还预期本发明的组合物和试剂盒基本上由或由所叙述的组分组成，并且根据本发明的过程和方法基本上由或由所叙述的处理步骤组成。
在本申请中，在要素或组分被称为包括在并且/或者选自所叙述的要素或组分的列表的情况下，应当理解，要素或组分可为所叙述的要素或组分中的任一种，或者要素或组分可选自所叙述的要素或组分中的两种或更多种。
另外，应当理解，本文所述的组合物或方法的要素和/或特征能够以多种方式组合而不脱离本发明的精神和范围，无论在本文中是明确的还是隐含的。例如，在提及到具体化合物的情况下，该化合物可用于本发明的组合物的各种实施方案中和/或本发明的方法中，除非从上下文中另外理解。换言之，在本申请内，已经以使得能够书写和绘制清楚而简明的应用的方式描述和描绘实施方案，但是意图并且将理解的是，在不脱离本发明教导和本发明的情况下，实施方案可以不同地组合或分开。例如，应当理解，本文描述和描绘的所有特征可应用于本文描述和描绘的本发明的所有方面。
除非上下文不适当，否则冠词“一个”和“一种”在本发明中用于指冠词的语法对象中的一个或多于一个(即，指至少一个)。以举例的方式，“一个要素”意指一个要素或多于一个要素。
术语“和/或”在本发明中用于意指“和”或者“或”，除非另外指明。
应当理解的是，表述“至少一个”包括在该表述之后所叙述对象中的单独每者以及所叙述对象中的两者或更多者的各种组合，除非从上下文和使用中另外理解。与三个或更多个所叙述对象相关的表述“和/或”应理解为具有相同的含义，除非从上下文中另外理解。
使用的术语“包括(include)”、“包括(includes)”、“包括(including)”、“具有(have)”、“具有(has)”、“具有(having)”、“含有(contain)”、“含有(contains)”、或“含有(containing)”，包括其语法等同物，应通常理解为开放式和非限制性的，例如，不排除额外的未叙述的要素或步骤，除非从上下文中另外具体叙述或理解。
在术语“约”在定量值之前使用的情况下，本发明还包括特定的定量值本身，除非另外特别叙述。如本文所用，术语“约”是指偏离标称值±10％的变化，除非另外指明或从上下文中推断。
在本说明书中的各种地方，变量或参数以组或范围公开。特别地，本说明书旨在包括这样的组和范围的成员的每个和每一个单独的子组合。例如，0至40范围内的整数特别地旨在单独公开0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39和40，并且1至20范围内的整数特别地旨在单独公开1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19和20。
本文中任何和所有实例或示例性语言(例如，“如”或“包括”)的使用仅旨在更好地说明本发明，并且不对本发明的范围构成限制，除非要求保护。说明书中的语言不应解释为指示任何未要求保护的要素是实践本发明所必需的。
一般情况下，指定百分比的组合物按重量计，除非另外指明。此外，如果变量不伴有定义，则以变量的先前定义为准。
如本文所用，“药物组合物”或“药物制剂”是指活性剂与惰性或活性载体的组合，使得组合物尤其适用于体内或离体诊断或治疗用途。
“药学上可接受的”意指经联邦或州政府的管理机构或者在除美国以外的国家的相应机构批准或可批准的，或者在美国药典(U.S.Pharmacopoeia)或其他公认药典中列出用于动物，更特别地用于人类。
如本文所用，“药学上可接受的盐”是指可存在于本发明的化合物(例如英菲格拉替尼)中的酸性或碱性基团的任何盐，该盐与药物给药相容。
如本领域的技术人员所知，化合物的“盐”可衍生自无机或有机酸和碱。酸的实例包括但不限于盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、乙磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸和苯磺酸。其他酸，如草酸，虽然本身不是药学上可接受的，但可用于制备可用作获得本文所述的化合物及其药学上可接受的酸加成盐的中间体的盐。
碱的实例包括但不限于碱金属(例如钠和钾)氢氧化物、碱土金属(例如镁和钙)氢氧化物、氨，以及式NW4 +(其中W为C1-4烷基)的化合物等。
盐的实例包括但不限于乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、葡萄糖酸盐、葡萄糖二酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、氟庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、苯丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一烷酸盐等。盐的其他实例包括与合适的阳离子如Na+、K+、Ca2+、NH4 +和NW4 +(其中W可为C1-4烷基)等复合的本发明的化合物的阴离子。
对于治疗用途，预期本发明的化合物的盐是药学上可接受的。然而，非药学上可接受的酸和碱的盐也可用于例如制备或纯化药学上可接受的化合物。
如本文所用，“药学上可接受的赋形剂”是指有助于将活性剂给药于受试者并且/或者被受试者吸收并且可包括在本发明的组合物中而不对患者造成显著不利毒理效应的物质。药学上可接受的赋形剂的非限制性实例包括水、NaCl、生理盐溶液如磷酸盐缓冲盐水溶液、乳剂(例如，如油/水或水/油乳剂)、乳酸林格氏液、生理蔗糖、生理葡萄糖、粘结剂、填充剂、崩解剂、润滑剂、包衣、甜味剂、调味剂、盐溶液(如林格氏液)、醇、油、明胶、碳水化合物如乳糖、直链淀粉或淀粉、脂肪酸酯、羟甲基纤维素、聚乙烯吡咯烷和着色剂等。可将这样的制剂灭菌，并且根据需要与辅剂混合，所述辅剂如润滑剂、防腐剂、稳定剂、润湿剂、乳化剂、用于影响渗透压的盐、缓冲剂、着色剂和/或芳族物质等，其不与本发明的化合物有毒地反应。对于赋形剂的实例，参见Martin,Remington’s Pharmaceutical Sciences,第15版,Mack Publ.Co.,Easton,PA(1975)。
术语“AUC”是指在给药药物组合物后时间/血浆浓度曲线下的面积。AUC0-无穷大代表从时间0到无穷大的血浆浓度与时间曲线下的面积；AUC0-t代表从时间0到时间t的血浆浓度与时间曲线下的面积。应当理解，AUC值可以通过本领域已知的方法测定。
考虑给药的“受试者”包括但不限于人类(即，任何年龄段的男性或女性，例如儿童受试者(例如，婴儿、儿童、青少年)或成年受试者(例如，年轻人、中年人或老年人))和/或非人动物，例如哺乳动物诸如灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在某些实施方案中，受试者是人类。在某些实施方案中，受试者是非人动物。
术语“C最大”是指在给药药物组合物后治疗剂(例如英菲格拉替尼)在血液(例如血浆)中的最大浓度。
术语“t最大”是指在给药包含治疗剂(例如英菲格拉替尼)的药物组合物后实现C最大时的时间(以小时计)。
如本文所用，“固体剂型”意指固体形式的一个或多个药物剂量，例如片剂、胶囊、颗粒剂、散剂、小药囊、可重构粉末、干粉吸入剂和可咀嚼剂。
如本文所用，“给药”意指向受试者口服给药、作为栓剂给药、局部接触、静脉内给药、肠胃外给药、腹膜内给药、肌内给药、病灶内给药、鞘内给药、颅内给药、鼻内给药或皮下给药、或植入缓释装置，例如微量渗透泵。给药是通过任何途径，包括肠胃外和经粘膜(例如颊面、舌下、腭、齿龈、鼻、阴道、直肠或透皮)。肠胃外给药包括例如静脉内、肌内、动脉内、皮内、皮下、腹膜内、心室内和颅内。其他递送模式包括但不限于使用脂质体制剂、静脉内输注、透皮贴剂等。所谓的“共同给药”意指本文所述的组合物在给药一种或多种额外疗法(例如，抗癌剂、化疗剂、或神经变性疾病的治疗)的同时、临在之前、或临在之后给药。英菲格拉替尼或其药学上可接受的盐可单独给药或者可共同给药于患者。共同给药意在包括单独或组合的化合物(多于一种化合物或药剂)同时或依序给药。因此，制备物也可根据需要与其他活性物质组合(例如，以减少代谢降解)。
术语“疾病”、“障碍”和“病症”在本文中可互换使用。
术语“治疗”是指对受试者进行的任何类型的干预或过程或向受试者施用活性剂，其目的是逆转、减轻、改善、抑制或减慢与疾病相关的症状、并发症、病状或生化标记的发作、进展、发展、严重程度或复发。
术语“预防”是指对受试者进行的任何类型的干预或过程或向其施用活性剂，目的是防范或预防疾病或病症的发展或至少不能完全发展(例如，减轻疾病或状况的症状或严重程度)，例如出现副作用。
术语“系统性治疗”是指全身性治疗，区别于局部性治疗(如局部放疗或局部化疗泵植入)。进一步地，在描述患者先前接受过至少两线系统性治疗时，“至少两线系统性治疗”一般是指一线治疗+二线治疗，或者一线治疗+三线治疗(当二线治疗不合适时)，等等，直至用尽了标准治疗指南里面的方法。
一般来讲，化合物的“有效量”是指足以引起期望的生物反应(例如治疗和/或预防局部进展期或复发/转移性胃癌或胃食管交界部腺癌)的量。如本领域的普通技术人员将理解，本发明的化合物的有效量可以根据如下因素变化：期望的生物学终点、化合物的药代动力学、所治疗的疾病、给药模式，以及受试者的年龄、体重、健康状态和病症。
英菲格拉替尼
如式(I)所示的英菲格拉替尼是选择性和ATP竞争性泛成纤维细胞生长因子受体(FGFR)激酶抑制剂，也称为3-(2,6-二氯-3,5-二甲氧基苯基)-1-{6-[4-(4-乙基-1-哌嗪-1-基)苯氨基]-嘧啶基-4-基}-1-甲基脲。英菲格拉替尼选择性地抑制FGFR1、FGFR2和FGFR3的激酶活性。
化学合成英菲格拉替尼(包括本文所提供的实施例1)、英菲格拉替尼的几种结晶和无定形形式(包括本文所述的无水结晶单磷酸盐)以及制备所述形式的方法(包括本文所提供的实施例2)描述于美国专利9,067,896中，其全文以引用方式并入本文。
在一个方面，本文提供了用于在有此需要的患者中治疗和/或预防局部进展期或复发/转移性胃癌或胃食管交界部腺癌的英菲格拉替尼或其药学上可接受的盐。在一些实施方案中，英菲格拉替尼的药学上可接受的盐是单磷酸盐。英菲格拉替尼的单磷酸盐也可称为BGJ398。
在一些实施方案中，英菲格拉替尼的单磷酸盐是无水结晶单磷酸盐。在一些实施方案中，无水结晶单磷酸盐具有X射线粉末衍射(XRPD)图谱，该图谱包含约15.0°或15.0°±0.2°处以2θ计的特征峰。在一些实施方案中，无水结晶单磷酸盐的X射线粉末衍射图谱还包含一个或多个以2θ计的特征峰，所述特征峰选自约13.7°±0.2°、约16.8°±0.2°、约21.3°±0.2°和约22.4°±0.2°处的峰。在一些实施方案中，无水结晶单磷酸盐的X射线粉末衍射图谱还包含一个或多个以2θ计的特征峰，所述特征峰选自约9.2°、约9.6°、约18.7°、约20.0°、约22.9°和约27.2°处的峰。在一些实施方案中，无水结晶单磷酸盐具有包括至少三个以2θ计的特征峰的XRPD图谱，所述特征峰 选自约13.7°、约15°、约16.8°、约21.3°和约22.4°处的峰。在一些实施方案中，无水结晶单磷酸盐的X射线粉末衍射图谱可包含一个、两个、三个、四个、五个、六个、七个、八个、九个、十个或十一个以2θ计的特征峰，所述特征峰选自约9.2°、约9.6°、约13.7°、约15°、约16.8°、约18.7°、约20.0°、约21.3°以及约22.4°、约22.9°和约27.2°处的峰。
药物组合物
英菲格拉替尼的药物组合物以及制备所述药物组合物的方法(例如，包括本文所述的实施例3)描述于美国专利公开2017/0007602中，其全文以引用方式并入本文。
在一个方面，本文提供了用于在有此需要的患者中治疗和/或预防局部进展期或复发/转移性胃癌或胃食管交界部腺癌的药物组合物，该药物组合物包含英菲格拉替尼或其药学上可接受的盐，以及药学上可接受的赋形剂。
在具体实施方案中，本发明教导的药物组合物包含：
(a)约20重量％至约60重量％的呈其游离碱形式的英菲格拉替尼或其药学上可接受的盐；
(b)约0.5重量％至约5重量％的羟丙基甲基纤维素；
(c)约1重量％至约4重量％的交联聚乙烯吡咯烷酮；以及
(d)选自纤维素、乳糖、甘露糖醇、以及它们的组合的填充剂；
其中重量百分比基于药物组合物的总重量计。
在具体实施方案中，药物组合物包含约30重量％至约45重量％的呈其游离碱形式的英菲格拉替尼或其药学上可接受的盐。
在具体实施方案中，药物组合物包含约2％至约4％的羟丙基甲基纤维素。在具体实施方案中，药物组合物包含约2％至约4％的交联聚乙烯吡咯烷酮。
在具体实施方案中，药物组合物还包含：
(e)基于药物组合物的总重量计约10重量％至约95重量％的一种或多种填充剂；
(f)基于药物组合物的总重量计约0.1重量％至约3重量％的一种或多种润滑剂；以及
(g)基于药物组合物的总重量计约0.1重量％至约2重量％的一种或多种助流剂。
在具体实施方案中，一种或多种填充剂选自微晶纤维素、乳糖和/或甘露糖醇。
在具体实施方案中，药物组合物中的一种或多种润滑剂以基于药物组合物的总重量计约0.2重量％至约2重量％的量存在。在一些实施方案中，一种或多种润滑剂是硬脂酸镁。
在具体实施方案中，一种或多种助流剂以基于药物组合物的总重量计约0.1重量％至约0.5重量％的量存在于药物制剂中。在一些实施方案中，一种或多种助流剂是胶态二氧化硅(胶态氧化硅)。
在具体实施方案中，药物组合物中的英菲格拉替尼或其药学上可接受的盐的量为约25mg至约150mg、约50mg至约150mg、约75mg至约150mg、约100mg至约150mg、约125mg至约150mg、约25mg至约125mg、约25mg至约100mg、约25mg至约75mg、约25mg至约50mg、约50mg至约125mg、约50mg至约100mg、约50mg至约75mg、约75mg至约125mg、约75mg至约100mg、或约100mg至约125mg。在一些实施方案中，药物组合物中的英菲格拉替尼或其药学上可接受的盐的量为约100mg至约150mg的英菲格拉替尼或其药学上可接受的盐。
在具体实施方案中，药物组合物中的英菲格拉替尼或其药学上可接受的盐的量为约25mg、约50mg、约75mg、约100mg、约125mg、约150mg、约175mg、或约200mg。在一些实施方案中，药物组合物中的英菲格拉替尼或其药学上可接受的盐的量为约125mg。在一些实施方案中，药物组合物中的英菲格拉替尼或其药学上可接受的盐的量为约100mg。在一些实施方案中，药物组合物中的英菲格拉替尼或其药学上可接受的盐的量为约25mg。
在另一方面，本文提供了用于在有此需要的患者中治疗和/或预防局部进展期或复发/转移性胃癌或胃食管交界部腺癌的药物组合物，该药物组合物包含约125mg英菲格拉替尼或其药学上可接受的盐；以及药学上可接受的赋形剂。
在具体实施方案中，药物组合物包含有效量的英菲格拉替尼的药学上可接受的盐。在一些实施方案中，英菲格拉替尼的药学上可接受的盐是单磷酸盐。在一些实施方案中，英菲格拉替尼的药学上可接受的盐是无水单磷酸盐。在一些实施方案中，英菲格拉替尼的药学上可接受的盐是多晶型的无水单磷酸盐，其特征在于15.0°±0.2°处的X射线粉末衍射(XRPD)峰(2θ)(并且可包括如本文所述的该形式的其他XRPD峰)。
本文所提供的药物组合物可以通过多种途径给药，包括但不限于口服(肠内)给药、肠胃外(通过注射)给药、直肠给药、透皮给药、皮内给药、鞘内给药、皮下(SC)给药、静脉内(IV)给药、肌内(IM)给药和鼻内给药。在一些实施方案中，将本文所公开的药物组合物口服给药。
本文所提供的药物组合物也可以长期地给药(“长期给药”)。长期给药是指化合物或其药物组合物在延长的时间段内，例如，在3个月、6个月、1年、2年、3年、5年等内给药，或者可以无限期地持续例如受试者的余生。在具体实施方案中，长期给药旨在提供在血液中恒定水平的化合物，例如，在延长时间段内的治疗窗之内。
本文所提供的药物组合物能够以单位剂型呈现以利于精确给予。术语“单位剂型”是指适合作为用于人类受试者和其他哺乳动物的单位剂量的物理离散单位，每个单位含有预定量的活性材料，其被计算成与合适的药物赋形剂结合起来产生期望的治疗效果。典型的单位剂型包括液体组合物的预填充的预测量安瓿或注射器，或者在固体组合物的情况下包括丸剂、片剂、胶囊等。
在具体实施方案中，将本文所提供的药物组合物以固体剂型给药于患者。在一些实施方案中，固体剂型是胶囊。
在具体实施方案中，本文所提供的化合物可以作为单独的活性剂给药，或者它们可以与其他活性剂组合给药。
虽然本文所提供的药物组合物的描述主要涉及适于向人类给药的药物组合物，但是技术人员将理解，此类组合物通常适于给药于所有种类的动物。对适于给药于人类的药物组合物改良以使得组合物适于给药于各种动物是公知的，并且普通的熟练兽医药理学家可以用普通的实验来设计和/或执行此类改良。药物组合物的配制和/或制造中的一般考虑可例如见于Remington:The Science and Practice of Pharmacy第21版,Lippincott Williams&Wilkins,2005。
局部进展期或复发/转移性胃癌或胃食管交界部腺癌
本发明的目标适应症为局部进展期或复发/转移性胃癌或胃食管交界部腺癌。进展期胃癌指的是癌组织侵达固有肌层或更深者，无论是否有淋巴结转移。胃食管交界部腺癌也称为胃食管结合部腺癌，表示肿瘤中心位于解剖学上食管胃交界处上、下各5cm这段范围内的腺癌，常用分型为Siewert分型。
在局部进展期或复发/转移性胃癌或胃食管交界部腺癌患者的疾病分期，通常采用AJCC(American Joint Committee on Cancer，美国癌症联合委员会)发布的TNM分期标准，最新一版TNM分期标准为AJCC第8版(2017)，如下所示。
其中：T：肿瘤原发病灶，N:区域淋巴结，M:远处转移
此外，图1展示了依据TNM分期标准，对胃癌患者的治疗方案。
胃癌患者如果存在腹膜转移(包括腹膜细胞学诊断阳性结果-发现恶性肿瘤细胞)，远隔转移或局部进展(N3或N4淋巴结浸润或淋巴结侵犯/包绕除了脾脏在内的主要血管结构)则被认为是不可切除类型。此外，胃癌手术不可切患者除主要有以下两类①因肿瘤原因不可切除，包括原发肿瘤外侵严重，与周围正常组织无法分离或已包绕大血管；区域淋巴结转移固定、融合成团，或转移淋巴结不在手术可清扫范围内；肿瘤远处转移或腹腔种植(包括腹腔灌洗液细胞学阳性)等。②因存在手术禁忌证不可切除或拒绝手术者，包括全身情况差(例如严重的低蛋白血症和贫血)、营养不良可能无法耐受手术，合并严重基础疾病不能耐受手术等。
FGFR抑制剂及其在胃癌适应症中的既往研发
成纤维细胞生长因子FGF(fibroblast growth factor)及其受体FGFR(fibroblast growth factor receptor)级联涉及多条细胞内信号传导通路，可调控细胞的增殖、肿瘤生长、血管生成和扩散。FGFR由5种不同的亚型组成，包括FGFR1、FGFR2、FGFR3、FGFR4，以及1种无胞内区域的FGFRL15。其中，4种不同的膜酪氨酸激酶受体(FGFR1-4)在与23种不同的配体之一相结合后被激活，导致新的二聚体转磷酸化。在肿瘤细胞中，FGFR作为癌基因参与肿瘤发生发展进程的多重步骤，通过诱导促有丝分裂和生存信号、促进肿瘤细胞侵袭转移、促进上皮间质转化、促进血管生成及参与肿瘤复发耐药作用。当FGFR信号失调则导致癌症的发生发展、增殖及转移。
目前选择性抑制剂包括BGJ398(英菲格拉替尼)、Erdafitinib、Pemigatinib等被FDA批准用于癌症治疗。
Erdafitinib(JNJ-42756493，Erdafitinib商品名为Balversa)：FDA于2019年4月批准其用于治疗以铂类为基础的化疗后伴有FGFR2/FGFR3改变的局部晚期或转移性尿路上皮癌患者。Erdafitinib常见的不良反应有高磷血症、乏力、口干、眼部不良反应(干眼症、角膜炎、视网膜色素上皮脱离、角膜糜烂等)、指甲不良反应、便秘、厌食等，有14.9％的患者因不良反应停止治疗。尤其要注意的是眼部不良反应，在Erdafitinib治疗中经常发生，约为28％，且多为3级不良反应。
Pemigatinib(商品名为Pemazyre)：FDA于2020年4月批准其用于治疗既往经过至少一线系统性治疗失败的、伴FGFR2融合或重排的、手术不可切除的局部晚期、复发性或转移性胆管癌。常见的不良反应有高磷血症、口腔炎、关节痛、口腔炎、低钠血症等，约19％的患者因不良反应停止治疗。2022年4月，中国NMPA批准了相同适应症。
Futibatinib/TAS-120：一种共价不可逆FGFR1-4抑制剂即泛FGFR抑制剂。FDA授予了Futibatinib突破性药物资格，用于治疗前接受过治疗的FGFR2基因融合或重排的局部晚期或转移性胆管癌。目前正在进行一项Ⅲ期研究，即FOENIX-CCA3试验，旨在比较Futibatinib与顺铂加吉西他滨作为具有FGFR2基因重排的晚期转移性肝内胆管癌患者的一线治疗疗效(NCT04093362)。
另外，在研的选择性FGFR抑制剂还有：Rogaratinib(BAY163877)、Derazantinib(ARQ)、LY2874455、Debio1347(CH5183284)、E7090、PRN1371、ABSK091(AZD4547)、ABSK061、Alofanib(RPT)、CPL304110。
综上所述，FGFR1-3作为一个肿瘤的重要驱动基因靶点，目前有多项研究正在进行中。适应症瘤种多集中在胆管癌，尿路上皮癌。胃癌由于其异质性强，治疗复杂，既往没有药物在该局部进展期或复发/转移性胃癌(GC)或胃食管交界部腺癌(GEJ)成人患者研发成功。基于LB1001-201数据，在末线患者且具有FGFR2基因扩增的患者中具有很好的反应，可能成为潜在的治疗药物。
FGFR2基因扩增的检测
FGFR2基因扩增可通过FISH检测法或NGS检测法确定。
在一个具体实施方案中，采用荧光原位杂交(FISH)方法对受试者的福尔马林固定石蜡包埋(FFPE)肿瘤组织切片样本进行FGFR2基因扩增确证性检测。
具体地，参考沿用基于美国临床肿瘤学会(ASCO)以及美国病理学会(CAP)于2007年颁发的人类表皮生长因子受体2(HER2)临床检测指南中对于FISH检测方法的阳性界限(cut-off)值的判定标准，并基于Nogova等在2016年中牵头的英菲格拉替尼的I期临床研究实践标准，拟定了如下FGFR2基因扩增情况的FISH检测判读办法：在显微镜视野下计数30个肿瘤细胞，计算FGFR2信号与10号染色体计数信号(CSP10)的比值，若FGFR2/CSP10比值≥2.2，或FGFR2信号呈簇状分布，则判读为阳性；若FGFR2/CSP10比值<1.8，则判读为阴性；若1.8≤FGFR2/CSP10比值<2.2，则再扩大20个肿瘤细胞计数，当FGFR2/CSP10比值≥2.0时，结果判读为阳性，而当FGFR2/CSP10比值＜2.0时，结果判读为阴性。
在另一个具体实施方案中，采用NGS检测方法对受试者的福尔马林固定石蜡包埋(FFPE)肿瘤组织切片样本进行FGFR2基因扩增确证性检测。
具体地，在接受由美国临床实验室委员会颁发的实验室资质证书(CLIA)或具有美国病理学家协会(CAP)认证的有资质的第三方NGS实验室中，基于患者FFPE肿瘤组织切片进行的下一代测序(NGS)检测所获取的FGFR2基因扩增阳性结果，均可被认定为有效的阳性检测结果。其中技术方法包括经过方法学验证的目标基因组捕获Panel测序或全外显子组测序(Whole Exome Sequencing，WES)。
使用和治疗方法
在一个方面，本文提供了在有此需要的患者中治疗和/或预防胃癌或胃食管交界部腺癌，尤其是局部进展期或复发/转移性胃癌或胃食管交界部腺癌的方法。在具体实施方案中，所述胃癌或胃食管交界部腺癌是进展期或转移性的。在具体实施方案中，患者在先前给药另一种疗法后具有所述胃癌或胃食管交界部腺癌进展。
在具体实施方案中，本文提供了在有此需要的患者中治疗和/或预防局部进展期或复发/转移性胃癌或胃食管交界部腺癌的方法，该方法包括：给药有效量的英菲格拉替尼或其药学上可接受的盐。
在具体实施方案中，其中患者在先前给药另一种疗法后具有所述胃癌或胃食管交界部腺癌进展。先前给药的另一种疗法是用于治疗所述胃癌或胃食管交界部腺癌的疗法。在一些实施方案中，先前给药另一种疗法是给药化疗剂。在一些实施方案中，先前给药的化疗剂是含吉西他滨的方案。 在一些实施方案中，含吉西他滨的方案包括吉西他滨。在一些实施方案中，含吉西他滨的方案包括吉西他滨和顺铂。
在具体实施方案中，先前给药另一种疗法是给药选自以下的另一种化疗剂：5-氟尿嘧啶、吉西他滨、顺铂、卡培他滨、奥沙利铂，及其组合。
在具体实施方案中，先前给药另一种疗法是给药受体酪氨酸激酶抑制剂。
在具体实施方案中，受体酪氨酸激酶抑制剂是FGFR1、FGFR2和/或FGFR3的选择性非共价结合抑制剂。在一些实施方案中，FGFR1、FGFR2和/或FGFR3的选择性非共价结合抑制剂选自佩米替尼、罗加替尼、德拉赞替尼、Debio1347、AZD4547、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。
在具体实施方案中，受体酪氨酸激酶抑制剂是FGFR1、FGFR2、FGFR3和/或FGFR4的选择性非共价结合抑制剂。在一些实施方案中，FGFR1、FGFR2、FGFR3和/或FGFR4的选择性非共价结合抑制剂选自厄达替尼、LY2874455、PRN 1371、ASP5878，及其组合。
在具体实施方案中，受体酪氨酸激酶抑制剂是FGFR1、FGFR2、FGFR3和/或FGFR4的选择性共价结合抑制剂。在一些实施方案中，FGFR1、FGFR2、FGFR3和/或FGFR4的选择性共价结合抑制剂是TAS120。
在具体实施方案中，受体酪氨酸激酶抑制剂是非选择性酪氨酸激酶抑制剂。在一些实施方案中，非选择性酪氨酸激酶抑制剂选自帕纳替尼、多韦替尼、levatanib、ACTB-1003、Ki8751、lucitinib、马赛替尼、木利替尼、尼达尼布、奥伦替尼、PD089828，及其组合。
在具体实施方案中，先前给药另一种疗法是给药另一种选择性FGFR抑制剂。在一些实施方案中，另一种选择性FGFR抑制剂选自佩米替尼、罗加替尼、德拉赞替尼、AZD4547、Debio1347、ASP5878、厄达替尼、LY2874455、PRN1371、TAS120、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。在一些实施方案中，另一种选择性FGFR抑制剂是选择性共价结合抑制剂。在一些实施方案中，选择性共价结合抑制剂是TAS120。在一些实施方案中，另一种选择性FGFR抑制剂是选择性非共价结合抑制剂。在一些实施方案中，选择性非共价结合抑制剂是佩米替尼、罗加替尼、德拉赞替尼、AZD4547、厄达替尼、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。
在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR1基因融合、易位或另一种遗传改变。在一些实施方案中，FGFR1基因融合包含选自以下的FGFR1基因融合配偶体：BAG4、ERLIN2、NTM、FGFR1OP2、TACC3和TRP。
在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR2基因融合、易位或另一种遗传改变。在一些实施方案中，FGFR2基因融合包含选自以下的FGFR2基因融合配偶体：10Q26.13、AFF1、AFF3、AFF4、AHCYL1、ALDH1L2、ARFIP1、BAG4、BAIAP2L1、BICC1、C10orf118、C10orf68、C7、CASC15、CASP7、CCDC147、CCDC6、CELF2、CIT、COL14A1、CREB5、CREM、DNAJC12、ERLIN2、HOOK1、INA、KCTD1、KIAA1217、KIAA1598、KIAA1967、KIFC3、MGEA5、NCALD、NOL4、NPM1、NRAP、OFD1、OPTN、PARK2、PAWR、PCMI、PDHX、PHLDB2、PPAPDC1A、PPHLN1、RASAL2、SFMBT2、SLC45A3、SLMAP、SLMAP2、SORBS1、STK26、STK3、TACC1、TACC2、TACC3、TBC1D1、TEL、TFEC、TRA2B、UBQLN1、VCL、WAC、ZMYM4、FGFROP2，及其组合。在一些实施方案中，FGFR2基因融合包含选自以下的FGFR2基因融合配偶体：10Q26.13、AFF1、AFF4、AHCYL1、ALDH1L2、ARFIP1、BICC1、C10orf118、C7、CCDC147、CCDC6、CELF2、CREB5、CREM、DNAJC12、HOOK1、KCTD1、KIAA1217、KIAA1598、KIFC3、MGEA5、NOL4、NRAP、OPTN、PARK2、PAWR、PCMI、PHLDB2、PPHLN1、RASAL2、SFMBT2、SLMAP、SLMAP2、SORBS1、STK26、STK3、TACC3、TBC1D1、TFEC、TRA2B、UBQLN1、VCL、WAC、ZMYM4，及其组合。
在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR3基因融合、易位或另一种遗传改变。在一些实施方案中，FGFR3基因融合包含选自以下的FGFR2基因融合配偶体：BAIAP2L1、JAKMIP1、TACC3、TNIP2、WHSC1，及其组合。在一些实施方案中，FGFR3基因融合包含FGFR3基因融合配偶体，其中FGFR基因融合配偶体是TACC3。
在具体实施方案中，患者经历分子预筛，例如使用第二代测序、循环肿瘤DNA分析或荧光原位杂交测定，以确定所述胃癌或胃食管交界部腺癌是否具有FGFR1、FGFR2、或FGFR3基因融合、易位或另一种遗传改变。在一些实施方案中，分子预筛发生在给药有效量的英菲格拉替尼或其药学上可接受的盐之前。在一些实施方案中，分子预筛发生在先前给药另一种疗法之前。
在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR1、FGFR2和/或FGFR3突变。在一些实施方案中，FGFR1、FGFR2和/或FGFR3突变选自FGFR1G818R、FGFR1K656E、FGFR1N546K、FGFR1R445W、FGFR1T141R、FGFR2A315T、FGFR2C382R、FGFR2D336N、FGFR2D471N、FGFR2E565A、FGFR2I547V、FGFR2K641R、FGFR2K659E、FGFR2K659M、FGFR2L617V、FGFR2N549H、FGFR2N549K、FGFR2N549S、FGFR2N549Y、FGFR2N550K、FGFR2P253R、FGFR2S252W、FGFR2V395D、FGFR2V564F、FGFR2Y375C、FGFR3A391E、FGFR3D785Y、FGFR3E627K、FGFR3G370C、FGFR3G380R、FGFR3K650E、FGFR3K650M、FGFR3K650N、FGFR3K650T、FGFR3K652E、FGFR3N540S、FGFR3R248C、FGFR3R399C、FGFR3S131L、FGFR3S249C、FGFR3S371C、FGFR3V555M、FGFR3V677I、FGFR3Y373C、FGFR4D425N、FGFR4R183S、FGFR4R394Q、FGFR4R610H、FGFR4V510L，及其组合。在一些实施方案中，FGFR1、FGFR2和/或FGFR3突变选自FGFR1N546K、FGFR1K656E、FGFR2S252W、FGFR2P253R、FGFR2A315T、FGFR2Y375C、FGFR2C382R、FGFR2N549K、FGFR2K659E、FGFR3R248C、FGFR3S249C、FGFR3G370C、FGFR3S371C、FGFR3Y373C、FGFR3G380R、FGFR3K650E、FGFR3K650M，及其组合。
在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR1基因融合和FGFR1突变。在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR1基因融合和FGFR2突变。在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR1基因融合和FGFR3突变。
在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR2基因融合和FGFR1突变。在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR2基因融合和FGFR2突变。在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR2基因融合和FGFR3突变。
在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR3基因融合和FGFR1突变。在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR3基因融合和FGFR2突变。在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR3基因融合和FGFR3突变。
在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR1、FGFR2和/或FGFR3的基因扩增。
在具体实施方案中，所述胃癌或胃食管交界部腺癌具有FGFR2基因扩增，并且所述FGFR2基因扩增通过FISH检测法或NGS检测法确定。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括给药约125mg的英菲格拉替尼或其药学上可接受的盐。
在具体实施方案中，将有效量的英菲格拉替尼或其药学上可接受的盐每天一次给药于患者。
在具体实施方案中，将有效量的英菲格拉替尼或其药学上可接受的盐口服给药于患者。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括每天一次口服给药约25mg的英菲格拉替尼或其药学上可接受的盐。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括每天一次口服给药约50mg的英菲格拉替尼或其药学上可接受的盐。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括每天一次口服给药约75mg的英菲格拉替尼或其药学上可接受的盐。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括每天一次口服给药约100mg的英菲格拉替尼或其药学上可接受的盐。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括每天一次口服给药约125mg的英菲格拉替尼或其药学上可接受的盐。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括28天周期，其中连续3周(21天)内每天一次向患者给药约25mg的英菲格拉替尼或其药学上可接受的盐，并且后续在1周(7天)内不给药英菲格拉替尼。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括28天周期，其中连续3周(21天)内每天一次向患者给药约50mg的英菲格拉替尼或其药学上可接受的盐，并且后续在1周(7天)内不给药英菲格拉替尼。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括28天周期，其中连续3周(21天)内每天一次向患者给药约75mg的英菲格拉替尼或其药学上可接受的盐，并且后续在1周(7天)内不给药英菲格拉替尼。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括28天周期，其中连续3周(21天)内每天一次向患者给药约100mg的英菲格拉替尼或其药学上可接受的盐，并且后续在1周(7天)内不给药英菲格拉替尼。
在具体实施方案中，给药有效量的英菲格拉替尼或其药学上可接受的盐包括28天周期，其中连续3周(21天)内每天一次向患者给药约125mg的英菲格拉替尼或其药学上可接受的盐，并且后续在1周(7天)内不给药英菲格拉替尼。
在具体实施方案中，将有效量的英菲格拉替尼或其药学上可接受的盐给药于患者两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个或十二个连续28天的周期。
在具体实施方案中，将约125mg的英菲格拉替尼或其药学上可接受的盐以单位剂量提供。在具体实施方案中，将约100mg的英菲格拉替尼或其药学上可接受的盐以单位剂量提供。在具体实施方案中，将约75mg的英菲格拉替尼或其药学上可接受的盐以单位剂量提供。在具体实施方案中，将约50mg的英菲格拉替尼或其药学上可接受的盐以单位剂量提供。在具体实施方案中，将约25mg的英菲格拉替尼或其药学上可接受的盐以单位剂量提供。
在一些实施方案中，将约125mg的英菲格拉替尼或其药学上可接受的盐以单位剂量提供。在一些实施方案中，将约125mg的英菲格拉替尼或其药学上可接受的盐以100mg单位剂量和25mg单位剂量提供。在一些实施方案中，将约125mg的英菲格拉替尼或其药学上可接受的盐以75mg单位剂量和50mg单位剂量提供。
在具体实施方案中，将约100mg的英菲格拉替尼或其药学上可接受的盐以75mg单位剂量和25mg单位剂量提供。在一些实施方案中，将约100mg的英菲格拉替尼或其药学上可接受的盐以两个50mg单位剂量提供。
在具体实施方案中，将约75mg的英菲格拉替尼或其药学上可接受的盐以50mg单位剂量和25mg单位剂量提供。
在具体实施方案中，将约50mg的英菲格拉替尼或其药学上可接受的盐以两个25mg单位剂量提供。
在具体实施方案中，将约125mg的英菲格拉替尼或其药学上可接受的盐口服给药于患者。在具体实施方案中，将约100mg的英菲格拉替尼或其药学上可接受的盐口服给药于患者。在具体实施方案中，将约75mg的英菲格拉替尼或其药学上可接受的盐口服给药于患者。在具体实施方案中，将约50mg的英菲格拉替尼或其药学上可接受的盐口服给药于患者。在具体实施方案中，将约25mg的英菲格拉替尼或其药学上可接受的盐口服给药于患者。
在一些实施方案中，该方法还包括将有效量的英菲格拉替尼或其药学上可接受的盐给药于处于禁食状态的有此需要的患者。在一些实施方案中，有效量的英菲格拉替尼或其药学上可接受的盐应当在患者进食前至少1小时给药于有此需要的患者。在一些实施方案中，有效量的英菲格拉替尼或其药学上可接受的盐应当在患者进食后至少2小时给药于有此需要的患者。
在具体实施方案中，所述胃癌或胃食管交界部腺癌经组织学或细胞学证实。在一些实施方案中，所述胃癌或胃食管交界部腺癌经组织学证实。在一些实施方案中，所述胃癌或胃食管交界部腺癌经细胞学证实。
在具体实施方案中，该方法包括将有效量的英菲格拉替尼的药学上可接受的盐给药于有此需要的患者。在一些实施方案中，英菲格拉替尼的药学上可接受的盐是单磷酸盐。在一些实施方案中，英菲格拉替尼的药学上可接受的盐是无水单磷酸盐。在一些实施方案中，英菲格拉替尼的药学上可接受的盐是多晶型的无水单磷酸盐，其特征在于15.0°±0.2°处的X射线粉末衍射(XRPD)峰(2θ)。在一些实施方案中，本文描述了英菲格拉替尼的无水结晶单磷酸盐的多晶型。
在另一方面，本文提供了在有此需要的患者中治疗和/或预防局部进展期或复发/转移性胃癌或胃食管交界部腺癌的方法，该方法包括：给药本文所公开的任一种药物组合物，其中患者在先前给药另一种疗法后具有所述胃癌或胃食管交界部腺癌进展。
实施例
为了可以更充分地理解本文所述的本发明，阐述了以下实施例。本申请中描述的合成和生物实施例被提供成用于说明本文所提供的化合物、药物组合物和方法，并且不以任何方式解释为限制其范围。
实施例1：3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-4-(4-乙基-哌嗪-1-基)-苯氨基-嘧啶-4-基}-1-甲基-脲(英菲格拉替尼)的合成
步骤A：N-4-(4-乙基-哌嗪-1-基)-苯基)-N'-甲基-嘧啶-4,6-二胺的合成
将4-(4-乙基哌嗪-1-基)-苯胺(1g，4.88mmol)、(6-氯-嘧啶-4-基)-甲基-胺(1.81g，12.68mmol，1.3当量)和4N HCl在二氧杂环己烷(15mL)中的混合物在密封管中加热至150℃达5小时。将反应混合物浓缩，用二氯甲烷(DCM)和饱和碳酸氢钠水溶液稀释。将水层分离并用DCM萃取。将有机相用盐水洗涤、干燥(硫酸钠)，过滤并浓缩。通过硅胶柱色谱法(DCM/MeOH，93:7)纯化残余物，然后在二乙醚中研磨，得到呈白色固体的标题化合物：ESI-MS:313.2[MH]+；tR＝1.10分钟(梯度J)；TLC：Rf＝0.21(DCM/MeOH，93:7)。
步骤B：4-(4-乙基哌嗪-1-基)-苯胺的合成
在氢气气氛下，将1-乙基-4-(4-硝基-苯基)-哌嗪(6.2g，26.35mmol)和雷尼镍(2g)在MeOH(120mL)中的悬浮液在室温下搅拌7小时。将反应混合物过滤通过硅藻土垫并浓缩，得到5.3g呈紫色固体的标题化合物：ESI-MS:206.1[MH]+；TLC：Rf＝0.15(DCM/MeOH+1％NH3 aq，9:1)。
步骤C：1-乙基-4-(4-硝基-苯基)-哌嗪的合成
将1-溴-4-硝基苯(6g，29.7mmol)和1-乙基哌嗪(7.6mL，59.4mmol，2当量)的混合物加热至80℃达15小时。在冷却至室温之后，将反应混合物用水和DCM/MeOH(9:1)稀释。将水层分离并用DCM/MeOH(9:1)萃取。将有机相用盐水洗涤、干燥(硫酸钠)，过滤并浓缩。通过硅胶柱色谱法(DCM/MeOH+1％NH3 aq，9:1)纯化残余物，得到6.2g呈黄色固体的标题化合物：ESI-MS:236.0[MH]+；tR＝2.35分钟(纯度：100％，梯度J)；TLC：Rf＝0.50(DCM/MeOH+1％NH3 aq，9:1)。
步骤D：(6-氯-嘧啶-4-基)-甲基-胺的合成
该材料通过文献中公开的改良程序制备(J.Appl.Chem.1955,5,358)：向市售的4,6-二氯嘧啶(20g，131.6mmol，1.0当量)在异丙醇(60mL)中的悬浮液添加含33％甲胺的乙醇(40.1mL，328.9mmol，2.5当量)，添加速率使得内部温度不升高超过50℃。在添加完成之后，将反应混合物在室温下搅拌1小时。然后，添加水(50mL)并使所形成的悬浮液在冰浴中冷却至5℃。将沉淀的产物滤出，用冷异丙醇/水2:1(45mL)和水洗涤。将收集的材料在45℃下真空干燥过夜，得到呈无色粉末的标题化合物：tR＝3.57分钟(纯度：>99％，梯度A)，ESI-MS:144.3/146.2[MH]+。
步骤E：3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-4-(4-乙基-哌嗪-1-基)-苯 氨基-嘧啶-4-基}-1-甲基-脲的合成
通过将2,6-二氯-3,5-二甲氧基苯基-异氰酸酯(1.25当量)添加到N-4-(4-乙基-哌嗪-1-基)-苯基)-N'-甲基-嘧啶-4,6-二胺(2.39g，7.7mmol，1当量)的甲苯溶液中，并将反应混合物回流搅拌1.5小时来制备标题化合物。通过硅胶柱色谱法(DCM/MeOH+1％NH3 aq，95:5)纯化粗产物，得到呈白色固体的标题化合物：ESI-MS:560.0/561.9[MH]+；tR＝3.54分钟(纯度：100％，梯度J)；TLC：Rf＝0.28(DCM/MeOH+1％NH3 aq，95:5)。分析：C26H31N7O3Cl2，计算值C，55.72％；H，5.57％；N，17.49％；O，8.56％；C1，12.65％。实测值C，55.96％；H，5.84％；N，17.17％；O，8.46％；C1，12.57％。
实施例2：3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-4-(4-乙基-哌嗪-1-基)-苯氨基-嘧啶-4-基}-1-甲基-脲的单磷酸盐形式A(BGJ398)的合成
向圆底烧瓶中添加3-(2,6-二氯-3,5-二甲氧基苯基)-1-(6-4-(4-乙基哌嗪-1-基)苯氨基-嘧啶-4-基)-1-甲基-脲(134g，240mmol)和异丙醇(IPA)(2000mL)。将悬浮液搅拌并加热至50℃，并向其中分批添加磷酸(73.5g，750mmol)的水(2000mL)溶液。将混合物在60℃下搅拌30分钟并过滤通过聚丙烯垫。将垫用温热的IPA/水(1:1，200mL)洗涤，并且合并滤液。向该澄清溶液中添加IPA(6000mL)，并将混合物回流搅拌20分钟，缓慢冷却至室温(25℃)，并搅拌24小时。将白色盐产物通过过滤收集，用IPA(2×500mL)洗涤并在60℃的烘箱中减压干燥两天，以提供无水结晶单磷酸盐(110g)。收率70％。纯度>98％，通过HPLC确定。分析：C26H34N7O7Cl2P，计算值C，47.42％；H，5.20％；N，14.89％；O，17.01％；C1，10.77％；P，4.70％。实测值C，47.40％；H，5.11％；N，14.71％；O，17.18％；Cl，10.73％；P，4.87％。
实施例3：25mg、100mg和125mg剂量英菲格拉替尼药物制剂的制造过程
在以下实施例中，概述了所有示例性剂量强度的制造过程。
在以下实施例3.1、3.2和3.3的配方中提供了各成分的相应量。
药物共混物的制造
将纤维素MK-GR、乳糖(研磨的)、英菲格拉替尼、纤维素HPM603和交联聚乙烯吡咯烷酮(PVP-XL)依序添加到立式湿法高剪切制粒机(例如TK Fiedler(底部驱动，65L)中，其中制粒机填充体积为约45-50％，然后，将五种组分在60-270rpm，优选地150rpm的叶轮设定；以及600-3000rpm，优选地1500rpm的切碎机设定下混合约5分钟，以获得干燥共混物。
在1.5巴的喷雾设定压力下(叶轮设定为60-270rpm，优选地150rpm；并且切碎机设定为600-3000rpm，优选地1500rpm)，将纯化水作为制粒液体以约385g/分钟的速率在7分钟内添加(添加多至约2.7kg的水)。将所得的制粒混合物捏合约3分钟(叶轮设定为60-270rpm，优选地150rpm；并且切碎机设定为600-3000rpm，优选地1500rpm)。使用Comil以90-600rpm将捏合的制粒团块通过3.0mm筛进行过筛。该工序是可选的并且可省略，但优选地执行该工序。
将颗粒在流化床干燥器(例如Glatt GPCG 15/30或等同物)中干燥，其中入口空气温度为55-65℃，优选地60℃，产物温度为约30-40℃，并且入口空气体积为300-1200m3/h，以达到≤2.2％的干燥终点。
在Comil中，将干燥的颗粒通过800-1000μm过筛。所得的干燥和过筛的颗粒也在本文中称为内相。
在Comil中约50-150rpm下，将外相赋形剂PVP XL和Aerosil 200通过900-1000μm过筛，然后在合适的容器(例如，箱式混合器turbula或等同物)中通过以4-25rpm，优选地17rpm混合约5分钟(33-66％粉末填充)与内相合并。
通过在扩散混合器(转鼓)或箱式混合器(例如，Bohle PM400，Turbula，或等同物)中以约17rpm共混约3分钟，通过添加500rpm过筛的硬脂酸镁作为额外的外相赋形剂来润滑固体，以获得准备用于胶囊填充的最终共混物。
胶囊的制造
然后，通过具有给予板原理或给予管的包囊机(例如，&Karg GKF 330、Bosch GKF 1500、Zanasi 12E、Zanasi 40E)，将最终共混物填充到0、1或3规格的硬明胶胶囊(HGC)中，其中包囊速度为10,000多至100,000个胶囊/小时且无预压缩。控制胶囊的重量并对胶囊除尘。
实施例3.1
表1：25mg剂量强度的配方
a盐因子为1.175。如果含量≤99.5％，则必须调整药物物质的量。通过调整乳糖含量进行相应的补偿。
b在干燥过程中除去制粒期间使用的水。
实施例3.2
表2：100mg剂量强度的配方

a盐因子为1.175。如果含量≤99.5％，则必须调整药物物质的量。通过调整乳糖含量进行相应的补偿。
b在干燥过程中除去制粒期间使用的水。
实施例3.3
表3：125mg剂量强度的配方
a盐因子为1.175。如果含量≤99.5％，则必须调整药物物质的量。通过调整乳糖含量进行相应的补偿。
b在干燥过程中除去制粒期间使用的水。
实施例4：英菲格拉替尼的临床前体外数据
生化试验中的激酶选择性：在生化试验中，已证明英菲格拉替尼是重组人FGFR1、FGFR2和FGFR3的强效ATP竞争性抑制剂，IC50值可分别达到1.1nM、1.0nM和2.0nM(研究RD-2018-00444)。FGFR4、VEGFR2/KDR、LYN(1-512)和KIT的IC50值分别为0.061μM(61nM)、0.21μM(210nM)、0.3μM(300nM)和0.81μM(810nM)。在包含126种激酶的组合试验中抑制所有其他激酶的IC50值均>1μM或10μM。总之，生化激酶数据为英菲格拉替尼作为一种强效选择性FGFR1-3抑制剂提供了支持。
细胞试验中靶激酶磷酸化的抑制：为了确认英菲格拉替尼对酶活性的抑制可转化为对细胞中相应靶激酶的抑制，在人胚肾(HEK)293细胞中评估了英菲格拉替尼抑制野生型FGFR1和FGFR2以及组成型激活突变型FGFR3磷酸化的能力(研究RD-2005-01708、RD-2005-01709、RD-2005-01712、RD-2005-01668)。英菲格拉替尼可抑制HEK293细胞中FGFR1和FGFR2的酪氨酸磷酸化，IC50值分别为4.6nM和4.3nM。英菲格拉替尼可抑制HEK293细胞中EFGFR3K650E和FGFR3S249C的酪氨酸磷酸化，IC50值分别为5.6nM和4.8nM。与英菲格拉替尼对FGFR1-3酪氨酸磷酸化的抑制作用相比，其对FGFR4酪氨酸磷酸化的抑制作用要低几个数量级(IC50值为164nM)。
英菲格拉替尼在人癌细胞系中的抗增殖活性：英菲格拉替尼选择性抑制携带FGFR遗传变异和/或蛋白质过表达的人癌细胞系的增殖，而不抑制其中FGFR1-3未表达或未变异的癌细胞系的增殖(研究RD-2006-01656、RD-2006-01990、RD-2006-01719、RD-2007-01092、RD-2009-00471)。通过监测(FGFR底物2(FRS2)酪氨酸磷酸化和ERK/MAPK活化，在敏感的癌细胞系中分析了英菲格拉替尼抑制FGFR下游信号传导的能力(研究RD-2006-01812)。英菲格拉替尼在抑制细胞增殖所需的英菲格拉替尼浓度下消除了FRS2酪氨酸磷酸化。根据pERK/pMAPK评估的结果，在抑制pFRS2的同时也抑制了RAS-MAPK途径。
主要人体代谢物BHS697、CQM157和乙酰基-CQM157与FGFR1-4的结合和细胞活性代谢物BHS697和CQM157在结合和药理学活性方面与英菲格拉替尼的活性相似；且其与英菲格拉替尼相似，对FGFR1-3的效力也高于FGFR4(研究QED003-01-s-00001、QED008-01-s-00001、QED016-01-s-00001、RD-2007-01094、RD-2005-01708、RD-2005-01709、RD-2005-01712、RD-2005-01668)。乙酰基-CQM157与英菲格拉替尼的结合受体相同(研究QED020-01-s-00001)。
实施例5：英菲格拉替尼的临床前体内研究
研究了英菲格拉替尼在FGFR引起的人脑癌、胃癌、乳腺癌和肝癌PDX模型中的抗肿瘤疗效。
在免疫功能低下的小鼠中建立皮下植入的各种组织来源的PDX肿瘤(每组n＝10)。平均肿瘤大小约为150mm3时开始治疗。经口给予溶媒和英菲格拉替尼(30mg/kg)，QD给药，持续3周。结果总结请见表4。
表4采用英菲格拉替尼(30mg/kg)治疗FGFR引起的脑、胃、乳腺和肝PDX模型的总结
缩写词:FGFR＝成纤维细胞生长因子受体；PDX＝患者来源的异种移植瘤；TGI＝肿瘤生长抑制率。
aTGI的计算公式为:TGI％＝[1-(Ti-T0)/(Ci-C0)]×100；Ti和Ci分别是治疗最后一天治疗组和对照组的平均肿瘤体积；T0和C0分别是第0天治疗组和对照组的平均肿瘤体积。
b通过Mann-Whitiey U检验比较预先规定日期两组间肿瘤体积的p值。
c该胶质瘤模型包含FGFR3-TACC3融合，伴有FGFR3激酶结构域缺失(KD del)和一致的FGFR1扩增曾(amp)。
该体内研究证明了英菲格拉替尼治疗FGFR引起人脑癌、胃癌、乳腺癌和肝癌，尤其是胃癌的有效性。
实施例6：安全药理学
为了评价对心脏传导的潜在影响，在HEK293细胞中检测了英菲格拉替尼对hERG钾离子通道电流的影响(研究0870331)。在1-10μM浓度范 围内，观察到英菲格拉替尼对hERG电流产生浓度依赖性抑制，抑制率范围为28.1％-93.8％。计算得出英菲格拉替尼抑制hERG电流的IC50值为2.0μM(1.1μg/mL)，相比人体暴露量约为104倍。在临床推荐剂量125mg QD英菲格拉替尼下，Cmax为330.3ng/mL(0.3303μg/mL)。基于英菲格拉替尼的平均未结合分数3.2％，预计未结合血浆Cmax为0.0106μg/mL，因此可在125mg QD英菲格拉替尼的推荐临床剂量下提供104倍的暴露比(1.1μg/mL/0.0106μg/mL)。因此，在具有临床意义的暴露量下，英菲格拉替尼不太可能引起QT间期延长(研究QEDT-NCA、BGJ398-872)。同时还分别在清醒遥测犬或夹套犬中评价了英菲格拉替尼单次给药(研究0870300)或给药2周(研究0770101)后的心血管不良反应。但在两项研究中均未观察到ECG、心率、动脉血压和/或体温方面与英菲格拉替尼给药相关的变化。此外还在持续时间≥4周的关键性犬重复给药毒性研究中评价了英菲格拉替尼对心血管参数(心率和ECG)的影响。在任何研究中均未观察到心率或ECG变化。成年雄性大鼠接受10mg/kg英菲格拉替尼单次经口给药后，基于定性或定量功能观察组合参数，在给药后24小时内未观察到对神经系统产生毒理学相关影响(研究0870302)。在同一研究中，也未在通过体积描记法测量的任何呼吸参数(潮气量、呼吸频率和分钟通气量)方面观察到与治疗相关的影响。
实施例7：英菲格拉替尼(Infigratinib,BGJ398)的IIa期临床试验
正在进行的研究LB1001-201，是一项评价口服英菲格拉替尼治疗伴有FGFR2基因扩增的局部进展期或转移性胃癌或胃食管结合部腺癌的多中心、开放、单臂的IIa期临床试验。研究关键信息如下：
研究目的
本研究被设计成通过估计客观缓解率来评价靶向选择性泛FGFR抑制剂BGJ398在伴有FGFR2基因扩增的局部进展期或转移性胃癌或胃食管结合部腺癌患者中的功效。
主要目的：
-评价英菲格拉替尼治疗伴有FGFR2基因扩增的GC/GEJ受试者的客观缓解率(ORR)；
次要目的：
-评价英菲格拉替尼治疗伴有FGFR2基因扩增的GC/GEJ受试者的DOR(缓解持续时间)、DCR(疾病控制率)、BOR(最佳总体缓解)、PFS(无进展生存期)和OS(总生存期)；
-评估英菲格拉替尼的安全性和耐受性；
-评价英菲格拉替尼治疗伴有FGFR1、FGFR2或FGFR3基因融合/重排/激活突变的GC/GEJ受试者中的疗效；
-评价英菲格拉替尼和活性代谢产物(必要时，可检测BHS697，CQM157和BQR917)的药代动力学(PK)特征
患者群体及主要入组标准
胃癌/胃食管结合部腺癌患者的关键入组要求
①年龄18-75周岁，男性或女性；
②经组织学或细胞学证实的局部进展期或转移性胃癌或胃食管交界处腺癌；
③既往接受过二线及以上治疗失败的患者，前期治疗允许为靶向药物、免疫抑制剂或放疗，化疗联合靶向药物等；但需要排外既往使用过高选择性FGFR抑制剂或MAPK-MEK通路抑制剂患者；
④皮质脑电图(ECOG)状态为0或1；
⑤适当的器官功能和实验室数值；
⑥疾病可通过RECIST v1.1测量；
⑦具有FGFR2基因扩增检测(FISH法)为阳性。
样本量
约20-30例受试者(伴有FGFR2基因扩增的GC/GEJ)。
终点指标
主要终点：
-ORR：确认缓解为CR或PR的受试者比例；由研究者或独立评审委员会根据实体瘤疗效评价标准(RECIST v1.1)进行肿瘤缓解状态的评估(时间范围：前33周，每8周1次；之后每12周1次)；
次要终点：
-DOR：从首次评价为CR或PR至首次评价为PD或任何原因死亡的时间间隔(将报告DOR≥6个月、≥9个月和≥12个月的受试者百分比)。(时间范围：前33周，每8周1次；之后每12周1次)；
-安全性：不良事件(AE)和严重AE(SAE)、实验室检查异常和其他安全性结果的类型、频率和严重程度(时间范围：第1周期(W2/W3/W4)，第2/3周期(W1/3)，第4周期(W1)，之后每个周期检查1次)；基于常见不良事件评价标准(CTCAE)第5.0版评估安全性。
-DCR：被确认为CR(完全缓解)或PR(部分缓解)或SD(疾病进展)(RECIST v1.1)的受试者比例(时间范围：前33周，每8周1次；之后每12周1次)；
-BOR：从治疗开始至疾病进展/复发时记录的最佳缓解。评估为CR者，需从评估之日起至少4周确认CR，评估为PR者，需从评估之日起至少4周确认PR；
-PFS：从首次治疗之日至由研究者确定的疾病进展或因任何原因死亡之日的时间(时间范围：前33周，每8周1次；之后每12周1次)；
-OS：从首次治疗之日至死亡之日的时间(时间范围：前33周，每8周1次；之后每12周1次)；
-PK参数包括Cmax，AUC，CL/F，t1/2，蓄积因子等，将采用非房室模型进行分析。
FGFR2基因扩增的检测：
-在LB1001-201研究中采用荧光原位杂交(FISH)方法对受试者的福尔马林固定石蜡包埋(FFPE)肿瘤组织切片样本进行FGFR2基因扩增确证性检测。
-研究中参考沿用基于美国临床肿瘤学会(ASCO)以及美国病理学会(CAP)于2007年颁发的人类表皮生长因子受体2(HER2)临床检测指南中对于FISH检测方法的阳性界限(cut-off)值的判定标准，并基于Nogova等在2016年中牵头的英菲格拉替尼的I期临床研究实践标准，拟定了如下FGFR2基因扩增情况的FISH检测判读办法：在显微镜视野下计数30个肿瘤细胞，计算FGFR2信号与10号染色体计数信号(CSP10)的比值，若FGFR2/CSP10比值≥2.2，或FGFR2信号呈簇状分布，则判读为阳性；若FGFR2/CSP10比值<1.8，则判读为阴性；若1.8≤FGFR2/CSP10比值<2.2，则再扩大20个肿瘤细胞计数，当FGFR2/CSP10比值≥2.0时，结果判读为阳性，而当FGFR2/CSP10比值＜2.0时，结果判读为阴性。
-由实验室进行肿瘤活检或FFPE样本的FGFR2扩增检测，通过FISH法。
治疗方案
筛选合格的受试者口服接受英菲格拉替尼(125mg，QD；以28天为一个给药周期，连续给药3周，停药1周)治疗，直至发生不可耐受的毒性、或疾病进展、或撤回知情同意、或死亡、失访、或开始接受新的抗肿瘤治疗等(以先发生者为准)。
根据方案要求，基于药物相关副作用及其严重程度进行剂量调整。
治疗期间，将在W9、W17、W25、W33及之后每12周(时间窗：±7天)通过CT/MRI对受试者进行肿瘤评估。安全性评估：第1周期(W2/W3/W4)、第2/3周期(W1/W3)、第4周期(W1)及之后每个周期评估1次，包括实验室检查、12导联心电图等。将采集血液样本用于PK分析。
评价
本研究将评价英菲格拉替尼的有效性、PK、安全性等指标，其中有效性评价包括ORR、DOR、DCR、BOR、PFS、OS；PK参数包括：单次给药：Cmax、Tmax、t1/2、AUC0-t、AUCinf、CL/F、Vz/F、MRT等；多次给药：Cmax,ss、Tmax,ss、t1/2,ss、Cav,ss、AUC0-t,ss、CLss/F、Vss/F、Rac、Cmin、代谢物：比率(代谢产物/原型药物)等；安全性评价将在筛选阶段和整个治疗期间进行访视时评估：包括不良事件(AE和SAE)、临床实验室检查(用于临床实验室参数的血样采集)、妊娠检查、生命体征、体格检查和心电图(ECG)、左室射血分数(LVEF)和眼科评估等。
统计方法
-客观缓解率(ORR)和疾病控制率(DCR)(研究者评估)：使用描述性统计，并提供准确的95％置信区间(CI)。BOR将使用描述性统计。
-到事件终点的时间(PFS,DOR和OS)使用Kaplan-Meier(KM)分析总结了接受至少一剂英菲格拉替尼的患者。
-使用频率和百分比分布分析了接受至少一剂英菲格拉替尼的患者的安全性终点。
结果
截至2023年2月15日，招募了21名患者，并接受至少一剂英菲格拉替尼。其中20名具有至少一个可评估的基线后肿瘤评估(根据RECIST v1.1)。人口统计学和基线疾病特征见表5。
表5
百分比基于完整分析集中每组受试者的受试者数量。
有效性
·前五的转移部位分别为淋巴结转移(71.4％)、腹膜转移(42.9％)、肝转移(28.6％)、骨转移(19.0％)和肺转移(19.00％)
·在20名可评估响应的患者中，确认的ORR(cORR)为25.0％(95％CI:8.7％-49.1％)，DCR为80.0％(95％CI:56.3％-94.3％)，见表6。
·中位mPFS为3.3个月(95％CI:2.3,4.5)，中位OS为8.0个月(95％CI:4.1,NE)，见表7。
·19名患者中有15名(78.9％)在至少一次肿瘤评估中发现肿瘤缩小，而且9名患者(47.3％)在至少一次肿瘤评估中取得了PR(包括5名患者具有确认的PR)，见图2。自基线的最大肿瘤消退为78.5％，见图3。
表6
ORR＝确认的CR+确认的PR。uORR＝CR+PR，不论是否确认。DCR＝确认的CR+确认的PR+SD。
表7

百分比基于完整分析集中每组受试者的受试者数量。
OS定义为从第一次治疗到死亡的时间。
最小值和最大值表示截尾观测。
对于四分位数，NE表示该值不可估计。
安全性
药物相关AE、严重(3级)药物相关AE见表8和表9；没有药物诱导的肝损伤(DILI)的病例。
表8：按SOC和PT分类的英菲格拉替尼相关CTCAE等级≥3TEAE汇总

表9：按SOC和PT分类的英菲格拉替尼治疗相关的SAE
表8和表9的TEAE定义为英菲格拉替尼首次给药后和最后一次给药之后30天内新发生或恶化的任何不良事件(首次给药前的不良反应或预先存在的情况)，或首次给药后与英菲格拉替尼治疗相关的任何不良反应。
在同一优选术语中多次发生不良反应的受试者在该优选术语中仅被计算一次。在同一系统器官类别中多次发生不利反应的受试者在该系统器官类别内仅被计算一次。系统器官类别按总频率的降序列出，优选术语按系统器官类别内的总频率降序列出。百分比基于安全性分析集中每组受试者的受试者数量。
数据截止：2023-02-15。
结论
■英菲格拉替尼单药治疗伴FGFR2基因扩增的局部进展期或转移性GC或EGJ患者，可带来有意义的临床获益；
-cORR 25.0％(95％CI 8.7,49.1)，ucORR 45.0％(95％CI 23.1,68.5)，
-mDCR 80.0％(95％CI 56.3,94.3)，mDoR,3.8(95％CI 3.6,NE)，
-mPFS 3.3个月(95％CI 2.3,4.5)，mOS 8.0个月(95％CI 4.1，NE)。
■英菲格拉替尼单药治疗在先前接受过至少两线系统性治疗的GC或EGJ患者中耐受性一般良好，不良反应可控且通常可逆。
局部进展期或转移的胃癌/胃食管结合部腺癌患者进展迅速，生存时间短。伴有FGFR2基因突变的患者预后更差。本研究中大部分患者仍具有良好的客观应答数据，即，该药物在FGFR2基因扩增的进展期胃癌/胃食管结合部腺癌患者中观察到良好的疗效。
引用参照
本申请涉及各种授权的专利、公开的专利申请、期刊文章和其他出版物，所有这些以引用方式并入本文。如果任何引入的参考文献与本说明书之间存在冲突，则以本说明书为准。此外，落入现有技术内的本发明的任何特定实施方案可以从任何一个或多个权利要求中明确地排除。因为这样的实施方案被认为是本领域的普通技术人员已知的，它们可以被排除，即使本文没有明确地阐述该排除。无论是否涉及到现有技术的存在，出于任何原因，本发明的任何特定实施方案可从任何权利要求中排除。
等同物
本发明能够以其他具体形式实施，而不脱离其精神或基本特征。因此，前述实施方案在所有方面都应被认为是例示性的而不是对本文所述的本发明的限制。因此，本发明的范围由所附权利要求而非前述具体实施方式来指示，并且落入权利要求书的等同物的含义和范围内的所有改变都旨在涵盖于其中。

Claims (38)

  1. 英菲格拉替尼或其药学上可接受的盐在制备用于治疗和/或预防局部进展期或复发/转移性胃癌或胃食管交界部腺癌的药物中的用途。
  2. 根据权利要求1的用途，其中所述胃癌或胃食管交界部腺癌具有FGFR1基因融合、易位或另一种遗传改变。
  3. 根据权利要求1或2的用途，其中所述胃癌或胃食管交界部腺癌具有FGFR2基因融合、易位或另一种遗传改变。
  4. 根据权利要求3的用途，其中所述FGFR2基因融合包含选自以下的FGFR2基因融合配偶体：10Q26.13、AFF1、AFF4、AHCYL1、ALDH1L2、ARFIP1、BICC1、C10orf118、C7、CCDC147、CCDC6、CELF2、CREB5、CREM、DNAJC12、HOOK1、KCTD1、KIAA1217、KIAA1598、KIFC3、MGEA5、NOL4、NRAP、OPTN、PARK2、PAWR、PCMI、PHLDB2、PPHLN1、RASAL2、SFMBT2、SLMAP、SLMAP2、SORBS1、STK26、STK3、TACC3、TBC1D1、TFEC、TRA2B、UBQLN1、VCL、WAC、ZMYM4，及其组合。
  5. 根据权利要求1-4中任一项的用途，其中所述胃癌或胃食管交界部腺癌具有FGFR3基因融合、易位或另一种遗传改变。
  6. 根据权利要求1-5中任一项的用途，其中所述胃癌或胃食管交界部腺癌具有FGFR1、FGFR2和/或FGFR3突变。
  7. 根据权利要求6的用途，其中所述FGFR1、FGFR2和/或FGFR3突变选自FGFR1 G818R、FGFR1 K656E、FGFR1 N546K、FGFR1 R445W、FGFR1 T141R、FGFR2 A315T、FGFR2 C382R、FGFR2 D336N、FGFR2 D471N、FGFR2 E565A、FGFR2 I547V、FGFR2 K641R、FGFR2 K659E、FGFR2 K659M、FGFR2 L617V、FGFR2 N549H、FGFR2 N549K、FGFR2 N549S、FGFR2 N549Y、FGFR2 N550K、FGFR2 P253R、FGFR2 S252W、FGFR2 V395D、FGFR2 V564F、FGFR2 Y375C、FGFR3 A391E、FGFR3 D785Y、FGFR3 E627K、FGFR3 G370C、FGFR3 G380R、FGFR3 K650E、FGFR3 K650M、FGFR3 K650N、FGFR3 K650T、FGFR3 K652E、FGFR3 N540S、FGFR3 R248C、FGFR3 R399C、FGFR3 S131L、FGFR3 S249C、FGFR3 S371C、FGFR3 V555M、FGFR3 V677I、FGFR3 Y373C、FGFR4 D425N、FGFR4 R183S、FGFR4 R394Q、FGFR4 R610H、FGFR4 V510L，及其组合。
  8. 根据权利要求1-7中任一项的用途，其中所述胃癌或胃食管交界部腺癌具有FGFR1、FGFR2和/或FGFR3的基因扩增。
  9. 根据权利要求8的用途，其中所述胃癌或胃食管交界部腺癌具有FGFR2基因扩增，优选地，所述FGFR2基因扩增通过荧光原位杂交检测法(FISH法)或下一代测序检测法(NGS法)确定。
  10. 根据权利要求1-9中任一项的用途，其中所述胃癌或胃食管交界部腺癌为先前接受过系统性治疗或无标准治疗可选的胃癌或胃食管交界部腺癌。
  11. 根据权利要求1-10中任一项的用途，其中所述药物用于先前接受过另一种疗法后具有进展的患者。
  12. 根据权利要求1-10中任一项的用途，其中所述药物用于无标准治疗可选的患者。
  13. 根据权利要求1-12中任一项的用途，其中所述胃癌或胃食管交界部腺癌为不可切除类型。
  14. 根据权利要求13的用途，其中所述胃癌或胃食管交界部腺癌因肿瘤原因不可切除或因身体状况不可切除，如原发肿瘤外侵严重、与周围正常组织无法分离或已包绕大血管，或者区域淋巴结转移固定、融合成团，或转移淋巴结不在手术可清扫范围内，或者患者全身情况差(例如严重的低蛋白血症和贫血)、营养不良、合并严重基础疾病。
  15. 根据权利要求13的用途，其中所述不可切除类型的胃癌或胃食管交界部腺癌特征在于存在腹膜转移、远隔转移或局部进展。
  16. 根据权利要求15的用途，其中所述腹膜转移由腹膜细胞学诊断阳性结果(发现恶性肿瘤细胞)确定，所述局部进展特征为N3或N4淋巴结浸润或淋巴结侵犯/包绕主要血管结构。
  17. 根据权利要求1-16中任一项的用途，其中所述患者先前接受过所述胃癌或胃食管交界部腺癌的既往治疗。
  18. 根据权利要求17的用途，其中所述既往治疗包括手术、放疗、新辅助治疗、辅助治疗以及一线、二线、三线或四线治疗，优选地，其中所述一线、二线、三线或四线治疗包括化疗、免疫治疗、靶向治疗、抗血管生成药物、细胞治疗(例如靶向Claudin 18.2的细胞治疗)，及其联合方案，优选地，所述药物选自顺铂、奥沙利铂、5-氟尿嘧啶、卡培他滨、替吉奥、紫杉醇、白蛋白紫杉醇、多西他赛、伊立替康、蒽环类、曲妥珠单抗、雷莫芦单抗、帕博利珠单抗、纳武利尤单抗、阿帕替尼、三氟吡啶、替普拉西酯、曲氟尿苷替匹嘧啶、表阿霉素、亚叶酸钙，及其联合方案或改良方案。
  19. 根据权利要求17或18中任一项的用途，其中所述患者先前接受过至少两线系统性治疗。
  20. 根据权利要求1-16中任一项的用途，其中所述患者先前接受过受体酪氨酸激酶抑制剂。
  21. 根据权利要求20的用途，其中所述受体酪氨酸激酶抑制剂是FGFR1、FGFR2和/或FGFR3的选择性非共价结合抑制剂。
  22. 根据权利要求21的用途，其中所述FGFR1、FGFR2和/或FGFR3的选择性非共价结合抑制剂选自佩米替尼、罗加替尼(Rogaratinib)、德拉赞替尼(Derazantinib)、Debio1347、AZD4547(ABSK091)、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。
  23. 根据权利要求20的用途，其中所述受体酪氨酸激酶抑制剂是FGFR1、FGFR2、FGFR3和/或FGFR4的选择性非共价结合抑制剂。
  24. 根据权利要求23的用途，其中所述FGFR1、FGFR2、FGFR3和/或FGFR4的选择性非共价结合抑制剂选自厄达替尼(Erdafitinib)、LY2874455、PRN 1371、ASP5878，及其组合。
  25. 根据权利要求20的用途，其中所述受体酪氨酸激酶抑制剂是FGFR1、FGFR2、FGFR3和/或FGFR4的选择性共价结合抑制剂。
  26. 根据权利要求25的用途，其中所述FGFR1、FGFR2、FGFR3和/或FGFR4的选择性共价结合抑制剂是TAS120。
  27. 根据权利要求20的用途，其中所述受体酪氨酸激酶抑制剂是非选择性酪氨酸激酶抑制剂。
  28. 根据权利要求27的用途，其中所述非选择性酪氨酸激酶抑制剂选自帕纳替尼、多韦替尼、levatanib、ACTB-1003、Ki8751、lucitinib、马赛替尼、木利替尼、尼达尼布、奥伦替尼、PD089828，及其组合。
  29. 根据权利要求1-28中任一项的用途，其中所述患者先前接受过另一种选择性FGFR抑制剂。
  30. 根据权利要求29的用途，其中所述另一种选择性FGFR抑制剂选自佩米替尼、罗加替尼、德拉赞替尼、AZD4547、Debio1347、ASP5878、厄达替尼、LY2874455、PRN1371、TAS120、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。
  31. 根据权利要求29的用途，其中所述另一种选择性FGFR抑制剂是选择性共价结合FGFR抑制剂。
  32. 根据权利要求31的用途，其中所述选择性共价结合FGFR抑制剂是TAS120。
  33. 根据权利要求29的用途，其中所述另一种选择性FGFR抑制剂是选择性非共价结合FGFR抑制剂。
  34. 根据权利要求33的用途，其中所述选择性非共价结合FGFR抑制剂是佩米替尼、罗加替尼、德拉赞替尼、AZD4547、厄达替尼、ABSK012、ABSK061、ABSK121、ABSK011，及其组合。
  35. 根据权利要求1-34中任一项的用途，其中所述药物与手术、放疗、新辅助治疗、辅助治疗、化疗、免疫治疗、靶向治疗、抗血管生成药物、细胞治疗(例如靶向Claudin 18.2的细胞治疗)，及其联合方案一起使用，优选地，所述化疗、免疫治疗、靶向治疗、抗血管生成药物如权利要求18-34中任一项中所述。
  36. 根据权利要求1-35中任一项的用途，其中所述药物以100mg单位剂量和/或25mg单位剂量提供。
  37. 根据权利要求1-36中任一项的用途，其中所述药物每天一次口服给药。
  38. 根据权利要求1-37中任一项的用途，其中所述药物以28天周期给药，其中连续3周内每天一次向所述患者口服给药约125mg的英菲格拉替尼或其药学上可接受的盐，并且在下1周内不给药。
PCT/CN2023/125264 2022-11-01 2023-10-18 英菲格拉替尼在治疗胃癌和腺癌中的用途 WO2024093681A1 (zh)

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