Pharmaceutical composition and application thereof

Abstract

The present invention provides a pharmaceutical composition containing a therapeutically effective amount of vomitinib or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier, and uses of the vomitinib or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparation of drugs for treatment and / or prevention of diseases mediated by PACC mutation. The pharmaceutical composition of the present invention shows an excellent therapeutic effect on PACC mutation-mediated diseases (such as non-small cell lung cancer (NSCLC)), and has small side effects and excellent safety.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier. The present invention also relates to vometinib or a pharmaceutically acceptable salt thereof, and the use of the pharmaceutical composition in the preparation of a drug for treating and / or preventing a disease mediated by a PACC mutation (a subgroup of EGFR mutations, i.e., a mutation located on the inner surface of the ATP binding pocket or the C-terminus of the αC helix, also known as a P-loop and αC helix compression mutation). The present invention also provides a method for treating and / or preventing a disease mediated by a PACC mutation, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient. Background Art

[0002] Lung cancer has been the malignant tumor with the highest morbidity and mortality rate in the world, which seriously endangers human health and life. In 2018, 1.76 million people died of lung cancer worldwide. Non-small cell lung cancer (NSCLC) accounts for about 80-85% of all lung cancers. Epidermal growth factor receptor (EGFR) is a multifunctional glycoprotein widely distributed on the cell membranes of various tissues in the human body. EGFR mutation is the most widely studied target in NSCLC.

[0003] Among EGFR mutations, common mutations include sensitive mutations (such as exon 19 deletions and point mutations in exon 21 (L858R), accounting for 85%-90% of all EGFR mutations), drug-resistant mutations (such as exon 20 T790M mutations, exon 20 C797S mutations), etc. By using hierarchical clustering analysis of WT EGFR selectivity in vitro and EGFR mutation localization, Robichaux et al. observed four unique EGFR mutation subgroups: classical-like mutations away from the ATP binding pocket, T790M-like mutations in the hydrophobic core, insertion mutations in the C-terminal loop region of the αC helix in exon 20, and mutations located on the inner surface of the ATP binding pocket or the C-terminus of the αC helix (presumed to be P-loop and αC helix compression mutations (PACC)). PACC mutations include mutations spanning exons 18-21, including G719X, L747X, S768I, L792X, E709X, L718X, G724S, V769X and T854I (Nature, Vol. 597, pp. 732-737, 2021).

[0004] Over the years, a large number of targeted drugs have been developed for EGFR mutations in NSCLC, such as the first-generation reversible tyrosinase inhibitors (TKI) gefitinib and erlotinib for EGFR sensitive mutations, the second-generation irreversible covalent binding inhibitor afatinib, and the third-generation inhibitor osimertinib for the drug-resistant mutation EGFR T790M, all of which have very good clinical effects.

[0005] However, currently no drugs targeting EGFR PACC mutations have been approved for marketing worldwide, so there is still a need to continue to develop effective, stable and safe small molecule drugs as EGFR PACC mutation inhibitors.

[0006] Patent CN105315259B records N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide (also known as "vometinib") shown in the following formula (I). Patent CN107163026B records the mesylate of the compound shown in the following formula (I) (also known as "vometinib mesylate"), and vometinib mesylate has been commercialized as a third-generation EGFR-TKI inhibitor, which is mainly used to treat diseases mediated by EGFR sensitive mutations and T790M resistance mutations. The Phase I escalation trial of vometinib mesylate has confirmed that vometinib mesylate has good tolerability and safety at a dose level of 20mg-240mg, taken orally once daily, with all adverse events in the subjects being mild or moderate, with no dose-limiting toxicity or dose-related toxic reactions. In addition, the Phase IIb clinical trial has confirmed that vometinib mesylate, when administered orally at a daily dose of 80mg, has a good anti-tumor effect in patients with EGFR T790M-positive advanced non-small cell lung cancer that has progressed after treatment, and can alleviate or stabilize the course of the disease.

[0007] Summary of the invention

[0008] In some embodiments, the present invention provides the use of vometinib or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, vometinib or a pharmaceutically acceptable salt thereof as an active compound can effectively inhibit PACC mutation, and thus, vometinib or a pharmaceutically acceptable salt thereof can be used to treat and / or prevent diseases mediated by PACC mutation.

[0010] Therefore, in some embodiments, the present invention provides the use of vometinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease mediated by a PACC mutation.

[0011] In some embodiments, the present invention provides the use of vometinib or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent in combination for the preparation of a medicament for treating and / or preventing a disease mediated by a PACC mutation.

[0012] In some embodiments, by using vometinib or a pharmaceutically acceptable salt thereof as an active compound at a certain dose, diseases mediated by PACC mutations, particularly non-small cell lung cancer, can be treated and / or prevented, and the treatment and / or prevention is accompanied by small side effects and excellent safety.

[0013] More specifically, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.

[0014] The present invention also provides a use of the pharmaceutical composition of the present invention in preparing a drug for treating and / or preventing a disease mediated by a PACC mutation.

[0015] The composition of the present invention can also be in the form of tablets or capsules. Each unit preparation contains 10 mg to 400 mg of vometinib or a pharmaceutically acceptable salt thereof.

[0016] When the pharmaceutical composition of the present invention is used to treat and / or prevent a disease mediated by a PACC mutation, the daily dose of vometinib or a pharmaceutically acceptable salt thereof needs to be 80 mg to 400 mg. At this time, the daily dose of vometinib or a pharmaceutically acceptable salt thereof can be easily adjusted by adjusting the amount of the above-mentioned preparation (e.g., tablets or capsules).

[0017] The present invention also provides a method for treating and / or preventing a disease mediated by PACC mutation, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient.

[0018] In the above treatment method of the present invention, the daily dose of vometinib or a pharmaceutically acceptable salt thereof needs to be 80 mg-400 mg.

[0019] The present invention also provides a method for treating and / or preventing a disease, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient positive for a PACC mutation.

[0020] The present invention also provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof.

[0021] The present invention also provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient confirmed to be positive for PACC mutation.

[0022] The present invention also provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient carrying a PACC mutation.

[0023] The present invention also provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient confirmed to be positive for PACC mutation, and the patient has not previously received systemic anti-tumor treatment.

[0024] The present invention also provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient confirmed to be positive for PACC mutation, and the patient has previously received systemic anti-tumor treatment but the disease has progressed.

[0025] Effects of the Invention

[0026] In the present invention, vometinib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising vometinib or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier exhibits excellent inhibitory activity against PACC mutation.

[0027] In addition, when the vometinib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising vometinib or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier of the present invention is used to treat and / or prevent diseases mediated by PACC mutations, side effects are small and safety is excellent.

[0028] The pharmaceutical composition of the present invention can be prepared into a preparation having an appropriate size and an appropriate active ingredient content by containing vometinib or a pharmaceutically acceptable salt thereof in a specific amount. DETAILED DESCRIPTION

[0029] The embodiments of the present invention will be described in more detail below in conjunction with specific embodiments, but those skilled in the art will understand that the specific embodiments described below are only used to illustrate the present invention and should not be regarded as limiting the scope of protection of the present invention. On the contrary, the present invention is intended to cover all substitutions, modifications and equivalents that may be included within the scope of the present invention defined by the claims.

[0030] Unless otherwise specified, the various embodiments of the present invention may be combined in any manner, and the conversion, deformation, and change of the technical solutions obtained thereby are also included in the scope of the present invention.

[0031] Vometinib is a compound known in the prior art, particularly described in patent CN105315259B, and its chemical name is: N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide; its structural formula is the compound shown in the following formula (I).

[0032]

[0033] In the present invention, the active ingredient for treating a disease is actually vometinib or a pharmaceutically acceptable salt thereof. Therefore, in the present invention, vometinib or a pharmaceutically acceptable salt thereof can be used in a separate form or in a form contained in a composition, in which case the composition can optionally contain a pharmaceutically acceptable carrier as required.

[0034] In addition, in the present invention, vometinib or a pharmaceutically acceptable salt thereof can also be used in combination with at least one second therapeutic agent.

[0035] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier.

[0036] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. In the present invention, the carrier is also referred to as "excipient". "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and its derivatives, cellulose acetate and its derivatives, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium / calcium stearate, hydrogenated vegetable oil, sodium stearyl fumarate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers, wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, etc., but are not limited to these.

[0037] The pharmaceutical composition of the present invention can be prepared by methods well known in the art, such as conventional mixing, dissolving, granulating, making sugar-coated pills, grinding, emulsifying and freeze-drying.

[0038] The pharmaceutical composition of the present invention can be prepared into a tablet or capsule preparation form, in which vometinib or a pharmaceutically acceptable salt thereof is mixed with at least one pharmaceutically acceptable carrier. In the present invention, the carrier is also referred to as an "excipient". The pharmaceutically acceptable carrier includes but is not limited to: (a) fillers or solubilizers, such as microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, colloidal silicon dioxide, calcium hydrogen phosphate, calcium phosphate, and calcium sulfate; (b) binders, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, alginate, gelatin, polyvinyl pyrrolidone, copovidone, sucrose and gum arabic, corn starch; (c) humectants, such as glycerol, etc. ; (d) disintegrants, for example, cross-linked sodium carboxymethylcellulose, crospovidone, sodium carboxymethyl starch, colloidal silicon dioxide, microcrystalline cellulose, potato starch or tapioca starch or corn starch, pregelatinized starch, alginic acid, certain complex silicates and sodium carbonate, ion exchange resins, etc.; (e) absorption promoters, for example, quaternary ammonium compounds, anionic or nonionic surfactants, cyclodextrins, etc.; (f) wetting agents, for example, cetyl alcohol and glyceryl monostearate, etc.; (g) adsorbents, for example, kaolin, colloidal silicon dioxide, ion exchange resins, etc.; and (h) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oils, etc., or mixtures thereof. The capsules and tablets may also contain buffers. The tablets and capsules may be coated or microencapsulated with coatings or shell materials such as enteric coatings or other materials known in the art.

[0039] The term "pharmaceutically acceptable salt" refers to a salt prepared from vometinib with a relatively nontoxic, pharmaceutically acceptable acid or base. Base addition salts can be obtained by contacting vometinib with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Representative base addition salts include, for example, salts formed with alkali metals, alkaline earth metals, and quaternary ammonium cations, such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, tetramethyl quaternary ammonium salts, tetraethyl quaternary ammonium salts, etc.; amine salts, including salts formed with ammonia (NH3), primary amines, secondary amines, or tertiary amines, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, etc. In addition, acid addition salts can also be obtained by contacting vometinib with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid salts include inorganic acid salts such as hydrochloride, sulfate, phosphate, nitrate, etc.; organic acid salts such as formates, acetates, propionates, methanesulfonates, toluenesulfonates, succinates, citrates, tartrates, etc. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0040] In the present invention, "therapeutically effective amount" refers to a sufficient amount of a non-toxic drug or pharmacologically active agent that can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the patient's age, weight and condition, and also on the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine experiments.

[0041] As used herein, "active ingredient," "active substance," or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0042] In the present invention, "patient", "individual" or "subject" includes humans, animals, vertebrates, mammals, rodents (e.g., guinea pigs, hamsters, rats, mice), murines (e.g., mice), canines (e.g., dogs), primates, apes (e.g., monkeys or anurans), monkeys (e.g., marmosets, baboons), anurans (e.g., gorillas, chimpanzees, orangutans, gibbons). In some embodiments, the "patient" is a human.

[0043] As used herein, "treat" refers to therapeutic therapy or palliative measures. When referring to a specific condition, treatment refers to: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition. "Treatment" may also refer to prolonging survival compared to expected survival without treatment.

[0044] As used herein, "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0045] In one embodiment of the present invention, the pharmaceutically acceptable salt of vometinib is the mesylate of vometinib, ie, vometinib mesylate.

[0046] In one embodiment of the present invention, the pharmaceutical composition of the present invention is in the form of a tablet or capsule.

[0047] In one embodiment of the present invention, in each unit preparation (eg, tablet or capsule) described above, the content of vometinib or a pharmaceutically acceptable salt thereof is 10 mg-400 mg, preferably 20 mg-320 mg. Specific content may be, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg. The preferred specific content may be 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg, more preferably 40 mg or 80 mg, and most preferably 40 mg.

[0048] In one embodiment of the present invention, in the pharmaceutical composition, the content of vometinib or its pharmaceutically acceptable salt is 80mg-400mg, for example, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg. As a preferred content, it can be 80mg, 160mg, 240mg or 320mg, more preferably 80mg, 160mg or 240mg, and most preferably 240mg.

[0049] In one embodiment of the present invention, when the pharmaceutical composition is used to treat and / or prevent a disease mediated by a PACC mutation, the composition is administered to a patient so that the dosage of vometinib or a pharmaceutically acceptable salt thereof is 80 mg to 400 mg. As a specific dosage, for example, it can be 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg. As a preferred dosage, it can be 80 mg, 160 mg, 240 mg or 320 mg, more preferably 80 mg, 160 mg or 240 mg, and most preferably 240 mg. In one embodiment of the present invention, the dosage is a daily dosage.

[0050] In other words, in the present invention, the content of vometinib or its pharmaceutically acceptable salt in the pharmaceutical composition of the present invention refers to the total amount of vometinib or its pharmaceutically acceptable salt in the pharmaceutical composition taken by the patient when the pharmaceutical composition is administered to the patient. For example, when the pharmaceutical composition is in the form of a tablet or capsule preparation, the content of vometinib or its pharmaceutically acceptable salt in the pharmaceutical composition refers to the total amount of vometinib or its pharmaceutically acceptable salt in all preparations when the tablet or capsule preparation is administered.

[0051] It can be understood by those skilled in the art that when administered to a patient, the daily dose of vometinib or a pharmaceutically acceptable salt thereof is not less than the amount of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation. Those skilled in the art can calculate the total number of preparations required for daily administration according to the daily dose of vometinib or a pharmaceutically acceptable salt thereof and the amount of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation. For example, when vometinib or a pharmaceutically acceptable salt thereof is contained in a tablet and the amount of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation (each tablet) is 40 mg, when the daily dose of vometinib or a pharmaceutically acceptable salt thereof is 240 mg, the total number of preparations (tablets) required for daily administration is 6 tablets.

[0052] In one embodiment of the present invention, when the pharmaceutical composition is used to treat and / or prevent a disease mediated by a PACC mutation, it is administered once, twice or three times a day, preferably once a day.

[0053] In one embodiment of the present invention, the pharmaceutical composition may further comprise at least one second therapeutic agent, which may be selected from chemotherapeutic drugs, targeted anti-tumor drugs, antibody drugs and immunotherapy drugs.

[0054] In one embodiment of the present invention, the chemotherapeutic drugs include platinum drugs (e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin, triplatin tetranitrate, phenaplatin, picoplatin, miplatin, satraplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, ancitabine, fluorouracil, bifurouracil, doxifluridine, tegafur, carmofur, trifluridine, tegafur), camptothecins (e.g., camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel), vinca alkaloids (vinorelbine, vinblastine, vincristine, vindesine, vinflunine, vinblast ... ne), anthracyclines (epirubicin, doxorubicin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, daunorubicin, pixantrone), antibiotics, podophyllums, antimetabolites, pemetrexed, carmustine, melphalan, etoposide (etoposide), teniplatin, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposomal doxorubicin, actinomycin D (dactinomycin), bleomycin, bleomycin, temozolomide, decarbazine, peplomycin, eribulin, plinabulin, sapacitabine, treosulfan, 153Sm-EDTMP, and one or more of encequidar.

[0055] In one embodiment of the present invention, the second therapeutic agent is one or more platinum drugs, and the platinum drugs include but are not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, triplatin tetranitrate, phenoplatin, picoplatin, satraplatin, miplatin, and levoplatin.

[0056] In one embodiment of the present invention, the chemotherapy drug is selected from one or more of etoposide, irinotecan, cisplatin, carboplatin, levoplatin, nedaplatin, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, gemcitabine, cyclophosphamide, doxorubicin, vincristine, bendamustine, epirubicin, methotrexate, amrubicin, tegafur, gimeracil, oteracil, and tegafur.

[0057] In one embodiment of the present invention, as the targeted anti-tumor drug, protein kinase inhibitors can be listed. Among them, the protein kinase inhibitors include but are not limited to tyrosine kinase inhibitors, serine and / or threonine kinase inhibitors, poly ADP-ribose polymerase (PARP, poly ADP-ribose polymerase) inhibitors, and the targets of the inhibitors include but are not limited to Fascin-1 protein, HDAC (histone deacetylase), proteasome (Proteasome), CD38, SLAMF7 (CS1 / CD319 / CRACC), RANKL, EGFR (epidermal growth factor receptor), anaplastic lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 (discoid death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene; the targets of the targeted anti-tumor drug also include COX-2 (cyclooxygenase-2), APE1 (apurinergic The proteins included TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, TNF-α, Targeted anti-tumor drugs that can be listed include, but are not limited to, imatinib, sunitinib, nilotinib, bosutinib, saracatinib, pazopanib, trabectedin, regorafenib, cediranib, bortezomib, panobinostat, carfilzomib, ixazomib, apatinib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib,Dabrafenib, Cabozantinib, Gefitinib, Dacomitinib, Almonertinib, Osimertinib, Osimertinib, Alectinib, Brigatinib, Lorlatinib, Trametinib, Larotrectinib, Icotinib, Lapatinib, Vandetanib, Selumetinib, Sorafenib, Olmutinib, Savolitinib, Fruquintinib, Entrectinib, Dasatinib ib), Ensartinib, Lenvatinib, Itacitinib, Pyrotinib, Binimetinib, Erdafitinib, Axitinib, Neratinib, Cobimetinib, Acalabrutinib, Famitinib, Masitinib, Ibrutinib, Anlotinib, Rociletinib, Nintedanib, Lenalidomide, LOXO-292, Vorolanib, Bemcentinib, Capmatinib, Entrectinib, TAK-931, ALT-803, Palbociclib, Famitinib L-malate, LTT-462, BLU-667, ningetinib, tipifarnib, poziotinib, DS-1205c, capivasertib, SH-1028, metformin, seliciclib, OSE-2101, APL-101, berzosertib, idelalisib, lerociclib, ceralasertib, PLB-1003, tomivosertib, SKLB-1028, D-0316, LY-3023414, allitinib, MRTX-849, AP-32788, AZD-4205, lifirafenib,vactosertib, mivebresib, napabucasin, sitravatinib, TAS-114, molibresib, CC-223, rivoceranib, CK-101, LXH-25 4. simotinib, GSK-3368715, TAS-0728, masitinib, tepotinib, HS-10296, AZD-4547, merestinib, olaptesedpegol, ga lunisertib, ASN-003, gedatolisib, defactinib, lazertinib, CKI-27, S-49076, BPI-9016M, RF-A-089, RMC-4630, AZD -3759, antroquinonol, SAF-189s, AT-101, TTI-101, naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, epitinib One or more of succinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparib tosylate, DV-281, Siremadlin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, tucidinostat, vorinostat, resminostat, epacadostat, tazemetostat, entinostat, mocetinostat, quisinostat, LCL-161, and KML-001. In some embodiments, the targeted anti-tumor drug is one or more of sorafenib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, lorlatinib, trametinib, larotrectinib, icotinib, lapatinib, vandetanib, selumetinib, omotinib, volitinib, fruquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib, bimetinib, erdatinib, axitinib, neratinib, cobimetinib, acalabrutinib, fametinib, masitinib, ibrutinib, anlotinib, and nintedanib.

[0058] In one embodiment of the present invention, the second therapeutic agent is an antibody drug. The targets of the antibody drug include, but are not limited to, PD-1, PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), platelet-derived growth factor receptor α (PDGFR-α), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor-2 (HER2), epidermal growth factor receptor (EGFR), ganglioside GD2, B cell surface protein CD20, B cell surface protein CD52, B cell surface protein CD38, B cell surface protein CD319, B cell surface protein CD30, and any one or more of B cell surface protein CD19 / CD3.

[0059] In one embodiment of the present invention, the antibody drug is an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1; in one embodiment of the present invention, the antibody drug is a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor. In one embodiment of the present invention, the antibody drug is a platelet-derived growth factor receptor alpha (PDGFR-α) inhibitor.

[0060] In one embodiment of the present invention, the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody or an antigen binding portion thereof that binds to programmed death receptor 1 (PD-1) and / or inhibits PD-1 activity, or an antibody or an antigen binding portion thereof that binds to programmed death ligand 1 (PD-L1) and / or inhibits PD-L1 activity, such as an anti-PD-1 antibody or an anti-PD-L1 antibody. In one embodiment of the present invention, the antibody or its antigen binding portion is (a) an anti-PD-1 monoclonal antibody or an antigen binding fragment thereof that specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; or (b) an anti-PD-L1 monoclonal antibody or an antigen binding fragment thereof that specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.

[0061] In one embodiment of the present invention, the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.

[0062] In one embodiment of the present invention, the anti-PD-1 or PD-L1 antibody is a human antibody or a murine antibody.

[0063] In one embodiment of the present invention, the anti-PD-1 antibody can be selected from any one or more of nivolumab, pembrolizumab, durvalumab, toripalimab (JS-001), sintilimab (IBI308, Sintilimab), camrelizumab, tislelizumab (BGB-A317), genol monoclonal antibody (GB226), lizhu monoclonal antibody (LZM009), HLX-10, BAT-1306, AK103 (HX008), AK104 (Kongfang Bio), CS1003, SCT-I10A, F520, SG001, and GLS-010.

[0064] In one embodiment of the present invention, the anti-PD-L1 antibody can be selected from any one or more of Atezolizumab, Avelumab, Durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014 (ZKAB0011), KN035, MSB2311, HLX-20, and CS-1001.

[0065] In one embodiment of the present invention, the anti-PD-1 antibody is toripalimab.

[0066] In one embodiment of the present invention, the anti-PD-1 antibody is pembrolizumab.

[0067] In one embodiment of the present invention, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor is an anti-CTLA-4 antibody. In one embodiment of the present invention, the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.

[0068] In one embodiment of the present invention, the anti-CTLA-4 antibody can be selected from any one or more of Ipilimumab, Tremelimumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, and IBI310.

[0069] In one embodiment of the present invention, the anti-CTLA-4 antibody is ipilimumab.

[0070] In one embodiment of the present invention, the platelet-derived growth factor receptor alpha (PDGFR-α) inhibitor is an anti-PDGFRα antibody. In one embodiment of the present invention, the anti-PDGFRα antibody is an anti-PDGFRα monoclonal antibody.

[0071] In one embodiment of the present invention, the anti-PDGFRα antibody is Olaratumab.

[0072] In one embodiment of the present invention, the antibody drug may also include but is not limited to bevacizumab, ramucirumab, pertuzumab, trastuzumab, cetuximab, nimotuzumab, panitumumab, necitumumab, dinutuximab, rituximab, ibritumomab, ofatumumab, obinutuzumab, alemtuzumab, daratumumab, gemtuzumab, elotuzumab, brentuximab, inotuzumab Ozogamicin), Blinatumomab, or any one or more thereof.

[0073] In one embodiment of the present invention, the immunotherapy drug may include one or more of interferons (interferon α, interferon α-1b, interferon α-2b), interleukins, temsirolimus, everolimus, ridaforolimus, and temsirolimus.

[0074] In one embodiment of the present invention, when a second therapeutic agent is used, those skilled in the art can adjust the content of the second therapeutic agent as needed.

[0075] The present invention also provides use of vometinib or a pharmaceutically acceptable salt thereof in preparing a drug for treating and / or preventing a disease mediated by a PACC mutation.

[0076] The present invention also provides the use of vometinib or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent in combination for preparing a drug for treating and / or preventing a disease mediated by a PACC mutation.

[0077] The present invention also provides a use of the above pharmaceutical composition in preparing a drug for treating and / or preventing a disease mediated by a PACC mutation.

[0078] In one embodiment of the present invention, in the above-mentioned use of the present invention, the pharmaceutically acceptable salt of vometinib is the mesylate of vometinib, namely, vometinib mesylate.

[0079] In one embodiment of the present invention, in the above-mentioned use of the present invention, the pharmaceutical composition of the present invention is in the form of a tablet or capsule.

[0080] In one embodiment of the present invention, in the above-mentioned use of the present invention, in each unit preparation (such as tablet or capsule), the content of vometinib or its pharmaceutically acceptable salt is 10 mg-400 mg, preferably 20 mg-320 mg. Specific content may be, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg. Preferably, the specific content may be 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg, more preferably 40 mg or 80 mg, most preferably 40 mg.

[0081] In one embodiment of the present invention, in the above-mentioned use of the present invention, in the pharmaceutical composition, the content of vometinib or its pharmaceutically acceptable salt is 80 mg-400 mg, for example, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg. The preferred content is 80 mg, 160 mg, 240 mg or 320 mg, more preferably 80 mg, 160 mg or 240 mg, and most preferably 240 mg.

[0082] In one embodiment of the present invention, in the above-mentioned use of the present invention, the pharmaceutical composition is administered to the patient so that the dosage of vometinib or a pharmaceutically acceptable salt thereof is 80 mg-400 mg. As a specific dosage, for example, it can be 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg. As a preferred dosage, it can be 80 mg, 160 mg, 240 mg or 320 mg, more preferably 80 mg, 160 mg or 240 mg, and most preferably 240 mg. In one embodiment of the present invention, the dosage is a daily dosage.

[0083] In other words, in the above-mentioned use of the present invention, the content of vometinib or its pharmaceutically acceptable salt in the pharmaceutical composition refers to the total amount of vometinib or its pharmaceutically acceptable salt in the pharmaceutical composition taken by the patient when the pharmaceutical composition is administered to the patient. For example, when the pharmaceutical composition is in the form of a tablet or capsule preparation, the content of vometinib or its pharmaceutically acceptable salt in the pharmaceutical composition refers to the total amount of vometinib or its pharmaceutically acceptable salt in all preparations when the tablet or capsule preparation is administered.

[0084] It can be understood by those skilled in the art that in the above-mentioned use of the present invention, when administered to a patient, the daily dose of vometinib or a pharmaceutically acceptable salt thereof is not less than the amount of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation. Those skilled in the art can calculate the total number of preparations required for daily administration according to the daily dose of vometinib or a pharmaceutically acceptable salt thereof and the amount of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation. For example, when vometinib or a pharmaceutically acceptable salt thereof is contained in a tablet and the amount of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation (each tablet) is 40 mg, when the daily dose of vometinib or a pharmaceutically acceptable salt thereof is 240 mg, the total number of preparations (tablets) required for daily administration is 6 tablets.

[0085] In one embodiment of the present invention, the disease mediated by PACC mutation is cancer, such as lung cancer, and further may be non-small cell lung cancer (NSCLC).

[0086] In one embodiment of the present invention, the disease mediated by PACC mutation is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

[0087] In one embodiment of the present invention, the disease mediated by PACC mutation is treatment-naive non-small cell lung cancer or treatment-experienced non-small cell lung cancer.

[0088] In the present invention, "initial treatment" refers to the situation that before receiving the treatment of vometinib or its pharmaceutically acceptable salt of the present invention, no other therapeutic agents (including but not limited to chemotherapy drugs, targeted anti-tumor drugs, antibody drugs or immunotherapy drugs) have been used for treatment, and it may also refer to the situation that no systemic anti-tumor treatment has been received before. "Previously treated" refers to the situation that before receiving the treatment of vometinib or its pharmaceutically acceptable salt of the present invention, other therapeutic agents (including but not limited to chemotherapy drugs, targeted anti-tumor drugs, antibody drugs or immunotherapy drugs) have been used for treatment, and it may also refer to the situation that the disease has progressed after receiving systemic anti-tumor treatment. In the case of "previously treated", the patient may have developed tolerance to other therapeutic agents, or may not have developed drug resistance.

[0089] In one embodiment of the present invention, the PACC mutation is at least one selected from the group consisting of EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-L718Q mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-Del19 / C797S mutation, EGFR-L858R / C797S mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-L858R-L718Q mutation, EGFR-E709K-G719A mutation and EGFR-L861Q mutation.

[0090] In one embodiment of the present invention, the PACC mutation is selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-L718Q mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGF At least one of EGFR-E709A mutation, EGFR-Del19 / C797S mutation, EGFR-L858R / C797S mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-L858R-L718Q mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation and EGFR-L861Q mutation.

[0091] In one embodiment of the present invention, the PACC mutation is at least one selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-E709K-G719A mutation and EGFR-L861Q mutation.

[0092] In one embodiment of the present invention, the PACC mutation is at least one selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation and EGFR-L861Q mutation.

[0093] In one embodiment of the present invention, in the above-mentioned use of the present invention, the pharmaceutical composition may further comprise at least one second therapeutic agent.

[0094] In the above-mentioned use of the present invention, the second therapeutic agent can be selected from chemotherapeutic drugs, targeted anti-tumor drugs, antibody drugs and immunotherapy drugs.

[0095] In the above-mentioned use of the present invention, the second therapeutic agent is the above-mentioned second therapeutic agent of the present invention.

[0096] The present invention provides a method for treating and / or preventing a disease mediated by PACC mutation, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient.

[0097] The present invention provides a method for treating and / or preventing a disease, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient positive for a PACC mutation.

[0098] The present invention provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof.

[0099] The present invention provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient confirmed to be positive for PACC mutation.

[0100] The present invention provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient carrying a PACC mutation.

[0101] The present invention provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient confirmed to be positive for PACC mutation, and the patient has not previously received systemic anti-tumor treatment.

[0102] The present invention provides a method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient confirmed to be positive for PACC mutation, and the patient has previously received systemic anti-tumor treatment and the disease has progressed.

[0103] In the above-mentioned treatment method of the present invention, vometinib or its pharmaceutically acceptable salt is administered at a dosage of 80mg-400mg. As a specific dosage, for example, it can be 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg. As a preferred dosage, it can be 80mg, 160mg, 240mg or 320mg, more preferably 80mg, 160mg or 240mg, and most preferably 240mg. In one embodiment of the invention, the dosage is a daily dosage.

[0104] In the above treatment method of the present invention, the frequency of administering vometinib or a pharmaceutically acceptable salt thereof to the patient is once a day, twice a day or three times a day, preferably once a day.

[0105] In the above treatment method of the present invention, vometinib or a pharmaceutically acceptable salt thereof is administered to the patient on an empty stomach, preferably in the morning on an empty stomach.

[0106] In the above-mentioned treatment method of the present invention, vometinib or a pharmaceutically acceptable salt thereof is orally administered to the patient.

[0107] In the above treatment method of the present invention, vometinib mesylate is administered to the patient.

[0108] In the above-mentioned treatment method of the present invention, vometinib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet or capsule.

[0109] In the above treatment method of the present invention, vometinib or a pharmaceutically acceptable salt thereof is administered to the patient in the form of each unit preparation. The number of unit preparations is adjusted so that the daily dose of vometinib or a pharmaceutically acceptable salt thereof is within the above range.

[0110] In the above treatment method of the present invention, the content of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation (eg, tablet or capsule) is 10 mg-400 mg, preferably 20 mg-320 mg. Specific content may be, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg. Preferably, the specific content may be 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg, more preferably 40 mg or 80 mg, most preferably 40 mg.

[0111] It can be understood by those skilled in the art that when administered to a patient, the daily dose of vometinib or a pharmaceutically acceptable salt thereof is not less than the amount of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation. Those skilled in the art can calculate the total number of preparations required for daily administration according to the daily dose of vometinib or a pharmaceutically acceptable salt thereof and the amount of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation. For example, when vometinib or a pharmaceutically acceptable salt thereof is contained in a tablet and the amount of vometinib or a pharmaceutically acceptable salt thereof in each unit preparation (each tablet) is 40 mg, when the daily dose of vometinib or a pharmaceutically acceptable salt thereof is 240 mg, the total number of preparations (tablets) required for daily administration is 6 tablets.

[0112] In the above treatment method of the present invention, at least one second therapeutic agent may be further administered to the patient. In the above treatment method of the present invention, the second therapeutic agent may be selected from chemotherapeutic drugs, targeted anti-tumor drugs, antibody drugs and immunotherapy drugs.

[0113] In the above treatment method of the present invention, the second therapeutic agent is the above-mentioned second therapeutic agent of the present invention.

[0114] In the above treatment method of the present invention, the disease is cancer, such as lung cancer, and further can be non-small cell lung cancer (NSCLC).

[0115] In the above treatment method of the present invention, vometinib or a pharmaceutically acceptable salt thereof is administered to the patient before or after the patient undergoes surgical resection of the tumor.

[0116] In the above treatment method of the present invention, the disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

[0117] In the above treatment method of the present invention, the disease is newly treated non-small cell lung cancer or previously treated non-small cell lung cancer.

[0118] In the above-mentioned treatment method of the present invention, the PACC mutation is at least one selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-L718Q mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-Del19 / C797S mutation, EGFR-L858R / C797S mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-L858R-L718Q mutation, EGFR-E709K-G719A mutation and EGFR-L861Q mutation.

[0119] In the above-mentioned treatment method of the present invention, the PACC mutation is selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-L718Q mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGF At least one of EGFR-E709A mutation, EGFR-Del19 / C797S mutation, EGFR-L858R / C797S mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-L858R-L718Q mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation and EGFR-L861Q mutation.

[0120] In one embodiment of the present invention, the PACC mutation is at least one selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-E709K-G719A mutation and EGFR-L861Q mutation.

[0121] In one embodiment of the present invention, the PACC mutation is at least one selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation and EGFR-L861Q mutation.

[0122] In the above-mentioned treatment method of the present invention, the patient is a human patient.

[0123] In the above treatment method of the present invention, the patient is aged between 18 and 75 years old.

[0124] In the above treatment method of the present invention, the patient has been diagnosed with primary non-small cell lung cancer (NSCLC) histologically or cytopathologically before receiving treatment with vometinib or a pharmaceutically acceptable salt thereof, and the main type is non-squamous cell tissue morphology.

[0125] In the above treatment method of the present invention, the patient has radiological disease progression after the last anti-tumor treatment before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

[0126] In the above treatment method of the present invention, the patient is confirmed to be positive for PACC mutation by laboratory test before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

[0127] In the above treatment method of the present invention, the patient suffers from locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer and is confirmed to have radiological or pathological disease progression during or after the last systemic anti-tumor treatment before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

[0128] In the above treatment method of the present invention, the patient suffers from locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer (NSCLC) and has not received systemic anti-tumor treatment before starting to receive treatment with vometinib or a pharmaceutically acceptable salt thereof.

[0129] In the above treatment method of the present invention, the patient has at least one measurable lesion before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

[0130] In the above treatment method of the present invention, before the patient starts to receive treatment with vometinib or a pharmaceutically acceptable salt thereof, laboratory tests show that the patient has sufficient organ function.

[0131] In the above treatment method of the present invention, before the patient starts to receive treatment with vometinib or a pharmaceutically acceptable salt thereof, an ECOGPS (Eastern Cooperative Oncology Group Performance Status) score is performed, for example, the ECOGPS score is 0-1.

[0132] The above-mentioned treatment methods of the present invention have acceptable safety.

[0133] The above-mentioned treatment method of the present invention can achieve the therapeutic effect of partial remission (PR).

[0134] The above-mentioned treatment method of the present invention can achieve the therapeutic effect of stable disease (SD).

[0135] The above-mentioned treatment method of the present invention can shrink the tumor in the target lesion.

[0136] In the above-described treatment methods of the present invention, the tumor in the target lesion is reduced in size when assessed by tumor radiological examinations (eg, computed tomography (CT) and / or magnetic resonance imaging (MRI)). BRIEF DESCRIPTION OF THE DRAWINGS

[0137] Figure 1 .Tumor volume change curve in test example 2.

[0138] Figure 2 . Test the weight change rate curve in Example 2.

[0139] Example

[0140] I. Preparation Examples

[0141] Preparation of 40 mg tablets of vometinib mesylate

[0142] Prescription: 46.76 mg of vometinib mesylate, 44.73 mg of microcrystalline cellulose, 68.2 mg of lactose, 13 mg of cross-linked carboxymethyl cellulose sodium, 17.8 mg of polyethylene glycol 4000, 10.9 mg of colloidal silicon dioxide, 2.7 mg of sodium stearyl fumarate, and 8.67 mg of sodium chloride. Contains 40 mg of vometinib.

[0143] Prescription process: The excipients and the raw materials are sieved for pretreatment and then mixed evenly, an appropriate amount of polyethylene glycol 4000 is added for wet granulation, the wet granules are sieved for whole granulation, the wet granules are dried, the whole granules are sieved, colloidal silicon dioxide and sodium stearyl fumarate are added, mixed evenly, and then tableted to obtain tablets.

[0144] II. Active Examples

[0145] Test Example 1: Evaluation of the anti-proliferative effect of vometinib mesylate on 18 cell lines

[0146] The purpose of Test Example 1 is to use the standard CellTiter Fluorescence cell viability assay was used to evaluate the effects of vometinib mesylate on 18 cell lines (Ba / F3 EGFR-G719S, Ba / F3 EGFR-S768I, Ba / F3 EGFR-G724S, Ba / F3 EGFR-L718Q, Ba / F3EGFR-Del19 / G724S, Ba / F3 EGFR-E709H, Ba / F3 EGFR-L747S, Ba / F3EGFR-E709V, Ba / F3 EGFR-L747V, Ba / F3 EGFR-E709-710>D, Ba / F3EGFR-E709A, Ba / F3 EGFR-Del19 / C797S, Ba / F3 EGFR-L858R / C797S, Ba / F3 The proliferation inhibitory activity of Ba / F3-EGFR-L747S / G719A, Ba / F3-EGFR-L858R-L718V, Ba / F3-EGFR-L858R-L718Q, Ba / F3-EGFR-E709K-G719A and Ba / F3 EGFR-L861Q) was measured. AZD9291 was used as a control compound.

[0147] Cell culture: Ba / F3 EGFR-G719S, Ba / F3 EGFR-S768I, Ba / F3 EGFR-G724S, Ba / F3EGFR-L718Q, Ba / F3 EGFR-Del19 / G724S, Ba / F3 EGFR-E709H, Ba / F3 EGFR-L747S, Ba / F3EGFR-E709V, Ba / F3 EGFR-L747V, Ba / F3 EGFR-E709-710>D, Ba / F3 EGFR-E709A, Ba / F3EGFR-Del19 / C797S, Ba / F3 EGFR-L858R / C797S, Ba / F3 EGFR-L747S / G719A, Ba / F3-EGFR-L858R-L718V, Ba / F3-EGFR-L858R-L718Q, Ba / F3-EGFR-E709K-G719A and Ba / F3 EGFR-L861Q engineered cells were provided by Kangyuan Broad Biotechnology (Beijing) Co., Ltd. and cultured in RPMI1640 complete medium containing 10% fetal bovine serum at 37°C and 5% CO2.

[0148] Take cells in the logarithmic growth phase and count them using a platelet counter. Ensure that the cell viability is greater than 90% by trypan blue staining. Adjust the cell density with complete culture medium. Then inoculate in 2 96-well cell culture plates, inoculate 90 μl of cell suspension in each well to make the final cell density 3000 cells / well. Culture in a 37°C, 5% CO2 incubator.

[0149] The test compound (vometinib mesylate and AZD9291) solution was first diluted 1000 times with DMSO. The DMSO solution was then diluted 100 times with PBS (phosphate buffered saline) to prepare a 10× working solution. In addition, a 10× control solution was prepared with phosphate buffered saline (PBS). 10 μl of the working solution (10×) was distributed per well (three replicate wells were set for each concentration). (The starting concentration was 3160 nM, 3.16-fold gradient dilution, and a total of 10 concentration gradients. The final concentration of DMSO in the complete culture medium was 0.1% [v / v]). The cell culture plate was placed under the above conditions and cultured continuously for 3 days.

[0150] On the third day, thaw CellTiter- Reagent (a luciferase ATP bioluminescence detection reagent) and equilibrate the cell culture plate at room temperature for about 30 minutes. Add 100 μl of CellTiter- Reagent, which is equal to the volume of complete cell culture medium present in each well. The resulting contents were shaken on an orbital shaker for 5 minutes to lyse the cells. The cell culture plate was incubated at room temperature for 20 minutes to stabilize the fluorescent signal. The fluorescence intensity (Lum) was detected by a microplate reader.

[0151]

[0152] Blank control: complete medium control

[0153] Solvent control: complete medium containing 0.1% DMSO

[0154] IC was calculated using GraphPad Prism 7.0 software. 50 Value, IC 50 The values ​​are shown in Table 1. Nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve.

[0155] Table 1

[0156]

[0157] The results show that fumetinib mesylate is effective against Ba / F3 EGFR-G719S, Ba / F3 EGFR-S768I, Ba / F3EGFR-G724S, Ba / F3 EGFR-L718Q, Ba / F3 EGFR-Del19 / G724S, Ba / F3 EGFR-E709H, Ba / F3EGFR-L747S, Ba / F3 EGFR-E709V, Ba / F3 EGFR-L747V, Ba / F3 EGFR-E709-710>D, Ba / F3EGFR-E709A, Ba / F3 EGFR-Del19 / C797S, Ba / F3 EGFR-L858R / C797S, Ba / F3EGFR-L747S / G719A, Ba / F3-EGFR-L858R-L718V, Ba / F3-EGFR-L858R-L718Q, Ba / F3-EGFR-E709K-G719A and Ba / F3 EGFR-L861Q cells had good proliferation inhibitory activity.

[0158] Test Example 2: Testing the anti-tumor effect of vometinib mesylate in a female immunodeficient mouse Ba / F3EGFR-G724S (KC-1385) cell xenograft model

[0159] This study was used to evaluate the antitumor effect of vometinib mesylate in female (B-NDG) immunodeficient mice bearing Ba / F3 EGFR-G724S engineered cell tumors.

[0160] Experimental animals: B-NDG mice, female, 6-8 weeks, weight 18-20 g.

[0161] Animal modeling and random grouping: Ba / F3 EGFR-G724S cells were cultured, collected, resuspended in serum-free medium and counted. The resuspended cells were added with matrix gel at a ratio of 1:1 and counted at 1×10 6 pcs / 0.1mL were inoculated subcutaneously in B-NDG mice. When the average tumor volume reached about 80-120mm 3 At 4 pm, the animals were randomly divided into 4 experimental groups according to the tumor size. Each group had 12 animals. The day of grouping was defined as day 0, i.e., D0.

[0162] Experimental plan: Ba / F3 EGFR-G724S cells were subcutaneously inoculated into B-NDG mice to establish a cell line xenograft model. The experiment was divided into 15 mg / kg group of vometinib mesylate, 30 mg / kg group of vometinib mesylate, 50 mg / kg group of vometinib mesylate and vehicle control group, with 12 animals in each group, and the administration volume was 10 μL / g. The vehicle control group was given an equal amount of vehicle, once a day, for two weeks. During the entire experiment, the body weight and tumor size of the mice were measured twice a week, and toxic reactions were observed.

[0163] The calculation formula of tumor volume (TV) is: TV = 0.5 × a × b 2 , where a represents the long diameter of the tumor and b represents the short diameter of the tumor.

[0164] The tumor volume change curves of the four experimental groups are shown in the attached Figure 1 The weight change curves of the four experimental groups are shown in the attached Figure 2 .

[0165] The results showed that the 15 mg / kg group of vometinib mesylate produced moderate antitumor activity; the 30 mg / kg group of vometinib mesylate and the 50 mg / kg group of vometinib mesylate showed very excellent antitumor activity, and the three vometinib mesylate groups had little effect on the body weight of nude mice, showing good safety.

[0166] Test Example 3: Clinical Trial

[0167] An open-label, multicenter, dose-escalation and dose-expansion clinical trial was designed and implemented to evaluate the safety, pharmacokinetics (PK) and preliminary antitumor activity of vometinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating (including rare) epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) mutations. The first phase of the trial was a dose-escalation trial, starting with 240 mg daily to evaluate the once-daily dose of vometinib, with subsequent patient cohorts receiving higher or lower doses of vometinib as needed, followed by expansion cohorts in specific patient groups, where specific patient groups received 240 mg of vometinib daily (and 160 mg for patients with EGFR PACC mutant NSCLC).

[0168] General inclusion criteria include:

[0169] 1) Locally advanced or metastatic non-small cell lung cancer (NSCLC) that is not suitable for curative surgery or radiotherapy based on histological or cytological records;

[0170] 2) patients whose disease has progressed after at least one available standard therapy, or for whom standard therapy has proven ineffective or intolerant, or for whom the clinical trial of the investigational drug is recognized as the standard of care;

[0171] 3) Radiographic disease progression was documented during or after the last systemic anticancer treatment before the first administration of vometinib;

[0172] 4) For patients with epidermal growth factor receptor (EGFR) mutations that are sensitive to osimertinib, patients must have received osimertinib treatment prior to study enrollment in regions where osimertinib is approved, including the United States.

[0173] Exclusion criteria include:

[0174] 1) Treatment with chemotherapy, targeted therapy, biological therapy or investigational drug as anticancer therapy within three or five elimination half-lives (whichever is shorter) before starting to take vometinib;

[0175] 2) Use of radiotherapy as anticancer treatment within 4 weeks before starting to take vometinib;

[0176] 3) palliative radiotherapy for bone metastases within 2 weeks before starting vometinib;

[0177] 4) Except for alopecia or peripheral neuropathy of grade ≤2, adverse events (AEs) of previous anticancer treatment have not been alleviated to grade ≤1.

[0178] Preliminary data from a clinical trial evaluating vometinib (240 mg once daily and 160 mg once daily) in NSCLC patients who had not received any TKI treatment and carried the EGFRPACC mutation showed tumor volume reduction and clinical activity. The preliminary tumor assessment data of the three patients with PACC mutations are shown in Table 2 below.

[0179] Table 2 Preliminary data of clinical trials

[0180]

[0181] SLD: the sum of the longest diameters of all target lesions

[0182] Industrial Applicability

[0183] The present invention provides a pharmaceutical composition containing a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier, and uses of vometinib or a pharmaceutically acceptable salt thereof and the pharmaceutical composition for preparing a drug for treating and / or preventing a disease mediated by a PACC mutation. The present invention also provides a method for treating and / or preventing a disease mediated by a PACC mutation, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient. The pharmaceutical composition of the present invention exhibits an excellent therapeutic effect on a disease mediated by a PACC mutation (e.g., non-small cell lung cancer (NSCLC)), has few side effects, and is excellent in safety.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to claim 1, wherein The pharmaceutically acceptable salt is the methanesulfonate salt.

3. The pharmaceutical composition according to claim 1 or 2, wherein The content of vometinib or a pharmaceutically acceptable salt thereof is 80 mg-400 mg, for example, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The content of vometinib or a pharmaceutically acceptable salt thereof is 80 mg, 160 mg, 240 mg or 320 mg.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The content of the vometinib or its pharmaceutically acceptable salt is 80 mg.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein The content of the vometinib or its pharmaceutically acceptable salt is 160 mg.

7. The pharmaceutical composition according to any one of claims 1 to 4, wherein The content of the vometinib or its pharmaceutically acceptable salt is 240 mg.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein The pharmaceutical composition is in the form of tablets or capsules.

9. The pharmaceutical composition according to claim 8, wherein In each unit preparation of the pharmaceutical composition, the content of vometinib or a pharmaceutically acceptable salt thereof is 10 mg-400 mg, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.

10. The pharmaceutical composition according to claim 8 or 9, wherein In each unit preparation of the pharmaceutical composition, the content of vometinib or a pharmaceutically acceptable salt thereof is 20 mg-320 mg.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein In each unit preparation of the pharmaceutical composition, the content of vometinib or a pharmaceutically acceptable salt thereof is 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg.

12. The pharmaceutical composition according to any one of claims 8 to 11, wherein In each unit preparation of the pharmaceutical composition, the content of vometinib or a pharmaceutically acceptable salt thereof is 40 mg.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein Further comprising at least one second therapeutic agent.

14. The pharmaceutical composition according to claim 13, wherein The second therapeutic agent is selected from chemotherapy drugs, targeted anti-tumor drugs, antibody drugs and immunotherapy drugs.

15. Use of a pharmaceutical composition comprising a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier in the preparation of a medicament for treating and / or preventing a disease mediated by a PACC mutation.

16. Use of vometinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a disease mediated by a PACC mutation.

17. Use of vometinib or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent in combination for the preparation of a medicament for treating and / or preventing a disease mediated by a PACC mutation.

18. The use according to any one of claims 15 to 17, wherein the pharmaceutically acceptable salt is a methanesulfonate.

19. The use according to claim 15, wherein The content of vometinib or a pharmaceutically acceptable salt thereof is 80 mg-400 mg, for example, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.

20. The use according to claim 15 or 19, wherein The content of vometinib or a pharmaceutically acceptable salt thereof is 80 mg, 160 mg, 240 mg or 320 mg.

21. The use according to any one of claims 15, 19-20, wherein The content of vometinib or its pharmaceutically acceptable salt is 80 mg.

22. The use according to any one of claims 15, 19-20, wherein The content of vometinib or its pharmaceutically acceptable salt is 160 mg.

23. The use according to any one of claims 15, 19-20, wherein The content of vometinib or a pharmaceutically acceptable salt thereof is 240 mg.

24. The use according to any one of claims 15, 19-23, wherein The pharmaceutical composition is in the form of tablets or capsules.

25. The use according to claim 24, wherein In each unit preparation, the content of vometinib or a pharmaceutically acceptable salt thereof is 10 mg-400 mg, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.

26. The use according to claim 24 or 25, wherein In each unit preparation, the content of vometinib or its pharmaceutically acceptable salt is 20 mg-320 mg.

27. The use according to any one of claims 24 to 26, wherein In each unit preparation, the content of vometinib or a pharmaceutically acceptable salt thereof is 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg.

28. The use according to any one of claims 24 to 27, wherein In each unit preparation, the content of vometinib or a pharmaceutically acceptable salt thereof is 40 mg.

29. The use according to any one of claims 15, 19-28, wherein The pharmaceutical composition further comprises at least one second therapeutic agent.

30. The use according to claim 17 or 29, wherein The second therapeutic agent is selected from chemotherapy drugs, targeted anti-tumor drugs, antibody drugs and immunotherapy drugs.

31. The use according to any one of claims 15 to 30, wherein The disease is cancer, such as lung cancer, such as non-small cell lung cancer (NSCLC).

32. The use according to any one of claims 15 to 31, wherein The disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

33. The use according to any one of claims 15 to 31, wherein The disease is treatment-naive non-small cell lung cancer or treatment-experienced non-small cell lung cancer.

34. The use according to any one of claims 15 to 33, wherein The PACC mutation is selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-L718Q mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-Del19 / C797S mutation, EGFR-L858R / C797S mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-L858R-L718Q mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation and EGFR-L861Q mutation.

35. The use according to any one of claims 15 to 34, wherein The PACC mutation is at least one selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation and EGFR-L861Q mutation.

36. A method for treating and / or preventing a disease mediated by a PACC mutation, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient.

37. A method for treating and / or preventing a disease, wherein: A therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient who is positive for a PACC mutation.

38. A method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof.

39. A method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient confirmed to be positive for a PACC mutation.

40. A method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient carrying a PACC mutation.

41. A method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient confirmed to be positive for PACC mutation, and the patient has not previously received systemic anti-tumor treatment.

42. A method for treating locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, wherein a therapeutically effective amount of vometinib or a pharmaceutically acceptable salt thereof is administered to a patient confirmed to be positive for PACC mutation, and the patient has previously received systemic anti-tumor treatment and the disease has progressed.

43. The method according to any one of claims 36 to 42, wherein: The vometinib or a pharmaceutically acceptable salt thereof is administered in an amount of 80 mg-400 mg, for example, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.

44. The method according to any one of claims 36 to 43, wherein: The dosage of vometinib or a pharmaceutically acceptable salt thereof is 80 mg, 160 mg, 240 mg or 320 mg.

45. The method according to any one of claims 36 to 44, wherein: The dosage of vometinib or a pharmaceutically acceptable salt thereof administered is 80 mg.

46. ​​The method according to any one of claims 36 to 44, wherein: The dosage of vometinib or a pharmaceutically acceptable salt thereof administered is 160 mg.

47. The method according to any one of claims 36 to 44, wherein: The dosage of vometinib or a pharmaceutically acceptable salt thereof administered is 240 mg.

48. The method according to any one of claims 36 to 47, wherein: The frequency of administration of vometinib or a pharmaceutically acceptable salt thereof is once a day, twice a day or three times a day.

49. The method according to any one of claims 36 to 48, wherein: Vometinib or a pharmaceutically acceptable salt thereof is administered to the patient once daily.

50. The method according to any one of claims 36 to 49, wherein: Vometinib or a pharmaceutically acceptable salt thereof is administered to the patient on an empty stomach.

51. The method according to any one of claims 36 to 50, wherein: Vometinib or a pharmaceutically acceptable salt thereof is administered to the patient in the morning on an empty stomach.

52. The method according to any one of claims 36 to 51, wherein: Vometinib or a pharmaceutically acceptable salt thereof is orally administered to the patient.

53. The method according to any one of claims 36 to 52, wherein: Vometinib mesylate was administered to patients.

54. The method according to any one of claims 36 to 53, wherein: Vometinib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet or capsule formulation.

55. The method according to any one of claims 36 to 54, wherein: Vometinib or a pharmaceutically acceptable salt thereof is administered in the form of a unit dosage form.

56. The method of claim 55, wherein: The unit dosage comprises 10 mg-400 mg, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg of vometinib or a pharmaceutically acceptable salt thereof.

57. The method of claim 55 or 56, wherein: The unit dosage form contains 20 mg to 320 mg of vometinib or a pharmaceutically acceptable salt thereof.

58. The method according to any one of claims 55 to 57, wherein: The unit dosage comprises 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg of vometinib or a pharmaceutically acceptable salt thereof.

59. The method according to any one of claims 55 to 58, wherein: The unit dosage form contains 40 mg of vometinib or a pharmaceutically acceptable salt thereof.

60. The method according to any one of claims 36 to 59, wherein: At least one second therapeutic agent is further administered.

61. The method of claim 60, wherein: The second therapeutic agent is selected from chemotherapy drugs, targeted anti-tumor drugs, antibody drugs and immunotherapy drugs.

62. The method according to any one of claims 36 to 61, wherein: The disease is cancer, such as lung cancer, such as non-small cell lung cancer (NSCLC).

63. The method according to any one of claims 36 to 62, wherein: Vometinib or a pharmaceutically acceptable salt thereof is administered to the patient before or after the patient undergoes surgical resection of the tumor.

64. The method according to any one of claims 36 to 63, wherein: The disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

65. The method according to any one of claims 36 to 63, wherein: The disease is treatment-naive non-small cell lung cancer or treatment-experienced non-small cell lung cancer.

66. The method according to any one of claims 36 to 65, wherein: The PACC mutation is selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-L718Q mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-Del19 / C797S mutation, EGFR-L858R / C797S mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-L858R-L718Q mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation and EGFR-L861Q mutation.

67. The method according to any one of claims 36 to 66, wherein: The PACC mutation is at least one selected from EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation and EGFR-L861Q mutation.

68. The method according to any one of claims 36 to 67, wherein: The patient is a human patient.

69. The method according to any one of claims 36 to 68, wherein: The patients were aged between 18 and 75 years.

70. The method according to any one of claims 36 to 69, wherein: The patient has been diagnosed with primary non-small cell lung cancer (NSCLC) histologically or cytopathologically before receiving treatment with vometinib or a pharmaceutically acceptable salt thereof, and the main type of the NSCLC is non-squamous cell tissue morphology.

71. The method according to any one of claims 36 to 70, wherein: The patient had radiographic disease progression after the last anti-tumor treatment before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

72. The method according to any one of claims 36 to 71, wherein: The patient is confirmed to be positive for PACC mutation by laboratory testing before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

73. The method according to any one of claims 36 to 72, wherein: The patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer and has been confirmed to have radiological or pathological disease progression during or after the last systemic anti-tumor treatment before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

74. The method according to any one of claims 36 to 73, wherein: The patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer and has not received systemic anti-tumor treatment before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

75. The method according to any one of claims 36 to 74, wherein: The patient has at least one measurable lesion before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

76. The method according to any one of claims 36 to 75, wherein: Before patients start treatment with vometinib or a pharmaceutically acceptable salt thereof, laboratory tests show that the patients have adequate organ function.

77. The method according to any one of claims 36 to 76, wherein: The patient's ECOGPS (Eastern Cooperative Oncology Group performance status) score was 0-1 before starting treatment with vometinib or a pharmaceutically acceptable salt thereof.

78. The method according to any one of claims 36 to 77, wherein: The method has acceptable safety.

79. The method according to any one of claims 36 to 78, wherein: The method can achieve a partial remission (PR) effect.

80. The method according to any one of claims 36 to 78, wherein: The method can achieve a stable disease (SD) therapeutic effect.

81. The method according to any one of claims 36 to 80, wherein: The method can shrink tumors in target lesions.

82. The method according to any one of claims 36 to 81, wherein: The method can result in tumor shrinkage in the target lesion as assessed by radiological examination of the tumor, such as computed tomography (CT) and / or magnetic resonance imaging (MRI).

Images