HK40116696A - Pharmaceutical composition and use thereof - Google Patents

Description

Pharmaceutical compositions and their uses

Technical Field

This invention relates to a pharmaceutical composition comprising a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier. The invention also relates to the use of vormetinib or a pharmaceutically acceptable salt thereof, and said pharmaceutical composition, in the preparation of a medicament for treating and/or preventing diseases mediated by human epidermal growth factor receptor-2 (HER2) exon 20 insertion mutations (hereinafter, sometimes also referred to as HER2 exon 20 insertion mutations) and/or by rare epidermal growth factor receptor (EGFR) mutations (hereinafter, sometimes also referred to as EGFR rare mutations). The invention also provides a method for treating and/or preventing diseases mediated by HER2 exon 20 insertion mutations and/or by rare EGFR mutations, wherein a patient is given a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof.

Background Technology

Lung cancer remains the leading cause of death and morbidity among malignant tumors worldwide, posing a serious threat to human health and life. In 2018, 1.76 million people died from lung cancer globally. Non-small cell lung cancer (NSCLC) accounts for approximately 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. It is a member of the ERBB receptor family, which includes four members: EGFR (HER1 or ERBB1), HER2 (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). EGFR mutations are the most widely studied target in NSCLC.

Among EGFR mutations, common mutations include sensitive mutations (such as exon 19 deletion and exon 21 point mutation (L858R), accounting for 85%-90% of all EGFR mutations) and drug-resistant mutations (such as exon 20T790M mutation and exon 20C797S mutation); rare mutations include EGFR G719S mutation, EGFR S768I mutation, EGFR G724S mutation, EGFRL861Q mutation, EGFR G719S/T263P mutation, etc.; in addition, there are also EGFR exon 20 insertion mutations (accounting for about 1-10% of all EGFR mutation types). 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 (TKIs) gefitinib and erlotinib for EGFR-sensitive mutations, the second-generation irreversible covalently bound inhibitor afatinib, and the third-generation inhibitor osimertinib for the drug-resistant mutation EGFR T790M, all of which have shown very good clinical efficacy.

HER2, another member of the ERBB family, is amplified and mutated in various cancers. In NSCLC, HER2 mutations account for approximately 4%, and about 90% of these are exon 20 insertion mutations. HER2 exon 20 contains two main regions: the c-helix (residues 770-774) and the loop following the c-helix (residues 775-783). The most common HER2 exon 20 insertion mutation is the ERBB2A775_G776insYVMA mutation, with less common mutations including the ERBB2V777_G778insGC mutation and the ERBB2P780_Y781insGSP mutation. Exon 20 insertion mutations lead to increased HER2 kinase activity and enhanced signal transduction via downstream pathways, resulting in increased survival, invasiveness, and tumorigenicity. Tumors with the ERBB2A775_G776insYVMA mutation are generally resistant to known EGFR inhibitors. Currently, there are no small molecule targeted drugs approved globally for HER2 exon 20 insertion mutations.

In recent years, compounds that can inhibit EGFR mutations and/or HER2 mutations (especially HER2 exon 20 insertion mutations) have been extensively studied. However, how to further improve their activity and reduce their toxic side effects remains a challenge.

Patent CN105315259B describes 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") as shown in formula (I). Patent CN107163026B describes the mesylate salt of the compound shown in formula (I) as known as "vometinib mesylate". Vometinib mesylate has been commercialized as a third-generation EGFR-TKI inhibitor and is mainly used to treat diseases mediated by EGFR sensitive mutations and T790M resistance mutations. The Phase I escalation trial of voremetinib mesylate has demonstrated that voremetinib mesylate, when taken orally once daily at dose levels of 20 mg to 240 mg, is well-tolerated and safe. All adverse events in the subjects were mild or moderate, and no dose-limiting toxicities or dose-related toxicities were observed. In addition, the Phase IIb clinical trial has demonstrated that oral administration of voremetinib mesylate at a daily dose of 80 mg has a good anti-tumor effect in patients with EGFR T790M-positive advanced non-small cell lung cancer who have progressed after treatment, and can alleviate or stabilize the disease progression.

Summary of the Invention

In some embodiments, the present invention provides the use of vormetinib or a pharmaceutically acceptable salt thereof.

In some embodiments, vormetinib or a pharmaceutically acceptable salt thereof, as an active compound, can effectively inhibit HER2 exon 20 insertion mutations and/or EGFR rare mutations, thereby allowing vormetinib or a pharmaceutically acceptable salt thereof to be used to treat and/or prevent diseases mediated by HER2 exon 20 insertion mutations and/or EGFR rare mutations.

Therefore, in some embodiments, the present invention provides the use of vormetinib or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the treatment and/or prevention of diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations.

In some embodiments, the present invention provides the use of vormetinib or a pharmaceutically acceptable salt thereof in combination with at least one second therapeutic agent for the preparation of a medicament for the treatment and/or prevention of diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations.

In some embodiments, by using vormetinib or a pharmaceutically acceptable salt thereof as the active compound in a certain dose, diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations, particularly non-small cell lung cancer, can be treated and/or prevented with minimal side effects and excellent safety profile.

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

The present invention also provides the use of the above-described pharmaceutical composition of the present invention in the preparation of a medicament for treating and/or preventing diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations.

The above-described compositions of the present invention are available in tablet or capsule formulations. Each unit of formulation contains 10 mg to 400 mg of vormetinib or a pharmaceutically acceptable salt thereof.

When using the pharmaceutical compositions of the present invention to treat and/or prevent diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations, a daily dose of voremtinib or a pharmaceutically acceptable salt thereof is required to be 80 mg to 400 mg. In this case, the daily dose of voremtinib or a pharmaceutically acceptable salt thereof can be easily adjusted by changing the number of tablets or capsules described above.

The present invention also provides a method for treating and/or preventing diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient in need.

In the above-described treatment methods of the present invention, the daily dose of vormetinib or a pharmaceutically acceptable salt thereof is required to be 80 mg to 400 mg.

The present invention also provides a method for treating and/or preventing disease, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to a patient who is positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations.

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

The present invention also provides a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC), wherein patients confirmed to be positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations are given a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC), wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to a patient carrying a HER2 exon 20 insertion mutation and/or a rare EGFR mutation.

The present invention also provides a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC), wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to a patient who has been confirmed to be positive for HER2 exon 20 insertion mutation and/or rare EGFR mutation, and who has not previously received systemic antitumor therapy.

The present invention also provides a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC), wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to a patient who has been previously treated with systemic antitumor therapy but whose disease has progressed.

Invention Effects

In this invention, vormetinib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising vormetinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier, exhibits excellent inhibitory activity against HER2 exon 20 insertion mutations and/or rare EGFR mutations, and therefore can demonstrate excellent clinical efficacy.

In addition, when vormetinib of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising vormetinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier, is used to treat and/or prevent diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations, it has few side effects and excellent safety.

The pharmaceutical compositions of the present invention can be formulated into preparations with appropriate size and appropriate content of active ingredient by containing vormetinib or a pharmaceutically acceptable salt thereof in a specific amount.

Detailed Implementation

The embodiments of the present invention will be described in more detail below with reference to specific examples. However, those skilled in the art will understand that the specific embodiments described below are for illustrative purposes only and should not be considered as limiting the scope of protection of the present invention. Rather, the present invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the present invention as defined by the claims.

Unless otherwise specified, the various embodiments of the present invention can be combined in any way, and the resulting transformations, modifications, and alterations of the technical solutions are also included within the scope of the present invention.

Vometinib is a known compound in the prior art, particularly described in patent CN105315259B, with the chemical name: 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; the structural formula is shown in formula (I).

In some embodiments, the active ingredient for treating the disease is actually voremerinib or a pharmaceutically acceptable salt thereof. Therefore, in some embodiments, voremerinib or a pharmaceutically acceptable salt thereof may be used alone or as part of a composition, in which case the composition may optionally contain a pharmaceutically acceptable carrier as needed.

In addition, in some embodiments, vometinib or a pharmaceutically acceptable salt thereof may be used in combination with at least one second therapeutic agent.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.

"Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. Such carriers are also called "excipients." "Compatibility" here refers to the ability of the components in the composition to be compatible with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include, but are not limited to, 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 fumarate stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers, wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, etc.

The pharmaceutical composition can be prepared using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, and freeze-drying.

The pharmaceutical composition may be present in the form of tablets or capsules, in which vormetinib or a pharmaceutically acceptable salt thereof is mixed with at least one pharmaceutically acceptable carrier, also referred to as an "excipient" in this invention. The pharmaceutically acceptable carrier includes, but is not limited to: (a) fillers or solubilizers, such as microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, colloidal silica, dicalcium phosphate, calcium phosphate, and calcium sulfate; (b) binders, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, alginate, gelatin, polyvinylpyrrolidone, copovidone, sucrose and gum arabic, and corn starch; (c) humectants, such as glycerin, etc. d) Disintegrants, such as croscarmellose sodium, crospovidone, sodium carboxymethyl starch, colloidal silica, microcrystalline cellulose, potato starch or cassava starch or corn starch, pregelatinized starch, alginic acid, certain complex silicates and sodium carbonate, ion exchange resins, etc.; (e) Absorption enhancers, such as quaternary ammonium compounds, anionic or nonionic surfactants, cyclodextrins, etc.; (f) Wetting agents, such as cetyl alcohol and glyceryl monostearate, etc.; (g) Adsorbents, such as kaolin, colloidal silica, ion exchange resins, etc.; and (h) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, sodium stearate 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 using coating or shell materials such as enteric coatings or other materials known in the art.

The term "pharmaceutically acceptable salt" refers to the salt obtained by preparing vometinib with a relatively non-toxic, 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, or quaternary ammonium cations, such as sodium, lithium, potassium, calcium, magnesium, tetramethyl, and tetraethyl quaternary ammonium salts; and amine salts, including salts formed with ammonia ( _NH₃ ), primary, secondary, or tertiary amines, such as methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine salts. Additionally, acid addition salts can 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 salts of inorganic acids such as hydrochloride, sulfate, phosphate, and nitrate; and organic acids such as formate, acetate, propionate, methanesulfonate, benzylsulfonate, succinate, citrate, and tartrate. 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).

In this invention, "therapeutic effective amount" refers to a sufficient amount of a non-toxic drug or pharmacologically active agent that achieves the desired effect. The determination of the effective amount varies from person to person, depending on the patient's age, weight, and condition, as well as the specific active substance. The appropriate effective amount in a case can be determined by a person skilled in the art based on routine testing.

In this invention, "active ingredient," "active substance," or "active agent" refers to a chemical entity that can effectively treat a target disorder, disease, or symptom.

In this invention, "patient," "individual," or "object" 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 tailless apes), monkeys (e.g., marmosets, baboons), and tailless apes (e.g., gorillas, chimpanzees, orangutans, gibbons). In some embodiments, "patient" refers to a human.

In this invention, “treatment” refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or induces the condition or (b) one or more biological manifestations of the condition; (3) improving 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 mean prolonging survival compared to expected survival without treatment.

In this invention, "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

In some embodiments, the pharmaceutically acceptable salt of vometinib is the mesylate of vometinib, namely vometinib mesylate.

In some embodiments, the pharmaceutical compositions of the present invention are present in the form of tablets or capsules.

In some embodiments, the content of vormetinib or a pharmaceutically acceptable salt thereof in each unit formulation (e.g., tablet or capsule) of the above pharmaceutical composition is 10 mg to 400 mg, for example, the content may be 20 mg to 320 mg. Specific amounts can 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. In one embodiment, the amounts can be 20 mg, 40 mg, 80 mg, 160 mg, 240 mg, or 320 mg, for example, 40 mg or 80 mg, or 40 mg.

In some embodiments, the pharmaceutical composition contains vometinib or a pharmaceutically acceptable salt thereof in a concentration of 80 mg to 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. As an exemplary embodiment, the concentration may be 80 mg, 160 mg, 240 mg, or 320 mg, for example, 80 mg, 160 mg, or 240 mg, such as 240 mg.

In some embodiments, when the pharmaceutical composition is used to treat and/or prevent diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations, the composition is administered to the patient at a dose of 80 mg to 400 mg. Specific doses may include, 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. As an exemplary embodiment, the dosage can be 80mg, 160mg, 240mg, or 320mg, for example, 80mg, 160mg, or 240mg, such as 240mg. In one embodiment of the invention, the dosage is a daily dose.

In some embodiments, the content of vormetinib or its pharmaceutically acceptable salts in the pharmaceutical composition refers to the total amount of vormetinib or its pharmaceutically acceptable salts in the pharmaceutical composition taken by the patient when the pharmaceutical composition is administered. For example, when the pharmaceutical composition is in the form of tablets or capsules, the content of vormetinib or its pharmaceutically acceptable salts in the pharmaceutical composition refers to the total amount of vormetinib or its pharmaceutically acceptable salts in all formulations (e.g., tablets or capsules) when the formulation (e.g., tablets or capsules) is administered.

Those skilled in the art will understand that, when administered to a patient, the daily dose of voremerinib or a pharmaceutically acceptable salt thereof is not less than the amount of voremerinib or a pharmaceutically acceptable salt thereof in each unit of the formulation. Those skilled in the art can calculate the total number of formulations required for daily administration based on the daily dose of voremerinib or a pharmaceutically acceptable salt thereof and the amount of voremerinib or a pharmaceutically acceptable salt thereof in each unit of the formulation (each tablet). For example, when voremerinib or a pharmaceutically acceptable salt thereof is contained in tablets, and the amount of voremerinib or a pharmaceutically acceptable salt thereof in each unit of the formulation (each tablet) is 40 mg, and when the daily dose of voremerinib or a pharmaceutically acceptable salt thereof is 240 mg, the total number of formulations (tablets) required for daily administration is 6 tablets.

In some embodiments, the pharmaceutical composition is used to treat and/or prevent diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations, administered once, twice, or three times daily. For example, once daily.

In some embodiments, the pharmaceutical composition may further comprise at least one second therapeutic agent. This second therapeutic agent may be selected from chemotherapy drugs, targeted antitumor drugs, antibody drugs, and immunotherapy drugs.

In some embodiments, the chemotherapeutic agents may include platinum-based drugs (e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin, triplatin tetranitrate, phenanthreneplatin, pyridine, miplatin, saxaplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, ancitabine, fluorouracil, diflufenican, deoxyfluorouracil, tegafur, carmoflu, trifluorouracil, tegafur), camptothecin derivatives (e.g., camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel), and vinblastine derivatives (vinorelbine, vinblastine, vincristine, vindesin, vinflunine). Anthracyclines (epurubicin, doxorubicin, daunorubicin, pirarubicin, amorubicin, idarubicin, mitoxantrone, amorubicin, pentorubicin, zorubicin, pisacocele), antibiotics, podophyllotoxin, antimetabolites, pemetrexed, carmustine, melphalan, etoposide, tenibolaside, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposomal doxorubicin, actinomycin D, bleomycin, bleomycin, temozolomide, amipromide, pepromycin, eribulin, plinabulin, sapacitabine, treosulfan, 153Sm-EDTMP, and encequidar.

In some embodiments, the second therapeutic agent is one or more platinum-based drugs, including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, triplatinum tetranitrate, phenanthreneplatin, pyridine, saxaplatin, miplatin, lorplatin, etc.

In some embodiments, the chemotherapeutic agent 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.

In some embodiments, protein kinase inhibitors may be listed as the targeted antitumor drugs. These protein kinase inhibitors include, but are not limited to, tyrosine kinase inhibitors, serine and/or threonine kinase inhibitors, and polyADP-ribose polymerase (PARP) inhibitors. The targets of these inhibitors include, but are not limited to, Fascin-1 protein, HDAC (histone deacetylase), 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 (disc cell death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, and KRAS gene. The targets of the targeted anti-tumor drugs also include COX-2 (cyclooxygenase-2), APE1 (depurinylpyrimidine endonuclease), VEGFR (vascular endothelial growth factor receptor), CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor), Ezrin, PEDF (pigmented epithelial-derived factor), AS, ES, OPG (bone protectant), Src, IFN, ALCAM (leukocyte ibuprofen-activated adhesion factor), HSP, JIP1, GSK-3 (glycogen synthesis kinase 3), Cyclin D1 (cell cycle regulator), CDK4 (cyclin-dependent kinase), TIMP1 (tissue metalloproteinase inhibitor), THBS3, PTHR1 (parathyroid hormone-associated protein receptor 1), TEM7 (human tumor vascular endothelial marker 7), COPS3, and cathepsin K. Targeted anti-tumor drugs that can be listed include, but are not limited to, imatinib, sunitinib, nilotinib, bosutinib, sercatinib, pazopanib, trabectedin, regorafenib, cedilanib, bortezomib, panobinostat, carfilzomib, ixazomib, and apatinib. Erlotinib, Afatinib, Crizotinib, Ceritinib, Vemurafenib, Dabrafenib, Cabozantinib, Gefitinib, Dacomitinib, Almonertinib, Osimertinib, Ometinib, Alectinib, Brigatinib, Lorlatinib, Trametinib tinib), larotrectinib, icotinib, lapatinib, vandetanib, selumetinib, sorafenib, olmutinib, savolitinib, fruquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib ib), Binimetinib, Erdafitinib, Axitinib, Neratinib, Cobimetinib, Acalabrutinib, Famitinib, Masitinib, Ibrutinib, Anlotinib, Rociletinib, Nintedanib, Lenalidomide, LOXO-292, Vorolanib, Bemcentinib, Capmatinib, Entr ectinib, TAK-931, ALT-803, palbociclib, famitinib L-malate, LTT-462, BLU-667, ningetinib, tipifarnib, poziotinib, DS-1205c, capivas ertib, 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, moli bresib, CC-223, rivoceranib, CK-101, LXH-254, simotinib, GSK-3368715, TAS-0728, masitinib, tepotinib, HS-10296, AZD-4547, merestinib, olapte sedpegol, galunisertib, ASN-003, gedatolisib, defactinib, lazertinib, CKI-27, S-49076, BPI-9016M, RF-A-089, RMC-4630, AZD-3759, antroquino nol, SAF-189s, AT-101, TTI-101, naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, epitinib succinate, tesevatinib, SPH-1188-11, BPI-1500 0. One or more of the following: copanlisib, niraparib, olaparib, veliparib, talazoparib tosylate, DV-281, Siredalin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, tucidinostat, vorinostat, resminostat, epacadostat, tazemetostat, entinostat, mocetinostat, quisinostat, LCL-161, and KML-001. In some implementations, the targeted antitumor drug is one or more of the following: sorafenib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, lorlatinib, trametinib, larotrectinib, icotinib, lapatinib, vandetanib, selmetinib, omalitinib, voritinib, fruquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib, bimetinib, erdatinib, axitinib, neratinib, cobitinib, acalatinib, famitinib, masitinib, ibrutinib, anlotinib, and nintedanib.

In some embodiments, the second therapeutic agent is an antibody drug. The antibody drug targets, but is not limited to, any one or more of, 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 B cell surface protein CD19/CD3.

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

In some embodiments, the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody or its antigen-binding fragment that binds to programmed death receptor 1 (PD-1) and/or inhibits PD-1 activity, or an antibody or its antigen-binding fragment 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 invention, the antibody or its antigen-binding fragment is (a) an anti-PD-1 monoclonal antibody or its antigen-binding fragment 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 its antigen-binding fragment that specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.

In some embodiments, the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.

In some embodiments, the anti-PD-1 or PD-L1 antibody is a human-derived antibody or a murine-derived antibody.

In some embodiments, the anti-PD-1 antibody may be selected from any one or more of nivolumab, pembrolizumab, durvalumab, toripalimab (JS-001), sintilimab (IBI308), camrelizumab, tislelizumab (BGB-A317), genolumab (GB226), livzon tuzumab (LZM009), HLX-10, BAT-1306, AK103 (HX008), AK104 (Kangfang Bio), CS1003, SCT-I10A, F520, SG001, and GLS-010.

In some embodiments, the anti-PD-L1 antibody may 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.

In some embodiments, the anti-PD-1 antibody is toripalimab.

In some embodiments, the anti-PD-1 antibody is pembrolizumab.

In some embodiments, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor is an anti-CTLA-4 antibody. In one embodiment of the invention, the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.

In some embodiments, the anti-CTLA-4 antibody may be selected from any one or more of ipilimumab, tremelimumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, and IBI310.

In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the platelet-derived growth factor receptor α (PDGFR-α) inhibitor is an anti-PDGFRα antibody. In one embodiment of the invention, the anti-PDGFRα antibody is an anti-PDGFRα monoclonal antibody.

In some embodiments, the anti-PDGFRα antibody is olamatumab.

In some embodiments, the antibody drug may also include, but is not limited to, bevacizumab, ramucirumab, pertuzumab, trastuzumab, cotuximab, nimotuzumab, panitumumab, necitumumab, dinutuximab, and rituximab. Any one or more of the following: Ibritumomab, Ofatumumab, Obinutuzumab, Alemtuzumab, Daratumumab, Gemtuzumab, Elotuzumab, Brentuximab, Inotuzumab Ozogamicin, and Blinatumomab.

In some implementations, one or more of interferon (interferon α, interferon α-1b, interferon α-2b), interleukin, sirolimus, everolimus, ridaforolimus, and tesimolimus may be listed as immunotherapeutic agents.

In some embodiments, when using a second therapeutic agent, those skilled in the art can adjust the content of the second therapeutic agent as needed.

In some embodiments, the use of vormetinib or a pharmaceutically acceptable salt thereof is provided in the preparation of a medicament for the treatment and/or prevention of diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations.

In some embodiments, the use of vormetinib or a pharmaceutically acceptable salt thereof, in combination with at least one second therapeutic agent, is provided for the preparation of a medicament for the treatment and/or prevention of diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations.

In some embodiments, the use of the above-described pharmaceutical composition in the preparation of a medicament for treating and/or preventing diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations is provided.

In some embodiments, in the above-described uses of the present invention, the pharmaceutically acceptable salt of vormetinib is the mesylate of vormetinib, namely vormetinib mesylate.

In some embodiments, in the above-described uses of the present invention, the pharmaceutical composition is present in the form of tablets or capsules.

In some embodiments of the present invention, in each unit formulation (e.g., tablet or capsule), the content of vormetinib or a pharmaceutically acceptable salt thereof is 10 mg to 400 mg, for example, the content may be 20 mg to 320 mg. Specific amounts can be, for example, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 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 an example, the specific content can be 20mg, 40mg, 80mg, 160mg, 240mg or 320mg, for example 40mg or 80mg, for example 40mg.

In some embodiments, in the above-described uses of the present invention, the content of vormetinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 80 mg to 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. As an example, the content can be 80mg, 160mg, 240mg or 320mg, for example 80mg, 160mg or 240mg, for example 240mg.

In some embodiments, in the above-described uses of the present invention, the pharmaceutical composition is administered to a patient at a dose of 80 mg to 400 mg. Specific doses may include, 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. As an example, the dosage can be 80 mg, 160 mg, 240 mg, or 320 mg, for example, 80 mg, 160 mg, or 240 mg, for example, 240 mg. In one embodiment of the invention, the dosage is a daily dose.

In some embodiments, in the above-described uses of the present invention, the content of vormetinib or its pharmaceutically acceptable salts in the pharmaceutical composition refers to the total amount of vormetinib or its pharmaceutically acceptable salts in the pharmaceutical composition taken by the patient when the pharmaceutical composition is administered. For example, when the pharmaceutical composition is in the form of a tablet or capsule, the content of vormetinib or its pharmaceutically acceptable salts in the pharmaceutical composition refers to the total amount of vormetinib or its pharmaceutically acceptable salts in all formulations (e.g., tablets or capsules) when the formulation (e.g., tablets or capsules) is administered.

Those skilled in the art will understand that, in the above-described uses of the present invention, when administered to a patient, the daily dose of voremerinib or a pharmaceutically acceptable salt thereof is not less than the amount of voremerinib or a pharmaceutically acceptable salt thereof in each unit of the formulation. Those skilled in the art can calculate the total number of formulations required for daily administration based on the daily dose of voremerinib or a pharmaceutically acceptable salt thereof and the amount of voremerinib or a pharmaceutically acceptable salt thereof in each unit of the formulation. For example, when voremerinib or a pharmaceutically acceptable salt thereof is contained in tablets, and the amount of voremerinib or a pharmaceutically acceptable salt thereof in each unit of the formulation (each tablet) is 40 mg, and when the daily dose of voremerinib or a pharmaceutically acceptable salt thereof is 240 mg, the total number of formulations (tablets) required for daily administration is 6 tablets.

In some implementations, the disease mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations is cancer, such as lung cancer, and further, non-small cell lung cancer (NSCLC).

In some implementations, the disease mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

In some implementations, the disease mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations is treatment-naïve or previously treated non-small cell lung cancer.

In this invention, "treatment-naïve" refers to a situation where, prior to receiving treatment with voremtinib or a pharmaceutically acceptable salt thereof, the patient has not received treatment with other therapeutic agents (including but not limited to chemotherapy drugs, targeted anti-tumor drugs, antibody drugs, or immunotherapy drugs), or it can refer to a situation where the patient has not previously received systemic anti-tumor therapy. In this invention, "treatment-experienced" refers to a situation where, prior to receiving treatment with voremtinib or a pharmaceutically acceptable salt thereof, the patient has received treatment with other therapeutic agents (including but not limited to chemotherapy drugs, targeted anti-tumor drugs, antibody drugs, or immunotherapy drugs), or it can refer to a situation where the patient has previously received systemic anti-tumor therapy but the disease has progressed. In the case of "treatment-experienced," the patient may have developed tolerance to other therapeutic agents, or may not have developed resistance.

In some implementations, the HER2 exon 20 insertion mutation is selected from at least one of the following: ERBB2A775_G776insYVMA mutation, ERBB2V777_G778insGC mutation, and ERBB2P780_Y781insGSP mutation.

In one embodiment of the present invention, the rare EGFR mutation is at least one selected from EGFR G719S mutation, EGFR S768I mutation, EGFR G724S mutation, EGFR L861Q mutation and EGFR G719S/T263P mutation.

In some embodiments, in the above-described uses of the present invention, the pharmaceutical composition may further comprise at least one second therapeutic agent.

In the above-described uses of the present invention, the second therapeutic agent may be selected from chemotherapy drugs, targeted anti-tumor drugs, antibody drugs, and immunotherapy drugs.

In some embodiments, in the above-described uses of the present invention, the second therapeutic agent is the second therapeutic agent described above.

In some embodiments, a method is provided for treating and/or preventing diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to the desired patient.

In some embodiments, a method for treating and/or preventing disease is provided, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to a patient who is positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations.

In some embodiments, a method for treating locally advanced or metastatic non-small cell lung cancer is provided, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient in need.

In some embodiments, a method for treating locally advanced or metastatic non-small cell lung cancer is provided, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to patients confirmed to be positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations.

In some embodiments, a method for treating locally advanced or metastatic non-small cell lung cancer is provided, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to a patient carrying a HER2 exon 20 insertion mutation and/or a rare EGFR mutation.

In some embodiments, a method for treating locally advanced or metastatic non-small cell lung cancer is provided, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to a patient who has been confirmed to be positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations, and who has not previously received systemic antitumor therapy.

In some embodiments, a method for treating locally advanced or metastatic non-small cell lung cancer is provided, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to a patient who has previously received systemic antitumor therapy and whose disease has progressed.

In some embodiments of the above treatment methods, the dose of vortexinib or a pharmaceutically acceptable salt thereof administered to the patient is 80 mg to 400 mg. Specific doses may include, 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. As an example, the dosage can be 80 mg, 160 mg, 240 mg, or 320 mg, for example, 80 mg, 160 mg, or 240 mg, for example, 240 mg. In one embodiment of the invention, the dosage is a daily dose.

In some embodiments of the above treatment methods, patients are given vortexinib or its pharmaceutically acceptable salts once daily, twice daily, or three times daily. For example, once daily.

In some embodiments of the above treatment methods, vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient on an empty stomach, for example, on an empty stomach in the morning.

In some embodiments of the above treatment methods, vometinib or a pharmaceutically acceptable salt thereof is administered orally to the patient.

In some embodiments of the above treatment methods, vometinib is administered in the form of mesylate.

In some embodiments of the above treatment methods, vometinib or a pharmaceutically acceptable salt thereof is administered in tablet or capsule form.

In some embodiments of the above-described treatment methods, vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient in the form of a unit dosage form. The number of unit dosage forms is adjusted so that the daily dose of vormetinib or a pharmaceutically acceptable salt thereof is within the range described above.

In some embodiments of the above treatment methods, each unit of formulation (e.g., tablets or capsules) contains 10 mg to 400 mg of vortexinib or a pharmaceutically acceptable salt thereof, for example, the content may be 20 mg to 320 mg. Specific amounts can be, for example, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 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 an example, the specific content can be 20mg, 40mg, 80mg, 160mg, 240mg or 320mg, for example 40mg or 80mg, for example 40mg.

Those skilled in the art will understand that, when administered to a patient, the daily dose of voremerinib or a pharmaceutically acceptable salt thereof is not less than the amount of voremerinib or a pharmaceutically acceptable salt thereof in each unit of the formulation. Those skilled in the art can calculate the total number of formulations required for daily administration based on the daily dose of voremerinib or a pharmaceutically acceptable salt thereof and the amount of voremerinib or a pharmaceutically acceptable salt thereof in each unit of the formulation (each tablet). For example, when voremerinib or a pharmaceutically acceptable salt thereof is contained in tablets, and the amount of voremerinib or a pharmaceutically acceptable salt thereof in each unit of the formulation (each tablet) is 40 mg, and when the daily dose of voremerinib or a pharmaceutically acceptable salt thereof is 240 mg, the total number of formulations (tablets) required for daily administration is 6 tablets.

In some embodiments of the above-described treatment methods, at least one second therapeutic agent may be further administered to the patient. In some embodiments of the above-described treatment methods, the second therapeutic agent may be selected from chemotherapy drugs, targeted antitumor drugs, antibody drugs, and immunotherapy drugs.

In some embodiments of the above-described treatment method, the second therapeutic agent is the second therapeutic agent described in this invention.

In some embodiments of the above treatment methods, the disease is cancer, such as lung cancer, and more specifically, non-small cell lung cancer (NSCLC).

In some embodiments of the above treatment methods, vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient before or after surgical removal of the tumor.

In some embodiments of the above treatment methods, the disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

In some embodiments of the above treatment methods, the disease is newly diagnosed non-small cell lung cancer or previously treated non-small cell lung cancer.

In the above-described treatment method of the present invention, the HER2 exon 20 insertion mutation is at least one selected from ERBB2 A775_G776insYVMA mutation, ERBB2 V777_G778insGC mutation and ERBB2 P780_Y781insGSP mutation.

In one embodiment of the present invention, the rare EGFR mutation is at least one selected from EGFR G719S mutation, EGFR S768I mutation, EGFR G724S mutation, EGFR L861Q mutation and EGFR G719S/T263P mutation.

In some embodiments of the above treatment methods, the patient is a human patient.

In some embodiments of the above treatment methods, the patient is between 18 and 75 years old.

In some embodiments of the above treatment methods, the patient has been histologically or cytopathologically diagnosed with primary non-small cell lung cancer (NSCLC) with a predominant non-squamous histological morphology prior to receiving vormetinib or a pharmaceutically acceptable salt thereof.

In some implementations of the above treatment methods, the patient experiences radiographic progression of the disease after the last antitumor treatment prior to starting vormetinib or its pharmaceutically acceptable salt therapy.

In some implementations of the above treatment methods, patients are tested positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations by laboratory tests before starting treatment with vormetinib or its pharmaceutically acceptable salts.

In some embodiments of the above treatment methods, the patient has locally advanced or metastatic non-small cell lung cancer (NSCLC) and has been shown to have radiographic or pathological disease progression during or after the last systemic antitumor therapy prior to starting voreminib or its pharmaceutically acceptable salts.

In some implementations of the above treatment methods, the patient has locally advanced or metastatic non-small cell lung cancer (NSCLC) and has not received systemic antitumor therapy prior to starting treatment with voremtinib or its pharmaceutically acceptable salts.

In some implementations of the above treatment methods, the patient has at least one measurable lesion before starting treatment with vometinib or its pharmaceutically acceptable salt.

In some implementations of the above treatment methods, laboratory tests show that the patient has adequate organ function before starting treatment with vormetinib or its pharmaceutically acceptable salts.

In some implementations of the above treatment methods, patients undergo an ECOGPS (Eastern Cooperative Oncology Group Performance Status) score, for example, an ECOGPS score of 0-1, before starting treatment with vortexinib or its pharmaceutically acceptable salts.

In some implementations, the above-described treatment methods have acceptable safety.

In some implementations, the above-described treatment methods can achieve partial remission (PR).

In some implementations, the above treatment methods can achieve a stable disease state (SD).

In some implementations, the above-described treatment methods can shrink tumors in the target lesion.

In some implementations of the above-described treatment methods, the tumor in the target lesion shrinks when assessed by tumor imaging examinations (e.g., computed tomography (CT) and/or magnetic resonance imaging (MRI)).

Attached Figure Description

Figure 1. Tumor volume change curve in test example 2.

Figure 2. Weight change rate curve in test example 2.

Figure 3. Tumor volume change curve in test example 3.

Figure 4. Weight change curve in test example 3.

Example

I. Preparation Examples

Preparation of vometinib mesylate 40mg tablets

Prescription: Vometinib mesylate 46.76 mg, microcrystalline cellulose 44.73 mg, lactose 68.2 mg, croscarmellose sodium 13 mg, polyethylene glycol 4000 17.8 mg, colloidal silica 10.9 mg, sodium stearate fumarate 2.7 mg, sodium chloride 8.67 mg. Contains 40 mg of vometinib.

Formulation process: After pretreatment by sieving the excipients and raw materials, they are mixed evenly. An appropriate amount of polyethylene glycol 4000 is added for wet granulation, followed by sieving and wet granulation. The wet granules are dried, sieved and granulated again. Colloidal silica and sodium stearate are added, mixed evenly, and then compressed into tablets.

II. Active Examples

Test Example 1: Inhibitory activity against the proliferation of Ba/F3 EGFR G719S, Ba/F3 EGFR G724S, Ba/F3 EGFR S768I, Ba/F3 EGFR L861Q, Ba/F3 EGFR G719S/T263P, Ba/F3 ERBB2 A775_G776insYVMA, Ba/F3 ERBB2 V777_G778insGC, and Ba/F3 ERBB2 P780_Y781insGSP stable transgenic cells.

The cell-titer-Glo method was used to determine the in vitro inhibitory activity of the compound (vometinib mesylate) on the proliferation of mouse proto-B cells (Ba/F3 EGFR G719S, Ba/F3 EGFR G724S, Ba/F3 EGFR RS768I, Ba/F3 EGFR L861Q cells stably expressing four rare EGFR mutant proteins, Ba/F3 EGFR G719S/T263P cells stably expressing one EGFR double mutant protein, and Ba/F3 ERBB2A775_G776insYVMA, Ba/F3 ERBB2 V777_G778insGC, Ba/F3 ERBB2P780_Y781insGSP cells stably expressing different ERBB2 exon 20 insertion mutant proteins.

Cell source: Ba/F3 EGFR G719S, Ba/F3 EGFR G724S, Ba/F3 EGFR S768I, Ba/F3 EGFR L861Q, Ba/F3 EGFR G719S/T263P, Ba/F3 ERBB2A775_G776insYVMA, Ba/F3 ERBB2V777_G778insGC, and Ba/F3 ERBB2P780_Y781insGSP cells were provided by Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.

Ba/F3 EGFR G719S, Ba/F3 EGFR G724S, Ba/F3 EGFR S768I, Ba/F3 EGFR L861Q, Ba/F3 EGFR G719S/T263P, Ba/F3 ERBB2A775_G776insYVMA, Ba/F3 ERBB2 V777_G778insGC, and Ba/F3 ERBB2P780_Y781insGSP cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum. Ba/F3 EGFR G719S, Ba/F3 EGFR G724S, Ba/F3 EGFR S768I, Ba/F3 EGFR L861Q, Ba/F3 EGFR G719S/T263P, Ba/F3 ERBB2 A775_G776insYVMA, Ba/F3ERBB2 V777_G778insGC, and Ba/F3 ERBB2 P780_Y781insGSP cells in logarithmic growth phase were seeded in 96-well plates at a density of 3000 cells/90 μl of complete culture medium/well and incubated at 37°C in a 5% _CO2 incubator for 24 hours. The compound was pre-dissolved in dimethyl sulfoxide (DMSO) to prepare a 30 mM stock solution, which was then diluted sequentially with DMSO and complete culture medium. Add 10 μl of different concentrations of compound to each well of a 96-well cell culture plate to achieve final concentrations of 3000, 950, 300, 95.0, 30, 9.5, 3, 0.95, and 0.3 nM. Each compound concentration was used in triplicate. A negative control group (containing cell culture medium) and a blank control group (containing no cell culture medium) were also included. The concentration of DMSO in each well was 0.1%. The plates were then incubated at 37°C in a 5% _CO2 incubator for 72 hours.

Melt CellTiter-Glo reagent (a luciferase-ATP bioluminescent assay reagent, purchased from Promega) and remove the 96-well cell culture plate from the _CO2 incubator to equilibrate to room temperature (approximately 30 minutes). Add 100 μl of CellTiter-Glo reagent to each well, and shake on a track-mounted shaker for 5 minutes to lyse the cells. Incubate at room temperature for 20 minutes until the fluorescence intensity stabilizes, and measure the fluorescence intensity (Lum) using a microplate reader. Calculate the cell viability at each compound concentration.

The data were analyzed using GraphPad Prism 7.0 software. The dose-response curve was obtained by fitting the data using nonlinear S-curve regression, and the _IC50 value was calculated from it. The results are shown in Table 1.

Table 1

The results showed that vormetinib mesylate had good inhibitory activity against the proliferation of stable transgenic Ba/F3 EGFR G719S, Ba/F3 EGFR G724S, Ba/F3 EGFRS768I, Ba/F3 EGFR L861Q, Ba/F3 EGFR G719S/T263P, Ba/F3 ERBB2 A775_G776insYVMA, Ba/F3 ERBB2 V777_G778insGC, and Ba/F3 ERBB2 P780_Y781insGSP cells.

Test Example 2: Testing the antitumor effect of voremiteinib mesylate in the Ba/F3 ERBB2A775_G776insYVMACDX tumor model

This experiment was used to evaluate the antitumor effect of vormetinib mesylate in a subcutaneous xenograft BALB/c female nude mouse model of Ba/F3 ERBB2A775_G776insYVMA, in which the ERBB2 exon 20 insertion mutant protein is stably expressed in Ba/F3 cells of the original B cells.

Laboratory animals: BALB/c Nude mice, female, 8-9 weeks old (mice's age at tumor cell inoculation), weighing 13.7-17.7g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Shanghai Branch.

Animal model establishment and randomization: Ba/F3 ERBB2 A775_G776insYVMA cells were cultured and expanded to two T175 ^cm² culture flasks. Cells were collected, resuspended in serum-free DMEM, counted, and mixed with matrix gel at a 1:1 ratio. 2 × ^10⁶ cells/0.1 mL were subcutaneously seeded into the right anterior segment of BALB/c Nude mice. When the average tumor volume reached approximately 160 ^mm³ , mice were randomly assigned to three experimental groups based on tumor size. Six mice were assigned to each group. The day of grouping was defined as day 0, or D0.

Experimental protocol: BALB/c nude mice were subcutaneously inoculated with Ba/F3 ERBB2A775_G776insYVMA cells to establish a cell line xenograft tumor model. The experiment was divided into three groups: an AZD9291 30 mg/kg group, a vormetinib mesylate 30 mg/kg group, and a solvent control group, with 6 mice in each group. All mice were administered the drugs orally at a volume of 10 μL/g. The solvent control group received an equal volume of solvent. Dosage was administered once daily for two weeks. Throughout the experiment, mouse body weight and tumor size were measured twice weekly to observe for any toxic reactions.

The formula for calculating tumor volume (TV) is: TV = 1/2 × a × b × b, where a and b represent the length and width of the tumor, respectively.

Weight change rate % = (weight / D0 weight - 1) × 100%.

The tumor volume change curves for the three experimental groups are shown in Figure 1, and the body weight change rate curves are shown in Figure 2.

The results showed that in the Ba/F3 ERBB2 A775_G776insYVMACDX subcutaneous xenograft BALB/c female nude mouse animal model, vormetinib mesylate exhibited good antitumor activity and had little impact on the body weight of nude mice, demonstrating good safety.

Test Example 3: Testing the antitumor effect of voremetinib mesylate in a female immunodeficient mouse model xenografted with Ba/F3V777_G778insGC(KC-1410) cells.

This study evaluated the antitumor effects of three compounds administered alone in a female immunodeficient mouse (B-NDG) tumor model in vivo inoculated with Ba/F3 V777_G778insGC engineered cells.

Experimental animals: B-NDG mice, female, 6-8 weeks old, weighing 18-20g.

Animal model establishment and randomization: Ba/F3 V777_G778insGC cells were cultured, collected, resuspended in serum-free medium, counted, and mixed 1:1 with matrix gel. Cells were then subcutaneously seeded into B-NDG mice at a concentration of 1× ^10⁶ cells/0.1 mL. When the average tumor volume reached approximately 80-120 ^mm³ , mice were randomly assigned to four experimental groups based on tumor size. Each group consisted of 12 mice. The day of grouping was defined as day 0, or D0.

Experimental protocol: B-NDG mice were subcutaneously inoculated with Ba/F3 V777_G778insGC cells to establish a cell line xenograft tumor model. The experiment was divided into four groups: voremetinib mesylate 15 mg/kg group, voremetinib mesylate 30 mg/kg group, voremetinib mesylate 50 mg/kg group, and a solvent control group, with 12 mice in each group. The mice were administered the drug orally at a volume of 10 μL/g. The solvent control group received an equal volume of solvent. The drugs were administered once daily for two weeks. Throughout the experiment, the mice's body weight and tumor size were measured twice weekly to observe for any toxic reactions.

The formula for calculating tumor volume (TV) is: TV = 1/2 × a × b ² , where a is the long axis of the tumor and b is the short axis of the tumor.

The tumor volume change curves for the four experimental groups are shown in Figure 3, and the body weight change curves for the four experimental groups are shown in Figure 4.

The results showed that voremetinib mesylate produced a moderate antitumor effect at a dose of 15 mg/kg; voremetinib mesylate at doses of 30 mg/kg and voremetinib mesylate at doses of 50 mg/kg produced extremely excellent antitumor effects; and the three voremetinib mesylate groups had little effect on the body weight of mice, showing good safety.

Test Example 4: Efficacy study of vormetinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) carrying HER2 activating mutations (including exon 20 insertion mutations).

A clinical trial was conducted in at least 100 patients with advanced or metastatic NSCLC carrying HER2 activating mutations (including exon 20 insertion mutations) to evaluate the safety, pharmacokinetics (PK), and antitumor efficacy of vortexinib.

Patient enrollment was divided into two phases: Phase 1 (dose escalation and backfilling) and Phase 2 (dose expansion). In each phase, vortexinib tablets were administered to previously treated NSCLC patients.

The primary outcome measures include the incidence and severity of adverse events (AEs), which serve as indicators of the safety and tolerability of vortexil (time range from the first dose to 36 months). Secondary outcome measures include, for example, overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival, central nervous system (CNS) ORR, and central nervous system (CNS) DOR from the first dose to 36 months.

Patients meeting the inclusion criteria included all sexes and were at least 18 years old. Inclusion criteria included, for example,

- Locally advanced or metastatic NSCLC that is not suitable for curative surgery or radiation therapy based on histological or cytological records;

- Patients whose disease has progressed after at least one available standard therapy, or who have demonstrated ineffectiveness or intolerance to standard therapy, or patients for whom clinical trials of investigational drugs are recognized as standard treatment;

- Patients with a history of treated central nervous system metastases or newly diagnosed asymptomatic central nervous system metastases during screening;

- Progression of radiological disease was recorded during or after the last systemic anticancer therapy prior to the first administration of vormetinib;

- For patients with EGFR mutations who are sensitive to osimertinib, they must have received osimertinib treatment before enrollment in studies in regions where osimertinib is approved, including the United States.

- Documented empirical results from local tests in blood or tumor tissue confirming the presence of a HER2 exon 20 insertion mutation; and

- The patient must have experienced disease progression or be intolerant to platinum-based chemotherapy.

Exclusion criteria include, for example,

- If chemotherapy, immunotherapy, biotherapy or investigational drugs are used as anticancer therapy within 3 weeks or five half-lives (whichever is shorter) before starting vometinib, or if endocrine therapy is used within 2 weeks before starting vometinib.

- Use radiation therapy as an anti-cancer treatment within 4 weeks before starting vometinib;

- Palliative radiotherapy to bone metastases within 2 weeks prior to starting vortexinib; and

- Except for alopecia or peripheral neuropathy of grade ≤2, adverse events from previous anticancer treatment have not been resolved to grade ≤1.

Industrial practicality

This invention provides a pharmaceutical composition comprising a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier, the use of vormetinib or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations. This invention also provides a method for the treatment and/or prevention of diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations, wherein a patient is given a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions of this invention exhibit excellent therapeutic efficacy against diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations (e.g., non-small cell lung cancer (NSCLC)), with few side effects and excellent safety profile.

Claims (82)

1. A pharmaceutical composition comprising a therapeutically effective amount of vormetinib 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 a mesylate. 3. The pharmaceutical composition according to claim 1 or 2, wherein the content of vormetinib or a pharmaceutically acceptable salt thereof is 80 mg to 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 1-3, wherein the content of vormetinib 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 1-4, wherein the content of vormetinib or a pharmaceutically acceptable salt thereof is 80 mg. 6. The pharmaceutical composition according to any one of claims 1-4, wherein the content of vormetinib or a pharmaceutically acceptable salt thereof is 160 mg. 7. The pharmaceutical composition according to any one of claims 1-4, wherein the content of vormetinib or a pharmaceutically acceptable salt thereof is 240 mg. 8. The pharmaceutical composition according to any one of claims 1-7, wherein the pharmaceutical composition is in the form of a tablet or capsule. 9. The pharmaceutical composition according to claim 8, wherein in each unit formulation of the pharmaceutical composition, the content of vormetinib or a pharmaceutically acceptable salt thereof is 10 mg to 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 formulation of the pharmaceutical composition, the content of vormetinib or a pharmaceutically acceptable salt thereof is 20 mg to 320 mg. 11. The pharmaceutical composition according to any one of claims 8-10, wherein in each unit formulation of the pharmaceutical composition, the content of vormetinib 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 8-11, wherein in each unit formulation of the pharmaceutical composition, the content of vormetinib or a pharmaceutically acceptable salt thereof is 40 mg. 13. The pharmaceutical composition according to any one of claims 1-12, wherein it further comprises at least one second therapeutic agent. 14. The pharmaceutical composition of claim 13, wherein the second therapeutic agent is selected from chemotherapy drugs, targeted antitumor drugs, antibody drugs, and immunotherapy drugs. 15. Use of a pharmaceutical composition comprising a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier in the preparation of a medicament for the treatment and/or prevention of diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations. 16. Use of vormetinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and/or prevention of diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations. 17. Use of vormetinib or a pharmaceutically acceptable salt thereof in combination with at least one second therapeutic agent for the preparation of a medicament for the treatment and/or prevention of diseases mediated by HER2 exon 20 insertion mutations and/or by rare EGFR mutations. 18. The use according to any one of claims 15-17, wherein the pharmaceutically acceptable salt is a mesylate. 19. The use according to claim 15, wherein the content of vormetinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 80 mg to 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 pharmaceutical composition contains vometinib or a pharmaceutically acceptable salt thereof in an amount of 80 mg, 160 mg, 240 mg or 320 mg. 21. The use according to any one of claims 15, 19-20, wherein the pharmaceutical composition contains 80 mg of vortexinib or a pharmaceutically acceptable salt thereof. 22. The use according to any one of claims 15, 19-20, wherein the pharmaceutical composition contains 160 mg of vortexinib or a pharmaceutically acceptable salt thereof. 23. The use according to any one of claims 15, 19-20, wherein the pharmaceutical composition contains 240 mg of vortexinib or a pharmaceutically acceptable salt thereof. 24. The use according to any one of claims 15, 19-23, wherein the pharmaceutical composition is in the form of a tablet or capsule. 25. The use according to claim 24, wherein in each unit of formulation, the content of vormetinib or a pharmaceutically acceptable salt thereof is 10 mg to 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 of formulation, the content of vormetinib or a pharmaceutically acceptable salt thereof is 20 mg to 320 mg. 27. The use according to any one of claims 24-26, wherein in each unit of formulation, the content of vormetinib 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 24-27, wherein in each unit of formulation, the content of vormetinib 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 antitumor drugs, antibody drugs, and immunotherapy drugs. 31. The use according to any one of claims 15-30, 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 15-31, 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 15-31, wherein the disease is newly diagnosed non-small cell lung cancer or previously treated non-small cell lung cancer. 34. The use according to any one of claims 15-33, wherein the HER2 exon 20 insertion mutation is at least one selected from ERBB2 A775_G776insYVMA mutation, ERBB2V777_G778insGC mutation and ERBB2 P780_Y781insGSP mutation. 35. The use according to any one of claims 15-33, wherein the rare EGFR mutation is at least one selected from the EGFR G719S mutation, EGFR S768I mutation, EGFR G724S mutation, EGFR L861Q mutation and EGFR G719S/T263P mutation. 36. A method for treating and/or preventing diseases mediated by HER2 exon 20 insertion mutations and/or rare EGFR mutations, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient in need. 37. Methods of treating and/or preventing disease, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is given to patients who are positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations. 38. A method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC) in which a therapeutically effective amount of voremtinib or a pharmaceutically acceptable salt thereof is administered to the patient in need. 39. Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in which patients confirmed to be positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations are given a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof. 40. A method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC) in which a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is given to patients carrying HER2 exon 20 insertion mutations and/or rare EGFR mutations. 41. Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in which a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is given to patients who have been confirmed to be positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations, and who have not previously received systemic antitumor therapy. 42. Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in which a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is given to patients who have been confirmed to be positive for HER2 exon 20 insertion mutations and/or rare EGFR mutations, and who have previously received systemic antitumor therapy and whose disease has progressed. 43. The method according to any one of claims 36-42, wherein the vortexinib or a pharmaceutically acceptable salt thereof is administered in an amount of 80 mg to 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 36-43, wherein the dose of vormetinib or a pharmaceutically acceptable salt thereof administered is 80 mg, 160 mg, 240 mg or 320 mg. 45. The method according to any one of claims 36-44, wherein the dose of vormetinib or a pharmaceutically acceptable salt thereof administered is 80 mg. 46. The method according to any one of claims 36-44, wherein the dose of vormetinib or a pharmaceutically acceptable salt thereof administered is 160 mg. 47. The method according to any one of claims 36-44, wherein the dose of vormetinib or a pharmaceutically acceptable salt thereof administered is 240 mg. 48. The method according to any one of claims 36-47, wherein vometinib or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, or three times daily. 49. The method according to any one of claims 36-48, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient once daily. 50. The method according to any one of claims 36-49, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient on an empty stomach. 51. The method according to any one of claims 36-50, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered in the morning on an empty stomach. 52. The method according to any one of claims 36-51, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered orally to the patient. 53. The method according to any one of claims 36-52, wherein vometinib is administered in the form of mesylate. 54. The method according to any one of claims 36-53, wherein vometinib or a pharmaceutically acceptable salt thereof is administered in the form of tablets or capsules. 55. The method according to any one of claims 36-54, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered in unit dosage form. 56. The method of claim 55, wherein the unit formulation comprises 10 mg to 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 vormetinib or a pharmaceutically acceptable salt thereof. 57. The method according to claim 55 or 56, wherein the unit formulation comprises 20 mg to 320 mg of vormetinib or a pharmaceutically acceptable salt thereof. 58. The method according to any one of claims 55-57, wherein the unit formulation comprises 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg of vormetinib or a pharmaceutically acceptable salt thereof. 59. The method according to any one of claims 55-58, wherein the unit formulation comprises 40 mg of vormetinib or a pharmaceutically acceptable salt thereof. 60. The method according to any one of claims 36-59, 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 antitumor drugs, antibody drugs, and immunotherapy drugs. 62. The method according to any one of claims 36-61, 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 36-62, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered before or after the patient undergoes surgical resection of the tumor. 64. The method according to any one of claims 36-63, 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 36-63, wherein the disease is newly diagnosed non-small cell lung cancer or previously treated non-small cell lung cancer. 66. The method according to any one of claims 36-65, wherein the HER2 exon 20 insertion mutation is at least one selected from ERBB2 A775_G776insYVMA mutation, ERBB2V777_G778insGC mutation and ERBB2 P780_Y781insGSP mutation. 67. The method according to any one of claims 36-65, wherein the rare EGFR mutation is at least one selected from the EGFR G719S mutation, EGFR S768I mutation, EGFR G724S mutation, EGFR L861Q mutation and EGFR G719S/T263P mutation. 68. The method according to any one of claims 36-67, wherein the patient is a human patient. 69. The method according to any one of claims 36-68, wherein the patient is 18-75 years old. 70. The method according to any one of claims 36-69, wherein the patient has been histologically or cytopathologically diagnosed with primary non-small cell lung cancer (NSCLC) with a predominant non-squamous histological morphology prior to treatment with vormetinib or a pharmaceutically acceptable salt thereof. 71. The method according to any one of claims 36-70, wherein the patient experiences radiographic progression of disease after the last antitumor treatment prior to initiating voremtinib or its pharmaceutically acceptable saline therapy. 72. The method according to any one of claims 36-71, wherein the patient is proven by laboratory testing to be positive for HER2 exon 20 insertion mutation and/or EGFR rare mutation before starting treatment with vormetinib or its pharmaceutically acceptable salt. 73. The method according to any one of claims 36-72, wherein the patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer, and has been shown to have radiographic or pathological disease progression during or after the last systemic antitumor therapy prior to starting vormetinib or its pharmaceutically acceptable salt therapy. 74. The method according to any one of claims 36-73, wherein the patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer and has not received systemic antitumor therapy prior to starting treatment with voremtinib or its pharmaceutically acceptable salt. 75. The method according to any one of claims 36-74, wherein the patient has at least one measurable lesion before starting treatment with vormetinib or its pharmaceutically acceptable salt. 76. The method according to any one of claims 36-75, wherein laboratory tests show that the patient has adequate organ function prior to starting treatment with vormetinib or its pharmaceutically acceptable salt. 77. The method according to any one of claims 36-76, wherein the patient has an ECOGPS (Eastern Cooperative Oncology Group Performance Status) score of 0-1 prior to starting treatment with vormetinib or its pharmaceutically acceptable saline. 78. The method according to any one of claims 36-77, wherein the method has acceptable security. 79. The method according to any one of claims 36-78, wherein the method can achieve partial remission (PR). 80. The method according to any one of claims 36-78, wherein the method can achieve the therapeutic effect of stable disease (SD). 81. The method according to any one of claims 36-80, wherein the method can shrink the tumor in the target lesion. 82. The method according to any one of claims 36-81, wherein the method can shrink the tumor in the target lesion by assessment by tumor imaging examinations (e.g., computed tomography (CT) and/or magnetic resonance imaging (MRI)).