HK40110967A - 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 voremtinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier. The invention also relates to the use of said pharmaceutical composition in the preparation of a medicament for treating and/or preventing diseases mediated by epidermal growth factor receptor exon 20 insertion (EGFRExon20Ins) mutations (hereinafter, sometimes also referred to as EGFR exon 20 insertion mutations). The invention also provides a method for treating and/or preventing diseases mediated by EGFR exon 20 insertion mutations, wherein a patient is given a therapeutically effective amount of voremtinib 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) mutations are the most widely studied target in NSCLC; EGFR mutations account for 17% and 50% of NSCLC patients in Western and Asian countries, respectively. Among EGFR gene mutations, common sensitive mutations are exon 19 deletions and exon 21 point mutations (L858R), accounting for 85%-90% of all EGFR mutations. EGFR exon 20 insertion mutations (EGFR Exon 20Ins) are another major category of EGFR mutations, accounting for approximately 1-10% of all EGFR mutation types and 1-2% of all NSCLC patients. These insertion mutations are heterogeneous and occur at multiple amino acid positions between 762 and 774, resulting in the insertion of 1-7 amino acids, some of which are localized. To date, 122 EGFR exon 20 insertion mutations have been identified, with the most common subtypes being the D770_N771insX mutation (25.5%), the V769_D770insX mutation (24.6%), and the H773_V774insX mutation (22.6%).

Over the years, numerous targeted therapies have been developed for EGFR mutations in NSCLC. These include first-generation reversible tyrosinase inhibitors (TKIs) gefitinib and erlotinib for EGFR-sensitive mutations, second-generation irreversible covalently bound inhibitor afatinib, and third-generation inhibitor osimertinib for the resistance mutation EGFR T790M, all of which have shown very good clinical efficacy. However, first- or second-generation EGFR-TKIs are generally ineffective against EGFR exon 20 insertion mutations. Furthermore, unlike typical EGFR-sensitive mutations and T790M resistance mutations, EGFR exon 20 insertion mutations show poor response to all FDA-approved EGFR-TKIs (including osimertinib).

EGFR inhibitors targeting exon 20 insertion mutations, such as poziotinib and TAK-788 (Mobocertinib), have entered clinical development and shown potential efficacy in clinical trials. Although these drugs have shown some efficacy, the effects are limited, suggesting that further research is needed to improve efficacy against EGFR exon 20 insertion mutations. Currently, no small-molecule targeted drugs for EGFR exon 20 insertion mutations have been approved globally, indicating a significant clinical need.

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"). Patent CN107163026B describes the mesylate salt of the compound of formula (I) (also 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, administered 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. The Phase IIb clinical trial has demonstrated that oral administration of 80 mg daily dose of voremetinib mesylate 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 EGFR exon 20 insertion mutations, thereby allowing vormetinib or a pharmaceutically acceptable salt thereof to be used to treat and/or prevent diseases mediated by EGFR exon 20 insertion mutations.

In some embodiments, by using vormetinib or a pharmaceutically acceptable salt thereof as the active compound in a certain dose, diseases mediated by EGFR exon 20 insertion 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 EGFR exon 20 insertion mutations.

The compositions of the present invention are available in tablet or capsule formulations. Each unit of the 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 EGFR exon 20 insertion mutations, a daily dose of vormetinib or a pharmaceutically acceptable salt thereof is required to be 80 mg to 400 mg. In this case, the daily dose of vormetinib 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 EGFR exon 20 insertion mutations, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to the desired patient.

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 EGFR exon 20 insertion 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 the patient in need.

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 patients whose EGFR exon 20 insertion mutation is confirmed to be positive.

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 an EGFR exon 20 insertion 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 have a positive EGFR exon 20 insertion 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 previously received 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 EGFR exon 20 insertion mutations. Furthermore, clinical trials have demonstrated that 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 therapeutic efficacy against diseases mediated by EGFR exon 20 insertion mutations (e.g., non-small cell lung cancer (NSCLC)).

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

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 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.

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 gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. Such carriers are also referred to as "excipients." "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. 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, alginate, 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. Tablets and capsules may be coated or microencapsulated with coatings or shells, 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, 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. In one embodiment, the content may be 20mg, 40mg, 80mg, 160mg, 240mg or 320mg, for example 40mg or 80mg, for example 40mg.

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 implementation, the content can be 80mg, 160mg, 240mg or 320mg, for example 80mg, 160mg or 240mg, for example 240mg.

In some embodiments, when the pharmaceutical composition is used to treat and/or prevent disease mediated by EGFR exon 20 insertion mutations, the 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 exemplary embodiment, the content may be 80mg, 160mg, 240mg, or 320mg, for example, 80mg, 160mg, or 240mg, for example, 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 a 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, 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, when the pharmaceutical composition is used to treat and/or prevent diseases mediated by EGFR exon 20 insertion mutations, it is 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 some embodiments, 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 the above-described pharmaceutical composition in the preparation of a medicament for treating and/or preventing diseases mediated by EGFR exon 20 insertion 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 of the present invention is present in the form of tablets or capsules.

In some embodiments, in the above-described uses of the present invention, the content of vormetinib or a pharmaceutically acceptable salt thereof in each unit formulation (e.g., tablet or capsule) 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 EGFR exon 20 insertion mutation is cancer, such as lung cancer, and further, non-small cell lung cancer (NSCLC).

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

In some implementations, the disease mediated by EGFR exon 20 insertion mutation is either 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 embodiments, EGFR exon 20 insertion mutations are characterized as multiple amino acid insertion mutations in the 762-774 amino acid region of the EGFR protein. That is, the exon 20 insertion mutation site is the 762-774 amino acid region. For example, EGFR exon 20 insertion mutations are selected from at least one of EGFR D770_N771insX mutation, EGFR V769_D770insX mutation, EGFR H773_V774insX mutation, and EGFR P772_H773insX mutation. For example, EGFR exon 20 insertion mutations are selected from at least one of EGFR D770_N771insSVD, EGFR V769_D770insASV, EGFR H773_V774insNPH, and EGFR D770_N771insNPG.

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 antitumor 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 for treating and/or preventing disease mediated by EGFR exon 20 insertion mutations is provided, 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 an EGFR exon 20 insertion mutation.

In some embodiments, a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) 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 (NSCLC) is provided, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to a patient whose EGFR exon 20 insertion mutation is confirmed to be positive.

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

In some embodiments, a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) 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 EGFR exon 20 insertion mutation 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 (NSCLC) 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 but 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, in some of the methods described above, 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, the patient may be further administered at least one second therapeutic agent. 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 methods, 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 some embodiments of the above-mentioned treatment methods, EGFR exon 20 insertion mutations are characterized as multiple amino acid insertion mutations in the 762-774 amino acid region of the EGFR protein. That is, the exon 20 mutation site is the 762-744 amino acid region. For example, EGFR exon 20 insertion mutations are selected from at least one of EGFR D770_N771insX mutation, EGFR V769_D770insX mutation, EGFR H773_V774insX mutation, and EGFRP772_H773insX mutation. For example, EGFR exon 20 insertion mutations are selected from at least one of EGFR D770_N771insSVD, EGFR V769_D770insASV, EGFRH773_V774insNPH, and EGFR D770_N771insNPG.

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 to demonstrate a positive EGFR exon 20 insertion mutation 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 and has been shown to have disease progression on imaging or pathology during or after the last systemic antitumor therapy prior to starting voremtinib 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 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 3.

Example

Abbreviation Explanation

PR: Partial remission; SD: Stable disease; Naive: Treatment-naive; DCR: Disease control rate; DOR: Duration of response; DepOR: Depth of response; PFS: Progression-free survival; OS: Overall survival; CNS ORR: Intracranial objective response rate; CTCAE: Commonly Used Terminology for Adverse Events; RECIST 1.1: Evaluation Criteria for Treatment Response in Solid Tumors (Version 1.1); ctDNA: Circulating tumor DNA; NYHA: New York Heart Association; AJCC: American Joint Committee on Cancer; CYP3A4: Cytochrome P450 3A4; QTc: Corrected QT interval.

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

1. Cell viability

Test Example 1: Inhibitory Activity on the Proliferation of Human Skin Cancer A431 (Wild-type EGFR) Adherent Cells

The inhibitory activity of the compound (vometinib mesylate) on the proliferation of human skin cancer A431 adherent cells expressing wild-type EGFR protein in vitro was determined by the sulfonylrhodamine B method (SRB method).

Cell source: A431 cells were purchased from Shanghai Dior Biotechnology Co., Ltd.

A431 cells were cultured in DMEM complete medium containing 10% fetal bovine serum. A431 cells in the logarithmic growth phase were seeded at a density of 5000 cells/135 μl of complete medium/well in 96-well plates and incubated at 37°C with ₅ % CO2 for 24 hours to ensure complete cell adhesion. The compound was pre-dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mM stock solution, which was then diluted sequentially with DMSO and complete medium. Remove the 96-well plates inoculated with cells. Take one well as a separate control group (a medium control group where cells showed no growth at 0 hours). Add 15 μl of different concentrations of the compound to each well of the other 96-well plates to make final concentrations of 2500, 625, 156.25, 39.06, 9.77, 2.44, 0.61, 0.15, 0.04, and 0.01 nM. Set up three replicates for each compound concentration. Also set up a negative control group (a medium control group containing cells and no compound). The concentration of DMSO in each well was 0.5%.

The control group without growth was immediately terminated, while the other 96-well plates were incubated at 37°C in a 5% _CO2 incubator for 72 hours before termination. The termination method was as follows: 50 μl of pre-cooled (4°C) 50% trichloroacetic acid aqueous solution was added to each well, and the plates were fixed at 4°C for 1 hour. The plates were then washed at least 5 times with purified water and allowed to air dry or dried in a 60°C oven.

Prepare a 4 mg/ml SRB solution using purified water containing 1% glacial acetic acid. Add 100 μl to each well and stain at room temperature for 1 hour. Discard the supernatant and wash at least 5 times with 1% glacial acetic acid to remove non-specific binding. Dry the solution before use. Dissolve the SRB in 150 μl of 10 mM Tris-HCl solution in each well. Measure the optical density (OD) at 510 nm and calculate the cell proliferation inhibition rate.

Cell proliferation inhibition rate = [(OD _{72-hour negative control group} - OD _{72-hour compound-treated group} ) / (OD _{72-hour negative control group} - OD _{no-growth control group} )] × 100%.

The data were analyzed using GraphPad Prism 8.3 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

Test Example 2: Inhibitory activity against the proliferation of Ba/F3 EGFR D770_N771insSVD, Ba/F3 EGFR V769_D770insASV, and Ba/F3 EGFR H773_V774insNPH stable transgenic cells

The cell-titer-Glo method was used to determine the inhibitory activity of the compound (vometinib mesylate) on the proliferation of mouse original B cells stably expressing EGFR exon 20 insertions: Ba/F3 EGFR D770_N771insSVD, Ba/F3 EGFR V769_D770insASV, and Ba/F3 EGFR H773_V774insNPH cells.

Cell source: Ba/F3 EGFR D770_N771insSVD, Ba/F3 EGFR V769_D770insASV, and Ba/F3 EGFR H773_V774insNPH cells were purchased from Shanghai WuXi AppTec Co., Ltd.

Ba/F3 EGFR D770_N771insSVD, Ba/F3 EGFR V769_D770insASV, and Ba/F3 EGFR H773_V774insNPH cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum. Ba/F3 EGFR D770_N771insSVD, Ba/F3 EGFR V769_D770insASV, and Ba/F3 EGFR H773_V774insNPH cells in logarithmic growth phase were seeded at a density of 2000 cells/50 μl of complete medium/well in 384-well plates and incubated at 37°C in a 5% _CO2 incubator for 24 hours. The compounds were pre-dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mM stock solution, which was then diluted sequentially with DMSO and complete medium. Remove the 384-well plate inoculated with cells and add the compound using Tecan HP D300 to achieve final concentrations of 2500, 625, 156.25, 39.06, 9.77, 2.44, 0.61, 0.15, and 0.04 nM. Set up two replicates for each compound concentration, and set up a cell-free culture medium control group and a cell control group with 0.2% DMSO.

After incubating at 37℃ and 5% _CO2 for 72 h, 25 μl of CellTiter-Glo reagent (luciferase-ATP bioluminescence assay reagent, purchased from Promega, catalog number G7573) was added to each well. The cells were shaken at 1000 rpm for 30 s and incubated at room temperature for 10 min until the fluorescence intensity stabilized. The fluorescence intensity (Lum) was then measured using a microplate reader. The inhibition rate of cell proliferation at each concentration of the compound was calculated.

Cell proliferation inhibition rate = (Lum _Max - Lum _compound ) / (Lum _Max - Lum _Min ) × 100% (Lum _Max represents the maximum fluorescence intensity, Lum _compound represents the fluorescence intensity of the compound, and Lum _Min represents the minimum fluorescence intensity).

The data were analyzed using XL-fit 5.0 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 2.

Table 2

Stable cells <![CDATA[Vometinib Mesylate IC₅₀(nM)]]> Ba/F3 EGFR D770_N771insSVD 11 Ba/F3 EGFR V769_D770insASV 14 Ba/F3 EGFR H773_V774insNPH 20

The results showed that vormetinib mesylate had good inhibitory activity against the proliferation of Ba/F3 EGFR D770_N771insSVD, Ba/F3 EGFR V769_D770insASV, and Ba/F3 EGFR H773_V774insNPH stable transgenic cells.

2. Animal in vivo experiments

Test Example 3: Testing the antitumor effect of voremiteinib mesylate in a lung cancer LU0387 tumor model

This experiment was conducted to evaluate the antitumor effect of vormetinib mesylate in a female BALB/c nude mouse model of lung cancer LU0387 (with EGFRH773_V774insNPH mutation) subcutaneously xenografted.

Experimental animals: BALB/c Nude mice, female, 7-8 weeks old (mice's age at tumor cell inoculation), weighing 18.1-24.7g, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

Animal modeling and randomization: Tumor tissue was collected from LU0387 tumor-bearing mice (a lung cancer xenograft model) and cut into tumor blocks with a diameter of 2-3 mm. These blocks were then subcutaneously injected into the right anterior scapula of Balb/c nude mice on June 16, 2020. When the average tumor volume reached 197.56 ^mm³ , the mice were randomly assigned to groups based on tumor size on July 15, 2020, which was 29 days after tumor transfer. The day of grouping was defined as day 0.

Experimental protocol: A human lung cancer subcutaneous tumor model was established by subcutaneously inoculating LU0387 tumor blocks into BALB/c nude mice. The experiment consisted of four groups (n=8 per group): 20 mg/kg, 30 mg/kg, and 50 mg/kg vortex mesylate groups, and a solvent control group. All mice were administered the drug orally at a volume of 10 μL/g. The solvent control group received an equal volume of solvent. Administration was once daily for three weeks. Throughout the experiment, tumor size was measured twice weekly to observe for any toxic reactions. Efficacy was evaluated based on the tumor growth index (TGI).

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.

Relative Tumor Inhibition Rate (TGI): Tumor inhibition rate (TGI) is one of the indicators of tumor response to treatment: Formula: TGI (%) = (1 - (T_{_i} - T_₀) / (V_i _{- V} _₀)) × 100%,

_Ti : Average tumor volume corresponding to the number of analysis days in the experimental group; _T0 : Average tumor volume corresponding to the day the experimental group was grouped; _Vi : Average tumor volume corresponding to the number of analysis days in the solvent control group; _V0 : Average tumor volume corresponding to the day the solvent control group was grouped.

The tumor volume change curves for the three experimental groups and one solvent control group are shown in Figure 1.

The results showed that vormetinib mesylate exhibited good antitumor activity in a female nude mouse model of subcutaneous xenograft of lung cancer LU0387.

3. Clinical trials

a. Plan

b. Clinical outcomes

At a daily dose of 160 mg, voremerinib mesylate showed good antitumor activity against non-small cell lung cancer (NSCLC) with EGFR exon20ins mutations; at a daily dose of 240 mg, voremerinib mesylate showed superior antitumor activity against treatment-naïve or previously treated NSCLC with EGFR exon20ins mutations.

c. Security

Long-term administration at doses of 160mg-240mg primarily resulted in gastrointestinal and skin adverse reactions, as well as abnormalities in liver and kidney-related laboratory tests. No other specific adverse events (AEs) were observed. The severity of AEs was mild, mostly CTCAE grade 1-2. Clinical trials have demonstrated that long-term administration at doses of 160mg-240mg has a good safety profile.

Industrial practicality

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

Claims (78)

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 in the preparation of a pharmaceutical composition comprising a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier for the treatment and/or prevention of diseases mediated by EGFR exon 20 insertion mutations. 16. The use according to claim 15, wherein the pharmaceutically acceptable salt is a mesylate. 17. The use according to claim 15 or 16, 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. 18. The use according to any one of claims 15-17, wherein the content of vormetinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 80 mg, 160 mg, 240 mg or 320 mg. 19. The use according to any one of claims 15-18, wherein the pharmaceutical composition contains 80 mg of vortexinib or a pharmaceutically acceptable salt thereof. 20. The use according to any one of claims 15-18, wherein the pharmaceutical composition contains 160 mg of vortexinib or a pharmaceutically acceptable salt thereof. 21. The use according to any one of claims 15-18, wherein the pharmaceutical composition contains 240 mg of vortexinib or a pharmaceutically acceptable salt thereof. 22. The use according to any one of claims 15-21, wherein the pharmaceutical composition is in the form of a tablet or capsule. 23. The use according to claim 22, 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. 24. The use according to claim 22 or 23, wherein in each unit of formulation, the content of vormetinib or a pharmaceutically acceptable salt thereof is 20 mg to 320 mg. 25. The use according to any one of claims 22-24, 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. 26. The use according to any one of claims 22-25, wherein in each unit of formulation, the content of vormetinib or a pharmaceutically acceptable salt thereof is 40 mg. 27. The use according to any one of claims 15-26, wherein the pharmaceutical composition further comprises at least one second therapeutic agent. 28. The use according to claim 27, wherein the second therapeutic agent is selected from chemotherapy drugs, targeted antitumor drugs, antibody drugs, and immunotherapy drugs. 29. The use according to any one of claims 15-28, wherein the disease is cancer, such as lung cancer, such as non-small cell lung cancer (NSCLC). 30. The use according to any one of claims 15-29, wherein the disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer. 31. The use according to any one of claims 15-29, wherein the disease is newly diagnosed non-small cell lung cancer or previously treated non-small cell lung cancer. 32. The use according to any one of claims 15-31, wherein the EGFR exon 20 insertion mutation is at least one selected from EGFR D770_N771insX mutation, EGFR V769_D770insX mutation, EGFR H773_V774insX mutation and EGFRP772_H773insX mutation, for example, at least one selected from EGFR D770_N771insSVD, EGFR V769_D770insASV, EGFR H773_V774insNPH and EGFR D770_N771insNPG. 33. A method for treating and/or preventing disease mediated by EGFR exon 20 insertion mutations, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient in need. 34. Methods of treating and/or preventing disease, wherein a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof is administered to patients who are positive for EGFR exon 20 insertion mutations. 35. 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. 36. Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in which patients with confirmed positive EGFR exon 20 insertion mutations are given a therapeutically effective amount of vormetinib or a pharmaceutically acceptable salt thereof. 37. 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 EGFR exon 20 insertion mutations. 38. 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 with confirmed positive EGFR exon 20 insertion mutations who have not previously received systemic antitumor therapy. 39. Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in which a therapeutically effective dose of vormetinib or a pharmaceutically acceptable salt thereof is given to patients with confirmed positive EGFR exon 20 insertion mutations who have previously received systemic antitumor therapy but whose disease has progressed. 40. The method according to any one of claims 33-39, 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. 41. The method according to any one of claims 33-40, wherein the dose of vormetinib or a pharmaceutically acceptable salt thereof administered is 80 mg, 160 mg, 240 mg or 320 mg. 42. The method according to any one of claims 33-41, wherein the dose of vormetinib or a pharmaceutically acceptable salt thereof administered is 80 mg. 43. The method according to any one of claims 33-41, wherein the dose of vormetinib or a pharmaceutically acceptable salt thereof administered is 160 mg. 44. The method according to any one of claims 33-41, wherein the dose of vormetinib or a pharmaceutically acceptable salt thereof administered is 240 mg. 45. The method according to any one of claims 33-44, wherein vometinib or a pharmaceutically acceptable salt thereof is administered once daily, twice daily, or three times daily. 46. The method according to any one of claims 33-45, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient once daily. 47. The method according to any one of claims 33-46, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered to the patient on an empty stomach. 48. The method according to any one of claims 33-47, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered in the morning on an empty stomach. 49. The method according to any one of claims 33-48, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered orally to the patient. 50. The method according to any one of claims 33-49, wherein vometinib is administered in the form of mesylate. 51. The method according to any one of claims 33-50, wherein vometinib or a pharmaceutically acceptable salt thereof is administered in the form of tablets or capsules. 52. The method according to any one of claims 33-51, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered in unit dosage form. 53. The method of claim 52, 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. 54. The method according to claim 52 or 53, wherein the unit formulation comprises 20 mg to 320 mg of vormetinib or a pharmaceutically acceptable salt thereof. 55. The method according to any one of claims 52-54, 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. 56. The method according to any one of claims 52-55, wherein the unit formulation comprises 40 mg of vormetinib or a pharmaceutically acceptable salt thereof. 57. The method according to any one of claims 33-56, wherein at least one second therapeutic agent is further administered. 58. The method of claim 57, wherein the second therapeutic agent is selected from chemotherapy drugs, targeted antitumor drugs, antibody drugs, and immunotherapy drugs. 59. The method according to any one of claims 33-58, wherein the disease is cancer, such as lung cancer, such as non-small cell lung cancer (NSCLC). 60. The method according to any one of claims 33-59, wherein vormetinib or a pharmaceutically acceptable salt thereof is administered before or after the patient undergoes surgical resection of the tumor. 61. The method according to any one of claims 33-60, wherein the disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer. 62. The method according to any one of claims 33-60, wherein the disease is newly diagnosed non-small cell lung cancer or previously treated non-small cell lung cancer. 63. The method according to any one of claims 33-62, wherein the EGFR exon 20 insertion mutation is at least one selected from EGFR D770_N771insX mutation, EGFR V769_D770insX mutation, EGFR H773_V774insX mutation and EGFRP772_H773insX mutation, for example, at least one selected from EGFR D770_N771insSVD, EGFR V769_D770insASV, EGFR H773_V774insNPH and EGFR D770_N771insNPG. 64. The method according to any one of claims 33-63, wherein the patient is a human patient. 65. The method according to any one of claims 33-64, wherein the patient is 18-75 years old. 66. The method according to any one of claims 33-65, 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. 67. The method according to any one of claims 33-66, wherein the patient experiences radiographic progression of disease after the last antitumor treatment prior to initiating vormetinib or its pharmaceutically acceptable saline therapy. 68. The method according to any one of claims 33-67, wherein the patient is confirmed by laboratory testing to be positive for EGFR exon 20 insertion mutation before starting treatment with vormetinib or a pharmaceutically acceptable salt thereof. 69. The method according to any one of claims 33-68, 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 saline therapy. 70. The method according to any one of claims 33-69, 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. 71. The method according to any one of claims 33-70, wherein the patient has at least one measurable lesion before starting treatment with vormetinib or its pharmaceutically acceptable salt. 72. The method according to any one of claims 33-71, wherein laboratory tests show that the patient has adequate organ function prior to starting treatment with vormetinib or its pharmaceutically acceptable salt. 73. The method according to any one of claims 33-72, 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. 74. The method according to any one of claims 33-73, wherein the method has acceptable security. 75. The method according to any one of claims 33-74, wherein the method can achieve partial relief of the therapeutic effect. 76. The method according to any one of claims 33-74, wherein the method can achieve the therapeutic effect of stabilizing the condition. 77. The method according to any one of claims 33-76, wherein the method can shrink the tumor in the target lesion. 78. The method according to any one of claims 33-77, wherein the method can shrink the tumor in the target lesion when evaluated by tumor imaging examinations (e.g., computed tomography (CT) and/or magnetic resonance imaging (MRI)).