Pharmaceutical compositions and uses thereof

Abstract

The present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of fulmonertinib or its pharma- ceutical acceptable salt and optionally a pharma-ceutical acceptable carrier, and the use of the pharmaceutical composition in the manufacture of a medicament for treating and / or preventing diseases mediated by EGFR exon 20 insertion mutation.The pharmaceutical composition of the present disclosure shows excellent therapeutic effect against diseases mediated by EGFR exon 20 insertion mutation (e.g., non-small cell lung cancer (NSCLC)) with little side effects and excellent safety.

Description

[Technical field]

[0001] Technical Field The present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of fulmonertinib or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable carrier.The present disclosure also relates to the use of said pharmaceutical composition in the manufacture of a medicament for treating and / or preventing a disease mediated by epidermal growth factor receptor exon 20 insertion (EGFR Exon 20Ins) mutation (hereinafter sometimes also referred to as EGFR Exon 20 insertion mutation).The present disclosure also provides a method for treating and / or preventing a disease mediated by EGFR Exon 20 insertion mutation, comprising administering to a patient a therapeutically effective amount of fulmonertinib or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] Background technology Globally, lung cancer has always been the malignant tumor with the highest morbidity and mortality rates, causing serious harm to human health and life, with 1.76 million people dying from lung cancer worldwide in 2018. Non-small cell lung cancer (NSCLC) constitutes approximately 80-85% of all lung cancers. Epidermal growth factor receptor (EGFR) mutations are the most widely studied target in NSCLC; EGFR mutations constitute 17% and 50% of Western and Asian NSCLC patients, respectively. Among EGFR genetic mutations, common susceptibility mutations are exon 19 deletions and exon 21 point mutations (L858R), which constitute 85%-90% of all EGFR mutations. EGFR exon 20 insertion mutations (EGFR Exon 20Ins) are another major class of mutations in EGFR mutations, which constitute 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 insertions of 1 to 7 amino acids, some of which are locally duplicated. To date, 122 EGFR exon 20 insertion mutations have been found, with the most common subtypes being D770_N771insX mutations (25.5%), V769_D770insX mutations (24.6%), and H773_V774insX mutations (22.6%).

[0003] Over the years, a great number of targeted drugs have been developed for EGFR mutations in NSCLC. For example, the first generation is the reversible tyrosinase inhibitors (TKIs), gefitinib and erlotinib, for EGFR-sensitive mutations, the second generation is the irreversible covalent inhibitor, afatinib, and the third generation is the inhibitor osimertinib for drug-resistant mutation EGFR T790M. These have very good clinical efficacy. However, the first and second generation of EGFR-TKIs are essentially ineffective in treating EGFR exon 20 insertion mutations. Moreover, unlike the representative EGFR-sensitive mutations and T790M drug-resistant mutations, EGFR exon 20 insertion mutations respond poorly to all FDA-approved EGFR-TKIs (including osimertinib).

[0004] EGFR inhibitors against EGFR exon 20 insertion mutations are also currently in clinical development (e.g., poziotinib, TAK-788 (mobocertinib), etc.) and have shown potential therapeutic effects in clinical trials. Although these drugs show some efficacy, their efficacy is limited, suggesting that more research is needed to improve the therapeutic efficacy against EGFR exon 20 insertion mutations. Currently, there are no small molecule targeted drugs approved worldwide for EGFR exon 20 insertion mutations, and therefore, there is a great clinical need. 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 referred to as "Flumonertinib") represented by the following formula (I) is described in patent, CN105315259B, and the mesylate salt of the compound of the following formula (I) (also referred to as "Flumonertinib mesylate") is described in patent, CN107163026B, and Flumonertinib mesylate is commercialized as a third generation EGFR-TKI inhibitor and is mainly used to treat diseases mediated by EGFR sensitivity mutations and T790M drug resistance mutations. The Phase I ascending study of flumonertinib mesylate clearly showed that flumonertinib mesylate taken orally once daily at a dosage level of 20 mg to 240 mg was well tolerated and safe, with subject adverse events being mild and moderate, no dose-limiting toxicity, and no dose-related toxic reactions; the Phase IIb clinical trial clearly showed that oral administration of 80 mg daily dose of flumonertinib mesylate showed relatively good antitumor effects and could alleviate or stabilize disease progression in patients with EGFR T790M-positive advanced non-small cell lung cancer who had progressive disease after previous systemic antitumor treatment. [ka] [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Chinese Patent No. 105315259 [Patent Document 2] Chinese Patent No. 107163026 Summary of the Invention [Means for solving the problem]

[0006] Abstract The present disclosure provides, in some embodiments, the use of flumonertinib, or a pharma- ceutically acceptable salt thereof.

[0007] In some embodiments, flumonertinib or a pharma- ceutically acceptable salt thereof as an active compound can effectively inhibit EGFR exon 20 insertion mutations, so that flumonertinib or a pharma- ceutically acceptable salt thereof can be used to treat and / or prevent diseases mediated by EGFR exon 20 insertion mutations.

[0008] In some embodiments, flumonertinib or a pharma- ceutically acceptable salt thereof is useful as an active compound at a certain dose, and can treat and / or prevent diseases mediated by EGFR exon 20 insertion mutations, in particular non-small cell lung cancer, and the treatment and / or prevention of the disease is accompanied by few side effects and is excellent in safety.

[0009] More specifically, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of flumonertinib or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable carrier.

[0010] The present disclosure also provides the use of the above-mentioned pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating and / or preventing a disease mediated by an EGFR exon 20 insertion mutation.

[0011] The composition of the present disclosure is in the form of a tablet or capsule formulation, and the content of flumonertinib or a pharma- ceutically acceptable salt thereof in each unit formulation is 10 mg to 400 mg.

[0012] When the pharmaceutical composition of the present disclosure is used to treat and / or prevent diseases mediated by EGFR exon 20 insertion mutation, the daily dose of fulmonertinib or its pharmaceutically acceptable salt can be 80mg-400mg. At this time, by adjusting the amount of the above-mentioned tablets or capsules, the daily dose of fulmonertinib or its pharmaceutically acceptable salt can be easily adjusted.

[0013] The present disclosure also provides a method for treating and / or preventing a disease mediated by EGFR exon 20 insertion mutation, comprising administering to a patient in need thereof a therapeutically effective amount of flumonertinib or a pharma- ceutically acceptable salt thereof.

[0014] In the above treatment methods of the present disclosure, it is preferable that the daily dose of flumonertinib or a pharma- ceutically acceptable salt thereof is 80 mg to 400 mg.

[0015] The present disclosure also provides a method for treating and / or preventing a disease, comprising administering to a patient having an EGFR exon 20 insertion mutation positive a therapeutically effective amount of flumonertinib or a pharma- ceutically acceptable salt thereof.

[0016] The present disclosure also provides a method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC), comprising administering to a patient in need thereof a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof.

[0017] The present disclosure also provides a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC), comprising administering to a patient confirmed to be EGFR exon 20 insertion mutation positive a therapeutically effective amount of flumonertinib, or a pharma- ceutical acceptable salt thereof.

[0018] The present disclosure also provides a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC), comprising administering to a patient having an EGFR exon 20 insertion mutation a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof.

[0019] The present disclosure also provides a method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC), comprising administering a therapeutically effective amount of flumonertinib, or a pharmacologic acceptable salt thereof, to a patient with confirmed EGFR exon 20 insertion mutation who has not previously received systemic anti-tumor therapy.

[0020] The present disclosure also provides a method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC), comprising administering a therapeutically effective amount of flumonertinib, or a pharmacologic acceptable salt thereof, to an EGFR exon 20 insertion mutation-positive confirmed patient who has progressive disease after prior systemic anti-tumor therapy.

[0021] In some embodiments, flumonertinib or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising flumonertinib or a pharma- ceutically acceptable salt thereof and optionally a pharma- ceutically acceptable carrier, has excellent inhibitory activity against EGFR exon 20 insertion mutations, and clinical trials show that flumonertinib or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the flumonertinib or a pharma- ceutically acceptable salt thereof of the present disclosure and optionally a pharma- ceutically acceptable carrier, exhibits excellent therapeutic effects against diseases mediated by EGFR exon 20 insertion mutations (e.g., non-small cell lung cancer (NSCLC)).

[0022] Furthermore, when flumonertinib or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising the flumonertinib or a pharma- ceutically acceptable salt thereof disclosed herein and optionally a pharma- ceutically acceptable carrier, is used to treat and / or prevent diseases mediated by EGFR exon 20 insertion mutations, side effects are small and safety is excellent.

[0023] The pharmaceutical composition of the present disclosure can be prepared into a formulation having an appropriate content of the active ingredient by including an appropriate size and a specific amount of flumonertinib or a pharma- ceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description Although the embodiments of the present disclosure will be described in more detail below with reference to specific embodiments, those skilled in the art will understand that the specific embodiments described below are merely illustrative of the present disclosure and should not be construed as limiting the scope of the present disclosure. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present disclosure as defined by the appended claims.

[0025] Unless otherwise specified, the embodiments of the present disclosure may be combined in any manner, and the conversions, modifications, and variations of the technical solutions obtained thereby are also included in the scope of the present disclosure.

[0026] Flumonertinib is a compound known in the art and is described in particular 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 the compound shown in formula (I). [ka]

[0027] In some embodiments, the active compound for treating the above disease is fulmonertinib or its pharmaceutically acceptable salt.Therefore, in some embodiments, fulmonertinib or its pharmaceutically acceptable salt can be used alone or can be used by being included in a composition, in which case, the composition can optionally include a pharmaceutically acceptable carrier if desired.

[0028] The present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of flumonertinib or a pharma- ceutically acceptable salt thereof, and optionally a pharma- ceutically acceptable carrier.

[0029] "Pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers or gelatinous substances suitable for human use, and should be of sufficient purity and sufficiently low toxicity. The carrier is also known as an "adjuvant." "Compatibility" means that the components in the composition can be mixed with the compounds of the present disclosure and with each other without significantly reducing the drug effect of the compound. Some examples of acceptable carriers include, but are not limited to, cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylmethylcellulose and its derivatives, cellulose acetate and its derivatives, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium / calcium stearate, hydrogenated vegetable oils, sodium stearyl fumarate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers, wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, and the like.

[0030] The pharmaceutical compositions may be prepared by methods well known in the art, such as by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, and lyophilizing processes.

[0031] The pharmaceutical composition is in the form of a tablet or capsule formulation, in which flumonertinib or a pharma- ceutically acceptable salt thereof is mixed with at least one pharma- ceutically acceptable carrier, which in the present disclosure is also known as an “adjuvant”, and which may include, but is not limited to: (a) fillers or solubilizers, such as microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, colloidal silica, calcium hydrogen phosphate, calcium phosphate, calcium sulfate; (b) binders, such as hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, alginates, gelatin, polyvinylpyrrolidone, copovidone, sucrose and acacia, corn starch; (c) humectants, such as glycerin; (d) disintegrants, such as croscarmellose sodium, crospovidone, sodium carboxymethyl starch, colloidal silica, microcrystalline cellulose, potato starch or tapioca starch or corn starch, pregelatinized starch, alginic acid, certain complex silicates. (e) absorption enhancers, such as quaternary ammonium compounds, anionic or nonionic surfactants, cyclodextrins, etc.; (f) wetting agents, such as cetyl alcohol and glycerol monostearate; (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 lauryl sulfate, sodium stearyl fumarate, hydrogenated vegetable oils, etc., or mixtures thereof. The capsules and tablets may also contain buffering agents. Tablets and capsules may be coated or microencapsulated with coating or shell materials, such as enteric coatings, or other materials known in the art.

[0032] The term "pharmaceutical acceptable salt" refers to a salt prepared from fulmonertinib and a relatively non-toxic pharmaceutical acceptable acid or base. Base addition salts can be obtained by contacting fulmonertinib with a sufficient amount of pharmaceutical acceptable base in pure solution or in a suitable inert solvent. Representative base addition salts include, for example, salts formed with alkali metals, alkaline earth metals, quaternary ammonium cations (e.g., sodium, lithium, potassium, calcium, magnesium, tetramethylquaternary ammonium, tetraethylquaternary ammonium, etc.); amine salts, including salts formed with ammonia (NH3), primary, secondary, or tertiary amines (e.g., methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, etc.). In addition, acid addition salts can be obtained by contacting fulmonertinib with a sufficient amount of pharmaceutical acceptable acid in pure solution or in a suitable inert solvent. The pharma- ceutically acceptable acid salts include inorganic acid salts (e.g., hydrochloride, sulfate, phosphate, and nitrate); and organic acid salts (e.g., formate, acetate, propionate, methanesulfonate, benzylsulfonate, succinate, citrate, and tartrate). In particular, reference may be made to 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).

[0033] As used herein, "therapeutically effective amount" refers to a sufficient amount of a drug or pharmacologic active agent that is non-toxic but still achieves the desired effect.The effective amount varies from person to person depending on the age, weight and condition of the patient, as well as on the specific active substance, and the appropriate effective amount in each case can be determined by those skilled in the art in light of routine testing.

[0034] As used herein, "active component," "active substance," or "active agent" refers to a chemical entity that is effective in treating a disorder, disease, or condition of interest.

[0035] As used herein, a "patient," "individual," or "subject" includes humans, animals, vertebrates, mammals, rodents (e.g., guinea pigs, hamsters, rats, mice), murines (e.g., mice), canines (e.g., dogs), primates, anthropoids (e.g., monkeys or apes), monkeys (e.g., marmosets, baboons), apes (e.g., gorillas, chimpanzees, orangutans, gibbons). In some embodiments, a "patient" is a human.

[0036] As used herein, "treatment" refers to therapeutic treatment or palliative measures. When a specific condition is involved, treatment refers to (1) alleviating one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or contributes to the disorder, or (b) one or more biological manifestations of the disorder, (3) improving one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or its treatment, or (4) slowing the progression of one or more biological manifestations of a disease or disorder. "Treatment" can also refer to increasing survival compared to expected survival in the absence of the treatment.

[0037] As used herein, "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0038] In some embodiments, the pharma- ceutically acceptable salt of flumonertinib is a mesylate salt of flumonertinib, ie, flumonertinib mesylate.

[0039] In some embodiments, the pharmaceutical compositions of the present disclosure are in tablet or capsule formulations.

[0040] In some embodiments, the content of flumonertinib or a pharma- ceutically acceptable salt thereof in each unit dosage form (eg, tablet or capsule) of the pharmaceutical composition is 10 mg to 400 mg, for example, 20 mg to 320 mg. As a specific content, for example, it can be 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 it may be 20mg, 40mg, 80mg, 160mg, 240mg or 320mg, for example 40mg or 80mg, for example 40mg.

[0041] In some embodiments, the content of flumonertinib or a pharma- ceutically 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. In exemplary embodiments, it is 80 mg, 160 mg, 240 mg or 320 mg, for example 80 mg, 160 mg or 240 mg, for example 240 mg.

[0042] In some embodiments, when the pharmaceutical composition is used to treat and / or prevent a disease mediated by EGFR exon 20 insertion mutation, the composition is administered to a patient so that the dose of fulmonertinib or its pharma- ceutical acceptable salt is 80mg to 400mg.Specific doses may be, for example, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg. As an exemplary embodiment, it may 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 present disclosure, the above dose is a daily dose.

[0043] In some embodiments, the content of fulmonertinib or its pharmaceutically acceptable salt in the pharmaceutical composition refers to the total amount of fulmonertinib or its pharmaceutically acceptable salt in the pharmaceutical composition that is taken by the patient when the pharmaceutical composition is administered to the patient.For example, when the pharmaceutical composition is in the form of tablet or capsule, the content of fulmonertinib or its pharmaceutically acceptable salt in the pharmaceutical composition refers to the total amount of fulmonertinib or its pharmaceutically acceptable salt in all formulations (e.g., tablet or capsule) when the formulation (e.g., tablet or capsule) is administered.

[0044] It is understood by those skilled in the art that when administered to patients, the daily dose of fulmonertinib or its pharmaceutically acceptable salt is equal to or greater than the content of fulmonertinib or its pharmaceutically acceptable salt per unit preparation.Those skilled in the art can calculate the total amount of preparations required to be administered per day based on the daily dose of fulmonertinib or its pharmaceutically acceptable salt and the content of fulmonertinib or its pharmaceutically acceptable salt in each unit preparation.For example, when fulmonertinib or its pharmaceutically acceptable salt is contained in a tablet, the content of fulmonertinib or its pharmaceutically acceptable salt in each unit preparation (each tablet) is 40mg, and the daily dose of fulmonertinib or its pharmaceutically acceptable salt is 240mg, the total amount of preparations (tablets) required to be administered per day is 6 tablets.

[0045] In some embodiments, the pharmaceutical composition is administered once, twice or three times per day (e.g., once per day) for the treatment and / or prevention of a disease mediated by an EGFR exon 20 insertion mutation.

[0046] In some embodiments, the pharmaceutical composition may further comprise at least one second therapeutic agent, which may be selected from chemotherapeutic agents, targeted anti-tumor agents, antibody agents, and immunotherapeutic agents.

[0047] In some embodiments, the chemotherapeutic agent may be exemplified by the following: platinum drugs (e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin, triplatinum tetranitrate, etc.); tetranitrate), phenanthreneplatin, picoplatin, miriplatin, satraplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, ancitabine, fluorouracil, tegadifur, doxifluridine, tegafur, carmofur, trifluridine, tegafur), camptothecins (e.g., camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan), taxels (e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel), vinblastines (vinorelbine, vinblastine, vincristine, vindesine, vinflunine), anthracenes (epirubicin, amycin, rubidoma), one or more of: isin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone, antibiotics, podophyllum, antimetabolite antineoplastic agents, pemetrexed, carmustine, melphalan, etoposide, teniposide, mitomycin, ifosfamide, cyclophosphamide, azacytidine, methotrexate, bendamustine, liposomal amycin, actinomycin D (dactinomycin), bleomycin, pingyangmycin, temozolomide, dacarbazine, peplomycin, eribulin, plinabulin, sapacitabine, treosulfan, 153Sm-EDTMP, and encequidar.

[0048] In some embodiments, the second therapeutic agent is one or more of platinum drugs, including, but not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, triplatinum tetranitrate, phenanthreneplatin, picoplatin, satraplatin, miriplatin, lobaplatin, and the like.

[0049] In some embodiments, the chemotherapeutic agent is selected from one or more of etoposide, irinotecan, cisplatin, carboplatin, lobaplatin, nedaplatin, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, gemcitabine, cyclophosphamide, amycin, vincristine, bendamustine, farmorubicin, methotrexate, amrubjcin, tegafur, gimeracil, oteracil, tegafur.

[0050] In some embodiments, the targeted antitumor drug may include protein kinase inhibitors.Among them, the protein kinase inhibitors include but are not limited to tyrosine kinase inhibitors, serine and / or threonine kinase inhibitors, and poly ADP-ribose polymerase (PARP) inhibitors. Targets of the 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 (discoidin domain receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, and KRAS gene. Targets of the targeted antitumor drugs also include COX-2 (epoxidase-2), APE1 (apurinic-apyrimidinic endonuclease), VEGFR (vascular endothelial growth factor receptor), CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor), ezrin, PEDF (pigment epithelium-derived factor), AS, ES, OPG (bone protective factor), Src, IFN, ALCAM (activated leukocyte cell adhesion molecule), and other proteins. (glycogen synthase kinase 3β), cyclin D1 (cell cycle regulator protein), CDK4 (cyclin-dependent kinase), TIMP1 (tissue inhibitor of metalloproteinases), THBS3, PTHR1 (parathyroid hormone-related protein receptor 1), TEM7 (human tumor endothelial marker 7), COPS3, and cathepsin K. Targeted antitumor drugs that may be mentioned include:These include, but are not limited to, one or more of the following: Imatinib, Sunitinib, Nilotinib, Bosutinib, Saracatinib, Pazopanib, Trabectedin, Regorafenib, Cediranib, Bortezomib, Panobinostat, Carfilzomib, Ixazomib, Apatinib, Erlotinib, Afatinib, Crizotinib, Ceritinib, Vemurafenib, Dabrafenib, Cabozantinib, Gefitinib, Dacomitinib, Almonertinib, Osimertinib, Olmutinib, Alectinib, Brigatinib, Lorlatinib, Trametinib, Nib, Larotrectinib, Icotinib, Lapatinib, Vandetanib, Selumetinib, Sorafenib, Olmutinib, Savolitinib, Fruquintinib, Entrectinib, Dasatinib, Ensartinib, Lenvatinib, Itacitinib, Pyrotinib, Binimetinib, Erdafitinib, Axitinib, Neratinib, Cobimetinib, Acalabrutinib utinib), Famitinib, Masitinib, Ibrutinib, Anlotinib, Rociletinib, Nintedanib, Revlimid, LOXO-292, Vorolanib, Bemcentinib, Capmatinib, Entrectinib, TAK-931, ALT-803, Palbociclib, Famitinib L-Malate, LTT-462, BLU-667, Ningetinib, Tipifarnib, poziotinib, DS-1205c, capivasertib, SH-1028, metformin, seliciclib, OSE-2101, APL-101, berzosertib, idelalisib, lerociclib, ceralasertib, PLB-1003, tomivosertib, SKLB-1028, D-0316, LY-3023414,Allitinib, MRTX-849, AP-32788, AZD-4205, lifirafenib, vactosertib, mivebresib, napabucasin, sitravatinib, TAS-114, molibresib, CC-223, rivoceranib, CK-101, LXH-254, simotinib, GSK-3368715, TAS-0728, masitinib, tepotinib, HS-10296, AZD-4547, merestinib, olapraced pegol pegol, galunisertib, ASN-003, gedatolisib, defactinib, lazertinib, CKI-27, S-49076, BPI-9016M, RF-A-089, RMC-4630, AZD-3759, antroquinonol, SAF-189s, AT-101, TTI-101, naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, epitinib succinate succinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparib tosylate, DV-281, siremadlin, telaglenstat, MP-0250, GLG-801, ABTL-0812, bortezomib, tucidinostat, vorinostat, resminostat, epacadostat, tazemetostat, entinostat, mocetinostat, quisinostat, LCL-161, and KML-001. In some embodiments, the targeted anti-tumor drug isOne or more of the following: Sorafenib, Erlotinib, Afatinib, Crizotinib, Ceritinib, Vemurafenib, Dabrafenib, Cabozantinib, Gefitinib, Dacomtinib, Osimertinib, Alectinib, Brigatinib, Lorlatinib, Trametinib, Larotrectinib, Icotinib, Lapatinib, Vandetanib, Selumetinib, Olmutinib, savolitinib, fruquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib, binimetinib, erdafitinib, axitinib, neratinib, cobimetinib, acalabrutinib, famitinib, masitinib, ibrutinib, anlotinib, nintedanib.

[0051] In some embodiments, the second therapeutic agent is an antibody drug. In particular, the targets of the antibody drug include, but are not limited to, any one or more of PD-1, PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), platelet-derived growth factor receptor alpha (PDGFR-alpha), 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.

[0052] 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 disclosure, the antibody drug is a cytotoxic T-lymphocyte antigen 4 inhibitor. In one embodiment of the disclosure, the antibody drug is a platelet-derived growth factor receptor alpha (PDGFR-α) inhibitor.

[0053] In some embodiments, the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody or antigen-binding portion thereof that binds to programmed death receptor 1 (PD-1) and / or inhibits the activity of PD-1, or an antibody or antigen-binding portion thereof that binds to programmed death ligand 1 (PD-L1) and / or inhibits the activity of PD-L1 (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody). In one embodiment of the disclosure, the antibody or antigen-binding portion thereof is (a) an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof, which specifically binds to human PD-1 and blocks the binding between human PD-L1 and human PD-1; or (b) an anti-PD-L1 monoclonal antibody or antigen-binding fragment thereof, which specifically binds to human PD-L1 and blocks the binding between human PD-L1 and human PD-1.

[0054] In some embodiments, the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.

[0055] In some embodiments, the anti-PD-1 or PD-L1 antibody is a human or murine antibody.

[0056] 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), Geptanolimab (GB226), Lizumab (LZM009), HLX-10, BAT-1306, AK103 (HX008), AK104 (Akesobio), CS1003, SCT-I10A, F520, SG001, and GLS-010.

[0057] 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.

[0058] In some embodiments, the anti-PD-1 antibody is toripalimab.

[0059] In one embodiment of the disclosure, the anti-PD-1 antibody is pembrolizumab.

[0060] In some embodiments, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor is an anti-CTLA-4 antibody. In one embodiment of the present disclosure, the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.

[0061] 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.

[0062] In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0063] In some embodiments, the platelet-derived growth factor receptor alpha (PDGFR-α) inhibitor is an anti-PDGFRα antibody. In one embodiment of the present disclosure, the anti-PDGFRα antibody is an anti-PDGFRα monoclonal antibody.

[0064] In some embodiments, the anti-PDGFRα antibody is olaratumab.

[0065] In some embodiments, the antibody drugs may also include, but are not limited to, any one or more of Bevacizumab, Ramucirumab, Pertuzumab, Trastuzumab, Cetuximab, Nimotuzumab, Panitumumab, Necitumumab, Dinutuximab, Rituximab, Ibritumomab, Ofatumumab, Obinutuzumab, Alemtuzumab, Daratumumab, Gemtuzumab, Elotuzumab, Brentuximab, Inotuzumab Ozogamicin, Blinatumomab.

[0066] In some embodiments, the immunotherapeutic agents may include one or more of the following: interferon (interferon alpha, interferon alpha-1b, interferon alpha-2b), interleukin, temsirolimus, everolimus, ridaforolimus, and temsirolimus.

[0067] In some embodiments, if a second therapeutic agent is used, the amount of the second therapeutic agent may be adjusted as desired by one of skill in the art.

[0068] In some embodiments, there is provided a use of the above-described pharmaceutical composition in the manufacture of a medicament for treating and / or preventing a disease mediated by an EGFR exon 20 insertion mutation.

[0069] In some embodiments, in the uses described herein, the pharma- ceutically acceptable salt of flumonertinib is the mesylate salt of flumonertinib, ie, flumonertinib mesylate.

[0070] In some embodiments, in the uses described herein, the pharmaceutical compositions of the present disclosure are in tablet or capsule formulations.

[0071] In some embodiments, in the uses described herein, the content of flumonertinib or a pharma- ceutically acceptable salt thereof in each unit preparation (e.g., tablet or capsule) is 10 mg to 400 mg, for example, 20 mg to 320 mg. As a specific content, it may be, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, or 400 mg. As an exemplary specific content, it may be 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg, for example 40 mg or 80 mg, for example 40 mg.

[0072] In some embodiments, in the uses described herein, the content of flumonertinib or a pharma- ceutically 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 exemplary contents it may be 80 mg, 160 mg, 240 mg or 320 mg, for example 80 mg, 160 mg or 240 mg, for example 240 mg.

[0073] In some embodiments, in the use described herein, the pharmaceutical composition is administered to a patient such that the dose of flumonertinib or its pharma- ceutically acceptable salt is 80mg to 400mg.Specific doses may be, for example, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg. As an exemplary dose, it may 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 present disclosure, the dose is a daily dose.

[0074] In some embodiments, in the use described herein, the content of fulmonertinib or its pharmaceutically acceptable salt in the pharmaceutical composition refers to the total amount of fulmonertinib or its pharmaceutically acceptable salt in the pharmaceutical composition that is taken by the patient when the pharmaceutical composition is administered to the patient.For example, when the pharmaceutical composition is in the form of tablet or capsule, the content of fulmonertinib or its pharmaceutically acceptable salt in the pharmaceutical composition refers to the total amount of fulmonertinib or its pharmaceutically acceptable salt in all formulations (e.g., tablet or capsule) when the formulation (e.g., tablet or capsule) is administered.

[0075] In the use described herein, when a patient is administered, it is understood by those skilled in the art that the daily dose of fulmonertinib or its pharmaceutically acceptable salt is equal to or greater than the content of fulmonertinib or its pharmaceutically acceptable salt per unit preparation.Those skilled in the art can calculate the total amount of preparations required to be administered per day based on the daily dose of fulmonertinib or its pharmaceutically acceptable salt and the content of fulmonertinib or its pharmaceutically acceptable salt in each unit preparation.For example, when fulmonertinib or its pharmaceutically acceptable salt is contained in a tablet, and the content of fulmonertinib or its pharmaceutically acceptable salt in each unit preparation (each tablet) is 40mg, and the daily dose of fulmonertinib or its pharmaceutically acceptable salt is 240mg, the total amount of preparations (tablets) required to be administered per day is 6 tablets.

[0076] In some embodiments, the disease mediated by the EGFR exon 20 insertion mutation may be cancer, such as lung cancer, and further may be non-small cell lung cancer (NSCLC).

[0077] In some embodiments, the disease mediated by EGFR exon 20 insertion mutations is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

[0078] In some embodiments, the EGFR exon 20 insertion mutation mediated disease is treatment-naïve or previously treated non-small cell lung cancer.

[0079] As used herein, the term "treatment-naive" refers to a state in which no treatment with another therapeutic agent (including but not limited to chemotherapy, targeted antitumor agents, antibody drugs, or immunotherapeutic agents) has been used before treatment with the present disclosure of fulmonertinib or a pharmaceutically acceptable salt thereof, or a state in which no systemic antitumor treatment has been administered. As used herein, the term "previously-treated" refers to a state in which no treatment with another therapeutic agent (including but not limited to chemotherapy, targeted antitumor agents, antibody drugs, or immunotherapeutic agents) has been used before treatment with the present disclosure of fulmonertinib or a pharmaceutically acceptable salt thereof, or a state in which a systemic antitumor treatment has been administered, but the disease has subsequently progressed. In the case of "previously treated," the patient may or may not have developed resistance to other therapeutic agents.

[0080] In some embodiments, the EGFR exon 20 insertion mutation is characterized by a plurality of amino acid insertion mutations in the region of amino acids 762-774 of the EGFR protein, i.e., the exon 20 insertion mutation site is located in the region of amino acids 762-774. For example, 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 EGFR P772_H773insX mutation, for example, the EGFR exon 20 insertion mutation is at least one selected from EGFR D770_N771insSVD, EGFR V769_D770insASV, EGFR H773_V774insNPH and EGFR D770_N771insNPG.

[0081] In some embodiments, in the uses described herein, the pharmaceutical composition may further comprise at least one second therapeutic agent.In the uses described herein, the second therapeutic agent may be selected from chemotherapeutic agents, targeted antitumor agents, antibody agents and immunotherapeutic agents.

[0082] In some embodiments, in the uses described herein, the second therapeutic agent is a second therapeutic agent as described above in this disclosure.

[0083] In some embodiments, a method for treating and / or preventing a disease mediated by EGFR exon 20 insertion mutation is provided, comprising administering to a patient a therapeutically effective amount of flumonertinib or a pharma- ceutically acceptable salt thereof.

[0084] In some embodiments, a method for treating and / or preventing a disease is provided, comprising administering to a patient with an EGFR exon 20 insertion mutation positive a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof.

[0085] In some embodiments, a method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC) is provided, comprising administering to a patient in need thereof a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof.

[0086] In some embodiments, a method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC) is provided, comprising administering to a patient confirmed to be EGFR exon 20 insertion mutation positive a therapeutically effective amount of flumonertinib or a pharmacologic acceptable salt thereof.

[0087] In some embodiments, a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC) is provided, comprising administering to a patient having an EGFR exon 20 insertion mutation a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof.

[0088] In some embodiments, a method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC) is provided comprising administering a therapeutically effective amount of flumonertinib, or a pharmacologic acceptable salt thereof, to a patient with confirmed EGFR exon 20 insertion mutation who has not previously received systemic anti-tumor therapy.

[0089] In some embodiments, a method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC) is provided comprising administering a therapeutically effective amount of flumonertinib, or a pharmacologic acceptable salt thereof, to a confirmed EGFR exon 20 insertion mutation-positive patient who has progressive disease after prior systemic anti-tumor therapy.

[0090] In some embodiments of the treatment method, flumonertinib or a pharma- ceutically acceptable salt thereof is administered at a dose of 80mg to 400mg.Specific doses may be, for example, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg. As an exemplary dose, it may 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 present disclosure, the dose is a daily dose.

[0091] In some embodiments of the treatment method, flumonertinib or a pharma- ceutically acceptable salt thereof is administered to the patient once per day (qd), twice per day (bid), or three times per day (tid), e.g., once per day.

[0092] In some embodiments of the treatment method, flumonertinib or a pharma- ceutically acceptable salt thereof is administered to the patient under fasting conditions, for example, in the morning under fasting conditions.

[0093] In some embodiments of the methods of treatment, flumonertinib or a pharma- ceutically acceptable salt thereof is orally administered to the patient.

[0094] In some embodiments, in the methods described herein, flumonertinib is administered in the form of a mesylate salt.

[0095] In some embodiments of the method of treatment, flumonertinib or a pharma- ceutically acceptable salt thereof is administered in a tablet or capsule formulation.

[0096] In some embodiments of the treatment method, fulmonertinib or its pharmaceutically acceptable salt is administered in the form of each unit preparation.By adjusting the amount of the unit preparation, the daily dose of fulmonertinib or its pharmaceutically acceptable salt is within the above range.

[0097] In some embodiments of the treatment method, the content of the flumonertinib or a pharma- ceutically acceptable salt thereof in each unit preparation (eg, tablet or capsule) is 10 mg to 400 mg, for example, 20 mg to 320 mg. As a specific content, it may be, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, or 400 mg. As an exemplary specific content, it may be 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg, for example 40 mg or 80 mg, for example 40 mg.

[0098] It is understood by those skilled in the art that when administered to a patient, the daily dose of fulmonertinib or its pharmaceutically acceptable salt is equal to or greater than the content of fulmonertinib or its pharmaceutically acceptable salt per unit preparation.Those skilled in the art can calculate the total amount of preparations required to be administered per day based on the daily dose of fulmonertinib or its pharmaceutically acceptable salt and the content of fulmonertinib or its pharmaceutically acceptable salt in each unit preparation.For example, when fulmonertinib or its pharmaceutically acceptable salt is contained in a tablet, and the content of fulmonertinib or its pharmaceutically acceptable salt in each unit preparation (each tablet) is 40mg, and the daily dose of fulmonertinib or its pharmaceutically acceptable salt is 240mg, the total amount of preparations (tablets) required to be administered per day is 6 tablets.

[0099] In some embodiments of the treatment method, at least one second therapeutic agent may be further administered to the patient. In some embodiments of the treatment method, the second therapeutic agent may be selected from chemotherapeutic agents, targeted anti-tumor agents, antibody agents and immunotherapeutic agents.

[0100] In some embodiments of the methods of treatment, the second therapeutic agent is a second therapeutic agent described above in this disclosure.

[0101] In some embodiments of the treatment methods, the disease is cancer, such as lung cancer, and may further be non-small cell lung cancer (NSCLC).

[0102] In some embodiments of the treatment method, flumonertinib or a pharma- ceutically acceptable salt thereof is administered to the patient before or after surgical resection of the tumor.

[0103] In some embodiments of the treatment methods, the disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

[0104] In some embodiments of the treatment methods, the disease is treatment-naïve or previously treated non-small cell lung cancer.

[0105] In some embodiments of the treatment method, the EGFR exon 20 insertion mutation is characterized by multiple amino acid insertion mutations in the region of amino acids 762-774 of the EGFR protein, i.e., the exon 20 insertion mutation site is located in the region of amino acids 762-774, for example, 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 EGFR P772_H773insX mutation, for example, the EGFR exon 20 insertion mutation is at least one selected from EGFR D770_N771insSVD, EGFR V769_D770insASV, EGFR H773_V774insNPH and EGFR D770_N771insNPG.

[0106] In some embodiments of the methods of treatment, the patient is a human patient.

[0107] In some embodiments of the treatment methods, the patient is between 18 and 75 years of age.

[0108] In some embodiments of the treatment methods, the patient has histologically or cytopathologically confirmed primary non-small cell lung cancer (NSCLC) with prominent non-squamous cell histology prior to initiating treatment with flumonertinib or a pharmaceutical acceptable salt thereof.

[0109] In some embodiments of the treatment methods, the patient has radiological disease progression after the last anti-tumor therapy prior to initiating treatment with flumonertinib or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments of the treatment methods, the patient has a documented positive EGFR exon 20 insertion mutation by clinical test prior to initiating treatment with flumonertinib or a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments of the treatment methods, the patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer and is confirmed to have radiological or pathological disease progression during or after the last systemic anti-tumor therapy prior to initiating treatment with flumonertinib or a pharmacologic salt thereof.

[0112] In some embodiments of the treatment method, the patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer and has not received prior systemic anti-tumor therapy prior to initiating treatment with flumonertinib or a pharmacologic acceptable salt thereof.

[0113] In some embodiments of the treatment methods, the patient has at least one measurable lesion prior to initiating treatment with flumonertinib or a pharma- ceutically acceptable salt thereof.

[0114] In some embodiments of the treatment methods, the patient has sufficient organ function as indicated by clinical tests prior to initiating treatment with flumonertinib or a pharma- ceutically acceptable salt thereof.

[0115] In some embodiments of the treatment method, the patient is subjected to an ECOG PS (Eastern Cooperative Oncology Group performance status) score test before starting treatment with flumonertinib or a pharma- ceutically acceptable salt thereof, for example, an ECOG PS score of 0-1.

[0116] In some embodiments, the treatment methods have an acceptable safety profile.

[0117] In some embodiments, the treatment methods can provide a therapeutic efficacy of partial response (PR).

[0118] In some embodiments, the treatment methods may provide therapeutic efficacy for stable disease (SD).

[0119] In some embodiments, the treatment methods may provide tumor shrinkage in target lesions.

[0120] In some embodiments, the treatment methods provide tumor shrinkage in target lesions as assessed by tumor radiology studies such as computed tomography (CT) and / or magnetic resonance imaging (MRI). [Brief description of the drawings]

[0121] [Figure 1] FIG. 1. Tumor volume change curve in Test Example 3. EXAMPLES

[0122] Working Example Explanation of Abbreviations PR: partial response; 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: central nervous system objective response rate; CTCAE: Common Terminology Criteria for Adverse Events; RECIST1.1: Response Evaluation Criteria in Solid Tumors guidelines (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.

[0123] I. Preparation Examples Preparation of Flumonertinib Mesylate, 40 mg, Standard Tablet Formulation: It contains 46.76 mg flumonertinib mesylate, 44.73 mg microcrystalline cellulose, 68.2 mg lactose, 13 mg croscarmellose sodium, 17.8 mg polyethylene glycol 4000, 10.9 mg colloidal silica, 2.7 mg sodium stearyl fumarate, 8.67 mg sodium chloride, and 40 mg flumonertinib.

[0124] Process: Sieve the adjuvants and active pharmaceutical ingredients for pretreatment, mix evenly, add appropriate amount of polyethylene glycol 4000 for wet granulation, sieve for wet granulation, dry the wet granules, sieve for granulation, add colloidal silica and sodium stearyl fumarate, mix evenly, and then compress to get tablets.

[0125] II. Activity Examples 1. Cell viability Test Example 1: Growth inhibitory activity against human skin cancer A431 adherent cells (wild-type EGFR)

[0126] The growth inhibitory activity of the compound (flumonertinib mesylate) against adherent cells of human skin cancer A431 expressing wild-type EGFR protein in vitro was determined by the sulforhodamine B method (SRB method).

[0127] Cell source: A431 cells were purchased from Shanghai Dobio Biology Technology Inc.

[0128] A431 cells were cultured in DMEM complete culture medium containing 10% fetal bovine serum. A431 cells in logarithmic growth phase were harvested and inoculated into 96-well plates according to a cell density of 5000 cells / 135 μL complete culture medium / well, and the plates were placed in a constant temperature incubator containing 5% CO2 at 37°C and cultured for 24 hours to ensure complete attachment of the cells. The compounds were pre-dissolved in dimethyl sulfoxide (DMSO) to prepare 10 mM stock solutions, and then the compounds were serially diluted with DMSO and complete culture medium. The 96-well plates inoculated with the cells were taken out, and one of the plates was taken out alone as a no-growth control group (culture medium control group without cell growth at 0 hours); for the other 96-well plates, 15 μL of different concentrations of the compounds were added to each well to achieve final concentrations of 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, 0.61 nM, 0.15 nM, 0.04 nM, 0.01 nM, and three replicate wells were set up for each compound concentration, and a negative control (cell-containing, compound-free culture medium control) was set up, and the DMSO concentration in each well was 0.5%.

[0129] The culture of the set aside no growth control group was immediately terminated, and the other 96-well plate was further placed in an incubator with 5% CO2 at 37°C for 72 hours and then terminated. The termination of the culture method was as follows: 50 μL of pre-chilled (4°C) 50% aqueous trichloroacetic acid solution was added to each well, kept at 4°C for 1 hour, washed at least five times with purified water, and air-dried or dried in an oven at 60°C.

[0130] 4mg / mL SRB solution was formulated in purified water containing 1% glacial acetic acid. 100μL of the above SRB solution was added to each well and stained at room temperature for 1 hour. The supernatant was discarded, and the residue was washed at least 5 times with 1% glacial acetic acid to remove non-specific binding, and dried for use. 150μL of 10mM trihydroxymethylaminomethane hydrochloride solution (Tris-HCl solution) was added to each well for dissolution, and the photometric density value (OD value) at a wavelength of 510nm was measured, and the data was collected to calculate the cell growth inhibition rate.

[0131] Cell proliferation inhibition rate = [(OD 72時間陰性コントロール群 -OD 72時間化合物投与群 ) / (OD 72時間陰性コントロール群 -OD 無増殖コントロール群 )] × 100%.

[0132] The data were analyzed using GraphPad Prism 8.3 software and fitted with nonlinear sigmoidal regression to obtain dose-effect curves and IC 50 Values ​​were calculated therefrom as shown in Table 1. [Table 1]

[0133] Test Example 2: Growth inhibitory activity against Ba / F3 EGFR D770_N771insSVD, Ba / F3 EGFR V769_D770insASV, and Ba / F3 EGFR H773_V774insNPH stably transfected cells

[0134] The growth inhibitory activity of the above compound (flumonertinib mesylate) against Ba / F3 EGFR D770_N771insSVD, Ba / F3 EGFR V769_D770insASV, and Ba / F3 EGFR H773_V774insNPH cells, which stably express EGFR exon 20 insertions in mouse pro-B cells Ba / F3 in vitro, was determined by the CellTiter Glo method.

[0135] Cell source: Ba / F3 EGFR D770_N771insSVD, Ba / F3 EGFR V769_D770insASV, and Ba / F3 EGFR H773_V774insNPH cells commercially available from Shanghai WuXi AppTec New Drug Development Co. Ltd.

[0136] Ba / F3 EGFR D770_N771insSVD, Ba / F3 EGFR V769_D770insASV, and Ba / F3 EGFR H773_V774insNPH cells were cultured in RPMI1640 complete culture medium containing 10% fetal bovine serum. Logarithmic growth phase Ba / F3 EGFR D770_N771insSVD, Ba / F3 EGFR V769_D770insASV, and Ba / F3 EGFR H773_V774insNPH cells were harvested and seeded into 384-well plates according to a cell density of 2000 cells / 50 μL complete culture medium / well, and the plates were placed in a constant temperature incubator containing 5% CO2 at 37°C for 24 hours. The compounds were pre-dissolved in dimethylsulfoxide (DMSO) to prepare a 10 mM stock solution, and then the compounds were serially diluted with DMSO and complete culture medium. The 384-well plate seeded with the cells was removed and the compounds were added with a Tecan HP D300 to achieve final concentrations of 2500 nM, 625 nM, 156.25 nM, 39.06 nM, 9.77 nM, 2.44 nM, 0.61 nM, 0.15 nM, and 0.04 nM, with two replicate wells set up for each compound concentration, a culture medium control group without cells, and a control group of cells with 0.2% DMSO added.

[0137] After culturing at 37°C for 72 hours in 5% CO2, 25μL CellTiter-Glo reagent (luciferase ATP bioluminescence detection reagent, commercially available from Promega, Cat # G7573) was added to each well, shaken at 1000rpm for 30 seconds, incubated at room temperature for 10 minutes, and after the luminescence intensity stabilized, the luminescence intensity (Lum) was measured with a microplate reader. The inhibition rate of the above compounds against cell proliferation at each concentration was calculated.

[0138] Cell proliferation inhibition rate = (Lum 最大 -Lum 化合物 ) / (Lum 最大 -Lum 最小 )×100%(Lum 最大 is the maximum luminescence intensity, Lum 化合物 is the luminescence intensity of the compound, and Lum 最小 is the minimum emission intensity).

[0139] The data were analyzed by using XL-fit 5.0 software and fitted with nonlinear sigmoidal regression to obtain dose-effect curves and IC 50 Values ​​were calculated therefrom as shown in Table 2. [Table 2]

[0140] The results showed that flumonertinib mesylate had good proliferation inhibitory activity against Ba / F3 EGFR D770_N771insSVD, Ba / F3 EGFR V769_D770insASV, and Ba / F3 EGFR H773_V774insNPH stably transfected cells.

[0141] 2. In Vivo Testing Test Example 3: Testing the antitumor efficacy of flumonertinib mesylate in the HuPrime® lung cancer LU0387 tumor model

[0142] This study was used to evaluate and test the antitumor efficacy of flumonertinib mesylate in a BALB / c female nude mouse animal model subcutaneously xenografted with HuPrime® lung cancer LU0387 (harboring EGFR H773_V774insNPH mutation).

[0143] Experimental animals: BALB / c nude mice, female, 7-8 weeks old (age of mice when inoculated with tumor cells), weighing 18.1-24.7 g, purchased from Jiangsu GemPharmatech Co. Ltd.

[0144] Animal model preparation and random grouping: Tumor tissues were collected from HuPrime® lung cancer xenograft model LU0387 tumor-bearing mice, cut into tumor blocks with a diameter of 2-3 mm, and inoculated subcutaneously into the right anterior scapula of Balb / c nude mice on June 16, 2020. The mean tumor volume was 197.56 mm 3 When the animals reached the age of 18, they were randomly assigned to groups according to tumor size, and the date of grouping was July 15, 2020, i.e., 29 days after tumor switching (day 29). The day of grouping was defined as day 0.

[0145] Experimental scheme: BALB / c nude mice were subcutaneously inoculated with HuPrime® model LU0387 tumor block to establish a human lung cancer subcutaneous xenograft tumor model. The experiment was divided into 20mg / kg, 30mg / kg and 50mg / kg groups of flumonertinib mesylate and vehicle group (where each group contains 8 animals), orally administered with a dose volume of 10μL / g, and the same amount of vehicle was administered to vehicle group, administration was performed once a day, and continued for 3 weeks. During the whole experiment, the tumor size of mice was measured twice a week, and the presence or absence of toxic reaction was observed. Efficacy was evaluated in terms of relative tumor growth inhibition (TGI).

[0146] Tumor volume (TV) was calculated by: TV = 1 / 2 × a × b × b, where a and b represented the length and width of the tumor, respectively.

[0147] Relative Tumor Growth Inhibition (TGI): Tumor growth inhibition (TGI) is one of the indicators of tumor response to treatment based on the following formula: TGI(%)=(1-(T i -T0) / (V i -V0)) × 100%, T i : Mean tumor volume of the experimental group corresponding to the number of the analysis day; T0: Mean tumor volume of the experimental group corresponding to the day the animals were grouped; V i : mean tumor volume of the vehicle group corresponding to the number on the day of analysis; and V0: mean tumor volume of the vehicle group corresponding to the day the animals were grouped.

[0148] The tumor volume change curves for the three experimental groups and one vehicle group are shown in FIG.

[0149] The results showed that flumonertinib mesylate exhibited good antitumor effect in HuPrime lung cancer LU0387 subcutaneous xenograft BALB / c female nude mice animal model.

[0150] 3. Clinical Trials a. Protocol [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0151] b. Results [Table 4]

[0152] Conclusion: Flumonertinib mesylate has good antitumor effects against non-small cell lung cancer (NSCLC) harboring EGFR exon 20ins mutations at a dose of 160mg QD, and excellent antitumor effects against treatment-naïve or previously treated NSCLC harboring EGFR exon 20ins mutations at a dose of 240mg QD.

[0153] c. Safety profile Long-term administration of flumonertinib mesylate at doses of 160 mg to 240 mg was well tolerated, and observed safety events mainly included gastrointestinal and cutaneous adverse reactions, and liver- and kidney-related laboratory abnormalities; no other specific adverse event (AE) categories were observed; AE severity was minimal, with most being CTCAE grade 1 to 2. Clinical trials have shown that administration at doses of 160 mg to 240 mg for long periods of time has a relatively good safety profile.

[0154] Industrial Applicability The present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of fulmonertinib or a pharma- ceutically acceptable salt thereof and optionally a pharma- ceutically acceptable carrier, and the use of the pharmaceutical composition in the manufacture of a medicament for treating and / or preventing diseases mediated by EGFR exon 20 insertion mutation.The present disclosure also provides a method for treating and / or preventing diseases mediated by EGFR exon 20 insertion mutation, wherein a therapeutically effective amount of fulmonertinib or a pharma- ceutically acceptable salt thereof is administered to a patient.The pharmaceutical composition of the present disclosure shows excellent therapeutic effect against diseases mediated by EGFR exon 20 insertion mutation (e.g., non-small cell lung cancer (NSCLC)) with little side effects and excellent safety.

Claims

1. A pharmaceutical composition for use in the treatment and / or prevention of a disease mediated by EGFR exon 20 insertion mutations in a patient in need thereof, comprising a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof, and optionally a pharma-ceutical acceptable carrier.

2. The pharmaceutical composition for use according to claim 1 , wherein the pharma- ceutically acceptable salt is a mesylate salt.

3. The pharmaceutical composition for use according to claim 1 or 2, wherein the content of flumonertinib or a pharma- ceutically 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.

4. The pharmaceutical composition for use according to claim 1 or 2, wherein the content of flumonertinib or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 80 mg, 160 mg, 240 mg, or 320 mg.

5. The pharmaceutical composition for use according to claim 1 or 2, wherein the content of flumonertinib or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 80 mg.

6. The pharmaceutical composition for use according to claim 1 or 2, wherein the content of flumonertinib or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 160 mg.

7. The pharmaceutical composition for use according to claim 1 or 2, wherein the content of flumonertinib or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 240 mg.

8. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the pharmaceutical composition is in the formulation of a tablet or capsule.

9. The pharmaceutical composition for use according to claim 8, wherein in each unit dosage form, the content of flumonertinib or a pharma- ceutically 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 for use according to claim 8, wherein the content of flumonertinib or a pharma- ceutically acceptable salt thereof in each unit dosage form is 20 mg to 320 mg.

11. The pharmaceutical composition for use according to claim 8, wherein the content of flumonertinib or a pharma- ceutically acceptable salt thereof in each unit dosage form is 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg.

12. The pharmaceutical composition for use according to claim 8, wherein the content of flumonertinib or a pharma- ceutically acceptable salt thereof in each unit dosage form is 40 mg.

13. The pharmaceutical composition for use according to claim 1 or 2, wherein the pharmaceutical composition further comprises at least one second therapeutic agent.

14. 14. The pharmaceutical composition for use according to claim 13, wherein the second therapeutic agent is selected from a chemotherapeutic agent, a targeted anti-tumor agent, an antibody agent, an immunotherapeutic agent, and combinations thereof.

15. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the disease is cancer, such as lung cancer, such as non-small cell lung cancer (NSCLC).

16. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

17. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the disease is treatment-naïve or previously treated non-small cell lung cancer.

18. 3. The pharmaceutical composition for use according to claim 1 or 2, 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 EGFR P772_H773insX mutation, such as at least one selected from EGFR D770_N771insSVD, EGFR V769_D770insASV, EGFR H773_V774insNPH and EGFR D770_N771insNPG.

19. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has been confirmed positive for an EGFR exon 20 insertion mutation.

20. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has an EGFR exon 20 insertion mutation.

21. A pharmaceutical composition for use as described in claim 1 or 2, comprising a therapeutically effective amount of flumonertinib or a pharma- ceutically acceptable salt thereof, wherein the patient has not previously received systemic anti-tumor treatment.

22. A pharmaceutical composition for use as described in claim 1 or 2, comprising a therapeutically effective amount of flumonertinib or a pharma- ceutically acceptable salt thereof, wherein the patient has progressive disease after previous systemic anti-tumor treatment.

23. A pharmaceutical composition for use as described in claim 1 or 2, wherein the flumonertinib or a pharma- ceutically acceptable salt thereof is for use qd, bid or tid.

24. A pharmaceutical composition for use according to claim 1 or 2, wherein the flumonertinib or a pharma- ceutically acceptable salt thereof is for use once a day.

25. A pharmaceutical composition for use as described in claim 1 or 2, wherein the flumonertinib or a pharma- ceutically acceptable salt thereof is for use in the patient under fasting conditions.

26. A pharmaceutical composition for use according to claim 1 or 2, wherein the flumonertinib or a pharma- ceutically acceptable salt thereof is for use in the patient in the morning under fasting conditions.

27. ​​A pharmaceutical composition for use according to claim 1 or 2, wherein the flumonertinib or a pharma- ceutically acceptable salt thereof is for oral use.

28. A pharmaceutical composition for use according to claim 1 or 2, wherein the flumonertinib or a pharma- ceutically acceptable salt thereof is for use in the patient before or after surgical resection of a tumor.

29. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient is a human patient.

30. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient is between 18 and 75 years old.

31. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has histologically or cytopathologically confirmed primary non-small cell lung cancer (NSCLC) with predominant non-squamous cell histology prior to initiating treatment with flumonertinib or a pharma- ceutical acceptable salt thereof.

32. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has radiological disease progression after the last anti-tumor treatment prior to initiating treatment with flumonertinib or a pharma- ceutical acceptable salt thereof.

33. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has a documented positive EGFR exon 20 insertion mutation by clinical testing prior to initiating treatment with flumonertinib or a pharma- ceutical acceptable salt thereof.

34. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has locally advanced or metastatic NSCLC and is confirmed to have radiological or pathological disease progression during or after the last systemic anti-tumor treatment prior to initiating treatment with flumonertinib or a pharmacologic acceptable salt thereof.

35. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has locally advanced or metastatic NSCLC and has not received any prior systemic anti-tumor treatment prior to initiating treatment with flumonertinib or a pharma- ceutical acceptable salt thereof.

36. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has at least one measurable lesion prior to initiating treatment with flumonertinib or a pharma- ceutically acceptable salt thereof.

37. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has sufficient organ function as shown by clinical tests prior to initiating treatment with flumonertinib or a pharma- ceutical acceptable salt thereof.

38. 3. The pharmaceutical composition for use according to claim 1 or 2, wherein the patient has an ECOG PS (Eastern Cooperative Oncology Group Performance Status) score of 0 to 1 before starting treatment with flumonertinib or a pharma- ceutical acceptable salt thereof.

39. 3. A pharmaceutical composition for use according to claim 1 or 2, having an acceptable safety profile.

40. 3. The pharmaceutical composition for use according to claim 1 or 2, which provides a partial response.

41. 3. A pharmaceutical composition for use according to claim 1 or 2, which provides a stable disease state.

42. 3. The pharmaceutical composition for use according to claim 1 or 2, which provides tumor shrinkage in the target lesion.

43. 3. A pharmaceutical composition for use according to claim 1 or 2, which provides tumor shrinkage in target lesions as assessed by oncological radiological studies such as computed tomography (CT) and / or magnetic resonance imaging (MRI).

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