Pharmaceutical compositions and uses thereof

Abstract

Provided herein is a pharmaceutical composition comprising a therapeutically effective amount of flumonertinib or its pharmaceutically acceptable salt and optionally a pharmaceutically acceptable carrier, and the use of flumonertinib or its pharmaceutically acceptable salt or said pharmaceutical composition in the manufacture of a medicament for treating and / or preventing diseases mediated by PACC mutation.The pharmaceutical composition shows excellent therapeutic effect against diseases mediated by PACC mutation (such as non-small cell lung cancer (NSCLC)), with little side effects and excellent safety.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier. The present invention also relates to the use of flumonertinib or a pharmaceutically acceptable salt thereof and the pharmaceutical composition in the manufacture of a medicament for treating and / or preventing diseases mediated by PACC mutations (a subgroup of EGFR mutations, also known as P-loop and αC-helix compression mutations, mutations on the inner surface of the ATP-binding pocket or at the C-terminus of the αC-helix). The present invention also provides a method for treating and / or preventing diseases mediated by PACC mutations, comprising administering to a patient a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Lung cancer remains the most common malignant tumor with the highest incidence and mortality rates worldwide, posing a serious threat to human health and well-being. In 2018, 1.76 million people died from lung cancer worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80%–85% of all lung cancers. The epidermal growth factor receptor (EGFR) is a multifunctional glycoprotein widely distributed on the cell membranes of various tissues in the human body. EGFR mutations are the most widely studied target in NSCLC.

[0003] Among EGFR mutations, common mutations include susceptibility mutations (e.g., exon 19 deletions and exon 21 point mutations (L858R), which account for 85%–90% of all EGFR mutations) and drug-resistance mutations (e.g., exon 20 T790M and exon 20 C797S mutations). Using hierarchical clustering of in vitro selectivity against WT EGFR and mutational mapping of EGFR mutations, Robichaux et al. observed four distinct subgroups of EGFR mutations: classical-like mutations away from the ATP-binding pocket, T790M-like mutations in the hydrophobic core, insertions in a loop at the C-terminus of the αC-helix in exon 20, and mutations on the inner surface of the ATP-binding pocket or at the C-terminus of the αC-helix that were predicted to be P-loop and αC-helix compaction (PACC). PACC mutations include mutations spanning exons 18 to 21, including G719X, L747X, S768I, L792X, E709X, L718X, G724S, V769X, and T854I (Nature, Vol. 597, pp. 732-737 (2021)).

[0004] Over the years, many targeted drugs have been developed for EGFR mutations in NSCLC, such as the first-generation reversible tyrosinase inhibitors (TKIs) gefitinib and erlotinib for EGFR-sensitive mutations, the second-generation irreversible covalent inhibitor afatinib, and the third-generation inhibitor osimertinib for drug-resistant EGFR T790M, which have very good clinical efficacy.

[0005] However, no drugs targeting EGFR PACC mutations have been approved worldwide, and therefore there remains a continuing need for the development of effective, stable, and safe small molecule inhibitors of EGFR PACC mutations. 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 "furmonertinib") represented by the following formula (I) is described in Patent CN105315259B, and the mesylate salt of the compound represented by the following formula (I) (also referred to as "furmonertinib mesilate") is described in Patent CN107163026B, and flumonertinib mesilate has been commercialized as a third-generation EGFR-TKI inhibitor and is mainly used to treat diseases mediated by EGFR-sensitizing mutations and T790M drug-resistant mutations. A phase I ascending study of flumonertinib mesylate demonstrated that when flumonertinib mesylate was taken orally once daily at a dosage level of 20 mg to 240 mg, its tolerability and safety were good, with only mild or moderate adverse events observed, and no dose-limiting or dose-related toxic reactions occurred; furthermore, a phase IIb clinical trial demonstrated that oral administration of flumonertinib mesylate at a daily dose of 80 mg demonstrated relatively good antitumor effects in patients with EGFR T790M-positive advanced non-small cell lung cancer (who had progressive disease after receiving prior systemic antitumor therapy), potentially reducing or stabilizing disease progression. [ka] [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Nature, Volume 597, Pages 732-737 (2021) Summary of the Invention [Means for solving the problem]

[0007] (overview) In some embodiments, the present invention provides the use of flumonertinib or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, flumonertinib or a pharmaceutically acceptable salt thereof as an active compound can effectively inhibit PACC mutation, and therefore, flumonertinib or a pharmaceutically acceptable salt thereof can be used to treat and / or prevent diseases mediated by PACC mutation.

[0009] Thus, in some embodiments, the present invention provides the use of flumonertinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing a disease mediated by PACC mutations.

[0010] In some embodiments, the present invention provides the use of flumonertinib or a pharmaceutically acceptable salt thereof in combination with at least one second therapeutic agent in the manufacture of a medicament for treating and / or preventing a disease mediated by PACC mutations.

[0011] In some embodiments, flumonertinib or a pharmaceutically acceptable salt thereof is useful as an active compound at a specific dose, and can treat and / or prevent diseases mediated by PACC mutations (particularly non-small cell lung cancer), and the treatment and / or prevention of the disease is accompanied by few side effects and has excellent safety.

[0012] More particularly, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0013] The present invention also provides the use of the above-described pharmaceutical composition of the present invention in the manufacture of a medicament for treating and / or preventing a disease mediated by PACC mutations.

[0014] The composition of the present invention can also be in the form of tablets or capsules, each containing 10 mg to 400 mg of flumonertinib or a pharmaceutically acceptable salt thereof.

[0015] When the pharmaceutical composition of the present invention is used to treat and / or prevent diseases mediated by PACC mutations, the daily dose of flumonertinib or a pharmaceutically acceptable salt thereof can be 80 mg to 400 mg. At present, the daily dose of flumonertinib or a pharmaceutically acceptable salt thereof can be easily adjusted by adjusting the amount of the above-mentioned formulation (e.g., tablet or capsule).

[0016] The present invention also provides a method for treating and / or preventing a disease mediated by a PACC mutation, the method comprising administering to a patient a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

[0017] In the above-mentioned treatment method of the present invention, the daily dose of flumonertinib or a pharmaceutically acceptable salt thereof is preferably 80 mg to 400 mg.

[0018] The present invention also provides a method for treating and / or preventing disease, which method comprises administering to a patient with a positive PACC mutation a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

[0019] The present invention also provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

[0020] The present invention also provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering to a patient with a confirmed positive PACC mutation a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

[0021] The present invention also provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering to a patient harboring a PACC mutation a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

[0022] The present invention also provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof to a patient with a confirmed positive PACC mutation who has not received any prior systemic anti-tumor therapy.

[0023] The present invention also provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering a therapeutically effective amount of flumonertinib, or a pharmaceutically acceptable salt thereof, to a patient with a confirmed positive PACC mutation who has progressive disease after receiving prior systemic anti-tumor therapy. [Effects of the Invention]

[0024] In the present invention, flumonertinib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing flumonertinib or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier, exhibits excellent inhibitory activity against PACC mutations, and therefore, can exhibit excellent clinical efficacy.

[0025] Furthermore, when flumonertinib or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising flumonertinib or a pharmaceutically acceptable salt thereof of the present invention and optionally a pharmaceutically acceptable carrier, is used to treat and / or prevent diseases mediated by PACC mutations, its side effects are small and its safety is excellent.

[0026] The pharmaceutical composition of the present invention can be prepared into a preparation having an appropriate size and an appropriate content of the active ingredient by including a specific amount of flumonertinib or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0027] (Detailed explanation) Although embodiments of the present invention are 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 exemplary of the present invention and should not be construed as limiting the scope of the present invention. Rather, the present invention is intended to cover all alternatives, modifications, and equivalents that are within the scope of the present invention as defined by the appended claims.

[0028] Unless otherwise specified, the embodiments of the present invention may be combined in any manner, and the conversions, modifications and variations of the technical solutions obtained thereby also fall within the scope of the present invention.

[0029] Flumonertinib is a compound known in the prior art and is described in detail in Patent CN105315259B, and has 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; its structural formula is the compound shown in (I). [ka]

[0030] In the present invention, the active ingredient for treating this disease is actually flumonertinib or its pharmaceutically acceptable salt.Therefore, in the present invention, flumonertinib or its pharmaceutically acceptable salt can be used alone or by being contained in a composition, in which case, the composition can optionally contain any pharmaceutically acceptable carrier.

[0031] Furthermore, in the present invention, flumonertinib or a pharmaceutically acceptable salt thereof may also be used in combination with at least one second therapeutic agent.

[0032] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

[0033] "Pharmaceutically acceptable carrier" means one or more compatible solid or liquid fillers or gelatinous substances that should be of sufficient purity and sufficiently low toxicity to be suitable for human use. In the present invention, the carrier is also known as an "adjuvant." "Compatible" means that the components in the composition can be mixed with the compound of the present invention and each other without substantially reducing the pharmaceutical effect of the compound. Some examples of pharmaceutically acceptable carriers include, but are not limited to, cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylmethylcellulose and their derivatives, cellulose acetate and its derivatives, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate / 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, flavoring agents, stabilizers, antioxidants, preservatives, etc.

[0034] The pharmaceutical compositions of the present invention can be prepared by methods well known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, and lyophilizing processes.

[0035] The pharmaceutical composition of the present invention may be prepared in the form of a tablet or capsule, in which flumonertinib or a pharmaceutically acceptable salt thereof is mixed with at least one pharmaceutically acceptable carrier, which in the present invention 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, alginate, gelatin, polyvinylpyrrolidone, copovidone, sucrose, gum arabic, and corn starch; (c) humectants, such as glycerin; (d) humectants, such as glycerin; (e) disintegrants, such as croscarmellose sodium, crospovidone, carboxymethyl starch sodium, colloidal silica, microcrystalline cellulose, potato starch or tapioca starch or corn starch, pregelatinized starch, alginic acid, certain complex silicates and sodium carbonate, ion exchange resins, etc.; (f) absorption enhancers, such as quaternary ammonium compounds, anionic or nonionic surfactants, cyclodextrins, etc.; (f) wetting agents, such as cetyl alcohol and glycerol monostearate, etc.; (g) absorbents, 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 a buffering agent. The tablets and capsules may be coated or microencapsulated with coating or shell materials (e.g., enteric coatings or other materials known in the art).

[0036] The term " pharmaceutically acceptable salt " refers to a salt prepared from flumonertinib and a relatively non-toxic pharmaceutically acceptable acid or base. Base addition salts can be obtained by contacting flumonertinib with a sufficient amount of pharmaceutically acceptable base in pure solution or in a suitable inert solvent. Representative base addition salts include, for example, base addition salts formed with alkali metal ions, alkaline earth metal ions, quaternary ammonium ions (such as sodium ions, lithium ions, potassium ions, calcium ions, magnesium ions, tetramethyl quaternary ammonium ions, tetraethyl quaternary ammonium ions, etc.); amine salts (including salts formed with ammonia (NH), primary amines, secondary amines or tertiary amines (such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, etc.)). In addition, acid addition salts can be obtained by contacting flumonertinib with a sufficient amount of pharmaceutically acceptable acid in pure solution or in a suitable inert solvent. The pharmaceutically acceptable acid salts include inorganic acid salts such as hydrochloride, sulfate, phosphate, and nitrate; and organic acid salts such as 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, eds., Wiley-VCH, 2002).

[0037] In the present invention, the term "therapeutically effective amount" refers to a non-toxic amount of a drug or pharmacologically active agent that is sufficient to achieve the desired effect. The effective amount varies from person to person depending on the patient's age, weight, and condition, as well as the specific active substance, and the appropriate effective amount in each individual case can be determined by those skilled in the art in light of routine testing.

[0038] As used herein, "active ingredient," "active substance," or "active agent" refers to a chemical compound that is effective in treating a disorder, disease, or condition of interest.

[0039] 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), and apes (e.g., gorillas, chimpanzees, orangutans, gibbons). In some embodiments, a "patient" is a human.

[0040] In the present invention, "treatment" refers to curative or palliative treatment. In the context of a particular condition, treatment refers to: (1) alleviating one or more biological symptoms of a disease or disorder; (2) interfering with (a) one or more points in the biological cascade that cause or contribute to the disorder, or (b) one or more biological symptoms of the disorder; (3) alleviating 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 symptoms of a disease or disorder. "Treatment" can also refer to an increase in survival compared to expected survival in the absence of that treatment.

[0041] In the present invention, "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0042] In one embodiment of the present invention, the pharmaceutically acceptable salt of flumonertinib is the mesylate salt of flumonertinib (ie, flumonertinib mesylate).

[0043] In one embodiment of the present invention, the pharmaceutical composition is in the form of a tablet or capsule.

[0044] In one embodiment of the present invention, the content of flumonertinib or a pharmaceutically acceptable salt thereof per unit dosage form (for example, tablet or capsule) as described above is 10 mg to 400 mg, preferably 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 a preferred specific content, it may be 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg, more preferably 40 mg or 80 mg, most preferably 40 mg.

[0045] In one embodiment of the present invention, the pharmaceutical composition contains flumonertinib or a pharmaceutically acceptable salt thereof 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. A preferred content may be 80 mg, 160 mg, 240 mg or 320 mg, more preferably 80 mg, 160 mg or 240 mg, most preferably 240 mg.

[0046] In one embodiment of the present invention, when the pharmaceutical composition is used to treat and / or prevent a disease mediated by a PACC mutation, the composition is administered to a patient at a dose of 80 mg to 400 mg of flumonertinib or a pharmaceutically acceptable salt thereof. Specific doses may be, 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. Preferred doses may be 80 mg, 160 mg, 240 mg or 320 mg, more preferably 80 mg, 160 mg or 240 mg, most preferably 240 mg. In one embodiment of the present invention, the dose is a daily dose.

[0047] In other words, in the present invention, the content of flumonertinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention refers to the total amount of flumonertinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition that is ingested by a patient when the pharmaceutical composition is administered to the patient.For example, when the pharmaceutical composition is in the form of a tablet or capsule, the content of flumonertinib or a pharmaceutically acceptable salt thereof in the pharmaceutical composition refers to the total amount of flumonertinib or a pharmaceutically acceptable salt thereof in all of the tablet or capsule formulations when the formulation is administered.

[0048] Those skilled in the art will understand that when administered to patients, the daily dose of flumonertinib or its pharmaceutically acceptable salt is equal to or greater than the content of flumonertinib or its pharmaceutically acceptable salt in each unit preparation.Those skilled in the art can calculate the total amount of flumonertinib or its pharmaceutically acceptable salt that needs to be administered per day based on the daily dose of flumonertinib or its pharmaceutically acceptable salt and the content of flumonertinib or its pharmaceutically acceptable salt in each unit preparation.For example, if flumonertinib or its pharmaceutically acceptable salt is contained in tablets, and the content of flumonertinib or its pharmaceutically acceptable salt in each unit preparation (each tablet) is 40mg, and the daily dose of flumonertinib or its pharmaceutically acceptable salt is 240mg, then the total amount of flumonertinib or its pharmaceutically acceptable salt that needs to be administered per day is 6 tablets.

[0049] In one embodiment of the present invention, the pharmaceutical composition is administered once, twice or three times per day, preferably once per day, for the treatment and / or prevention of diseases mediated by PACC mutations.

[0050] In one embodiment of the present invention, the pharmaceutical composition may further comprise at least one second therapeutic agent, which may be selected from a chemotherapeutic agent, a targeted anti-tumor agent, an antibody agent, and an immunotherapeutic agent.

[0051] In one embodiment of the present invention, the chemotherapeutic agent may be exemplified by the following: platinum agents (e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin, triplatinum 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), taxel (e.g., paclitaxel, albumin-bound paclitaxel, and doxifluridine), Cetaxel), vinblastine (vinorelbine, vinblastine, vincristine, vindesine, vinflunine), anthracenes (epirubicin, amycin, rubidomycin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone), antibiotics, podophyllum, antimetabolites, antineoplastic agents, pemetrexed, carmustine, melphalan, etoposide, teniposide, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposomal amycin amycin), actinomycin D (dactinomycin), bleomycin, pingyangmycin, temozolomide, dacarbazine, peplomycin, eribulin, plinabulin, sapacitabine, treosulfan, 153Sm-EDTMP, and encequidar.

[0052] In one embodiment of the present invention, the second therapeutic agent is one or more platinum agents, including, but not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, triplatinum tetranitrate, phenanthreneplatin, picoplatin, satraplatin, miriplatin, lobaplatin, and the like.

[0053] In one embodiment of the invention, 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, amrubicin, tegafur, gimeracil, oteracil, tegafur.

[0054] In one embodiment of the present invention, the targeted antitumor drug may be a protein kinase inhibitor. Among them, 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 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 signal pathway, DDR2 (discoidin domain receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophin tyrosine kinase type 1 receptor) gene, and KRAS gene. Targets for the targeted antitumor drugs also include COX-2 (epoxidase 2), APE1 (apurinating apyrimidinic site 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 (osteoprotective factor), Src, IFN, ALCAM (activated leukocyte cell adhesion molecule), HSP, JIP1, GSK-3β (glycogen synthase kinase 3β), cyclin D1 (cell cycle regulatory protein), CDK4 (cyclin-dependent kinase), TIMP1 (tissue inhibitor of metalloproteinase), THBS3, PTHR1 (parathyroid hormone-related protein receptor 1), TEM7 (human tumor vascular endothelial marker 7), COPS3, and cathepsin K. Targeted antitumor drugs that may be mentioned include 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, brigutinib, lorlatinib, trametinib, larotrectinib, icotinib, lapatinib, vandetanib, selumetinib, sorafenib, olmutinib, savolitinib, fruquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib, binimetinib, erdafitinib, axitinib, neratinib, cocaine, Bimetinib, Acalabrutinib, 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, Ningetini Ningetinib, tipifarnib, poziotinib, DS-1205c, capivasertib, SH-1028, metformin, seliciclib, OSE-2101, APL-101, beruzosertib, idelalisib, relociclib, selalasertib, PLB-1003, tomivosertib, SKLB-1028, D-0316, LY-3023414, allitinib, MRTX-849, AP-32788, AZD-4205 , lifirafenib, vactosertib, mibebresib, napabucasin, sitravatinib, TAS-114, molybresil, CC-223, riboselanib, CK-101, LXH-254, simotinib, GSK-3368715, TAS-0728, masitinib, tepotinib, HS-10296, AZD-4547, merestinib, olaptesed 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,Examples of therapeutic agents include, but are not limited to, one or more of: HH-SCC-244, ASK-120067, CT-707, epitinib succinate, tecevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparib tosylate, DV-281, siremadlin, telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, tucidinostat, vorinostat, resminostat, epacadostat, tazemetostat, entinostat, mocetinostat, xinostat, LCL-161, and KML-001. In some embodiments, the targeted anti-tumor drug is sorafenib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigutinib, lorlatinib, trametinib, larotrectinib, icotinib, lapatinib, vandetanib, selumetinib, olmutinib, savolitinib, sarfenib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigutinib, lorlatinib, trametinib, larotrectinib, icotinib, lapatinib, vandetanib, selumetinib, olmutinib, savolitin ... The drug is one or more of: cyclophosphamide, fruquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib, binimetinib, erdafitinib, axitinib, nirotrinib, cobimetinib, acalabrutinib, famitinib, masitinib, ibrutinib, anlotinib, and nintedanib.

[0055] In one embodiment of the present invention, the second therapeutic agent is an antibody drug, among which targets targeted by 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-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.

[0056] In one embodiment of the present invention, the antibody drug is an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1; in one embodiment of the present invention, the antibody drug is a cytotoxic T-lymphocyte antigen 4 inhibitor. In one embodiment of the present invention, the antibody drug is a platelet-derived growth factor receptor α (PDGFR-α) inhibitor.

[0057] In one embodiment of the present invention, the inhibitor of the interaction between the PD-1 receptor and its ligand, PD-L1, is an antibody or 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 present invention, the antibody or antigen-binding portion thereof is (a) an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof that 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 that specifically binds to human PD-L1 and blocks the binding between human PD-L1 and human PD-1.

[0058] In one embodiment of the invention, the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.

[0059] In one embodiment of the invention, the anti-PD-1 or PD-L1 antibody is a human or murine antibody.

[0060] In one embodiment of the invention, 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.

[0061] In one embodiment of the invention, 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.

[0062] In one embodiment of the present invention, the anti-PD-1 antibody is toripalimab.

[0063] In one embodiment of the present invention, the anti-PD-1 antibody is pembrolizumab.

[0064] In one embodiment of the invention, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor is an anti-CTLA-4 antibody, and in one embodiment of the invention, the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.

[0065] In one embodiment of the invention, 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.

[0066] In one embodiment of the present invention, the anti-CTLA-4 antibody is ipilimumab.

[0067] In one embodiment of the present invention, the platelet-derived growth factor receptor alpha (PDGFR-α) inhibitor is an anti-PDGFRα antibody. In one embodiment of the present invention, the anti-PDGFRα antibody is an anti-PDGFRα monoclonal antibody.

[0068] In one embodiment of the present invention, the anti-PDGFRα antibody is olaratumab.

[0069] In one embodiment of the present invention, the antibody drug may also include, but is not limited to, any one or more of bevacizumab, ramucirumab, pertuzumab, trastuzumab, cetuximab (Cotuximab), nimotuzumab, panitumumab, necitumumab, dinutuximab, rituximab, ibritumomab, ofatumumab, obinutuzumab, alemtuzumab, daratumumab, gemtuzumab, elotuzumab, brentuximab, inotuzumab ozogamicin, and blinatumomab.

[0070] In one embodiment of the present invention, 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.

[0071] In one embodiment of the present invention, if a second therapeutic agent is used, the amount of the second therapeutic agent can be adjusted as desired by one skilled in the art.

[0072] The present invention also provides the use of flumonertinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing a disease mediated by PACC mutations.

[0073] The present invention also provides the use of flumonertinib, or a pharmaceutically acceptable salt thereof, in combination with at least one second therapeutic agent in the manufacture of a medicament for treating and / or preventing a disease mediated by PACC mutations.

[0074] The present invention also provides the use of the pharmaceutical composition described above in the manufacture of a medicament for treating and / or preventing a disease mediated by PACC mutations.

[0075] In one embodiment of the present invention, in the above uses of the present invention, the pharmaceutically acceptable salt of flumonertinib is a mesylate salt of flumonertinib (ie, flumonertinib mesylate).

[0076] In one embodiment of the present invention, in the above-mentioned uses of the present invention, the pharmaceutical composition of the present invention is in the dosage form of a tablet or capsule.

[0077] In one embodiment of the present invention, in the above-mentioned use of the present invention, the content of the flumonertinib or a pharmaceutically acceptable salt thereof per unit dosage form (e.g., tablet or capsule) as described above is 10 mg to 400 mg, preferably 20 mg to 320 mg. The specific content may be, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg. Preferably, the specific content may be 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg, preferably 40 mg or 80 mg, most preferably 40 mg.

[0078] In one embodiment of the present invention, in the above-mentioned use of the present invention, the content of flumonertinib or a pharmaceutically acceptable salt thereof in the above-mentioned 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. A preferred content may be 80 mg, 160 mg, 240 mg or 320 mg, more preferably 80 mg, 160 mg or 240 mg, most preferably 240 mg.

[0079] In one embodiment of the present invention, in the above-mentioned use of the present invention, the pharmaceutical composition is administered to a patient so that the dose of flumonertinib or a pharmaceutically acceptable salt thereof is 80 mg to 400 mg. Specific doses may be, 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. Preferred doses may be 80 mg, 160 mg, 240 mg or 320 mg, more preferably 80 mg, 160 mg or 240 mg, most preferably 240 mg. In one embodiment of the present invention, the dose is a daily dose.

[0080] In other words, in the above-mentioned use of the present invention, the content of flumonertinib or its pharmaceutically acceptable salt in the pharmaceutical composition refers to the total amount of flumonertinib or its pharmaceutically acceptable salt in the pharmaceutical composition that is ingested by the patient when the pharmaceutical composition is administered to the patient.For example, when the pharmaceutical composition is in the form of a tablet or capsule, the content of flumonertinib or its pharmaceutically acceptable salt in the pharmaceutical composition refers to the total amount of flumonertinib or its pharmaceutically acceptable salt in all of the tablet or capsule formulations when the formulation is administered.

[0081] In the use described herein, those skilled in the art will understand that when administered to patients, the daily dose of flumonertinib or its pharmaceutically acceptable salt is equal to or greater than the content of flumonertinib or its pharmaceutically acceptable salt in each unit preparation.Those skilled in the art can calculate the total amount of flumonertinib or its pharmaceutically acceptable salt that needs to be administered per day based on the daily dose of flumonertinib or its pharmaceutically acceptable salt and the content of flumonertinib or its pharmaceutically acceptable salt in each unit preparation.For example, if flumonertinib or its pharmaceutically acceptable salt is contained in tablets, and the content of flumonertinib or its pharmaceutically acceptable salt in each unit preparation (each tablet) is 40mg, and the daily dose of flumonertinib or its pharmaceutically acceptable salt is 240mg, then the total amount of flumonertinib or its pharmaceutically acceptable salt that needs to be administered per day is 6 tablets.

[0082] In one embodiment of the present invention, the disease mediated by PACC mutations is cancer (eg, lung cancer), and further the disease can be non-small cell lung cancer (NSCLC).

[0083] In one embodiment of the present invention, the disease mediated by PACC mutations is locally advanced or metastatic non-small cell lung cancer.

[0084] In one embodiment of the present invention, the disease mediated by PACC mutations is untreated or previously treated non-small cell lung cancer.

[0085] As used herein, the term "naive" refers to a state in which, before receiving treatment with flumonertinib of the present invention or a pharmaceutically acceptable salt thereof, no treatment with another therapeutic agent (including, but not limited to, a chemotherapeutic agent, a targeted anti-tumor agent, an antibody drug, or an immunotherapeutic agent) has been used, or no systemic anti-tumor therapy has been received. The term "previously treated" refers to a state in which, before receiving treatment with flumonertinib of the present invention or a pharmaceutically acceptable salt thereof, a treatment with another therapeutic agent (including, but not limited to, a chemotherapeutic agent, a targeted anti-tumor agent, an antibody drug, or an immunotherapeutic agent) has been used, or a systemic anti-tumor therapy has been received, but the disease has progressed since then. In the case of a "previously treated" case, the patient may or may not have developed resistance to the other therapeutic agent.

[0086] In one embodiment of the present invention, the PACC mutation is at least one selected from the group consisting of an EGFR-G719S mutation, an EGFR-S768I mutation, an EGFR-G724S mutation, an EGFR-L718Q mutation, an EGFR-Del19 / G724S mutation, an EGFR-E709H mutation, an EGFR-L747S mutation, an EGFR-E709V mutation, an EGFR-L747V mutation, an EGFR-E709-710>D mutation, an EGFR-E709A mutation, an EGFR-Del19 / C797S mutation, an EGFR-L858R / C797S mutation, an EGFR-L747S / G719A mutation, an EGFR-L858R-L718V mutation, an EGFR-L858R-L718Q mutation, an EGFR-E709K-G719A mutation, and an EGFR-L861Q mutation.

[0087] In one embodiment of the present invention, the PACC mutation is an EGFR-G719S mutation, an EGFR-S768I mutation, an EGFR-G724S mutation, an EGFR-L718Q mutation, an EGFR-Del19 / G724S mutation, an EGFR-E709H mutation, an EGFR-L747S mutation, an EGFR-E709V mutation, an EGFR-L747V mutation, an EGFR-E709-710>D mutation, an EGFR-E709A mutation, The mutation is at least one selected from the group consisting of EGFR-Del19 / C797S mutation, EGFR-L858R / C797S mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-L858R-L718Q mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation, and EGFR-L861Q mutation.

[0088] In one embodiment of the present invention, the PACC mutation is at least one selected from the group consisting of an EGFR-G719S mutation, an EGFR-S768I mutation, an EGFR-G724S mutation, an EGFR-Del19 / G724S mutation, an EGFR-E709H mutation, an EGFR-L747S mutation, an EGFR-E709V mutation, an EGFR-L747V mutation, an EGFR-E709-710>D mutation, an EGFR-E709A mutation, an EGFR-L747S / G719A mutation, an EGFR-L858R-L718V mutation, an EGFR-E709K-G719A mutation, and an EGFR-L861Q mutation.

[0089] In one embodiment of the present invention, the PACC mutation is at least one selected from the group consisting of an EGFR-G719S mutation, an EGFR-S768I mutation, an EGFR-G724S mutation, an EGFR-Del19 / G724S mutation, an EGFR-E709H mutation, an EGFR-L747S mutation, an EGFR-E709V mutation, an EGFR-L747V mutation, an EGFR-E709-710>D mutation, an EGFR-E709A mutation, an EGFR-L747S / G719A mutation, an EGFR-L858R-L718V mutation, an EGFR-E709K-G719A mutation, an EGFR-G719A mutation, an EGFR-V769L mutation, and an EGFR-L861Q mutation.

[0090] In one embodiment of the present invention, for the uses described herein, the pharmaceutical composition may further comprise at least one second therapeutic agent.

[0091] In the uses described herein, the second therapeutic agent may be selected from a chemotherapeutic agent, a targeted anti-tumor agent, an antibody agent, and an immunotherapeutic agent.

[0092] In the uses described herein, the second therapeutic agent is a second therapeutic agent of the invention as described above.

[0093] The present invention provides a method for treating and / or preventing a disease mediated by a PACC mutation, the method comprising administering to a patient a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

[0094] The present invention provides a method for treating and / or preventing disease, which method comprises administering to a patient with a positive PACC mutation a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

[0095] The present invention provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

[0096] The present invention provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof to a patient confirmed to be PACC mutation-positive.

[0097] The present invention provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof to a patient harboring a PACC mutation.

[0098] The present invention provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof to a patient with a confirmed positive PACC mutation who has not received any prior systemic anti-tumor therapy.

[0099] The present invention provides a method for treating locally advanced or metastatic non-small cell lung cancer, the method comprising administering a therapeutically effective amount of flumonertinib, or a pharmaceutically acceptable salt thereof, to a patient with a confirmed positive PACC mutation who has progressive disease after receiving prior systemic anti-tumor therapy.

[0100] In the above-mentioned treatment method of the present invention, the flumonertinib or its pharmaceutically acceptable salt is administered at a dose of 80 mg to 400 mg. Specific doses may be, 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. Preferred doses may be 80 mg, 160 mg, 240 mg or 320 mg, more preferably 80 mg, 160 mg or 240 mg, most preferably 240 mg. In one embodiment of the present invention, the dose is a daily dose.

[0101] In the above-mentioned treatment method of the present invention, flumonertinib or a pharmaceutically acceptable salt thereof is administered to the patient once a day (qd), twice a day (bid), or three times a day (tid), preferably once a day.

[0102] In the above-mentioned treatment methods of the present invention, flumonertinib or a pharmaceutically acceptable salt thereof is administered to a patient under fasting conditions (preferably in the morning under fasting conditions).

[0103] In the above treatment methods of the present invention, flumonertinib or a pharmaceutically acceptable salt thereof is orally administered to the patient.

[0104] In the above treatment methods of the present invention, flumonertinib mesylate is administered to the patient.

[0105] In the above-mentioned treatment methods of the present invention, flumonertinib or a pharmaceutically acceptable salt thereof is administered in the form of a tablet or capsule.

[0106] In the above-mentioned treatment method of the present invention, flumonertinib or its pharmaceutically acceptable salt is administered to the patient in the form of a dosage unit.By adjusting the amount of the dosage unit, the daily dose of flumonertinib or its pharmaceutically acceptable salt is within the above-mentioned range.

[0107] In the above-mentioned treatment method of the present invention, the content of the above-mentioned flumonertinib or a pharmaceutically acceptable salt thereof in each unit preparation (for example, tablet or capsule) is 10 mg to 400 mg, preferably 20 mg to 320 mg. The specific content may be, for example, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg. Preferably, the specific content may be 20 mg, 40 mg, 80 mg, 160 mg, 240 mg or 320 mg, more preferably 40 mg or 80 mg, most preferably 40 mg.

[0108] Those skilled in the art will understand that when administered to patients, the daily dose of flumonertinib or its pharmaceutically acceptable salt is equal to or greater than the total amount of flumonertinib or its pharmaceutically acceptable salt in each unit preparation.Those skilled in the art can calculate the total amount of its preparation that needs to be administered per day based on the daily dose of flumonertinib or its pharmaceutically acceptable salt and the content of flumonertinib or its pharmaceutically acceptable salt in each unit preparation.For example, if flumonertinib or its pharmaceutically acceptable salt is contained in tablets, and the content of flumonertinib or its pharmaceutically acceptable salt in each unit preparation (each tablet) is 40mg, and the daily dose of flumonertinib or its pharmaceutically acceptable salt is 240mg, then the total amount of its preparation (tablet) that needs to be administered per day is 6 tablets.

[0109] In the treatment method of the present invention, at least one second therapeutic agent may be further administered to the patient, which may be selected from chemotherapeutic agents, targeted anti-tumor agents, antibody agents, and immunotherapeutic agents.

[0110] In the above treatment methods of the present invention, the second therapeutic agent is the above second therapeutic agent of the present invention.

[0111] In the above treatment methods of the present invention, the disease is cancer (for example, lung cancer), and further the disease can be non-small cell lung cancer (NSCLC).

[0112] In the above treatment methods of the present invention, flumonertinib or a pharmaceutically acceptable salt thereof is administered to the patient before or after surgical resection of the tumor.

[0113] In the above treatment method of the present invention, the disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

[0114] In the above treatment methods of the present invention, the disease is untreated or previously treated non-small cell lung cancer.

[0115] In the above-mentioned treatment methods of the present invention, the PACC mutation is at least one selected from the group consisting of EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-L718Q mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation, EGFR-Del19 / C797S mutation, EGFR-L858R / C797S mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-L858R-L718Q mutation, EGFR-E709K-G719A mutation, and EGFR-L861Q mutation.

[0116] In the above-mentioned treatment method of the present invention, the PACC mutation is EGFR-G719S mutation, EGFR-S768I mutation, EGFR-G724S mutation, EGFR-L718Q mutation, EGFR-Del19 / G724S mutation, EGFR-E709H mutation, EGFR-L747S mutation, EGFR-E709V mutation, EGFR-L747V mutation, EGFR-E709-710>D mutation, EGFR-E709A mutation. , EGFR-Del19 / C797S mutation, EGFR-L858R / C797S mutation, EGFR-L747S / G719A mutation, EGFR-L858R-L718V mutation, EGFR-L858R-L718Q mutation, EGFR-E709K-G719A mutation, EGFR-G719A mutation, EGFR-V769L mutation, and EGFR-L861Q mutation.

[0117] In one embodiment of the present invention, the PACC mutation is at least one selected from the group consisting of an EGFR-G719S mutation, an EGFR-S768I mutation, an EGFR-G724S mutation, an EGFR-Del19 / G724S mutation, an EGFR-E709H mutation, an EGFR-L747S mutation, an EGFR-E709V mutation, an EGFR-L747V mutation, an EGFR-E709-710>D mutation, an EGFR-E709A mutation, an EGFR-L747S / G719A mutation, an EGFR-L858R-L718V mutation, an EGFR-E709K-G719A mutation, and an EGFR-L861Q mutation.

[0118] In one embodiment of the present invention, the PACC mutation is at least one selected from the group consisting of an EGFR-G719S mutation, an EGFR-S768I mutation, an EGFR-G724S mutation, an EGFR-Del19 / G724S mutation, an EGFR-E709H mutation, an EGFR-L747S mutation, an EGFR-E709V mutation, an EGFR-L747V mutation, an EGFR-E709-710>D mutation, an EGFR-E709A mutation, an EGFR-L747S / G719A mutation, an EGFR-L858R-L718V mutation, an EGFR-E709K-G719A mutation, an EGFR-G719A mutation, an EGFR-V769L mutation, and an EGFR-L861Q mutation.

[0119] In the above treatment methods of the present invention, the patient is a human patient.

[0120] In the above treatment method of the present invention, the patient is between 18 and 75 years old.

[0121] In the above treatment methods of the present invention, the patient has histologically or cytopathologically confirmed primary non-small cell lung cancer (NSCLC) with predominantly non-squamous cell histology prior to the initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0122] In the above treatment methods of the present invention, the patient has radiological disease progression after the last anti-tumor therapy before initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0123] In the above treatment methods of the present invention, the patient has a documented positive PACC mutation by laboratory testing prior to the initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0124] In the above-mentioned treatment methods of the present invention, the patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer and has been confirmed to have radiological disease progression or pathological disease progression during or after the last systemic anti-tumor therapy before the start of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0125] In the above treatment methods of the present invention, the patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer and has not received any prior systemic anti-tumor therapy before the start of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0126] In the above treatment methods of the present invention, the patient has at least one measurable lesion prior to the initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0127] In the above treatment methods of the present invention, the patient has sufficient organ function as shown by laboratory tests before initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0128] In the above-mentioned treatment method of the present invention, the patient is subjected to an ECOG PS (Eastern Cooperative Oncology Group Performance Status) score test (e.g., ECOG PS score of 0 to 1) before the start of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0129] The treatment methods of the present invention have an acceptable safety profile.

[0130] The treatment method of the present invention can provide a partial response (PR) therapeutic effect.

[0131] The treatment method of the present invention can provide a therapeutic effect for stable disease (SD).

[0132] The treatment methods of the present invention can provide tumor shrinkage in target lesions.

[0133] In the above treatment methods of the present invention, tumor shrinkage is provided in the target lesion as assessed by radiological tumor examination, such as computed tomography (CT) and / or magnetic resonance imaging (MRI). [Brief explanation of the drawings]

[0134] [Figure 1] FIG. 1: Curve of tumor volume change in Test Example 2. [Figure 2] FIG. 2: Curve of body weight change in Test Example 2. [Example]

[0135] I. PREPARATION EXAMPLES (Preparation of flumonertinib mesylate (40 mg, standard tablet)) Formulation: Flumonertinib 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 stearyl fumarate 2.7 mg, sodium chloride 8.67 mg, and 40 mg of flumonertinib. Process: The adjuvants and the above active pharmaceutical ingredients are sieved for pre-treatment, mixed uniformly, added with an appropriate amount of polyethylene glycol 4000 for wet granulation, sieved for wet granulation, the wet granules are dried, sieved for granulation, added with colloidal silica and sodium stearyl fumarate and mixed uniformly, and then tableted to obtain tablets.

[0136] II. Active Examples Test Example 1: Evaluation of the antiproliferative effect of flumonertinib mesylate on 18 cell lines The purpose of Test Example 1 was to demonstrate the viability of 18 cell lines (Ba / F3 EGFR-G719S, Ba / F3 EGFR-S768I, Ba / F3 EGFR-G724S, Ba / F3 EGFR-L718Q, Ba / F3 EGFR-Del19 / G724S, Ba / F3 EGFR-E709H, Ba / F3 EGFR-L747S, Ba / F3 EGFR-E709V, Ba / F3 EGFR-L747V, Ba / F3 EGFR-E709-710>D, Ba / F3 EGFR-E709A, Ba / F3 EGFR-Del19 / C797S, Ba / F3 EGFR-L858R / C797S, Ba / F3 The objective of this study was to evaluate the antiproliferative effects of flumonertinib mesylate on Ba / F3-EGFR-L747S / G719A, Ba / F3-EGFR-L858R-L718V, Ba / F3-EGFR-L858R-L718Q, Ba / F3-EGFR-E709K-G719A, and Ba / F3-EGFR-L861Q. Additionally, AZD9291 was used as a control compound. Cell culture: Ba / F3 EGFR-G719S, Ba / F3 EGFR-S768I, Ba / F3 EGFR-G724S, Ba / F3 EGFR-L718Q, Ba / F3 EGFR-Del19 / G724S, Ba / F3 EGFR-E709H, Ba / F3 EGFR-L747S, Ba / F3 EGFR-E709V, Ba / F3 EGFR-L747V, Ba / F3 EGFR-E709-710>D, Ba / F3 EGFR-E709A, Ba / F3 EGFR-Del19 / C797S, Ba / F3 EGFR-L858R / C797S, Ba / F3 EGFR-L747S / G719A, Ba / F3-EGFR-L858R-L718V, Ba / F3-EGFR-L858R-L718Q, Ba / F3-EGFR-E709K-G719A, and Ba / F3 EGFR-L861Q engineered cells were obtained from Kyinno and maintained in RPMI1640 medium supplemented with 10% fetal bovine serum at 37°C with 5% CO . Cells in the logarithmic growth phase were harvested and counted using a hemocytometer. Cell viability was greater than 90% as determined by trypan blue assay. Cell concentration was adjusted with culture medium. 90 μl of cell suspension was added to two 96-well plates to obtain a final cell density of 3,000 cells per well. Plates were incubated in a humidified incubator at 37°C with 5% CO2. The solutions of the tested compounds (flumonertinib mesylate and AZD9291) were diluted 1000-fold with DMSO. The DMSO solution was then diluted 100-fold with PBS (phosphate-buffered saline) to obtain a 10x working solution. A 10x reference control solution was then prepared with phosphate-buffered saline (PBS). 10 μl of the working solution (10x) was distributed to each well (three for each concentration). (The highest concentration was 3160 nM, with 3.16-fold dilutions and 10 different concentrations. The final concentration of DMSO in the culture medium was 0.1% [v / v].) The plates were incubated for 3 days. On day 3, CellTiter-Glo® reagent (luciferase ATP bioluminescence detection reagent) was thawed, and the cell plate was then equilibrated at room temperature for approximately 30 minutes. 100 μl of CellTiter-Glo® reagent, equal to the volume of cell culture medium present in each well, was added. The resulting contents were mixed on an orbital shaker for 5 minutes to induce cell lysis. The cell plate was incubated at room temperature for 20 minutes to stabilize the luminescence signal. Luminescence was recorded using a Multi-mode Microplate Reader.

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[0137] Test Example 2: Testing the antitumor effect of flumonertinib mesylate in a Ba / F3 EGFR-G724S (KC-1385) cell xenograft model in female immunodeficient mice This study was used to evaluate the antitumor efficacy of flumonertinib mesylate in female (B-NDG) immunodeficient mice bearing tumors of Ba / F3 EGFR-G724S engineered cells. Experimental animals: B-NDG mice, female, 6-8 weeks old, weighing 18-20g. Animal modeling and randomization: Ba / F3 EGFR-G724S cells were cultured, harvested, resuspended in serum-free medium, counted, and resuspended in 1:1 Matrigel medium. 1 × 10 cells were injected into B-NDG mice. 6 The cells were subcutaneously inoculated at 0.1 mL per 1000 cells. The average tumor volume was approximately 80 mm 3 ~approx. 120mm 3 When the animals were in the 3rd year of life, they were randomly assigned to four experimental groups according to tumor size. Each group contained 12 mice. The day of assignment was defined as day 0 (i.e., D0). Experimental scheme: B-NDG mice were subcutaneously inoculated with Ba / F3 EGFR-G724S cells to establish a cell line-derived xenograft model. The experiment was divided into a 15 mg / kg flumonertinib mesylate group, a 30 mg / kg flumonertinib mesylate group, a 50 mg / kg flumonertinib mesylate group, and a vehicle group. Each group contained 12 animals, and they were orally administered with a dose volume of 10 μL / g. The vehicle group was administered with the same amount of vehicle, and the administration was carried out once daily for 2 weeks. During the entire experiment, the body weight and tumor size of the mice were measured twice a week, regardless of whether toxic reactions were observed. Tumor volume (TV) is TV = 0.5 × a × b 2 where a was the longest diameter of the tumor and b was the shortest diameter of the tumor. The curves for the changes in tumor volume for the four experimental groups are shown in FIG. 1, and the curves for the changes in body weight for the four experimental groups are shown in FIG. In summary, 15 mg / kg flumonertinib mesylate produced moderate antitumor activity; 30 mg / kg flumonertinib mesylate and 50 mg / kg flumonertinib mesylate produced highly significant antitumor activity, and the three flumonertinib mesylate groups had less effect on mouse body weight and showed good safety.

[0138] Test Example 3: Clinical Trial We designed and conducted an open-label, multicenter, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics (PK), and preliminary antitumor activity of flumonertinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring activating (including rare) epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) mutations. The first stage of the study included a dose-escalation segment evaluating once-daily dosing of flumonertinib, starting at 240 mg daily, with subsequent patient cohorts receiving higher or lower doses of flumonertinib, and then, if necessary, expansion cohorts in defined patient groups receiving flumonertinib at 240 mg daily (and 160 mg for EGFR PACC-mutant NSCLC). General registration criteria include: 1) Histologically or cytologically proven locally advanced or metastatic non-small cell lung cancer (NSCLC) that is not amenable to curative surgery or radiotherapy; 2) Disease has progressed after at least one available standard therapy; or standard therapy has proven ineffective or intolerable; or clinical trials of investigational drugs are the accepted standard of care; 3) documented radiological disease progression during or after the last systemic anticancer therapy prior to the first flumonertinib administration; 4) For patients with epidermal growth factor receptor (EGFR) mutations that are sensitive to osimertinib, patients must have received osimertinib prior to study enrollment in regions where osimertinib is approved (including the United States). Exclusion criteria included: 1) Treatment with chemotherapy, targeted therapy, biologic therapy, or investigational drug as anticancer therapy within 3 or 5 elimination half-lives (whichever is shorter) prior to initiation of flumonertinib; 2) Radiotherapy as cancer therapy within 4 weeks prior to initiation of flumonertinib; 3) Palliative radiation therapy for bone metastases within 2 weeks prior to initiation of flumonertinib; 4) AEs from prior anticancer therapy that have not resolved to Grade 1 or less, excluding alopecia or peripheral neuropathy of Grade 2 or less. Preliminary data from a clinical trial evaluating flumonertinib (240 mg QD and 160 mg QD) in NSCLC patients with EGFR PACC mutations who had not previously received any TKI treatment demonstrated a reduction in tumor size and clinical activity. Preliminary tumor assessment data from three PACC patients are listed in Table 2 below. [Table 2] [Industrial Applicability]

[0139] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof, optionally with a pharmaceutically acceptable carrier; the use of flumonertinib or a pharmaceutically acceptable salt thereof and the pharmaceutical composition in the manufacture of a medicament for treating and / or preventing a disease mediated by PACC mutation.The present invention also provides a method for treating and / or preventing a disease mediated by PACC mutation, in which a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof is administered to a patient.The pharmaceutical composition of the present invention shows excellent therapeutic effect against a disease mediated by PACC mutation (e.g., non-small cell lung cancer (NSCLC)) with little side effects and excellent safety.

Claims

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

2. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is a mesylate salt.

3. The pharmaceutical composition according to claim 1 or 2, wherein the content of flumonertinib 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 to 3, wherein the content of flumonertinib or a pharmaceutically acceptable salt thereof is 80 mg, 160 mg, 240 mg, or 320 mg.

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

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

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

8. The pharmaceutical composition according to any one of claims 1 to 7, which is in the form of a tablet or capsule.

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

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

12. The pharmaceutical composition according to any one of claims 8 to 11, wherein the content of flumonertinib or a pharmaceutically acceptable salt thereof in each unit dosage form of the pharmaceutical composition is 40 mg. 。

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

14. 14. The pharmaceutical composition of claim 13, wherein the second therapeutic agent is selected from a chemotherapeutic agent, a targeted anti-tumor agent, an antibody agent, and an immunotherapeutic agent.

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

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

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

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

19. The use according to claim 15, wherein the content of flumonertinib 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.

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

21. The use according to any one of claims 15 and 19 to 20, wherein the content of flumonertinib or a pharmaceutically acceptable salt thereof is 80 mg.

22. The use according to any one of claims 15 and 19 to 20, wherein the content of flumonertinib or a pharmaceutically acceptable salt thereof is 160 mg.

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

24. The use according to any one of claims 15 and 19 to 23, wherein the pharmaceutical composition is in the form of a tablet or capsule.

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

26. The use according to claim 24 or 25, wherein the content of flumonertinib or a pharmaceutically acceptable salt thereof in each unit dosage form is 20 mg to 320 mg.

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

28. The use according to any one of claims 24 to 27, wherein the content of flumonertinib or a pharmaceutically acceptable salt thereof in each unit dosage form is 40 mg.

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

30. 30. The use of claim 17 or 29, wherein the second therapeutic agent is selected from a chemotherapeutic agent, a targeted anti-tumor agent, an antibody agent, and an immunotherapeutic agent.

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

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

33. The use according to any one of claims 15 to 31, wherein the disease is untreated or previously treated non-small cell lung cancer.

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

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

36. A method for treating and / or preventing a disease mediated by a PACC mutation, comprising administering to a patient a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

37. A method for treating and / or preventing a disease, comprising administering a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof to a patient with a positive PACC mutation.

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

39. A method for treating locally advanced or metastatic non-small cell lung cancer, comprising administering a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof to a patient with a confirmed positive PACC mutation.

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

41. A method for treating locally advanced or metastatic non-small cell lung cancer, comprising administering a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof to a patient with a confirmed positive PACC mutation who has not received any prior systemic anti-tumor therapy.

42. A method for treating locally advanced or metastatic non-small cell lung cancer, comprising administering a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof to a patient with a confirmed positive PACC mutation who has progressive disease after receiving prior systemic anti-tumor therapy.

43. 43. The method of any one of claims 36 to 42, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof at a dose of 80 mg to 400 mg, e.g., 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg.

44. 44. The method of any one of claims 36 to 43, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof at a dose of 80 mg, 160 mg, 240 mg or 320 mg.

45. 45. The method of any one of claims 36 to 44, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof at a dose of 80 mg.

46. 45. The method of any one of claims 36 to 44, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof at a dose of 160 mg.

47. 45. The method of any one of claims 36 to 44, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof at a dose of 240 mg.

48. 48. The method of any one of claims 36 to 47, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof once daily, twice daily, or three times daily.

49. 49. The method of any one of claims 36 to 48, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof to said patient once daily.

50. 50. The method of any one of claims 36 to 49, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof to said patient under fasting conditions.

51. 51. The method of any one of claims 36 to 50, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof to said patient in the morning under fasting conditions.

52. 52. The method of any one of claims 36 to 51, comprising orally administering to said patient flumonertinib or a pharmaceutically acceptable salt thereof.

53. 53. The method of any one of claims 36 to 52, comprising administering to the patient flumonertinib mesylate.

54. 54. The method of any one of claims 36 to 53, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof in the form of a tablet or capsule.

55. 55. The method of any one of claims 36 to 54, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof in a unit dosage form.

56. 56. The method of claim 55, wherein the unit dosage form contains 10 mg to 400 mg, e.g., 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 flumonertinib or a pharmaceutically acceptable salt thereof.

57. 57. The method of claim 55 or claim 56, wherein the unit dosage form comprises 20 mg to 320 mg of flumonertinib or a pharmaceutically acceptable salt thereof.

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

59. 59. The method of any one of claims 55 to 58, wherein the unit dosage form comprises 40 mg of flumonertinib or a pharmaceutically acceptable salt thereof.

60. 60. The method of any one of claims 36 to 59, further comprising administering at least one second therapeutic agent.

61. 61. The method of claim 60, wherein the second therapeutic agent is selected from a chemotherapeutic agent, a targeted anti-tumor agent, an antibody agent, and an immunotherapeutic agent.

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

63. 63. The method of any one of claims 36 to 62, comprising administering flumonertinib or a pharmaceutically acceptable salt thereof to said patient before or after surgical resection of a tumor.

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

65. 64. The method of any one of claims 36 to 63, wherein the disease is untreated or previously treated non-small cell lung cancer.

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

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

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

69. 69. The method of any one of claims 36 to 68, wherein the patient is between 18 and 75 years of age.

70. The method of any one of claims 36 to 69, wherein the patient has histologically or cytopathologically confirmed primary non-small cell lung cancer (NSCLC) with predominant non-squamous cell histology prior to initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

71. The method of any one of claims 36 to 70, wherein the patient has radiological disease progression after the last anti-tumor therapy before initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

72. The method of any one of claims 36 to 71, wherein the patient has a documented positive PACC mutation by laboratory testing prior to initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

73. The method of any one of claims 36 to 72, wherein the patient has locally advanced or metastatic NSCLC and has been confirmed to have radiological or pathological disease progression during or after the last systemic anti-tumor therapy prior to initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

74. The method of any one of claims 36 to 73, wherein the patient has locally advanced or metastatic NSCLC and has not received any prior systemic anti-tumor therapy prior to initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

75. The method of any one of claims 36 to 74, wherein the patient has at least one measurable lesion prior to initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

76. 76. The method of any one of claims 36 to 75, wherein the patient has adequate organ function as shown by laboratory tests prior to initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

77. The method of any one of claims 36 to 76, wherein the patient has an ECOG PS (Eastern Cooperative Oncology Group Performance Status) score of 0 to 1 before initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

78. 78. The method of any one of claims 36 to 77, having an acceptable safety profile.

79. 79. The method of any one of claims 36 to 78, which provides a partial response (PR).

80. 79. The method of any one of claims 36 to 78, which provides stability (SD).

81. 81. The method of any one of claims 36 to 80, which provides tumor shrinkage in target lesions.

82. 82. The method of any one of claims 36 to 81, which provides tumor shrinkage in the target lesion as assessed by radiological tumor examination, for example computed tomography (CT) and / or magnetic resonance imaging (MRI).

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