Pharmaceutical compositions and uses thereof

Abstract

The present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of fulmonertinib or a pharma- ceutical acceptable salt thereof, and optionally a pharma- ceutical acceptable carrier, and the use of fulmonertinib or a pharma- ceutical acceptable salt thereof, or the pharmaceutical composition, in the manufacture of a medicament for treating and / or preventing diseases mediated by HER2 exon 20 insertion mutation and / or EGFR rare mutation.The pharmaceutical composition of the present disclosure shows excellent therapeutic effect against diseases mediated by HER2 exon 20 insertion mutation and / or EGFR rare 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 fulmonertinib or a pharma- ceutically acceptable salt thereof, and said pharmaceutical composition, in the manufacture of a medicament for treating and / or preventing diseases mediated by human epidermal growth factor receptor 2 (HER2) exon 20 insertion (HER2 exon 20 insertion) mutations (hereinafter sometimes referred to as HER2 exon 20 insertion mutations) and / or epidermal growth factor receptor (EGFR) rare mutations (hereinafter sometimes referred to as EGFR rare mutations). The present disclosure also provides a method for treating and / or preventing diseases mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations, comprising administering to a patient a therapeutically effective amount of fulmonertinib or a pharma- ceutically acceptable salt thereof. [Background technology]

[0002] (Background technology) Worldwide, lung cancer is the malignant tumor with the highest morbidity and mortality rate at any given time, a serious harm to human health and life, and 1.76 million people died 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) is a multifunctional glycoprotein widely distributed on the cell membrane of various tissues in the human body, and it is a member of the ERBB receptor family, which includes four members: EGFR (HER1 or ERBB1), HER2 (ERBB2), HER3 (ERBB3) and HER4 (ERBB4). EGFR mutations are the most widely studied target in NSCLC.

[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), drug resistance mutations (e.g., exon 20 T790M mutation, exon 20 C797S mutation), etc.; rare mutations include EGFR G719S mutation, EGFR S768I mutation, EGFR G724S mutation, EGFR L861Q mutation, EGFR G719S / T263P mutation, etc.; in addition, EGFR mutations also include EGFR exon 20 insertion mutations (which account for approximately 1%-10% of all types of EGFR mutations).

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

[0005] HER2, another member of the ERBB family, is amplified and mutated in various cancers. Among them, HER2 mutations constitute about 4% in NSCLC, and about 90% of HER2 mutations are exon 20 insertion mutations. Exon 20 of HER2 contains two major regions, the c-helix (residues 770-774) and the loop behind the c-helix (residues 775-783 in HER2). The most common HER2 exon 20 insertion mutation is the ERBB2 A775_G776insYVMA mutation, and less common HER2 exon 20 insertion mutations are the ERBB2 V777_G778insGC mutation, ERBB2 P780_Y781insGSP mutation, etc. Exon 20 insertion mutations result in increased HER2 kinase activity and enhanced signaling through downstream pathways, thereby resulting in increased survival, invasiveness, and tumorigenicity. Tumors with ERBB2 A775_G776insYVMA mutations are substantially resistant to known EGFR inhibitors. Currently, no small molecule targeted drugs against HER2 exon 20 insertion mutations are approved worldwide.

[0006] In recent years, compounds that inhibit EGFR mutations and / or HER2 mutations (especially HER2 exon 20 insertion mutations) have been extensively studied. However, how to further improve their activity and reduce their toxic effects and side effects remains an ongoing problem.

[0007] 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 called "furmonertinib") represented by the following formula (I) is described in patent CN105315259B, and mesylate of the compound represented by the following formula (I) (also called "furmonertinib mesilate") is described in patent CN107163026B, and fulmonertinib mesilate 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. A phase I dose-escalation study of flumonertinib mesylate showed that when flumonertinib mesylate was taken orally once daily at dose levels of 20 mg to 240 mg, its tolerability and safety were good, the adverse events of interest were mild or moderate, no dose-limiting toxicities occurred, and no dose-related toxic reactions occurred; a phase IIb clinical trial showed that oral administration of flumonertinib mesylate at a daily dose of 80 mg showed relatively good antitumor effects in patients with EGFR T790M-positive advanced non-small cell lung cancer (with progressive disease after receiving prior systematic antitumor therapy) and could reduce or stabilize their disease progression. [ka] [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Chinese Patent No. 105315259 [Patent Document 2] Chinese Patent No. 107163026 Summary of the Invention [Means for solving the problem]

[0009] (overview) The present disclosure provides, in some embodiments, the use of flumonertinib or a pharma- ceutically acceptable salt thereof.

[0010] In some embodiments, flumonertinib or a pharma- ceutically acceptable salt thereof as an active compound can effectively inhibit HER2 exon 20 insertion mutations and / or EGFR rare mutations, and thus flumonertinib or a pharma- ceutically acceptable salt thereof can be used to treat and / or prevent diseases mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations.

[0011] Thus, in some embodiments, the present disclosure provides the use of flumonertinib or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating and / or preventing a disease mediated by a HER2 exon 20 insertion mutation and / or an EGFR rare mutation.

[0012] In some embodiments, the present disclosure provides the use of flumonertinib, or a pharma- ceutically 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 HER2 exon 20 insertion mutations and / or EGFR rare mutations.

[0013] In some embodiments, flumonertinib or a pharma- ceutically acceptable salt thereof is useful as an active compound at a particular dosage, and can treat and / or prevent diseases mediated by HER2 exon 20 insertion mutations and / or EGFR rare 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.

[0014] More particularly, 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.

[0015] The present disclosure also provides the use of the above pharmaceutical composition of the present disclosure in the manufacture of a medicament for treating and / or preventing a disease mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations.

[0016] The composition of the present disclosure is in the form of tablets or capsules, and each unit dosage form contains 10 mg to 400 mg of flumonertinib or a pharma- ceutically acceptable salt thereof.

[0017] When the pharmaceutical composition of the present disclosure is used to treat and / or prevent diseases mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations, the daily dose of fulmonertinib or its pharmaceutically acceptable salt can be 80mg-400mg. At present, the daily dose of fulmonertinib or its pharmaceutically acceptable salt can be easily adjusted by adjusting the amount of the above tablets or capsules.

[0018] The present disclosure also provides a method for treating and / or preventing a disease mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations, the method comprising administering to a patient in need thereof a therapeutically effective amount of flumonertinib or a pharma- ceutically acceptable salt thereof.

[0019] In the above treatment methods of the present disclosure, the daily dose of flumonertinib or a pharma- ceutically acceptable salt thereof is desirably 80 mg to 400 mg.

[0020] The present disclosure also provides a method for treating and / or preventing a disease, the method comprising administering a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof to a patient with a positive HER2 exon 20 insertion mutation and / or an EGFR rare mutation.

[0021] The present disclosure also provides a method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC), the method comprising administering to a patient in need thereof a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof.

[0022] The present disclosure also provides a method of treating locally advanced or metastatic non-small cell lung cancer (NSCLC), the method comprising administering a therapeutically effective amount of flumonertinib, or a pharmacologic acceptable salt thereof, to a patient with confirmed positive HER2 exon 20 insertion mutations and / or EGFR rare mutations.

[0023] The present disclosure also provides a method for treating locally advanced or metastatic non-small cell lung cancer (NSCLC), the method comprising administering a therapeutically effective amount of flumonertinib or a pharmacologic acceptable salt thereof to a patient harboring a HER2 exon 20 insertion mutation and / or an EGFR rare mutation.

[0024] 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 positive HER2 exon 20 insertion mutations and / or EGFR rare mutations who has not received any prior systemic anti-tumor therapy.

[0025] 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 positive HER2 exon 20 insertion mutations and / or EGFR rare mutations who has progressive disease after receiving prior systemic anti-tumor therapy.

[0026] 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 comprising a pharma- ceutically acceptable carrier, exhibits excellent inhibitory activity against HER2 exon 20 insertion mutations and / or EGFR rare mutations, and thus, it may exhibit excellent clinical efficacy.

[0027] 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 comprising a pharma- ceutically acceptable carrier, is used to treat and / or prevent diseases mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations, its side effects are small and its safety is excellent.

[0028] The pharmaceutical compositions of the present disclosure may be prepared into formulations having an appropriate size and appropriate content of active ingredient by including a specific amount of flumonertinib or a pharma- ceutically acceptable salt thereof.

[0029] (Detailed Description) Although the embodiments of the present disclosure are described in more detail below with respect to specific embodiments, those skilled in the art will appreciate that the specific embodiments described below are merely exemplary of the present disclosure and should not be construed as limiting the scope of the present disclosure. Rather, 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.

[0030] 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 within the scope of the present disclosure.

[0031] Flumonertinib is a compound known in the prior art and described in detail in Patent CN105315259B, having 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]

[0032] In some embodiments, the active ingredient for treating the disease is actually fulmonertinib or its pharmaceutically acceptable salt.Therefore, in some embodiments, fulmonertinib or its pharmaceutically acceptable salt can be used alone or by being included in a composition, in which case the composition can optionally include any pharmaceutically acceptable carrier.

[0033] Additionally, in some embodiments, flumonertinib, or a pharma- ceutically acceptable salt thereof, may also be used in combination with at least one second therapeutic agent.

[0034] 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.

[0035] "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. The carrier is also known as an "adjuvant". "Compatible" means that each component in the composition can be mixed with the compound of the present disclosure and with each other without substantially reducing the medicinal effect of the compound. Some examples of pharma- ceutically 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 / 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, and the like.

[0036] The pharmaceutical compositions may be prepared by methods well known in the art, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, and lyophilizing processes.

[0037] The pharmaceutical composition may be in the form of a tablet or capsule, in which formulation, 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", 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, and gum arabic, corn starch; (c) humectants, such as glycerin; and (d) disintegrants. Disintegrants, such as croscarmellose sodium, crospovidone: carboxymethyl starch sodium, colloidal silica, microcrystalline cellulose, potato or tapioca or corn starch, pregelatinized starch, alginic acid, certain complex silicates and sodium carbonate, ion exchange resins, etc.; (e) absorption promoters, 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 buffering agents. Tablets and capsules may be coated or microencapsulated with coating or shell materials (e.g., enteric coatings or other materials known in the art).

[0038] The term "pharmaceutical acceptable salt" refers to a salt prepared from fulmonertinib and a relatively non-toxic pharmaceutical acceptable acid or base. A base addition salt can be obtained by contacting fulmonertinib with a sufficient amount of a pharmaceutical 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 (e.g., sodium ions, lithium ions, potassium ions, calcium ions, magnesium ions, tetramethylquaternary ammonium ions, tetraethylquaternary ammonium ions, etc.); amine salts (including salts formed with ammonia (NH3), primary amines, secondary amines or tertiary amines (e.g., methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, etc.)). In addition, an acid addition salt can be obtained by contacting fulmonertinib with a sufficient amount of a pharmaceutical acceptable acid in pure solution or in a suitable inert solvent. The pharma- ceutically 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. Reference may be made in particular to Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 66:1-19 (1977), or to "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (P. Heinrich Stahl and Camille G. Wermuth, eds., Wiley-VCH, 2002).

[0039] As used herein, "therapeutically effective amount" refers to a non-toxic amount of a drug or pharmacologically active agent that is sufficient to still achieve the desired effect.The effective amount varies from person to person depending on the age, weight and condition of the patient, and also on the specific active substance, and the effective amount appropriate in each individual case can be determined by those skilled in the art in view of routine testing.

[0040] As used herein, "active ingredient," "active substance," or "active agent" refers to a chemical entity that is effective in treating a disorder, disease, or condition of interest.

[0041] 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.

[0042] As used herein, "treatment" refers to curative or palliative treatment. In relation to a particular condition, treatment refers to: (1) alleviating one or more biological signs of a disease or disorder; (2) (a) interfering with one or more points in the biological cascade that cause or contribute to the disorder, or (b) one or more biological signs 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 down the progression of one or more biological signs of a disease or disorder. "Treatment" can also refer to increasing survival compared to expected survival if not treated.

[0043] As used herein, "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0044] In some embodiments, the pharma- ceutically acceptable salt of flumonertinib is a mesylate salt of flumonertinib, (ie, flumonertinib mesylate).

[0045] In some embodiments, the pharmaceutical compositions of the present disclosure are in tablet or capsule form.

[0046] 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 may 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.

[0047] In some embodiments, the pharmaceutical composition contains flumonertinib or a pharma- ceutically 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. As exemplary embodiments, 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.

[0048] In some embodiments, when the pharmaceutical composition is used to treat and / or prevent diseases mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations, the composition is administered to a patient such that the dosage of flumonertinib or its pharma- ceutical acceptable salt is 80mg to 400mg.Specific dosage amounts, for example, may be 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg. As 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 disclosure, the dosage is a daily dose.

[0049] 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 the formulations (e.g., tablet or capsule) when the formulations (e.g., tablet or capsule) are administered.

[0050] 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 in 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 fulmonertinib or its pharmaceutically acceptable salt and the content of fulmonertinib or its pharmaceutically acceptable salt in each unit preparation.For example, if 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 its preparation (tablet) that needs to be administered per day is 6 tablets.

[0051] 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 disease mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations.

[0052] In some embodiments, 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.

[0053] In some embodiments, 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 doxorubicin), cetaxel), vinblastine (vinorelbine, vinblastine, vincristine, vindesine, vinflunine), anthracene (epirubicin, amycin, rubidomycin, pirarubicin, amrubicin, idarubicin, mitoxantrone, aclarubicin, valrubicin, zorubicin, pixantrone), antibiotics, podophyllum, antimetabolites, antineoplastic drugs, pemetrexed, carmustine, melphalan, etoposide, teniposide, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposome amycin amycin), actinomycin D (dactinomycin), bleomycin, pingyangmycin, temozolomide, dacarbazine, peplomycin, eribulin, plinabulin, sapacitabine, treosulfan, 153Sm-EDTMP, and encequidar.

[0054] In some embodiments, 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.

[0055] 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, amrubicin, tegafur, gimeracil, oteracil, and tegafur.

[0056] In some embodiments, the targeted antitumor drug may include protein kinase inhibitors.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.The targets of these inhibitors include, but are not limited to, fascin 1 protein, HDAC (histone deacetylase), proteasome, CD38, SLAMF7 (CS1 / CD319 / CRACC), RANKL, EGFR (epidermal growth factor receptor), anaplastic lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K 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. The targeted antitumor drug targets 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 (bone protective factor), Src, IFN, ALCAM (activated leukocyte cell adhesion molecule), HSP, JIP1, GSK-3β (glycogen synthase kinase 3β), cyclin D1 (cell cycle control 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 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, co 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, selarasertib, PLB-1003, tomivosertib, SKLB-1028, D-0316, LY-3023414, allitinib, MRTX-849, AP-32788, AZD-4205 , lifirafenib, vactosertib, mivebresib, napabucasin, sitravatinib, TAS-114, molybresur, CC-223, rivoselanib, 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,These 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, telagrenastat, 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 therapeutic agent is one or more of the following: nivolumab, fruquintinib, entrectinib, dasatinib, ensartinib, lenvatinib, itacitinib, pyrotinib, binimetinib, erdafitinib, axitinib, nirotrinib, cobimetinib, acalabrutinib, famitinib, masitinib, ibrutinib, anlotinib, and nintedanib.

[0057] In some embodiments, 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-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.

[0058] 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.

[0059] 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 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.

[0060] In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is an anti-PD-1 monoclonal antibody or an anti-PD-L1 monoclonal antibody.

[0061] In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is a human or murine antibody.

[0062] 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.

[0063] 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.

[0064] In some embodiments, the anti-PD-1 antibody is toripalimab.

[0065] In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0066] In some embodiments, the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor is an anti-CTLA-4 antibody, and in one embodiment of the disclosure, the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.

[0067] 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.

[0068] In some embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0069] In some embodiments, the platelet-derived growth factor receptor alpha (PDGFR-α) inhibitor is an anti-PDGFRα antibody. In one embodiment of the disclosure, the anti-PDGFRα antibody is an anti-PDGFRα monoclonal antibody.

[0070] In some embodiments, the anti-PDGFRα antibody is olaratumab.

[0071] 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.

[0072] 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.

[0073] In some embodiments, if a second therapeutic agent is used, the amount of the second therapeutic agent can be adjusted as desired by one of skill in the art.

[0074] In some embodiments, there is provided a use of flumonertinib or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating and / or preventing a disease mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations.

[0075] In some embodiments, there is provided flumonertinib or a pharma- ceutically 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 HER2 exon 20 insertion mutations and / or EGFR rare mutations.

[0076] In some embodiments, there is provided a use of the above pharmaceutical composition in the manufacture of a medicament for treating and / or preventing a disease mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations.

[0077] In some embodiments, in the above uses of the present disclosure, the pharma- ceutically acceptable salt of flumonertinib is a mesylate salt of flumonertinib (ie, flumonertinib mesylate).

[0078] In some embodiments, for the uses described herein, the pharmaceutical compositions of the present disclosure are in tablet or capsule form.

[0079] In some embodiments, in the uses described herein, the content of flumonertinib or a pharma- ceutically acceptable salt thereof in each unit dosage form (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, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg. As exemplary specific contents 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.

[0080] 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.

[0081] In some embodiments, in the use described herein, the pharmaceutical composition is administered to a patient such that the dosage of flumonertinib or its pharma- ceutically acceptable salt is 80mg to 400mg.Specific dosage amounts 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 dosage, 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 disclosure, the dosage is a daily dose.

[0082] 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 the formulations (e.g., tablet or capsule) when the formulations (e.g., tablet or capsule) are administered.

[0083] In the use described herein, it is understood by those skilled in the art that when administered to a patient, the daily amount of fulmonertinib or its pharmaceutically acceptable salt is equal to or greater than the content of fulmonertinib or its pharmaceutically acceptable salt in 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 amount of fulmonertinib or its pharmaceutically acceptable salt and the content of fulmonertinib or its pharmaceutically acceptable salt in each unit preparation.For example, if 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 amount of fulmonertinib or its pharmaceutically acceptable salt is 240mg, the total amount of its preparation (tablet) that needs to be administered per day is 6 tablets.

[0084] In some embodiments, the disease mediated by the HER2 exon 20 insertion mutation and / or the EGFR rare mutation is cancer (e.g., lung cancer), and further the disease may be non-small cell lung cancer (NSCLC).

[0085] In some embodiments, the HER2 exon 20 insertion and / or EGFR rare mutation mediated disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

[0086] In some embodiments, the HER2 exon 20 insertion and / or EGFR rare mutation mediated disease is untreated or previously treated non-small cell lung cancer.

[0087] As used herein, the term "naive" refers to a state in which no treatment with another therapeutic agent (including but not limited to chemotherapy, targeted antitumor agent, antibody drug or immunotherapy agent) has been used before treatment with the present disclosure of fulmonertinib or its pharmaceutically acceptable salt, or no systemic antitumor therapy has been received.As used herein, the term "previously treated" refers to a state in which a treatment with another therapeutic agent (including but not limited to chemotherapy, targeted antitumor agent, antibody drug or immunotherapy agent) has been used before treatment with the present disclosure of fulmonertinib or its pharmaceutically acceptable salt, or a systemic antitumor therapy has been received, but the disease has progressed thereafter.When "previously treated", the patient may or may not have developed resistance to other therapeutic agents.

[0088] In some embodiments, the HER2 exon 20 insertion mutation is at least one selected from the group consisting of an ERBB2 A775_G776insYVMA mutation, an ERBB2 V777_G778insGC mutation, and an ERBB2 P780_Y781insGSP mutation.

[0089] In one embodiment of the present invention, the EGFR rare mutation is at least one selected from the group consisting of EGFR G719S mutation, EGFR S768I mutation, EGFR G724S mutation, EGFR L861Q mutation, and EGFR G719S / T263P mutation.

[0090] In some embodiments, in 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 some embodiments, in the uses described herein, the second therapeutic agent is a second therapeutic agent described above in this disclosure.

[0093] In some embodiments, a method for treating and / or preventing a disease mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations is provided, the method comprising administering to a patient a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof.

[0094] In some embodiments, a method for treating and / or preventing a disease is provided, the method comprising administering a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof to a patient with a positive HER2 exon 20 insertion mutation and / or an EGFR rare mutation.

[0095] In some embodiments, a method of treating locally advanced or metastatic non-small cell lung cancer is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of flumonertinib or a pharma- ceutical acceptable salt thereof.

[0096] In some embodiments, a method of treating locally advanced or metastatic non-small cell lung cancer is provided, the method comprising administering a therapeutically effective amount of flumonertinib or a pharmacologic acceptable salt thereof to a patient with confirmed positive HER2 exon 20 insertion mutations and / or EGFR rare mutations.

[0097] In some embodiments, a method for treating locally advanced or metastatic non-small cell lung cancer is provided, the method comprising administering a therapeutically effective amount of flumonertinib or a pharmacologic acceptable salt thereof to a patient harboring a HER2 exon 20 insertion mutation and / or an EGFR rare mutation.

[0098] In some embodiments, a method of treating locally advanced or metastatic non-small cell lung cancer is provided, the method comprising administering a therapeutically effective amount of flumonertinib or a pharmacologic acceptable salt thereof to a patient with confirmed positive HER2 exon 20 insertion mutations and / or EGFR rare mutations who has not received any prior systemic anti-tumor therapy.

[0099] In some embodiments, a method of treating locally advanced or metastatic non-small cell lung cancer is provided, the method comprising administering a therapeutically effective amount of flumonertinib, or a pharmacologic acceptable salt thereof, to a patient with confirmed positive HER2 exon 20 insertion mutations and / or EGFR rare mutations who has progressive disease after receiving prior systemic anti-tumor therapy.

[0100] In some embodiments of the method of treatment, the flumonertinib or a pharma- ceutically acceptable salt thereof is administered in a dosage of 80 mg to 400 mg.Specific dosage amounts 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. As an exemplary dosage, 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 disclosure, the dosage is a daily dose.

[0101] In some embodiments of the treatment method, flumonertinib or a pharma- ceutically acceptable salt thereof is administered to the patient once a day (qd), twice a day (bid), or three times a day (tid), for example, once a day.

[0102] In some embodiments of the method of treatment, flumonertinib or a pharma- ceutically acceptable salt thereof is administered to the patient under fasted conditions (eg, in the morning under fasted conditions).

[0103] In some embodiments of the method of treatment, flumonertinib or a pharma- ceutically acceptable salt thereof is administered orally to the patient.

[0104] In some embodiments, in the treatment methods described herein, flumonertinib is administered in the form of a mesylate salt.

[0105] In some embodiments of the method of treatment, flumonertinib or a pharma- ceutically acceptable salt thereof is administered in tablet or capsule form.

[0106] In some embodiments of the treatment method, fulmonertinib or its pharmaceutically acceptable salt is administered to the patient 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.

[0107] In some embodiments of the treatment method, the content of the above-mentioned 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, 10mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg or 400mg. As exemplary specific contents 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.

[0108] 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 more than the total amount of fulmonertinib or its pharmaceutically acceptable salt in the 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 fulmonertinib or its pharmaceutically acceptable salt and the content of fulmonertinib or its pharmaceutically acceptable salt in each unit preparation.For example, if 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 its preparation (tablet) that needs to be administered per day is 6 tablets.

[0109] In some embodiments of the treatment method, at least one second therapeutic agent can be further administered to the patient. In some embodiments of the treatment method, the second therapeutic agent can be selected from a chemotherapeutic agent, a targeted anti-tumor agent, an antibody agent, and an immunotherapeutic agent.

[0110] In some embodiments of the method of treatment, the second therapeutic agent is a second therapeutic agent described above in this disclosure.

[0111] In some embodiments of the methods of treatment, the disease is cancer (eg, lung cancer), and further the disease can be non-small cell lung cancer (NSCLC).

[0112] In some embodiments of the method of treatment, flumonertinib or a pharma- ceutically acceptable salt thereof is administered to the patient before or after surgical resection of the tumor.

[0113] In some embodiments of the treatment methods, the disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

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

[0115] In the above treatment methods of the present disclosure, the HER2 exon 20 insertion mutation is at least one selected from the group consisting of ERBB2 A775_G776insYVMA mutation, ERBB2 V777_G778insGC mutation, and ERBB2 P780_Y781insGSP mutation.

[0116] In one embodiment of the present invention, the EGFR rare mutation is at least one selected from the group consisting of EGFR G719S mutation, EGFR S768I mutation, EGFR G724S mutation, EGFR L861Q mutation, and EGFR G719S / T263P mutation.

[0117] In some embodiments of the treatment methods, the patient is a human patient.

[0118] In some embodiments of the treatment methods, the patient is between 18 and 75 years of age.

[0119] In some embodiments of the treatment method, 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 pharmaceutical acceptable salt thereof.

[0120] In some embodiments of the treatment methods, the patient has radiological disease progression after the last anti-tumor therapy prior to initiation of treatment with flumonertinib or a pharma- ceutically acceptable salt thereof.

[0121] In some embodiments of the treatment method, the patient has a documented positive HER2 exon 20 insertion mutation and / or EGFR rare mutation by laboratory testing prior to initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments of the treatment method, the patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer (NSCLC) and has been confirmed to have radiological disease progression or pathological disease progression during or after the last systemic anti-tumor therapy prior to initiation of treatment with flumonertinib or a pharmaceutical acceptable salt thereof.

[0123] In some embodiments of the treatment method, the patient has locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer (NSCLC) and has not received any prior systemic anti-tumor therapy prior to initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments of the treatment methods, the patient has at least one measurable lesion prior to the initiation of treatment with flumonertinib or a pharma- ceutically acceptable salt thereof.

[0125] In some embodiments of the treatment methods, the patient has sufficient organ function as indicated by laboratory tests prior to initiation of treatment with flumonertinib or a pharma- ceutically acceptable salt thereof.

[0126] In some embodiments of the treatment method, the patient is subjected to an ECOG PS (Eastern Cooperative Oncology Group performance status) score test (e.g., ECOG PS score 0-1) before starting treatment with flumonertinib or a pharma- ceutical acceptable salt thereof.

[0127] In some embodiments, the treatment method has an acceptable safety profile.

[0128] In some embodiments, the treatment method may provide a therapeutic effect of partial response (PR).

[0129] In some embodiments, the treatment methods may provide a therapeutic effect in stable state (SD).

[0130] In some embodiments, the treatment methods may provide tumor shrinkage in target lesions.

[0131] Some embodiments of the treatment methods provide tumor shrinkage in target lesions as assessed by radiological tumor studies, such as computed tomography (CT) and / or magnetic resonance imaging (MRI). [Brief description of the drawings]

[0132] [Figure 1] FIG. 1: Curve of tumor volume change in Test Example 2. [Diagram 2] FIG. 2: Curve of weight change rate in Test Example 2. [Diagram 3] FIG. 3: Curve of tumor volume change in Test Example 3. [Figure 4] FIG. 4: Curve of body weight change in Test Example 3. EXAMPLES

[0133] (Example) I. PREPARATION EXAMPLES (Preparation of flumonertinib mesylate (40 mg, standard tablet)) Formulation: 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.

[0134] Process: Adjuvants and above active pharmaceutical ingredients are sieved for pre-treatment, mixed uniformly, added with 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, then tableted to get tablets.

[0135] II. Activity Examples (Test Example 1: Growth Inhibitory Activity against Stably Transfected Cells Ba / F3 EGFR G719S, Ba / F3 EGFR G724S, Ba / F3 EGFR S768I, Ba / F3 EGFR L861Q, Ba / F3 EGFR G719S / T263P, Ba / F3 ERBB2 A775_G776insYVMA, Ba / F3 ERBB2 V777_G778insGC, and Ba / F3 ERBB2 P780_Y781insGSP)

[0136] Four types of mouse pro-B cell lines, Ba / F3 EGFR G719S, Ba / F3 EGFR G724S, Ba / F3 EGFR S768I, and Ba / F3 EGFR L861Q, stably express EGFR rare mutant proteins in vitro in mouse pro-B cell lines, Ba / F3 EGFR G719S / T263P, stably express EGFR double mutant proteins in vitro in mouse pro-B cell lines, Ba / F3 EGFR G719S / T263P, and Ba / F3 ERBB2 A775_G776insYVMA, Ba / F3 ERBB2 V777_G778insGC, and Ba / F3 ERBB2 V777_G778insGC, stably express various ERBB2 exon 20 insertion mutant proteins in vitro in mouse pro-B cell lines, Ba / F3 ERBB2 V777_G778insGC, and Ba / F3 ERBB2 V777_G778insGC, respectively. The growth inhibitory activity of the above compound (flumonertinib mesylate) against three types of cells, P780_Y781insGSP, was determined by the CellTiter Glo method.

[0137] Cell source: Ba / F3 EGFR G719S cells, Ba / F3 EGFR G724S cells, Ba / F3 EGFR S768I cells, Ba / F3 EGFR L861Q cells, Ba / F3 EGFR G719S / T263P cells, Ba / F3 ERBB2 A775_G776insYVMA cells, Ba / F3 ERBB2 V777_G778insGC cells, and Ba / F3 ERBB2 P780_Y781insGSP cells were provided by KYinno Biotechnology (Beijing) Co., Ltd.

[0138] Ba / F3 EGFR G719S cells, Ba / F3 EGFR G724S cells, Ba / F3 EGFR S768I cells, Ba / F3 EGFR L861Q cells, Ba / F3 EGFR G719S / T263P cells, Ba / F3 ERBB2 A775_G776insYVMA cells, Ba / F3 ERBB2 V777_G778insGC cells, and Ba / F3 ERBB2 P780_Y781insGSP cells were cultured in RPMI1640 complete culture medium containing 10% fetal bovine serum. Ba / F3 EGFR G719S cells, Ba / F3 EGFR G724S cells, Ba / F3 EGFR S768I cells, Ba / F3 EGFR L861Q cells, Ba / F3 EGFR G719S / T263P cells, Ba / F3 ERBB2 A775_G776insYVMA cells, Ba / F3 ERBB2 V777_G778insGC cells, and Ba / F3 ERBB2 P780_Y781insGSP cells in logarithmic growth phase were seeded into 96-well plates according to a cell density of 3000 cells per well in 90 μL of complete culture medium, and the plates were placed in a constant temperature incubator at 37° C. with 5% CO2 and cultured for 24 hours. The compounds were dissolved in dimethyl sulfoxide (DMSO) in advance to prepare 30 mM stock solutions, and then serially diluted with DMSO and complete culture medium. The 96-well plates seeded with the cells were taken and 10 μL of various concentrations of the compounds were added to each well to achieve final concentrations of 3000 nM, 950 nM, 300 nM, 95.0 nM, 30 nM, 9.5 nM, 3 nM, 0.95 nM, and 0.3 nM, with three replicate wells for each compound concentration, one negative control (culture medium control with cells) and one blank control (culture medium control without cells), and the DMSO concentration in each well was 0.1%. The plates were placed in a constant temperature incubator at 37° C. with 5% CO2 and cultured for 72 hours.

[0139] The CellTiter-Glo reagent (a luciferase ATP bioluminescence detection reagent available from Promega) was melted, and the 96-well plate inoculated with the above cells was removed from the CO2 constant temperature incubator and equilibrated to room temperature (about 30 minutes), 100 μL of CellTiter-Glo reagent was added to each well, and the cells were lysed by shaking on an orbital shaker for 5 minutes, and the cells were inoculated at room temperature for 20 minutes to allow the luminescence intensity to stabilize, and then the luminescence intensity (Lum) was measured with a microplate reader. The cell viability of each concentration of the above compound was calculated.

[0140] Cell viability (%)=(Lum 72時間化合物投与群 -Lum ブランク対照 ) / (Lum 72時間陰性対照群 -Lum ブランク対照 )×100%.

[0141] The data were analyzed using GraphPad Prism 7.0 software and fitted with nonlinear sigmoidal regression to obtain dose-effect curves, which were then calculated using IC 50 values ​​were calculated. [Table 1]

[0142] The results showed that flumonertinib mesylate had good proliferation inhibitory activity against the stably transfected cells of Ba / F3 EGFR G719S, Ba / F3 EGFR G724S, Ba / F3 EGFR S768I, Ba / F3 EGFR L861Q, Ba / F3 EGFR G719S / T263P, Ba / F3 ERBB2 A775_G776insYVMA, Ba / F3 ERBB2 V777_G778insGC, and Ba / F3 ERBB2 P780_Y781insGSP.

[0143] (Test Example 2: Testing the antitumor effect of flumonertinib mesylate in Ba / F3 ERBB2 A775_G776insYVMA CDX tumor model) This study was used to evaluate and test the antitumor efficacy of flumonertinib mesylate in Ba / F3 ERBB2 A775_G776insYVMA (murine pro-B cells Ba / F3 stably expressing ERBB2 exon 20 insertion mutant protein) subcutaneous xenograft BALB / c female nude mice animal model.

[0144] Experimental animals: BALB / c nude mice, female, 8-9 weeks old (age of mice when inoculated with tumor cells), weighing 13.7-17.7 g, purchased from the Shanghai branch of Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0145] Animal model and randomization: Ba / F3 ERBB2 A775_G776insYVMA cells were cultured and two T175cm 2 After expansion in culture flasks, cells were harvested, resuspended 1:1 in serum-free DMEM supplemented with matrix gel, counted, and implanted subcutaneously in the anterior right scapula of Balb / c nude mice at 2 × 10 6 The average tumor volume was approximately 160 mm 3 When the animals were in the 100-mL oocyte subpopulation, they were randomly assigned to three experimental groups according to tumor size, with each group containing six animals. The day of assignment was defined as day 0 (i.e., D0).

[0146] Experimental scheme: BALB / c nude mice were subcutaneously inoculated with Ba / F3 ERBB2 A775_G776insYVMA cells to establish a cell line xenograft tumor model. The experiment was divided into 30mg / kg AZD9291 group, 30mg / kg flumonertinib mesylate group and vehicle control group, each group included 6 animals, which were orally administered with a dose volume of 10μL / g, and the vehicle control group was administered with the same amount of vehicle, which was administered once a day for 2 weeks. During the whole experiment, the body weight and tumor size of the mice were measured twice a week, regardless of whether the presence of toxic reaction was observed or not.

[0147] Tumor volume (TV) was calculated by TV=1 / 2×a×b×b, where a was the length of the tumor and b was the width of the tumor.

[0148] Percentage of weight change = body weight / body weight at D0-1) × 100%.

[0149] The curves for the changes in tumor volume in the three experimental groups are shown in FIG. 1, and the curves for the rate of change in body weight are shown in FIG.

[0150] The results showed that flumonertinib mesylate showed good antitumor effect in Ba / F3 ERBB2 A775_G776insYVMA CDX subcutaneous xenograft BALB / c female nude mice animal model, had less effect on nude mice body weight, and showed better safety.

[0151] (Test Example 3: Testing the antitumor effect of flumonertinib mesylate in Ba / F3 ERBB2 V777_G778insGC (KC-1410) cell xenograft model in female immunodeficient mice) This study was used to evaluate the antitumor efficacy of the three compounds alone in female (B-NDG) immunodeficient mice bearing Ba / F3 ERBB2 V777_G778insGC modified cell tumors.

[0152] Experimental animals: B-NDG mice, female, 6-8 weeks old, weighing 18-20g.

[0153] Animal model and randomization: Ba / F3 ERBB2 V777_G778insGC cells were cultured, the cells were harvested, resuspended in serum-free medium, counted, and resuspended cells supplemented with Matrigel at 1:1 were injected into B-NDG mice at 1 × 10 6 The cells were inoculated subcutaneously at 0.1 mL per cell. The average tumor volume was approximately 80 mm 3 ~approx. 120mm 3 When the animals were in the 100-mL oocyte subpopulation, they were randomly assigned to four experimental groups according to tumor size, with each group containing 12 mice. The day of assignment was defined as day 0 (i.e., D0).

[0154] Experimental scheme: B-NDG mice were subcutaneously inoculated with Ba / F3 ERBB2 V777_G778insGC cells to establish cell line-derived xenograft models. The experiment was divided into 15mg / kg fulmonertinib mesylate group, 30mg / kg fulmonertinib mesylate group, 50mg / kg fulmonertinib mesylate group and vehicle group, each group included 12 mice, which were orally administered with a dose volume of 10μL / g, and the vehicle group was administered with the same amount of vehicle, which was administered once a day for 2 weeks. During the entire experiment, the body weight and tumor size of the mice were measured twice a week, regardless of whether the presence of toxic reactions was observed or not.

[0155] Tumor volume (TV) is TV=1 / 2×a×b 2 where a was the longest diameter of the tumor and b was the shortest diameter of the tumor.

[0156] The curves for the changes in tumor volume in the four experimental groups are shown in FIG. 3, and the curves for the changes in body weight in the four experimental groups are shown in FIG.

[0157] 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.

[0158] (Study Example 4: Study of flumonertinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with activating HER2 mutations (including exon 20 insertion mutations)) A clinical trial will be conducted to evaluate the safety, pharmacokinetics (PK), and antitumor activity of flumonertinib in at least 100 patients with advanced or metastatic NSCLC with activating HER2 mutations, including exon 20 insertion mutations.

[0159] Patients will be enrolled in two stages: Stage 1 (dose escalation and backfill cohorts) and Stage 2 (dose expansion). In each stage, previously treated NSCLC patients will receive flumonertinib tablets.

[0160] The primary endpoints include the frequency and severity of adverse events (AEs) as a measure of the safety and tolerability of fulmonertinib (with the time frame being up to 36 months after the first dose).Secondary endpoints include, for example, objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival, central nervous system (CNS) ORR, and central nervous system (CNS) DOR up to 36 months after the first dose.

[0161] Eligible patients included all genders and were at least 18 years of age. Inclusion criteria included, for example, - histologically or cytologically proven locally advanced or metastatic NSCLC not amenable to curative surgery or radiotherapy; - Patients with disease that has progressed after at least one available standard treatment, or for whom standard treatments have proven ineffective or intolerable, or for whom a clinical trial of an investigational agent is recognized as the standard of care; - Patients with a history of treated CNS metastases or newly detected asymptomatic CNS metastases after screening; - Documented radiologic disease progression during or after last systemic anticancer therapy prior to first flumonertinib dose; -For patients with EGFR mutations sensitive to osimertinib, patients must have received osimertinib prior to study enrollment in regions where osimertinib is approved (including the United States); - Have valid documented results from local testing of either blood or tumor tissue confirming the presence of a HER2 exon 20 insertion mutation; and - The patient must have experienced disease progression or have intolerance to treatment with platinum-based chemotherapy Examples include:

[0162] Exclusion criteria include, for example: - Treatment with chemotherapy, immunotherapy, biologic therapy, or investigational agent as anticancer therapy within 3 weeks or 5 half-lives (whichever is shorter) prior to starting flumonertinib, or treatment with endocrine therapy within 2 weeks prior to starting flumonertinib; - Radiation therapy for cancer treatment within 4 weeks prior to initiating flumonertinib; Palliative radiation for bone metastases within 2 weeks prior to initiating flumonertinib; and - Adverse events from prior anticancer therapy that have not resolved to Grade 1 or less, except for alopecia or peripheral neuropathy of Grade 2 or less Examples include:

[0163] (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; the use of fulmonertinib or a pharma- ceutically acceptable salt thereof, and the above pharmaceutical composition, in the manufacture of a medicament for treating and / or preventing a disease mediated by HER2 exon 20 insertion mutation and / or EGFR rare mutation. The present disclosure also provides a method for treating and / or preventing a disease mediated by HER2 exon 20 insertion mutation and / or EGFR rare mutation, in which 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 a disease mediated by HER2 exon 20 insertion mutation and / or EGFR rare mutation (e.g., non-small cell lung cancer (NSCLC)) with little side effects and excellent safety.

Claims

1. A composition for use in the treatment and / or prevention of a disease mediated by HER2 exon 20 insertion mutations and / or EGFR rare mutations in a patient in need of such treatment and / or prevention, the composition comprising a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

2. A composition for use in treating disease in patients with a positive HER2 exon 20 insertion mutation and / or a rare EGFR mutation, comprising a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

3. A composition for use in treating locally advanced or metastatic non-small cell lung cancer (NSCLC) in a patient in need of such treatment, comprising a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

4. A composition described in any one of claims 1 to 3, wherein the patient has not received any prior systematic antitumor therapy, a therapeutically effective amount of flumonertinib or a pharmaceutically acceptable salt thereof.

5. A composition described in any one of claims 1 to 3, wherein the patient has progressive disease after receiving prior systematic anti-tumor therapy.

6. The composition of claim 1, wherein the flumonertinib or a pharmaceutically acceptable salt thereof is for use in a dosage equivalent to 80 mg to 400 mg of flumonertinib free salt, 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 of flumonertinib free salt.

7. The composition described in claim 6, wherein the flumonertinib or a pharmaceutically acceptable salt thereof is for use in a dosage equivalent to 80 mg of flumonertinib free salt.

8. The composition described in claim 6, wherein the flumonertinib or a pharmaceutically acceptable salt thereof is for use in a dosage equivalent to 160 mg of flumonertinib free salt.

9. The composition described in claim 6, wherein the flumonertinib or a pharmaceutically acceptable salt thereof is for use in a dosage equivalent to 240 mg of flumonertinib free salt.

10. A composition described in any one of claims 1 to 3, for use once a day, twice a day, or three times a day.

11. The composition of claim 10, for use once a day.

12. A composition described in any one of claims 1 to 3, characterized in that it is administered to the patient under fasting conditions.

13. A composition described in any one of claims 1 to 3, characterized in that it is administered to the patient in the morning under fasting conditions.

14. A composition described in any one of claims 1 to 3, for oral use.

15. A composition described in any one of claims 1 to 3, wherein the flumonertinib is in the form of a mesylate salt.

16. A composition according to any one of claims 1 to 3 for use in tablet or capsule dosage form.

17. A composition according to any one of claims 1 to 3 for use in a unit dosage form.

18. The unit dosage form is equivalent to 10 mg to 400 mg of flumonertinib free salt, 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 18. The composition of claim 17, comprising flumonertinib or a pharmaceutically acceptable salt thereof in an amount equivalent to 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 free base.

19. 19. The composition of claim 18, wherein the unit dosage form comprises the flumonertinib or a pharmaceutically acceptable salt thereof in an amount equivalent to 20 mg, 40 mg, 80 mg, 160 mg, 240 mg, or 320 mg of flumonertinib free base.

20. 17. The composition of claim 16, wherein the unit dosage form comprises the flumonertinib or a pharmaceutically acceptable salt thereof in an amount equivalent to 40 mg of flumonertinib free base.

21. The composition of any one of claims 1 to 3, for use in combination with at least one second therapeutic agent.

22. 22. The composition of claim 21, wherein the second therapeutic agent is selected from a chemotherapeutic agent, a targeted anti-tumor agent, an antibody agent, and an immunotherapeutic agent.

23. 3. The composition of claim 1 or 2, wherein the disease is cancer, such as lung cancer, such as non-small cell lung cancer (NSCLC).

24. A composition described in any one of claims 1 to 3, for use in the patient before or after surgical resection of a tumor.

25. The composition of claim 1 or 2, wherein the disease is locally advanced non-small cell lung cancer or metastatic non-small cell lung cancer.

26. The composition of any one of claims 1 to 3, wherein the disease is untreated or previously treated non-small cell lung cancer.

27. The composition of any one of claims 1 to 3, wherein the HER2 exon 20 insertion mutation is at least one selected from the group consisting of an ERBB2 A775_G776insYVMA mutation, an ERBB2 V777_G778insGC mutation, and an ERBB2 P780_Y781insGSP mutation.

28. The EGFR rare mutation is at least one selected from the group consisting of EGFR G719S mutation, EGFR S768I mutation, EGFR G724S mutation, EGFR L861Q mutation, and EGFR G719S / T263P mutation. The composition of any one of claims 1 to 3.

29. The composition of any one of claims 1 to 3, wherein the patient is a human patient.

30. 30. The composition of claim 29, wherein the patient is between 18 and 75 years of age.

31. The composition of any one of claims 1 to 3, 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.

32. The composition of any one of claims 1 to 3, 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.

33. The composition of any one of claims 1 to 3, wherein the patient has locally advanced NSCLC 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.

34. The composition of any one of claims 1 to 3, 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.

35. The composition of any one of claims 1 to 3, wherein the patient has at least one measurable lesion prior to initiation of treatment with flumonertinib or a pharmaceutically acceptable salt thereof.

36. The composition of any one of claims 1 to 3, 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.

37. The composition of any one of claims 1 to 3, 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.

38. The composition of any one of claims 1 to 3, having an acceptable safety profile.

39. The composition of any one of claims 1 to 3, which provides a partial response (PR).

40. The composition of any one of claims 1 to 3, which provides a stable state (SD).

41. The composition of any one of claims 1 to 3, which provides tumor shrinkage in target lesions.

42. 4. The composition of any one of claims 1 to 3, which provides tumor shrinkage in target lesions as assessed by radiological tumor examination, e.g., computed tomography (CT) and / or magnetic resonance imaging (MRI).

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