EGFR inhibitor for use in the treatment of lung cancer positive for an EGFR exon 20 mutation

Abstract

This disclosure features methods for treating a lung cancer (e.g., small-cell lung cancer) that is positive for an EGFR exon 20 mutation in a patient in need thereof, the methods include administering to the patient a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof: [Formula I]

Description

[0001] EGFR INHIBITOR FOR USE IN THE TREATMENT OF LUNG CANCER POSITIVE FOR AN EGFR EXON 20 MUTATION

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 535,905, filed on August 31, 2023, which is incorporated by reference herein in its entirety.

[0004] SEQUENCE LISTING

[0005] This application contains a Sequence Listing that has been submitted electronically as an XML file named 50006-0118WO1 ST26 SL.XML.” The XML file, created on August 29, 2024, is 3,075 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0006] TECHNICAL FIELD

[0007] This disclosure features methods for treating a lung cancer (e.g., small-cell lung cancer) that is positive for an EGFR exon 20 mutation in a patient in need thereof, the methods include administering to the patient a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0008] BACKGROUND

[0009] Epidermal growth factor receptor (EGFR, ERBB1) and Human epidermal growth factor receptor 2 (HER2, ERBB2) are members of a family of proteins which regulate cellular processes implicated in tumor growth, including proliferation and differentiation. Several investigators have demonstrated the role of EGFR and HER2 in development and cancer (Reviewed in Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19: 183-232, Klapper, et al., Adv. Cancer Res. (2000) 77, 25-79 and Hynes and Stem, Biochim. Biophys. Acta (1994) 1198: 165-184). EGFR overexpression is present in at least 70% of human cancers, such as non-small cell lung carcinoma (NSCLC), breast cancer, glioma, and prostate cancer. HER2 overexpression occurs in approximately 30% of all breast cancer. It has also been implicated in other human cancers including colon, ovary, bladder, stomach, esophagus, lung, uterus and prostate. HER2 overexpression has also been correlated with poor prognosis in human cancer, including metastasis, and early relapse.

[0010] EGFR and HER2 are, therefore, widely recognized as targets for the design and development of therapies that can specifically bind and inhibit tyrosine kinase activity and its signal transduction pathway in cancer cells, and thus can serve as diagnostic or therapeutic agents. For example, EGFR tyrosine kinase inhibitors (TKIs) are effective clinical therapies for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. However, the vast majority of patients develop disease progression following successful treatment with an EGFR TKI. Common mechanisms of resistance include acquired, secondary mutation T790M, C797S, and EGFR exon 20 insertion mutations. For example, NSCLC tumors can have EGFR exon 20 insertion mutations that are intrinsically resistant to current EGFR TKIs.

[0011] Overexpression of another protein, BUB1 (Budding uninhibited by benzimidazole, BUB1) kinase, is often associated with proliferating cells, including cancer cells, and tissues (Bolanos-Garcia VM and Blundell TL, Trends Biochem. Sci. 36, 141 , 2010). This protein is an essential part of the complex network of proteins that form the mitotic checkpoint. The major function of an unsatisfied mitotic checkpoint is to keep the anaphase-promoting complex / cyclosome (APC / C) in an inactive state. As soon as the checkpoint gets satisfied the APC / C ubiquitin-ligase targets cyclin B and securin for proteolytic degradation leading to separation of the paired chromosomes and exit from mitosis.

[0012] Incomplete mitotic checkpoint function has been linked with aneuploidy and tumourigenesis (see Weaver BA and Cleveland DW, Cancer Res. 67, 10103, 2007; King RW, Biochim Biophys Acta 1786, 4, 2008). In contrast, complete inhibition of the mitotic checkpoint has been recognized to result in severe chromosome mis segregation and induction of apoptosis in tumour cells (see Kops GJ et al., Nature Rev. Cancer 5, 773, 2005; Schmidt M and Medema RH, Cell Cycle 5, 159, 2006; Schmidt M and Bastians H, Drug Res. Updates 10, 162, 2007). Thus, mitotic checkpoint inhibition through inhibition of BUB 1 kinase represents an approach for the treatment of proliferative disorders, including solid tumors such as carcinomas, sarcomas, leukemias and lymphoid malignancies or other disorders, associated with uncontrolled cellular proliferation.

[0013] WO 2022 / 066734, which is incorporated herein by reference in its entirety, discloses compounds having the following generic formula:

[0014] Said compounds are described as having activity as inhibitors of EGFR and / or

[0015] HER.2.

[0016] SUMMARY

[0017] This disclosure features methods for treating a lung cancer (e.g., small-cell lung cancer) that is positive for an EGFR exon 20 mutation in a patient in need thereof, the methods include administering to the patient a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof:

[0018] This disclosure is based, in part, on the finding that the compound of Formula (I) is useful for treating a lung cancer (e.g., non-small cell lung cancer) that is positive for an EGFR exon 20 mutation.

[0019] The compound of Formula (I) is described as Compound 362 in WO 2022 / 066734. Said compound exhibits potent and selective inhibition of EGFR, e.g., exhibiting greater inhibition of EGFR containing one or more mutations relative to inhibition of wild type EGFR. For example, Compound 362 in WO 2022 / 066734 exhibits greater inhibition of EGFR containing an EGFR kinase protein insertion, e.g., an exon 20 insertion, relative to inhibition of wild type EGFR.

[0020] Accordingly, in one aspect, this disclosure features methods for treating a lung cancer that is positive for an EGFR exon 20 mutation in a patient in need thereof, the methods include administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0021] In another aspect, this disclosure features methods for treating a non-small cell lung cancer that is positive for an EGFR exon 20 mutation in a patient in need thereof, the methods include administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] In a further aspect, this disclosure features methods for treating a lung cancer that is positive for an EGFR exon 20 insertion mutation in a patient in need thereof, the methods include administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0023] In still another aspect, this disclosure features methods for treating a non-small cell lung cancer that is positive for an EGFR exon 20 insertion mutation in a patient in need thereof, the methods include administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0024] Embodiments can include one or more of the following features.

[0025] The lung cancer can be non-small cell lung cancer, small cell lung cancer or lung adenocarcinoma, pulmonary sarcomatoid carcinoma or any combination thereof.

[0026] The lung cancer can be non-small cell lung cancer.

[0027] The methods can further include determining (or having determined) that the lung cancer (e.g., non-small cell lung cancer) is positive for an EGFR exon 20 mutation.

[0028] The methods can further include identifying a patient having a lung cancer (e.g., non-small cell lung cancer) that is positive for an EGFR exon 20 mutation (e.g., identifying a patient having a clinical record that indicates that the patient has a lung cancer (e.g., non- small cell lung cancer) that is positive for an EGFR exon 20 mutation. The EGFR exon 20 mutation can be an EGFR exon 20 insertion mutation.

[0029] In some embodiments, the exon 20 insertion is selected from the group consisting of: V769 D770insX, D770_N771insX, N771_P772insX, P772 H773insX, and

[0030] H773_V774insX. For example, the exon 20 insertion is selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP,

[0031] H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP; or any combination thereof; e.g., any two or more independently selected exon 20 insertions; e.g., any two independently selected exon 20 insertions (e.g., V769_D770insASV and D770_N771insSVD).

[0032] In certain embodiments, the cancer is lung cancer, and the exon 20 insertion is V769_D770insASV.

[0033] In certain embodiments, the cancer is lung cancer, and the exon 20 insertion is D770_N771insSVD.

[0034] In certain embodiments, the cancer is non-small cell lung cancer, and the exon 20 insertion is V769_D770insASV.

[0035] In certain embodiments, the cancer is non-small cell lung cancer, and the exon 20 insertion is D770_N771insSVD.

[0036] The patient can have a histologically- or cytologically-confirmed diagnosis of NSCLC Stage IIIB / C or IV not eligible for curative intent surgery or chemoradiation.

[0037] The presence of the EGFR exon 20 mutation can be determined by a polymerase chain reaction (PCR) or NGS-based FDA approved test or as part of normal clinical care in a CLIA or similarly-certified laboratory.

[0038] The patient can have new or recent tumor biopsy (collected at screening, if feasible) or archival tumor specimen collected in the past 10 years available for genomic profiling.

[0039] The patient can have at least 1 (e.g., at least 2, at least 3, at least 4, at least 5) measurable tumor lesion per RECIST vl .1.

[0040] The patient can be >18 years of age at the time of signing the ICF. The patient can have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or E

[0041] The methods can further include providing a biological sample from the patient.

[0042] The methods can further include determining (or having determined) the absence of concurrent T790M and C797S resistance mutations in the patient.

[0043] The patient can be relapsed or resistant to treatment with one or more prior anticancer therapies.

[0044] In certain embodiments, the one or more prior anti-cancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti -cancer therapies or kinase inhibitors, or any combination thereof.

[0045] For example, the one or more prior anti-cancer therapies comprises carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitor, an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR, an inhibitor of AXL, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib or sunitinib, or any combination thereof. In embodiments, the patient has been or is currently being treated with one or more of the foregoing therapies.

[0046] The patient can be treatment naive.

[0047] The methods can further include administering one or more anti-cancer therapies to the patient.

[0048] In certain embodiments, the one or more anti-cancer therapies include chemotherapy, radiation therapy, surgery, a targeted anti -cancer therapy, a kinase inhibitor, or any combination thereof.

[0049] In certain embodiments, the kinase inhibitor is an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR or an inhibitor of AXL. For example, the kinase inhibitor can be lazertinib, poziotinib, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib or sunitinib. The patient can be a human.

[0050] Additional Definitions

[0051] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0052] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the patient being treated.

[0053] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0054] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed. Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. , Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed. Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.. Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0055] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt is not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein form with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0056] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0057] As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0058] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the methods described herein will be apparent from the description and the claims.

[0059] DETAILED DESCRIPTION

[0060] This disclosure features methods for treating a lung cancer (e.g., small-cell lung cancer) that is positive for an EGFR exon 20 mutation in a patient in need thereof, the methods include administering to the patient a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof.

[0061] General

[0062] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that includes the compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0063] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, P, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK. 2012).

[0064] Routes of Administration and Composition Components

[0065] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered to a patient in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e g., intratumoral).

[0066] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0067] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0068] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0069] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0070] Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795.

[0071] Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, pol oxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p- oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[0072] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[0073] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0074] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two- compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0075] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0076] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP / NF standard is usually sufficient.

[0077] In certain embodiments, solid oral dosage forms can further include one or more components that chemically and / or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and / or transverse colon and / or distal colon and / or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

[0078] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0079] Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric / pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

[0080] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0081] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing.

[0082] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0083] Dosages

[0084] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treated and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[0085] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg / Kg to about 500 mg / Kg (e.g., from about 0.001 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 150 mg / Kg; from about 0.01 mg / Kg to about 100 mg / Kg; from about 0.01 mg / Kg to about 50 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 5 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from about 0.01 mg / Kg to about 0.5 mg / Kg; from about 0.01 mg / Kg to about 0.1 mg / Kg; from about 0. 1 mg / Kg to about 200 mg / Kg; from about 0. 1 mg / Kg to about 150 mg / Kg; from about 0. 1 mg / Kg to about 100 mg / Kg; from about 0.1 mg / Kg to about 50 mg / Kg; from about 0. 1 mg / Kg to about 10 mg / Kg; from about 0. 1 mg / Kg to about 5 mg / Kg; from about 0. 1 mg / Kg to about 1 mg / Kg; from about 0. 1 mg / Kg to about 0.5 mg / Kg).

[0086] Regimens

[0087] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0088] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

[0089] In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes an insertion of one or more residues in exon 20 of the EGFR gene (e.g., any of the exon 20 insertions described in Table la and Table lb). Exon 20 of EGFR has two major regions, the c -helix (residues 762-766) and the loop following the c-helix (residues 767-774). Studies suggest that for some exon 20 insertions (e.g., insertions after residue 764), a stabilized and ridged active conformation induces resistance to first generation EGFR inhibitors. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes an insertion of one or more residues in exon 20 selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. For example, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP; or any combination thereof; e.g., any two or more independently selected exon 20 insertions; e.g., any two independently selected exon 20 insertions (e.g., V769_D770insASV and D770_N771insSVD).

[0090] Table la. EGFR Protein Amino Acid Substitutions / Insertions / DeletionsA

[0091]

[0092] AThe EGFR mutations shown may be activating mutations and / or confer increased resistance of EGFR to an EGFR inhibitor and / or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type EGFRBPotentially oncogenic variant. See, e.g., Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566.

[0093] 1PCT Patent Application Publication No. WO2019 / 246541.

[0094] 2Grosse A, Grosse C, Rechsteiner M, Soltermann A. Diagn Pathol. 2019; 14(1): 18. Published 2019 Feb 11. doi : 10.1186 / sl 3000-019-0789- 1.3Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4(1):67— 81. doi: 10.3978 / j.issn.2218-6751.2014.11.06.

[0095] 4Pines, Gur, Wolfgang J. Kostler, and Yosef Yarden. FEBS letters 584.12 (2010): 2699- 2706.

[0096] 3Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31.

[0097] 6Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237-245. doi: 10.1080 / 15384047.2016.1139235.

[0098] 7Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019).8Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390 / ijms20225701.

[0099] 9Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016 / j.semcancer.2019.09.015.

[0100] 10Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053 / j.seminoncol.2019.08.004.

[0101] 11Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566.

[0102] 12Vyse and Huang et al. Signal Transduct Target Ther. 2019 Mar 8;4:5. doi: 10.1038 / s41392-019-0038-9.

[0103] 13PCT Patent Application Publication No. WO2019 / 046775.14PCT Patent Application Publication No. WO 2018 / 094225.

[0104] Table lb. EGFR Protein Amino Acid Substitutions / Insertions / DeletionsA

[0105]

[0106]

[0107] AThe EGFR mutations shown may be activating mutations and / or confer increased resistance of EGFR to an EGFR inhibitor and / or a multi -kinase inhibitor (MKI), e.g., as compared to a wild type EGFRBPotentially oncogenic variant. See, e.g., Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566.

[0108] 1PCT Patent Application Publication No. WO2019 / 246541.

[0109] 2Grosse A, Grosse C, Rechsteiner M, Soltermann A. Diagn Pathol. 2019; 14(1): 18.

[0110] Published 2019 Feb 11. doi:10.1186 / sl3000-019-0789-l.

[0111] 3Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4( 1):67— 81. doi:10.3978 / j.issn.2218-6751.2014.11.06.

[0112] 4Pines, Gur, Wolfgang J. Kostler, and Yosef Yarden. FEBS letters 584.12 (2010): 2699- 2706.

[0113] 5Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31.

[0114] 6Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237-245. doi:10.1080 / 15384047.2016.1139235.

[0115] 7Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019).

[0116] 8Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390 / ijms20225701.

[0117] 9Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016 / j.semcancer.2019.09.015.

[0118] 10Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053 / j.seminoncol.2019.08.004.

[0119] 11Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566.

[0120] 12Vyse and Huang et al. Signal Transduct Target Ther. 2019 Mar 8;4:5. doi: 10.1038 / s41392-019-0038-9.

[0121] 13PCT Patent Application Publication No. WO2019 / 046775.

[0122] 14PCT Patent Application Publication No. WO 2018 / 094225.

[0123] 15Mondal, Gourish, et al. Acta Neuropathol. 2020; 139(6): 1071-1088

[0124] 16Udager, Aaron M., et al. Cancer Res, 2015; 75(13): 2600-2606

[0125] In some embodiments, the dysregulation of an KGI gene, an EGFR kinase, or expression or activity or level of any of the same, includes a splice variation in an EGFR mRNA which results in an expressed protein that is an alternatively spliced variant of EGFR having at least one residue deleted (as compared to the wild type EGFR kinase) resulting in a constitutive activity of an EGFR kinase domain.

[0126] In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acid substitutions or insertions or deletions in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acids inserted or removed, as compared to the wild type EGFR kinase. In some cases, the resulting EGFR kinase is more resistant to inhibition (e.g., inhibition of its signaling activity) by one or more first EGFR inhibitors, as compared to a wild type EGFR kinase or an EGFR kinase not including the same mutation. Such mutations, optionally, do not decrease the sensitivity of the cancer cell or tumor having the EGFR kinase to treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof (e.g., as compared to a cancer cell or a tumor that does not include the particular EGFR inhibitor resistance mutation).

[0127] In other embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acid substitutions as compared to the wild type EGFR kinase, and which has increased resistance to the compound of Formula (I), or a pharmaceutically acceptable salt thereof, as compared to a wild type EGFR kinase or an EGFR kinase not including the same mutation. In such embodiments, an EGFR inhibitor resistance mutation can result in an EGFR kinase that has one or more of an increased Vmax, a decreased Km, and a decreased KD in the presence of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, as compared to a wild type EGFR kinase or an EGFR kinase not having the same mutation in the presence of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0128] Exemplary Sequence of Mature Human EGFR Protein (UniProtKB entry P00533) (SEQ ID NO: 1)

[0129] MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS

[0130] LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYVL IALNTVERIP

[0131] LENLQI IRGN MY YENS YALA VLSNYDANKT GLKELPMRNL QEILHGAVRF SNNPALCNVE S IQWRDIVSS DFLSNMSMDF QNHLGSCQKC DPSCPNGSCW GAGEENCQKL TKI ICAQQCS GRCRGKSPSD CCHNQCAAGC TGPRESDCLV CRKFRDEATC KDTCPPLMLY NPTTYQMDVN PEGKYSFGAT CVKKCPRNYV VTDHGSCVRA CGADSYEMEE DGVRKCKKCE GPCRKVCNGI GIGEFKDSLS INATNIKHFK NCTS ISGDLH ILPVAFRGDS FTHTPPLDPQ ELDILKTVKE ITGFLLIQAW PENRTDLHAF ENLEI IRGRT KQHGQFSLAV VSLNITSLGL RSLKEISDGD VI ISGNKNLC YANTINWKKL FGTSGQKTKI ISNRGENSCK ATGQVCHALC SPEGCWGPEP RDCVSCRNVS RGRECVDKCN LLEGEPREFV ENSECIQCHP ECLPQAMNIT CTGRGPDNCI QCAHYIDGPH CVKTCPAGVM GENNTLVWKY ADAGHVCHLC HPNCTYGCTG PGLEGCPTNG PKIPSIATGM VGALLLLLW ALGIGLFMRR RHIVRKRTLR RLLQERELVE PLTPSGEAPN QALLRILKET EFKKIKVLGS GAFGTVYKGL WIPEGEKVKI PVAIKELREA TSPKANKEIL DEAYVMASVD NPHVCRLLGI CLTSTVQLIT QLMPFGCLLD YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH VKITDFGLAK LLGAEEKEYH AEGGKVPIKW MALESILHRI YTHQSDVWSY GVTVWELMTF GSKPYDGIPA SEISSILEKG ERLPQPPICT IDVYMIMVKC WMIDADSRPK FRELI IEFSK MARDPQRYLV IQGDERMHLP SPTDSNFYRA LMDEEDMDDV VDADEYLIPQ QGFFSSPSTS RTPLLSSLSA TSNNSTVACI DRNGLQSCPI KEDSFLQRYS SDPTGALTED S IDDTFLPVP EYINQSVPKR PAGSVQNPVY HNQPLNPAPS RDPHYQDPHS TAVGNPEYLN TVQPTCVNST FDSPAHWAQK GSHQISLDNP DYQQDFFPKE AKPNGIFKGS TAENAEYLRV APQSSEFIGA

[0132] In some embodiments, dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes at least one EGFR inhibitor resistance mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more of the amino acid substitutions, insertions, or deletions as described in Table 2a and Table 2b. In some embodiments, the compound of Formula (I) and pharmaceutically acceptable salts and solvates thereof are useful in treating patients that develop cancers with EGFR inhibitor resistance mutations (e.g., that result in an increased resistance to a first EGFR inhibitor, e.g., a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A), and / or one or more EGFR inhibitor resistance mutations listed in Table 2a and Table 2b) by either dosing in combination or as a subsequent or additional (e g., follow-up) therapy to existing drug treatments (e.g., other inhibitors of EGFR; e.g., first and / or second EGFR inhibitors). Table 2a. EGFR Protein Amino Acid Resistance Mutations 1PCT Patent Application Publication No. WO2019 / 246541

[0133] 2Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4( 1):67— 81. doi:10.3978 / j.issn.2218-6751.2014.11.063Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1

[0134] (2012): e23-e31.

[0135] 4Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237-245. doi: 10.1080 / 15384047.2016.1139235

[0136] ’Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019).6Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences

[0137] 20.22 (2019): 5701. doi: 10.3390 / ijms20225701.

[0138] 7Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016 / j.semcancer.2019.09.015

[0139] 8Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053 / j.seminoncol.2019.08.004

[0140] Table 2b. EGFR Protein Amino Acid Resistance Mutations

[0141] 1PCT Patent Application Publication No. WO2019 / 246541

[0142] 2Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4( 1):67— 81. doi:10.3978 / j.issn.2218-6751.2014.11.063Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1

[0143] (2012): e23-e31.

[0144] 4Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237-245. doi: 10.1080 / 15384047.2016.1139235

[0145] 5Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019).6Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences

[0146] 20.22 (2019): 5701. doi: 10.3390 / ijms20225701.7Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016 / j.semcancer.2019.09.015

[0147] 8Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053 / j.seminoncol.2019.08.0049Papadimitrakopoulou, V.A., et al. Annals of Oncology 2018; 29 Supplement 8 VIII741

[0148] In some embodiments, the EGFR Protein Amino Acid Substitutions / Insertions / Deletions include any one or more, or any two or more (e.g., any two), of the EGFR Protein Amino Acid Substitutions / Insertions / Deletions delineated in Table la, lb and / or Table 2a, 2b; e.g., any one or more, or any two or more (e.g., any two), of the following and independently selected EGFR Protein Amino Acid Substitutions / Insertions / Deletions: V769L; V769M; M766delinsMASVx2;

[0149] A767_V769dupASV; A767delinsASVDx3; A767delinsASVG; S768_V769insX; V769_D770insX; V769_D770insASV; D770delinsDN; D770delinsDNPH; D770_N771insSV; N771delinsNPH; N771_H773dup; L858R / C797S (or C797G); or Del_19 and C797S (or C797G), or any combination thereof.

[0150] As used herein, a “first inhibitor of EGFR” or “first EGFR inhibitor” is an EGFR inhibitor as defined herein, but which does not include the compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined herein. As used herein, a “second inhibitor of EGFR” or a “second EGFR inhibitor” is an EGFR inhibitor as defined herein, but which does not include the compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined herein. When both a first and a second inhibitor of EGFR are present in a method provided herein, the first and second inhibitors of EGFR are different. In some embodiments, the first and / or second inhibitor of EGFR bind in a different location than the compound of Formula (I). For example, in some embodiments, a first and / or second inhibitor of EGFR can inhibit dimerization of EGFR, while the compound of Formula (I) can inhibit the active site. In some embodiments, a first and / or second EGFR inhibitor can be an allosteric inhibitor of EGFR, while the compound of Formula (I) can inhibit the EGFR active site.

[0151] Exemplary first and second inhibitors of EGFR are described herein. In some embodiments, a first or second inhibitor of EGFR can be selected from the group consisting of osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO- 1686, or WZ4002.

[0152] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salts and solvates thereof are useful for treating a cancer that has been identified as having one or more EGFR inhibitor resistance mutations (that result in an increased resistance to a first or second inhibitor of EGFR, e.g., a substitution described in Table 2a and Table 2b including substitutions at amino acid position 747, 761, 790, 797, or 854 (e g., L718Q, L747S, D761Y, T790M, C797S, T854A)). In some embodiments, the one or more EGFR inhibitor resistance mutations occurs in a nucleic acid sequence encoding a mutant EGFR protein (e.g., a mutant EGFR protein having any of the mutations described in Table 2a and Table 2b) resulting in a mutant EGFR protein that exhibits EGFR inhibitor resistance.

[0153] The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTKs) and provides critical functions in epithelial cell physiology (Schlessinger J (2014) Cold Spring Harb Perspect Biol 6, a008912). It is frequently mutated and / or overexpressed in different types of human cancers and is the target of multiple cancer therapies currently adopted in the clinical practice (Yarden Y and Pines G (2012) Nat Rev Cancer 12, 553-563).

[0154] Accordingly, provided herein are methods for treating a patient diagnosed with (or identified as having) a cancer that include administering to the patient a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0155] Also provided herein are methods for treating a patient identified or diagnosed as having an EGFR-associated cancer that include administering to the patient a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the patient that has been identified or diagnosed as having an EGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, in a patient or a biopsy sample from the patient or by performing any of the non-limiting examples of assays described herein. Tn some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an EGFR-associated cancer. For example, the EGFR-associated cancer can be a cancer that includes one or more EGFR inhibitor resistance mutations.

[0156] The term "regulatory agency" refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0157] Also provided are methods for treating cancer in a patient in need thereof, the method comprising: (a) detecting an EGFR-associated cancer in the patient; and (b) administering to the patient a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the patient another anticancer agent (e.g., a second EGFR inhibitor, or a pharmaceutically acceptable salt thereof, or an immunotherapy). In some embodiments, the patient was previously treated with a first EGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the patient is determined to have an EGFR-associated cancer through the use of a regulatory agency- approved, e.g., FDA-approved test or assay for identifying dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, in a patient or a biopsy sample from the patient or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an EGFR-associated cancer. For example, the EGFR- associated cancer can be a cancer that includes one or more EGFR inhibitor resistance mutations.

[0158] Also provided are methods of treating a patient that include performing an assay on a sample obtained from the patient to determine whether the patient has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to the patient determined to have a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. Some embodiments of these methods further include administering to the patient another anticancer agent (e.g., a second EGFR inhibitor, or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments of these methods, the patient was previously treated with a first EGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the patient is a patient suspected of having an EGFR-associated cancer, a patient presenting with one or more symptoms of an EGFR-associated cancer, or a patient having an elevated risk of developing an EGFR-associated cancer. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency- approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations.

[0159] Also provided is the compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for use in treating an EGFR- associated cancer in a patient identified or diagnosed as having an EGFR-associated cancer through a step of performing an assay (e g., an in vitro assay) on a sample obtained from the patient to determine whether the patient has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, where the presence of a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, identifies that the patient has an EGFR-associated cancer. Also provided is the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating an EGFR-associated cancer in a patient identified or diagnosed as having an EGFR-associated cancer through a step of performing an assay on a sample obtained from the patient to determine whether the patient has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same where the presence of dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, identifies that the patient has an EGFR-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the patient’ s clinical record (e.g., a computer readable medium) that the patient is determined to have a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, through the performance of the assay, should be administered the compound of Formula (I), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency -approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations.

[0160] Also provided is the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a patient in need thereof or a patient identified or diagnosed as having an EGFR-associated cancer. Also provided is the use of the compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a cancer in a patient identified or diagnosed as having an EGFR-associated cancer. In some embodiments, the cancer is an EGFR- associated cancer, for example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, a patient is identified or diagnosed as having an EGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, in a patient or a biopsy sample from the patient. As provided herein, an EGFR-associated cancer includes those described herein and known in the art.

[0161] In some embodiments of any of the methods or uses described herein, the patient has been identified or diagnosed as having a cancer with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the patient has a tumor that is positive for a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the patient can be a patient with a tumor(s) that is positive for a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the patient can be a patient whose tumors have a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the patient is suspected of having an EGFR-associated cancer (e.g., a cancer having one or more EGFR inhibitor resistance mutations). In some embodiments, provided herein are methods for treating an EGFR-associated cancer in a patient in need of such treatment, the method comprising a) detecting a dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same in a sample from the patient; and b) administering a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more EGFR kinase protein point mutations / insertions / deletions. Non-limiting examples of EGFR kinase protein point mutations / insertions / deletions are described in Table la and Table lb. In some embodiments, the EGFR kinase protein point mutations / insertions / deletions are selected from the group consisting of G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, a deletion in exon 19 (e.g., L747_A750del), and an insertion in exon 20. In some embodiments, the EGFR kinase protein point mutations / insertions / deletions are selected from the group consisting of L858R, deletions in exon 19 (e.g., L747_A750del), L747S, D761Y, T790M, and T854A. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations. Non-limiting examples of EGFR inhibitor resistance mutations are described in Table 2a and Table 2b. In some embodiments, the EGFR inhibitor resistance mutation is a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, and T854A). In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more point mutations / insertions / deletions in exon 20. Non-limiting examples of EGFR exon 20 mutations are described in Tables la, lb, 2a and 2b . In some embodiments, the EGFR exon 20 mutation is an exon 20 insertion such as V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. For example, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP,

[0162] H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP. In some embodiments, the cancer with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor that is positive for a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same is a tumor positive for one or more EGFR inhibitor resistance mutations. In some embodiments, the tumor with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit.

[0163] In some embodiments of any of the methods or uses described herein, the patient has a clinical record indicating that the patient has a tumor that has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same (e.g., a tumor having one or more EGFR inhibitor resistance mutations). Also provided are methods of treating a patient that include administering a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a patient having a clinical record that indicates that the patient has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same.

[0164] In some embodiments, the methods provided herein include performing an assay on a sample obtained from the patient to determine whether the patient has a dysregulation of an EGFR gene, an EGFR protein, or expression or level of any of the same. In some such embodiments, the method also includes administering to a patient determined to have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining that a patient has a dysregulation of an EGFR gene, an EGFR protein, or expression or level of any of the same via an assay performed on a sample obtained from the patient. In such embodiments, the method also includes administering to a patient a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more point mutation in the EGFR gene (e.g., any of the one or more of the EGFR point mutations described herein). The one or more point mutations in an EGFR gene can result, e.g., in the translation of an EGFR protein having one or more of the following amino acid substitutions, deletions, and insertions: G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, a deletion in exon 19 (e.g., L747_A750del), and an insertion in exon 20 (e.g., V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX). The one or more mutations in an EGFR gene can result, e.g., in the translation of an EGFR protein having one or more of the following amino acid substitutions or deletions: L858R, deletions in exon 19 (e.g., L747_A750del), L747S, D761Y, T790M, and T854A. In some embodiments, the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more EGFR inhibitor resistance mutations (e.g., any combination of the one or more EGFR inhibitor resistance mutations described herein). In some embodiments, the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more EGFR exon 20 insertions (e.g., any of the exon 20 insertions described herein). In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV,

[0165] D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770 N771insGL,

[0166] N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV,

[0167] P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP. Some embodiments of these methods further include administering o the patient another anticancer agent (e.g., a second EGFR inhibitor, or a pharmaceutically acceptable salt thereof, or immunotherapy).

[0168] In some embodiments of any of the methods or uses described herein, an assay used to determine whether the patient has a dysregulation of an EGFR gene, or an EGFR kinase, or expression or activity or level of any of the same, using a sample from a patient can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigenbinding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or levels of any of the same (see, e.g., the references cited herein). In some embodiments, the dysregulation of the ECiFR gene, the EGFR kinase, or expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations. In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin- embedded biopsy sample) from the patient. In some embodiments, the patient is a patient suspected of having an EGFR-associated cancer, a patient having one or more symptoms of an EGFR-associated cancer, and / or a patient that has an increased risk of developing an EGFR-associated cancer).

[0169] In some embodiments, dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and / or the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same. Liquid biopsies can be performed on biological samples obtained relatively easily from a patient (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same at an earlier stage than traditional methods. In some embodiments, the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same.

[0170] Combinations

[0171] In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors and / or monoclonal antibodies. For example, a surgery may be open surgery or minimally invasive surgery. The compound of Formula (I), or pharmaceutically acceptable salts or solvates thereof therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a patient in need thereof can be administered one or more doses of the compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of the compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a patient in need thereof can be administered one or more doses of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of the compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0172] In some embodiments, a patient has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a first EGFR inhibitor, a first HER2 inhibitor, or a multikinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a patient has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a first EGFR inhibitor, a first HER2 inhibitor, or a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a patient has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a patient is EGFR inhibitor naive. For example, the patient is naive to treatment with a selective EGFR inhibitor. In some embodiments, a patient is not EGFR inhibitor naive. In some embodiments, a patient is HER2 inhibitor naive. For example, the patient is naive to treatment with a selective HER2 inhibitor. In some embodiments, a patient is not HER2 inhibitor naive. In some embodiments, a patient has undergone prior therapy. For example, treatment with a multi-kinase inhibitor (MKI), an EGFR tyrosine kinase inhibitor (TKI), osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD- 9291, CL-387785, CO-1686, or WZ4002. In some embodiments of any the methods described herein, the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents.

[0173] Non-limiting examples of additional therapeutic agents include: other EGFR- targeted therapeutic agents (i.e., a first or second EGFR inhibitor), other HERZ -targeted therapeutic agents (i.e., a first or second HERZ inhibitor), RAS pathway targeted therapeutic agents, PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase- targeted therapeutic agents (e.g., Trk inhibitors or multi-kinase inhibitors)), famesyl transferase inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., obataclax); cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.

[0174] In some embodiments, the other EGFR-targeted therapeutic is a multi-kinase inhibitor exhibiting EGFR inhibition activity. In some embodiments, the other EGFR- targeted therapeutic inhibitor is selective for an EGFR kinase.

[0175] Non-limiting examples of EGFR-targeted therapeutic agents (e.g., a first EGFR inhibitor or a second EGFR inhibitor) include an EGFR-selective inhibitor, a panHER inhibitor, and an anti-EGFR antibody. In some embodiments, the EGFR inhibitor is a covalent inhibitor. In some embodiments, the EGFR-targeted therapeutic agent is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO- 1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS- 816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e g., deoxyshikonin, isobutyryl shikonin, acetylshikonin, P,P-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI- 15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ- 61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002.

[0176] Additional EGFR-targeted therapeutic agents (e.g., a first EGFR inhibitor or a second EGFR inhibitor) include those disclosed in WO 2019 / 246541; WO 2019 / 165385; WO 2014 / 176475; and US 9,029,502, each of which is incorporated by reference in its entirety.

[0177] In some embodiments, the other HER2 -targeted therapeutic is a multi-kinase inhibitor exhibiting HER2 inhibition activity. In some embodiments, the other HER2- targeted therapeutic inhibitor is selective for a HER2 kinase.

[0178] Non-limiting examples of HERZ -targeted therapeutic agents (e.g., a first HERZ inhibitor or a second HERZ inhibitor) include a HER2-selective inhibitor, a panHER inhibitor, and an anti-HERZ antibody. Exemplary HER2-targeted therapeutic agents include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 22261 1, and AEE-788.

[0179] Additional HER2-targeted therapeutic agents (e.g., a first HER2 inhibitor or a second HER2 inhibitor) include those disclosed in WO 2019 / 246541; WO 2019 / 165385; WO 2014 / 176475; and US 9,029,502, each of which is incorporated by reference in its entirety.

[0180] A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Nonlimiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K / AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K / AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor. Non-limiting examples of a KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include BI 1701963, AMG 510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849.

[0181] Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVITM), BMS-908662 (XL281), sorafenib, LGX818, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC- 0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof. In some embodiments, the MEK inhibitor is trametinib (MEKTNIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof.

[0182] In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-l le, 25- OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK- 8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG- 7482), ASN007, FR148083, 5-7-Oxozeaenol, 5 -iodotub erci din, GDC0994, ONC201, or a combination thereof.

[0183] In some embodiments, PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC- 907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC- 0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI- 402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN- 193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof.

[0184] In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC 120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SRI 3668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin- 3 -yl)benzyl)-3 -fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof.

[0185] In some embodiments, the mTOR inhibitor is selected from MLN0128, AZD-2014, CC-223, AZD2014, CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), or a combination thereof.

[0186] Non-limiting examples of farnesyl transferase inhibitors include lonafamib, tipifamib, BMS-214662, L778123, L744832, and FTI-277.

[0187] In some embodiments, a chemotherapeutic agent includes an anthracycline, cyclophosphamide, a taxane, a platinum-based agent, mitomycin, gemcitabine, eribulin (HALAVEN™), or combinations thereof.

[0188] Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.

[0189] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0190] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof

[0191] Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-lOOl, and JPI-289.

[0192] Non-limiting examples of immunotherapy include immune checkpoint therapies, atezolizumab (TECENTRIQ®), albumin-bound paclitaxel. Non-limiting examples of immune checkpoint therapies include inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI -444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin-Acevedo, et al., J Hematol Oncol. 11: 39 (2018).

[0193] In some embodiments, the additional therapy or therapeutic agent is a combination of atezolizumab and nab-paclitaxel.

[0194] Accordingly, also provided herein is a method of treating cancer, comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer.

[0195] In some embodiments, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of an EGOR gene, an EGFR protein, or expression or activity, or level of any of the same.

[0196] In some embodiments, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity, or level of any of the same.

[0197] These additional therapeutic agents may be administered with one or more doses of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and / or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.

[0198] Also provided herein is (i) a pharmaceutical combination for treating a cancer in a patient in need thereof, which comprises (a) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound ofFormula (I), or pharmaceutically acceptable salt thereof, and of the additional therapeutic agent are together effective in treating the cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer in a patient in need thereof. In some embodiments, the cancer is an EGFR-associated cancer. For example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER2-associated cancer. For example, a HER2-associated cancer having one or more HER2 inhibitor resistance mutations.

[0199] The term "pharmaceutical combination", as used herein, refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent), are both administered to a patient simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are formulated as separate compositions or dosages such that they may be administered to a patient in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient. These also apply to cocktail therapies, e.g., the administration of three or more active ingredients.

[0200] Accordingly, also provided herein is a method of treating a cancer, comprising administering to a patient in need thereof a pharmaceutical combination for treating cancer which comprises (a) the compound of Formula (I), or pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, wherein the compound ofFormula (I) and the additional therapeutic agent are administered simultaneously, separately or sequentially, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g., in daily or intermittently dosages. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the cancer is an EGFR-associated cancer. For example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER2-associated cancer. For example, a HER2-associated cancer having one or more HER2 inhibitor resistance mutations.

[0201] In some embodiments, the presence of one or more EGFR inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a first EGFR inhibitor. Methods useful when an EGFR inhibitor resistance mutation causes the tumor to be more resistant to treatment with a first EGFR inhibitor are described below. For example, provided herein are methods of treating a patient having a cancer that include: identifying a patient having a cancer cell that has one or more EGFR inhibitor resistance mutations; and administering to the identified patient the compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with the first EGFR inhibitor. Also provided are methods of treating a patient identified as having a cancer cell that has one or more EGFR inhibitor resistance mutations that include administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is administered in combination with the first EGFR inhibitor. In some embodiments, the one or more EGFR inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor. In some embodiments, the one or more EGFR inhibitor resistance mutations include one or more EGFR inhibitor resistance mutations listed in Table 2a and Table 2b. For example, the one or more EGFR inhibitor resistance mutations can include a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, and T854A).

[0202] For example, provided herein are methods for treating an EGFR-associated cancer in a patient in need of such treatment, the method comprising (a) detecting a dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same in a sample from the patient; and (b) administering to the patient a therapeutically effective amount of a first EGFR inhibitor, wherein the first EGFR inhibitor is selected from the group consisting of osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD- 9291, CL-387785, CO- 1686, or WZ4002. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the patient has at least one EGFR inhibitor resistance mutation; and (d) administering the compound of Formula (I), or a pharmaceutically acceptable salt thereof as a monotherapy or in conjunction with another anticancer agent to the patient if the patient has been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation; or (e) administering additional doses of the first EGFR inhibitor of step (b) to the patient if the patient has not been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation.

[0203] Compound Preparation

[0204] The compound disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compound disclosed herein can be achieved by generally following the scheme below, with modification for specific desired substituents. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001 ; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compound of the present disclosure.

[0205] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0206] Example 1

[0207] The compound of formula (I) described herein can be using the procedure describing the synthesis of compound 362 in WO 2022 / 066734.

[0208] Example 2

[0209] Study Description

[0210] Study: Compound of Formula (I) is an open label, Phase 1 / 2 study evaluating the safety, tolerability, pharmacokinetic (PK) exposure, and preliminary antitumor activity of Compound of Formula (I) in participants with non-small cell lung cancer (NSCLC) carrying EGFR / HER2 exon 20 insertion (ex20ins) mutations.

[0211] Conditions Conditions: Non-Small Cell Lung Cancer

[0212] NSCLC

[0213] EGFR Exon 20 Insertion Mutation

[0214] Keywords:

[0215] Study Design

[0216] Study Type: Interventional

[0217] Primary Purpose: Treatment

[0218] Study Phase: Phase 1 / Phase 2

[0219] Interventional Study Model: Sequential Assignment

[0220] Number of Arms: 3

[0221] Masking: None (Open Label)

[0222] Allocation: Non-Randomized

[0223] Enrollment: 120 [Anticipated]

[0224] Arms and Interventions

[0225] ; Arms ( Assigned Interventions

[0226] Experimental: Part 1 : Dose Escalation j Drug: Compound of Formula (I)

[0227] [ Compound of Formula (I) dose will be escalated per

[0228] [ Safety Evaluation Team (SET)

[0229] [ decision and BLRM-design.

[0230] Experimental: Part 2: RP2D Selection Drug: Compound of Formula (I)

[0231] Participants will receive doses of Compound of Formula (I).

[0232] Experimental: Part 3: Dose Expansion Drug: Compound of Formula (I) participants will receive pie RP2D of Compound of Formula (I).

[0233] Outcome Measures

[0234] Primary Outcome Measure:

[0235] 1 . Part 1 Dose Escalation (MTD): Dose Escalation - Number of participants who experience at least 1 DLT during the first 28 days of treatment

[0236] [Time Frame: 28 days]

[0237] 2. Part 2 RP2D Selection: Mean plasma pharmacokinetics (PK) exposure concentrations of Compound of Formula (I)

[0238] [Time Frame: 1 year]

[0239] 3. Part 2 RP2D Selection: Pharmacodynamic (PD) marker data change from baseline

[0240] [Time Frame: 1 year]

[0241] 4. Part 2 RP2D Selection: PD marker data change in absolute value versus time [Time Frame: 1 year]

[0242] 5. Part 2 RP2D Selection: Number of participants with confirmed objective response rate (ORR) defined as the percentage of participants with partial response (PR) or complete response (CR) based on RECIST v1.1 per investigator assessment.

[0243] [Time Frame: 1 year]

[0244] 6. Part 3 Dose Expansion: Number of participants with confirmed ORR defined as the percentage of participants with PR or complete response CR based on RECIST v1 .1 per investigator assessment.

[0245] [Time Frame: 1 year]

[0246] Eligibility

[0247] Minimum Age: 18 Years

[0248] Maximum Age:

[0249] Sex: All

[0250] Gender Based:

[0251] Accepts Healthy No Volunteers:

[0252] Criteria: Key Inclusion Criteria:

[0253] 1 . Has histologically- or cytologically-confirmed diagnosis of NSCLC Stage IIIB / C or IV not eligible for curative intent surgery or chemoradiation.

[0254] 2. Has a tumor that harbors one of the following confirmed mutations as determined by a polymerase chain reaction (PCR) or NGS-based FDA approved test or as part of normal clinical care in a CLIA or similarly-certified laboratory.

[0255] 3. Has new or recent tumor biopsy (collected at screening, if feasible) or archival tumor specimen collected in the past 10 years available for genomic profiling (see lab manual for minimum tissue requirements).

[0256] 4. Is >18 years of age at the time of signing the ICF.

[0257] 5. Has Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 .

[0258] Key Exclusion Criteria:

[0259] 1 . Has a tumor that is known to harbor concurrent T790M and C797S resistance mutations.

[0260] 2. Has history (within <2 years before screening) of solid tumor or hematological malignancy that is histologically distinct from NSCLC.

[0261] 3. Has symptomatic brain or spinal metastases.

[0262] 4. Has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness / social situation that would limit compliance with study requirements.

[0263] 5. Has had treatment with any local or systemic antineoplastic therapy or investigational anticancer agent within 14 days or 4 half-lives, whichever is longer, prior to the initiation of study treatment, up to a maximum wash-out period of 28 days.

[0264] 6. Has toxicities from previous anticancer therapies that have not resolved to baseline levels or to CTCAE Grade <1 , except for alopecia and peripheral neuropathy.

[0265] 7. Has had radiotherapy within 14 days before the initiation of study treatment.

[0266] 8. Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, could compromise the participant’s well-being) or would prevent, limit, or confound the protocol-specified assessments.

[0267] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a lung cancer that is positive for an EGFR exon 20 mutation in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I):or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the lung cancer is non-small cell lung cancer, small cell lung cancer or lung adenocarcinoma, pulmonary sarcomatoid carcinoma or any combination thereof.

3. The method of claim 1 or 2, wherein the lung cancer is non-small cell lung cancer.

4. The method of any one of claims 1-3, wherein the EGFR exon 20 mutation is an EGFR exon 20 insertion mutation.

5. The method of any one of claims 1-4, wherein the exon 20 insertion is selected from the group consisting of: A767 V769dupASV, V769 D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH,H773_V774insPH, H773_V774insAH, and P772_H773insPNP; or any combination thereof6. The method of any one of claims 1-5, wherein the exon 20 insertion is selected from the group consisting of V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.

7. The method of any one of claims 1-6, wherein the exon 20 insertion is V769_D770insASV or D770_N771insSVD.

8. The method of any one of claims 1-7, wherein the exon 20 insertion is V769_D770insASV.

9. The method of any one of claims 1-8, wherein the exon 20 insertion is D770_N771insSVD.

10. The method of any one of claims 1-9, wherein the lung cancer is non-small cell lung cancer, and the exon 20 insertion is V769_D770insASV.

11. The method of any one of claims 1-9, wherein the lung cancer is non-small cell lung cancer, and the exon 20 insertion is D770_N771insSVD.

12. The method of any one of claims 1-11, wherein the patient has a histologically- or cytologically-confirmed diagnosis of NSCLC Stage IIIB / C or IV not eligible for curative intent surgery or chemoradiation.

13. The method of any one of claims 1-12, wherein the presence of the EGFR exon20 mutation is determined by a polymerase chain reaction (PCR) or NGS-based FDA approved test or as part of normal clinical care in a CLIA or similarly-certified laboratory.

14. The method of any one of claims 1-13, wherein the patient has new or recent tumor biopsy (collected at screening, if feasible) or archival tumor specimen collected in the past 10 years available for genomic profiling.

15. The method of any one of claims 1-14, wherein the patient has at least 1 measurable tumor lesion per RECIST vl .1.

16. The method of any one of claims 1-15, wherein the patient is >18 years of age at the time of signing the ICF.

17. The method of any one of claims 1-16, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

18. The method of any one of claims 1-17, wherein the method further comprises providing a biological sample from the patient.

19. The method of claim 18, wherein the method further comprises determining the absence of concurrent T790M and C797S resistance mutations.

20. The method of any one of claims 1-19, wherein the patient is relapsed or resistant to treatment with one or more prior anti-cancer therapies.

21. The method of claim 20, wherein the one or more prior anti-cancer therapies comprises one or more chemotherapeutic agents, checkpoint inhibitors, targeted anticancer therapies or kinase inhibitors, or any combination thereof.

22. The method of claim 20, wherein the one or more prior anti-cancer therapies comprises carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitor, an inhibitor of EGFR, an inhibitor of c- Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor ofVEGFR, an inhibitor of AXL, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib or sunitinib, or any combination thereof.

23. The method of any one of claims 1-19, wherein the patient is treatment naive.

24. The method of any one of claim 1-19, wherein the patient has previously been treated for lung cancer.

25. The method of any one of claims 1-24, wherein the method further comprises administering one or more anti-cancer therapies to the patient.

26. The method of claim 25, wherein the one or more anti-cancer therapies comprises chemotherapy, radiation therapy, surgery, a targeted anti-cancer therapy, a kinase inhibitor, or any combination thereof.

27. The method of claim 26, wherein the kinase inhibitor is an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR or an inhibitor of AXL.

28. The method of claim 27, wherein the kinase inhibitor is lazertinib, poziotinib, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib or sunitinib.

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