Methods and compositions comprising KRASG12C inhibitors and EGFR inhibitors for the treatment of solid tumors

Abstract

To provide a pharmaceutical for treating KRasG12C mutant colorectal cancer.SOLUTION: The present invention provides a pharmaceutical for use in combination with a compound represented by the following formula and a chemical therapy comprising (i) cetuximab and (ii) FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or FOLFIRI (leucovorin, fluorouracil, and irinotecan).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This application claims the interests of U.S. Provisional Patent Application No. 63 / 122,702, filed on 8 December 2020, which is incorporated herein by reference in its entirety for all purposes.

[0002] Technical field KRas G12C This specification provides combination therapies comprising an inhibitor (e.g., compound 1) and an EGFR inhibitor, as well as methods for using such combination therapy. [Background technology]

[0003] The Carsten rat sarcoma virus oncogene homolog (KRAS) is a central component of the RAS / MAPK signaling pathway, an intracellular network of proteins that transmit extracellular growth factor signals to regulate cell proliferation, differentiation, and survival. Mutations in KRAS are commonly found in solid tumors and can result in alterations in several amino acids, including glycine 12 (G12), glycine 13, and glutamine 61, which are associated with tumorigenesis and aggressive tumor growth (Der et al. Proc Natl Acad Sci USA 1982;79:3637-40; Parada et al. Nature 1982;297:474-8; Santos et al. Nature 1982;298:343-7; Taparowsky et al. Nature 1982;300:762-5; Capon et al. Nature 1983;304:507-13). Oncogenic KRAS mutations that result in a change from G12 to cysteine ​​(G12C) are common in non-small cell lung cancer (NSCLC) (approximately 12%), colorectal cancer (CRC) (approximately 4%), and other tumor types (≤4%) (Bailey et al. Nature 2016;531:47-52; Campbell et al. Nat Genet 2016;48:607-16; Giannakis et al. Cell Reports 2016;15:857-65; Hartmaier et al. Genome Med 2017;9(16); Jordan et al. Cancer Discov 2017;7:596-609).

[0004] For example, KRas, including lung cancer (e.g., NSCLC), CRC, and pancreatic cancer. G12C Advanced tumors with mutations (hereinafter referred to as KRas) G12C KRas (referred to as positive tumors) are incurable and have a poor prognosis (Roman et al. Mol Cancer 2018;17:33; Wan et al. World J Gastroenterol 2019;25:808-23). ​​Furthermore, advanced KRas G12CPatients with positive cancer may have limited benefits from selected chemotherapy and targeted therapies, and therefore have limited effective treatment options (Roman et al. 2018).

[0005] Therefore, KRas G12C Effective therapies and combination therapies are needed to treat cancers such as lung cancer, colorectal cancer, and pancreatic cancer that carry mutations. [Overview of the Initiative]

[0006] This specification provides solutions to these and other problems in the art.

[0007] In one embodiment, a combination therapy comprising Compound 1 described herein or a pharmaceutically acceptable salt thereof and an EGFR inhibitor is provided herein. In one embodiment, the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib or afatinib, or an anti-EGFR antibody. In one embodiment, the EGFR inhibitor is erlotinib or cetuximab.

[0008] In another embodiment, a combination therapy comprising compound 1 described herein or a pharmaceutically acceptable salt thereof, administered by QD on days 1 to 21 of a first 21-day cycle, and erlotinib, administered by QD on days 1 to 21 of a first 21-day cycle, is provided herein.

[0009] In another embodiment, a combination therapy comprising compound 1 described herein or a pharmaceutically acceptable salt thereof, administered in QD on days 1 to 21 of a first 21-day cycle, and cetuximab, administered in Q1W, starting on day 1 of a first 21-day cycle.

[0010] In another embodiment, KRas G12CA method for treating lung cancer in a patient having mutation-mediated lung cancer is provided herein, comprising administering an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof as described herein, administered by QD on days 1 to 21 of a first 21-day cycle, and an EGFR inhibitor. In one embodiment, the lung cancer is NSCLC.

[0011] In another embodiment, in patients with colorectal cancer (CRC), KRas G12C A method for treating mutation-mediated CRC is provided herein, comprising administering an effective dose of combination therapy comprising compound 1 described herein or a pharmaceutically acceptable salt thereof, administered by QD on days 1 to 21 of a first 21-day cycle, and an EGFR inhibitor.

[0012] In another aspect, KRas G12C A method for treating a patient having mutation-mediated pancreatic cancer is provided herein, comprising administering an effective dose of combination therapy comprising compound 1 described herein or a pharmaceutically acceptable salt thereof, administered by QD on days 1 to 21 of a first 21-day cycle, and an EGFR inhibitor.

[0013] In another embodiment, the use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and an EGFR inhibitor for the treatment of lung cancer, CRC, or pancreatic cancer as described herein is provided herein.

[0014] In another embodiment, the use of a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and an EGFR inhibitor for the manufacture of a medicament for the treatment of lung cancer, CRC, or pancreatic cancer is provided herein. [Brief explanation of the drawing]

[0015] [Figure 1]Figure 1 shows the effects of compound 1 and erlotinib administered alone or in combination to NCI-H2122 NSCLC tumor xenografts in nude mice. Vehicle = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80 (trademark). Group-matched tumor volume is shown after oral administration of compound 1 or erlotinib administered alone or in combination in QD over 21 days. Dose levels are expressed as free base equivalents.

[0016] [Figure 2] Figure 2 shows the body weight of nude mice treated with compound 1 and erlotinib, administered alone or in combination, in xenografts of NCI-H2122 NSCLC. QD = once daily (21 doses). Vehicle = 0.5% (w / v) methylcellulose (150 μL), 0.5% (w / v) methylcellulose / 0.2% Tween 80 (trademark) (100 μL).

[0017] [Figure 3] Figure 3 shows the effects of compound 1 and cetuximab administered alone or in combination in a CR6256 colorectal patient-derived xenograft model in nude mice. Vehicle = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80 (trademark). Group-matched tumor volume is shown after oral administration of compound 1 administered alone or in combination via PO, QD, or cetuximab administered via IP, BIW over 21 days. Dose levels are expressed as free base equivalents.

[0018] [Figure 4]Figure 4 shows the effects of compound 1 and cetuximab administered alone or in combination in a CR5048 colorectal patient-derived xenograft model in nude mice. Vehicle = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80 (trademark). Group-matched tumor volume is shown after oral administration of compound 1 alone or in combination via PO, QD, or cetuximab administered via IP, BIW over 21 days. Dose levels are expressed as free base equivalents.

[0019] [Figure 5] Figure 5 shows the effects of compound 1 and cetuximab administered alone or in combination in a CR6243 colorectal patient-derived xenograft model in nude mice. Vehicle = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80 (trademark). Group-matched tumor volume is shown after oral administration of compound 1 administered alone or in combination via PO, QD, or cetuximab administered via IP, BIW over 21 days. Dose levels are expressed as free base equivalents.

[0020] [Figure 6] Figure 6 shows the effects of compound 1 and cetuximab administered alone or in combination in a CR6927 colorectal patient-derived xenograft model in nude mice. Vehicle = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80 (trademark). Group-matched tumor volume is shown after oral administration of compound 1 administered alone or in combination via PO, QD, or cetuximab administered via IP, BIW over 21 days. Dose levels are expressed as free base equivalents.

[0021] [Figure 7]Figure 7 shows the effects of compound 1 and cetuximab administered alone or in combination in a CR2528 colorectal patient-derived xenograft model in nude mice. Vehicle = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80 (trademark). Group-matched tumor volume is shown after oral administration of compound 1 administered alone or in combination via PO, QD, or cetuximab administered via IP, BIW over 21 days. Dose levels are expressed as free base equivalents.

[0022] [Figure 8] Figure 8 shows the effects of compound 1 and cetuximab administered alone or in combination in a CR1451 colorectal patient-derived xenograft model in nude mice. Vehicle = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80 (trademark). Group-matched tumor volume is shown after oral administration of compound 1 alone or in combination via PO, QD, or cetuximab administered via IP, BIW over 21 days. Dose levels are expressed as free base equivalents. [Modes for carrying out the invention]

[0023] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains. See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, apparatus, and materials similar to or equivalent to those described herein may be used in carrying out this invention.

[0024] The following definitions are provided to facilitate understanding of certain terms frequently used in this specification and are not meant to limit the scope of the disclosure. All references mentioned in this specification are incorporated by reference in their entirety.

[0025] As used herein, unless otherwise specified, the terms "about" and "approximately" when referring to the dosage, amount, or weight percentage of a component of a composition or dosage form mean a dosage, amount, or weight percentage recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dosage, amount, or weight percentage. Equivalent dosages, amounts, or weight percentages can be within the range of 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dosage, amount, or weight percentage.

[0026] As used herein, "KRas G12C inhibitor" refers to a covalent inhibitor that specifically binds to a mutant KRas protein containing a Gly-to-Cys mutation at the position corresponding to residue 12.

[0027] "Compound 1" has the structure: TIFF0007852103000001.tif49170 and has the chemical name 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one. In one embodiment, Compound 1 is the adipate salt.

[0028] "Erlotinib" has the structure: TIFF0007852103000002.tif29170 and has the chemical name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. In one embodiment, erlotinib is commercially available under the trade name TARCEVA®.

[0029] Gefitinib has the following structure: It has the chemical name: 4-Quinazolinamine N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy], and the product code TIFF0007852103000003.tif30170. In one embodiment, gefitinib is marketed under the trade name IRESSA®.

[0030] Osimertinib has the following structure: It has the chemical name: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindole-3-yl)pyrimidine-2-yl]amino}phenyl)propaneamide mesylate salt. In one embodiment, osimertinib is marketed under the trade name TAGRISSO®.

[0031] "Afatinib" has the following structure: It has TIFF0007852103000005.tif45170 and has the chemical name: 2-butenamide, N-[4-[(3-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-,(2Z)-2-butenedioate (1:2). In one embodiment, afatinib is marketed under the trade name GILOTRIF®.

[0032] "Dacomitinib" has the following structure: It has the product code TIFF0007852103000006.tif34170 and the chemical name: (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}-4-(piperidine-1-yl)buta-2-enamide monohydrate. In one embodiment, dacomitinib is marketed under the trade name VIZIMPRO®.

[0033] The term "pharmaceutically acceptable" refers to molecular entities and compositions that, when administered appropriately to animals, such as humans, do not produce side effects, allergic reactions, or other adverse reactions.

[0034] The compounds of the present invention may also be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "Pharmacologically acceptable acid addition salt" means a salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, or phosphoric acid, which retains the biological efficacy and properties of the free base and is biologically or otherwise desirable. The organic acid can be selected from the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid categories of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In one embodiment, the salt is formed with adipic acid.

[0035] Examples of "pharmaceutically acceptable base addition salts" include salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Specific examples of base addition salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples of pharmaceutically acceptable salts derived from organic non-toxic bases include primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines containing basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and salts of polyamine resins. Specific examples of organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0036] In some embodiments, the salt is hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipine, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, phloate (e.g., 2-phloate or 3-phloate), napadisylate (naphthalene-1,5-disulfonate, or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonic acid Salt, or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethyl sulfonate), 2-mesitylene sulfonate, 2-naphthalene sulfonate, 2,5-dichlorobenzene sulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipine, esylate, malonate, mesicylate (2-mesitylene sulfonate), napsylate (2-na Selected from phthalene sulfonates, cansylates (camphor 10-sulfonates, e.g., (1S)-(+)-10-camphor-sulfonates), glutamates, glutarates, hippuric acid (2-(benzoylamino)acetate), orotinates, xylates (p-xylene-2-sulfonates), and pamoates (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylates).

[0037] The terms “inhibit” and “reduce / decrease,” or any variation thereof, include any measurable reduction / decrease or complete inhibition to achieve the desired result. For example, there may be a reduction of approximately, at most approximately, or at least approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range of these variables, a decrease in activity compared to normal.

[0038] The terms “EGFR antagonist,” “EGFR inhibitor,” or “EGFR-specific antagonist” are used interchangeably herein and refer to molecules that can bind to EGFR, reduce EGFR expression levels, or neutralize, block, inhibit, suppress, reduce, or interfere with the biological activity of EGFR. EGFR-specific antagonists useful in the methods of the present invention include, alongside the compounds provided herein, polypeptides that specifically bind to EGFR, anti-EGFR antibodies and their antigen-binding fragments, and molecules and derivatives that specifically bind to EGFR, thereby blocking its binding to one or more receptors or ligands. Other examples of EGFR-specific antagonists include antagonist variants of EGFR polypeptides, antisense nucleic acid base oligomers complementary to at least a fragment of a nucleic acid molecule encoding an EGFR polypeptide, small RNAs complementary to at least a fragment of a nucleic acid molecule encoding an EGFR polypeptide, EGFR-targeting ribozymes, peptide bodies for EGFR, and EGFR aptamers. Therefore, the term “EGFR activity” specifically includes the EGFR-mediated biological activity of EGFR. In certain embodiments, EGFR antagonists reduce or inhibit the expression level or biological activity of EGFR by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0039] An "anti-EGFR antibody" is an EGFR inhibitor as defined herein, and is an antibody that binds to EGFR with sufficient affinity and specificity. In certain embodiments, the antibody has a sufficiently high binding affinity to EGFR, for example, the antibody has a K2-100 nM d It can bind to hEGFR at a certain value. Antibody affinity can be determined by, for example, surface plasmon resonance assays (such as the BIAcore® assay described in PCT application publication WO2005 / 012359), enzyme-linked immunosorbent assays (ELISA), and competitive assays (e.g., radioimmunoassays (RIA)).

[0040] In certain embodiments, EGFR inhibitors (e.g., compounds described herein, or anti-EGFR antibodies described herein) may be used as therapeutic agents to target and interfere with diseases or conditions involving EGFR activity. EGFR inhibitors may also be subjected to other biological activity assays to evaluate their efficacy, for example, as therapeutic agents. Such assays are known in the Art and, in the case of anti-EGFR antibodies, depend on the target antigen and the intended use of the antibody. In one embodiment, the anti-EGFR antibody is a monoclonal antibody. In another embodiment, the anti-EGFR antibody is a recombinant humanized anti-EGFR monoclonal antibody.

[0041] As used herein, "cetuximab" is a recombinant human / mouse chimeric monoclonal antibody that specifically binds to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab consists of the Fv region of a mouse anti-EGFR antibody having a human IgG1 heavy chain constant region and a kappa light chain constant region, and has an approximate molecular weight of 152 kDa. Cetuximab is produced in mammalian (mouse myeloma) cell culture. In one embodiment, cetuximab is marketed under the trade name ERBITUX®.

[0042] As used herein, “panitumumab” refers to a human IgG2 kappa monoclonal antibody with an approximate molecular weight of 147 kDa, produced in genetically modified mammalian (Chinese hamster ovary) cells. Panitumumab specifically binds to EGFR in both normal and tumor cells and competitively inhibits ligand binding to EGFR. In one embodiment, panitumumab is marketed under the trade name VECTIBIX®.

[0043] The term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. In one embodiment, cancer is lung cancer. In another embodiment, cancer is NSCLC. In another embodiment, cancer is colorectal cancer (e.g., metastatic CRC). In another embodiment, cancer is pancreatic cancer. As used herein, "cancer" refers to KRas G12C This refers to cancer characterized by the presence of mutations.

[0044] As used herein, “treating” includes treatment with an effective amount of a therapeutic agent (e.g., an EGFR inhibitor or compound 1) or a combination of therapeutic agents (e.g., an EGFR inhibitor and compound 1). In one embodiment, treating refers to treatment with an effective amount of compound 1 or a pharmaceutically acceptable salt thereof and erlotinib. In one embodiment, treating refers to treatment with an effective amount of compound 1 or a pharmaceutically acceptable salt thereof and cetuximab. Treatment may be first-line treatment (e.g., the patient may not have been treated previously or has not received prior systemic therapy), second-line treatment, or subsequent treatment. For example, a patient is “successfully treated” if one or more of the cancer-related symptoms described herein are reduced or eliminated, including, but not limited to, a reduction in the proliferation (or destruction) of cancerous cells, a reduction in symptoms caused by the disease, an improvement in the quality of life of the person with the disease, a reduction in the dose of other drug therapies required to treat the disease, and / or an extension of the patient’s survival.

[0045] The term “delay in disease progression” refers to delaying, preventing, slowing, postponing, stabilizing, and / or postponing the onset of the cancers described herein. This delay may vary in length depending on the cancer being treated and / or the patient’s medical history. As will be apparent to those skilled in the art, a sufficient or significant delay may substantially encompass prevention in that the patient does not develop cancer.

[0046] In this specification, “effective dose” refers to the amount of the therapeutic agent described herein (e.g., an EGFR inhibitor and / or compound 1) that achieves a therapeutic outcome. In some examples, the effective dose of a therapeutic agent or combination of therapeutic agents is the amount of the agent or combination of agents that achieves the clinical endpoint provided herein. In one embodiment, the effective dose refers to the amount of compound 1 or a pharmaceutically acceptable salt thereof and the amount of erlotinib. In one embodiment, the effective dose refers to the amount of compound 1 or a pharmaceutically acceptable salt thereof and the amount of cetuximab. The effective dose as described herein may vary depending on factors such as the patient’s disease state, age, sex, and weight, and the agent’s ability to induce the desired response in the patient. The effective dose is also the amount at which the therapeutically beneficial effects outweigh any toxic or adverse effects of the treatment. In some embodiments, an effective dose of a drug may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., delaying or stopping) the invasion of cancer cells into peripheral organs, inhibiting (i.e., delaying or stopping) tumor metastasis, inhibiting (i.e., delaying or stopping) tumor growth, and / or alleviating one or more of the symptoms associated with the disease. An effective dose may be administered in one or more doses. The effective dose of a drug, compound, pharmaceutical composition, or combination therapy described herein may be sufficient to achieve therapeutic treatment directly or indirectly.

[0047] "Objective response rate" or "ORR" refers to the percentage of patients who achieved a complete or partial response in two consecutive opportunities separated by 4 weeks, as determined by the principal investigator in accordance with RECIST v1.1.

[0048] "Duration of response" or "DOR" refers to the time from the first occurrence of a recorded objective response to the earlier of the following dates: disease progression as determined by the principal investigator in accordance with RECIST v1.1, or death from any cause.

[0049] "Progression-free survival" or "PFS" refers to the time from enrollment to the earlier of the date of the first recorded disease progression or death from any cause, as determined by the principal investigator using RECIST v1.1.

[0050] As used herein, “complete response” and “CR” refer to the disappearance of all target lesions and (if applicable) the normalization of tumor marker levels.

[0051] As used herein, “partial response” and “PR” refer to the persistence and / or (where applicable) maintenance of tumor marker levels above the normal limit in one or more non-target lesions. PR may also refer to CR, a reduction of ≥30% in the sum of the diameters of target lesions in the absence of new lesions and apparent progression in non-target lesions.

[0052] "Administration period" or "cycle" means a period including the administration of one or more of the drugs described herein (e.g., compound 1 and an EGFR inhibitor), and any period not including the administration of one or more of the drugs described herein. For example, a cycle may be 21 days in total, with each day of the cycle including the administration of one or more of the drugs described herein (e.g., compound 1 and an EGFR inhibitor). In another example, a cycle may be 28 days in total, including the administration of one or more of the drugs described herein (e.g., compound 1 and an EGFR inhibitor) over a 21-day and a 7-day rest period. "Rest period" means a period during which at least one of the drugs described herein (i.e., compound 1 and an EGFR inhibitor) is not administered. In one embodiment, a rest period means a period during which none of the drugs described herein (i.e., compound 1 and an EGFR inhibitor) is administered. The rest periods provided herein may, in some cases, include the administration of another drug other than compound 1 or an EGFR inhibitor. In such cases, the administration of another drug during the rest period should not interfere with or disadvantage the administration of the drugs described herein. For example, the term "cycle" as used herein refers to a 21-day cycle without a drug-free period.

[0053] "Medication regimen" means a period of administration of the drugs described herein, comprising one or more cycles, each cycle of which may include administration of the drugs described herein at different times or in different amounts.

[0054] "QD" refers to administering the drug described herein once daily.

[0055] "BID" refers to administering the drug described herein twice a day.

[0056] "Q1W" refers to administering the medication described herein once a week.

[0057] "PO" refers to oral administration of the drugs described herein.

[0058] "IV" refers to the intravenous administration of any of the drugs described herein.

[0059] A graded adverse event refers to a severity grading scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table. TIFF0007852103000007.tif56170

[0060] The term "patient" refers to a human patient. The patient may be an adult.

[0061] The term "antibody" specifically encompasses monoclonal antibodies (such as full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired biological activity. In one example, the antibody is a full-length monoclonal antibody.

[0062] As used herein, the terms IgG “isotype” or “subclass” mean any of the subclasses of immunoglobulins defined by the chemical and antigenic properties of their constant regions.

[0063] Depending on the amino acid sequence of the constant domains of their heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, γ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and are generally described, for example, in Abbas et al., Cellular and Mol. Immunology, 4th ed. (WBSaunders, Co., 2000). Antibodies may be part of a larger fusion molecule formed by the covalent or non-covalent association of an antibody with one or more other proteins or peptides.

[0064] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein synonymously to refer to an antibody in its substantially intact form, not to the antibody fragments described below. This term refers to an antibody containing an Fc region.

[0065] The term “Fc region” is used herein to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more amino acids, particularly one or two, from the C-terminus of the heavy chain. Thus, by expression of a particular nucleic acid molecule encoding a full-length heavy chain, antibodies produced by host cells may contain the full-length heavy chain or a cleaved variant of the full-length heavy chain. This may occur when the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Thus, C-terminal lysine (Lys447), or C-terminal glycine (Gly446) and lysine (Lys447), may or may not be present in the Fc region. The amino acid sequence of the heavy chain containing the Fc region is shown herein without the C-terminal lysine (Lys447) unless otherwise indicated. In one embodiment, the heavy chain containing the Fc region as specified herein, as contained in the antibody disclosed herein, includes a further C-terminal glycine-lysine dipeptide (G446 and K447). In one embodiment, the heavy chain containing the Fc region as specified herein, as contained in the antibody disclosed herein, includes a further C-terminal glycine residue (G446). In one embodiment, the heavy chain containing the Fc region as specified herein, as contained in the antibody disclosed herein, includes a further C-terminal lysine residue (K447). In one embodiment, the Fc region includes the single amino acid substitution N297A of the heavy chain. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0066] A "naked antibody" refers to an antibody that is not bound to a heterogeneous site (e.g., a cytotoxic site) or a radioactive label. Naked antibodies may be present in a pharmaceutical composition.

[0067] An "antibody fragment" preferably comprises a portion of an intact antibody, including its antigen-binding region. In some examples, the antibody fragments described herein are antigen-binding fragments. Examples of antibody fragments include Fab, F(ab')2, and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0068] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous collection of antibodies; that is, except for possible variant antibodies (such variants are generally present in small amounts), including, for example, naturally occurring mutations or mutations arising during the manufacture of the monoclonal antibody preparation, the individual antibodies constituting the collection are identical and / or bind to the same epitope. In contrast to polyclonal antibody preparations, which typically contain various antibodies against various determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is against a single determinant on an antigen. Therefore, the modifier “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous collection of antibodies and should not be interpreted as requiring antibody production by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be produced by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of a human immunoglobulin locus.

[0069] As used herein, the terms “hypervariable region” or “HVR” refer to regions of an antibody variable domain that are hypervariable in sequence and determine antigen-binding specificity, such as “complementarity-determining regions” (CDRs).

[0070] Generally, an antibody contains six CDRs, three located in the VH (CDR-H1, CDR-H2, CDR-H3) and three located in the VL (CDR-L1, CDR-L2, CDR-L3). Examples of CDRs used herein include: (a) Hypervariable loops formed at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987); (b) CDRs present in amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) Antigen contact occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J.Mol.Biol.262:732-745 (1996)).

[0071] Unless otherwise specified, the CDR shall be determined in accordance with Kabat et al. above. Those skilled in the art will understand that the notation of the CDR may be determined in accordance with Chothia above, McCallum above, or any other scientifically recognized nomenclature system.

[0072] "Framework" or "FR" refers to variable domain residues other than the complementarity-determining region (CDR). The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR-L3)-FR4.

[0073] The terms “Kabat-like variable domain residue numbering” or “Kabat-like amino acid position numbering,” and their variations, refer to the numbering system used in the heavy-chain or light-chain variable domains of antibody edits as described by Kabat et al. (see above). Using this numbering scheme, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to the shortening or insertion of FR or HVR in the variable domain. For example, a heavy-chain variable domain may contain a single amino acid insertion after H2 residue 52 (Kabat-like residue 52a) and a residue inserted after heavy-chain FR residue 82 (e.g., Kabat-like residues 82a, 82b, and 82c). The Kabat numbering of residues can be determined for a given antibody by the alignment of homologous regions between the antibody sequence and the “standard” Kabat-numbered sequence.

[0074] The Kabat numbering system is generally used to refer to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU numbering system" or "EU index" is generally used when referring to residues in the constant region of the immunoglobulin heavy chain (e.g., the EU index reported by Kabat et al. (see above)). "EU index as in Kabat" refers to the residue numbering of human IgG1 EU antibodies.

[0075] The term “package insert” is used to refer to the instructions that are customarily included in the market packaging of a therapeutic product, including information relating to indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings for the use of such therapeutic product.

[0076] As used herein, “in combination with” means administering one treatment regimen in addition to another treatment regimen, for example, the administration of an EGFR inhibitor described herein (e.g., erlotinib or cetuximab) and compound 1 or a pharmaceutically acceptable salt thereof. Thus, “in combination with” means administering one treatment regimen before, during, or after administration of the other treatment regimen to the patient.

[0077] Drugs administered "concurrently" with one or more other drugs are administered on the same treatment day as the other drugs, and at the same time as the other drugs, if necessary, within the same treatment cycle. For example, in cancer therapy administered every three weeks, each drug administered concurrently is given on day 1 of the three-week cycle. Combination therapy

[0078] This specification provides combination therapies (compositions) comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and an EGFR inhibitor described herein. In one embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and gefitinib is provided herein. In another embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and osimertinib is provided herein. In yet another embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and dacomitinib is provided herein. In yet another embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and afatinib is provided herein. In yet another embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and panitumumab is provided herein. In one preferred embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and erlotinib or cetuximab is provided herein. In another preferred embodiment, the combination therapy comprises erlotinib. In yet another such embodiment, the combination therapy comprises cetuximab.

[0079] The following combination therapies (compositions) comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and an EGFR inhibitor compound (e.g., gefitinib, erlotinib, osimertinib, dacomitinib, or afatinib) are further provided herein. In one such embodiment, the EGFR inhibitor is erlotinib.

[0080] Furthermore, combination therapies (compositions) comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and an anti-EGFR antibody (e.g., panitumumab or cetuximab) are provided herein. In one such embodiment, the anti-EGFR antibody is cetuximab.

[0081] In one embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and an EGFR inhibitor (e.g., erlotinib or cetuximab) is provided herein. In one embodiment, the combination therapy described herein is KRas G12C It is useful for treating certain solid tumors, including those with mutations. In one such embodiment, the combination therapy involves EGFR inhibitors, which are not approved for administration in such tumors, and KRas G12C It is useful in treating certain solid tumors, including those with mutations.

[0082] In one embodiment, the combination therapy described herein is KRas G12C It is useful for treating certain types of lung cancer described herein, including mutations. In one such embodiment, lung cancer is KRas G12C This is non-small cell lung cancer (NSCLC) with a mutation.

[0083] In another embodiment, the combination therapy described herein is KRas G12C It is useful in the treatment of colorectal cancer including mutations. In such an embodiment, KRas G12C The combination therapies described herein, useful for treating colorectal cancer including mutations, are administered in combination with one or more additional agents. In another such embodiment, the additional agent is irinotecan. In another such embodiment, the additional agent comprises FOLFIRI (i.e., administration of leucovorin, fluorouracil, and irinotecan). In another such embodiment, the additional agent comprises FOLFOX (i.e., administration of leucovorin, fluorouracil, and oxaliplatin).

[0084] In another embodiment, the combination therapy described herein is KRas G12C It is useful in the treatment of pancreatic cancer including mutations. In such an embodiment, KRas G12C The combination therapies described herein, useful for treating pancreatic cancer including mutations, are administered in combination with one or more additional agents. In one such embodiment, the additional agents include gemcitabine.

[0085] In one embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof administered via QD on days 1 to 21 of a first 21-day cycle and an EGFR inhibitor (e.g., erlotinib or cetuximab) is provided herein. In such embodiments, the combination therapy is provided by the KRas described herein. G12C It is useful in treating solid tumors containing mutations (e.g., lung cancer, colorectal cancer, pancreatic cancer).

[0086] In one embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof administered by QD on days 1 to 21 of a first 21-day cycle is provided herein, along with beerlotinib administered by QD on days 1 to 21 of the first cycle.

[0087] In another embodiment, the present invention provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof administered in QD on days 1 to 21 of a first 21-day cycle, and cetuximab administered in Q1W starting on day 1 of the first 21-day cycle.

[0088] In one embodiment of the combination therapy described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered as a fixed-dose QD (quick dose). In one embodiment, administration is oral (PO), and compound 1 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In such an embodiment, compound 1 or a pharmaceutically acceptable salt thereof is formulated (and administered) as a film-coated tablet.

[0089] In one embodiment of the combination therapy described herein, compound 1 or a pharmaceutically acceptable salt thereof is approximately 5 mg to 600 mg, 5 mg to 500 mg, 5 mg to 400 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 600 mg, 25 mg to 500 mg, 25 mg to 400 mg, 25 mg to 3 The compound is administered via QD in amounts of 00 mg, 25 mg to 250 mg, 25 mg to 200 mg, 25 mg to 150 mg, 25 mg to 100 mg, 25 mg to 50 mg, 50 mg to 800 mg, 50 mg to 700 mg, 50 mg to 600 mg, 50 mg to 500 mg, 50 mg to 400 mg, 50 mg to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 150 mg, or 50 mg to 100 mg. In another embodiment, compound 1 or a pharmaceutically acceptable bryangel salt thereof is administered in amounts of approximately 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg. In another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts of about 300 to 600 mg. In another such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts of about 400 mg. In a preferred embodiment, compound 1 of the combination therapy described herein is administered as an adipine salt. In such embodiments, the amount of compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts relative to the free base form.

[0090] In one embodiment of the combination therapy described herein, the EGFR inhibitor is administered in accordance with the package insert.

[0091] In one embodiment, the combination therapy described herein comprises erlotinib, administered in amounts of approximately 25 mg to 200 mg, 25 mg to 150 mg, 25 mg to 100 mg, or 25 mg to 50 mg. In one embodiment, erlotinib is administered in amounts of approximately 100 mg. In another embodiment, erlotinib is administered in amounts of approximately 150 mg.

[0092] In one embodiment, erlotinib is administered in an amount of 150 mg QD as an ingredient in the combination therapy described herein. In another embodiment, erlotinib is administered in an amount of 100 mg QD as an ingredient in the combination therapy described herein. In such embodiments, erlotinib may be administered in combination with compound 1 or a pharmaceutically acceptable salt thereof in a dosing regimen that includes administration of each drug QD in a 21-day cycle. In such one embodiment, erlotinib is administered simultaneously with compound 1 or a pharmaceutically acceptable salt thereof, with water between doses. In one embodiment, the amount of erlotinib administered in the combination therapy described herein may be reduced. In one embodiment, the amount of erlotinib is reduced in increments of 25 mg or 50 mg.

[0093] In another embodiment, the combination therapy described herein includes cetuximab, which is administered at approximately 200-400 mg / m². 2 It is administered in the amount of [amount]. In one embodiment, cetuximab is administered as a first dose / initial dose of approximately 400 mg / m². 2 It is administered in the amount of [amount]. In another embodiment, cetuximab is approximately 250 mg / m². 2 It is administered in the following amounts. In one such embodiment, cetuximab is administered at approximately 400 mg / m² on day 1 of the first 21-day cycle. 2 The amount is 250 mg / m² for the first 21-day cycle. 2 It is administered in Q1W.

[0094] A combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and gefitinib is also provided herein, in which gefitinib is administered in a dose of 250 mg QD per 21-day cycle.

[0095] A combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and osimertinib is further provided herein, wherein osimertinib is administered in a dose of 80 mg QD per 21-day cycle.

[0096] A combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and dacomitinib is further provided herein, wherein dacomitinib is administered in a dose of 45 mg QD per 21-day cycle.

[0097] A combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and afatinib is further provided herein, wherein afatinib is administered in a dose of 40 mg QD per 21-day cycle.

[0098] A combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and panitumumab is further provided herein, wherein panitumumab is administered at a dose of 6 mg / kg Q2W for each 21-day cycle.

[0099] In one preferred embodiment, the combination therapy described herein comprises compound 1 described herein or a pharmaceutically acceptable salt thereof, administered in QDs, and erlotinib, with erlotinib administered to the patient in doses of approximately 150 mg QD. In another preferred embodiment, the combination therapy described herein comprises compound 1 described herein or a pharmaceutically acceptable salt thereof, administered in QDs, and cetuximab, with cetuximab administered in doses of approximately 400 mg / m² on day 1 of the first 21-day cycle. 2 The amount is 250 mg / m² for the first 21-day cycle. 2 It is administered in Q1W.

[0100] In one embodiment, the combination therapy described herein is KRas G12CIt is used to treat lung cancer including mutations. In one such embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and an EGRF inhibitor compound selected from the group consisting of erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib. In another such embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and erlotinib, and the combination therapy is KRas as described herein. G12C This is for the treatment of lung cancer including mutations. In one embodiment, the combination therapy described herein is KRas G12C Used to treat lung cancer including mutations, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and an anti-EGFR antibody (e.g., panitumumab). In such embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In such embodiments, the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0101] In another embodiment, KRas G12C A combination therapy useful for treating lung cancer including mutations, comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1), wherein compound 1 is administered as a QD on days 1 to 21 of the first 21-day cycle, and erlotinib is administered as a QD on days 1 to 21 of the first 21-day cycle. In a preferred embodiment, the lung cancer is NSCLC (e.g., metastatic NSCLC).

[0102] In yet another embodiment, KRas G12CA combination therapy useful for the treatment of lung cancer including mutations, comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1), wherein compound 1 is administered in a dose of approximately 50 mg to 500 mg in a QD on days 1 to 21 of the first 21-day cycle, and erlotinib is administered in a dose of approximately 150 mg in a QD on days 1 to 21 of the first 21-day cycle. In one preferred embodiment, the lung cancer is NSCLC. In one embodiment, erlotinib is administered according to the package insert.

[0103] In yet another embodiment, KRas G12C The combination therapy described herein is useful for treating CRC including mutations. In a particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and an anti-EGFR antibody selected from cetuximab or panitumumab, wherein the combination therapy is KRas as described herein. G12C This is for treating CRCs including mutations. In a preferred embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and cetuximab, the combination therapy being KRas as described herein. G12C This is for treating CRCs containing mutations. In one such embodiment, the CRC is metastatic CRC (mCRC). In one embodiment, the combination therapy is KRas G12C This is for first-line use treatment of CRCs including mutations. In another embodiment, combination therapy is KRas G12C This is for the second-line treatment of CRC including mutations. In one such embodiment, the patient has KRas G12C The disease has progressed previously and has been treated with inhibitors in the past.

[0104] The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and cetuximab, and KRas G12C In such embodiments useful for treating CRCs including mutations, the FOLFIRI regimen or irinotecan may be administered to the patient described herein.

[0105] The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and an anti-EGFR antibody (e.g., panitumumab), and KRas G12C In such embodiments, which are useful for treating CRCs including mutations, the FOLFOX regimen may be administered to the patient described herein.

[0106] In another embodiment, KRas G12C This combination therapy is useful for treating CRCs, including those with mutations. The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1), with compound 1 administered in QD doses on days 1-21 of the first 21-day cycle, and cetuximab administered at approximately 400 mg / m² on day 1 of the first 21-day cycle. 2 The dose is 250 mg / m² for the first 21-day cycle. 2 It is administered in Q1W. In a preferred embodiment, the CRC is metastatic CRC (mCRC).

[0107] In another embodiment, KRas G12C This combination therapy is useful for treating CRCs, including those with mutations. The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1), with compound 1 administered in a QD at a dose of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and cetuximab at approximately 400 mg / m² on day 1 of the first 21-day cycle. 2 The dose is 250 mg / m² for the first 21-day cycle. 2 It is administered in Q1W. In one preferred embodiment, the CRC is metastatic CRC (mCRC). In one embodiment, cetuximab is administered according to the package insert.

[0108] In one embodiment, the combination therapy described herein is KRas G12C It is used to treat pancreatic cancer including mutations. In a particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipine) and erlotinib, and the combination therapy is as described herein for KRasG12C It is intended to treat pancreatic cancer, including mutated cancers.

[0109] In one such embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1), wherein compound 1 is administered in QDs on days 1–21 of the first 21-day cycle, and erlotinib is administered in QDs on days 1–21 of the first 21-day cycle.

[0110] In another such embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1), wherein compound 1 is administered in a quantity of about 50 mg to 500 mg in QDs on days 1 to 21 of the first 21-day cycle, and erlotinib is administered in a quantity of 100 mg or 150 mg in QDs on days 1 to 21 of the first 21-day cycle. In one such embodiment, erlotinib is administered in a quantity of about 150 mg QD as described herein. In another such embodiment, erlotinib is administered in a quantity of about 100 mg QD as described herein. In one embodiment, erlotinib is administered according to the package insert. Treatment method

[0111] KRas in patients with such solid tumors as described herein (e.g., lung cancer, CRC, or pancreatic cancer) G12C Methods for treating solid tumors containing mutations are also provided herein. In one embodiment, KRas G12C A method for treating solid tumors in patients with lung cancer, CRC, or pancreatic cancer containing mutations, comprising administering to the patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipinate of compound 1) and an EGFR inhibitor as described herein (e.g., an EGFR inhibitor compound selected from the group consisting of erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib, or an anti-EGFR antibody comprising panitumumab or cetuximab). In one embodiment, KRas G12CA method for treating a solid tumor in a patient having lung cancer, CRC, or pancreatic cancer containing a mutation, comprising administering to the patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and erlotinib or cetuximab.

[0112] In one aspect, KRas G12C The present invention provides a method for treating lung cancer in patients having a mutation, comprising administering to the patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine of compound 1) and an EGFR inhibitor compound selected from the group consisting of erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib. In one embodiment, KRas G12C This specification provides a method for treating lung cancer in a patient having mutation-mediated lung cancer, comprising administering to the patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and erlotinib.

[0113] In one embodiment provided herein, the lung cancer is non-small cell lung cancer (NSCLC). In another embodiment of the method provided herein, the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. In one such embodiment, the cancer is lung adenocarcinoma. In another such embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is an adenoma, a carcinoid tumor, or an undifferentiated carcinoma. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0114] Also, KRas G12CThis specification provides a method for treating NSCLC in patients having mutations, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen comprising: (i) administering a pharmaceutically acceptable dose of compound 1 or a pharmaceutically acceptable salt thereof in a QD (quadruplicate dose) on days 1 to 21 of a first 21-day cycle; and (ii) administering an effective amount of erlotinib in a QD on days 1 to 21 of a first 21-day cycle. In one embodiment of the method provided herein, the method is for treating adenocarcinoma. In one embodiment of the method provided herein, the method comprises two or more cycles. In such one embodiment, the method is for treating first-line NSCLC.

[0115] Also, KRas G12C A method for treating NSCLC in patients having mutations, comprising administering an effective amount of the combination therapy described herein, comprising a drug regimen comprising: (i) administering 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of a first 21-day cycle; and (ii) administering approximately 150 mg / kg of erlotinib in a QD on days 1 to 21 of a first 21-day cycle.

[0116] In another aspect, KRas in patients with CRC G12C A method for treating CRC including mutations is provided herein, comprising administering to a patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and an anti-EGFR antibody as described herein (e.g., panitumumab or cetuximab). In another embodiment of the above method, KRas in a patient having CRC G12C A method for treating a mutation-containing CRC is provided herein, comprising administering to a patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipine) and cetuximab.

[0117] Also, KRas G12CA method for treating cancer in patients with CRC containing mutations is provided herein, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 21 of a first 21-day cycle, and (ii) administering an effective amount of cetuximab as a Q1W starting on day 1 of a first 21-day cycle. In one such embodiment, 250 or 400 mg / m² as described herein is provided. 2 In one embodiment of the method provided herein, the method comprises two or more cycles.

[0118] Also, KRas G12C A method for treating cancer in patients with CRC containing mutations, comprising: (i) administering 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of the first 21-day cycle; and (ii) approximately 400 mg / m² 2 Cetuximab is administered on day 1 of the first 21-day cycle, followed by approximately 250 mg / m². 2 A method is provided herein that includes administering cetuximab in Q1W and administering an effective amount of the combination therapy described herein, comprising a drug regimen including the above.

[0119] KRas G12C In one embodiment of such a method for treating CRC including mutations, the method further comprises administering to a patient an effective amount of FOLFIRI or irinotecan as described herein.

[0120] Also, KRas G12C A method for treating pancreatic cancer in a patient having a mutation in the pancreatic cancer is provided herein, comprising administering to the patient an effective dose of combination therapy comprising compound 1 described herein or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and erlotinib.

[0121] In another embodiment, KRas G12CThis specification provides a method for treating a patient having pancreatic cancer including mutations, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen comprising: (i) administering a pharmaceutically acceptable dose of compound 1 or a pharmaceutically acceptable salt thereof in a QD dose on days 1 to 21 of a first 21-day cycle; and (ii) administering an effective amount of erlotinib in a QD dose on days 1 to 21 of a first 21-day cycle. In one such embodiment, erlotinib is administered in an amount of about 100 mg or 150 mg as described herein. In one embodiment, erlotinib is administered in an amount of 100 mg. In another such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg as described herein.

[0122] In one embodiment of the method described herein, compound 1 or a pharmaceutically acceptable salt thereof is approximately 5 mg to 600 mg, 5 mg to 500 mg, 5 mg to 400 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 600 mg, 25 mg to 500 mg, 25 mg to 400 mg, 25 mg to 30 mg The compound is administered in QDs in amounts of 0 mg, 25 mg to 250 mg, 25 mg to 200 mg, 25 mg to 150 mg, 25 mg to 100 mg, 25 mg to 50 mg, 50 mg to 800 mg, 50 mg to 700 mg, 50 mg to 600 mg, 50 mg to 500 mg, 50 mg to 400 mg, 50 mg to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 150 mg, or 50 mg to 100 mg. In another embodiment, compound 1 or its pharmaceutically acceptable bryangel salt is administered in amounts of approximately 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg. In another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts of about 300 to 600 mg. In another such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts of about 400 mg. In a preferred embodiment, compound 1 of the combination therapy described herein is administered as an adipine salt. In such embodiments, the amount of compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts relative to the free base form.

[0123] The methods provided herein may include the administration of the combination therapies described herein as part of a drug regimen. In one such embodiment, the drug regimen comprises one or more cycles. In another embodiment, the drug regimen comprises at least two cycles. In yet another embodiment, the drug regimen comprises two to three cycles. In yet another embodiment, the drug regimen provided herein comprises two, three, four, five, six, eight, ten, twelve, sixteen, eighteen, twenty, twofour, threeteen, fourteen, fourteen, fourteen, fourteen, fourteen, fourteen, fourteen, sixteen, sixteen, or seventeen cycles. In yet another embodiment, the drug regimen comprises approximately two to seventeen, two to sixteen, two to sixteen, two to sixteen, two to fiveteen, two to fourteen, two to fourteen, two to threeteen, two to twoteen, two to twoteen, two to eightteen, two to twelve, or two to sixteen cycles. In one embodiment, the drug regimen comprises administering the combination therapy described herein in any number of cycles until a desired response (e.g., PFS, OS, ORR, and / or DOR) is achieved (e.g., PFS, OS, ORR, and / or DOR are increased compared to the control described herein). In another embodiment, the drug regimen comprises administering the combination therapy described herein in any number of cycles until toxicity occurs or the patient experiences one or more adverse events (AEs) that otherwise prevent further administration. In yet another embodiment, the drug regimen comprises administering the combination therapy described herein in any number of cycles until disease progression.

[0124] In one embodiment of the method described herein, the patient receives a total of 1 to 50 doses, for example, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 Anti-EGFR antibodies are administered in doses of 1, 4-35, 4-30, 4-25, 4-20, 4-15, 4-10, 4-5, 5-50, 5-45, 5-40, 5-35, 5-30, 5-25, 5-20, 5-15, 5-10, 1-50, 1-45, 1-40, 1-35, 1-30, 1-25, 1-20, 1-15, 1-10, 1-8, 1-6, 1-5, 10-50, 10-45, 10-40, 10-35, 10-30, 10-25, or 10-20 doses. In one such embodiment, the patient is administered a total of 1 to 10 doses of anti-EGFR antibody (e.g., cetuximab). In another such embodiment, the patient is administered a total of 5, 6, 7, 8, 9, or 10 doses of anti-EGFR antibody (e.g., cetuximab). In one preferred embodiment, the doses of anti-EGFR antibody (e.g., cetuximab) are administered intravenously.

[0125] In certain embodiments, the therapeutic agents of the combination therapy described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof, and erlotinib or cetuximab) may be administered in any suitable manner known in the art. For example, an EGFR inhibitor (e.g., erlotinib or cetuximab) may be administered sequentially (on different days) or simultaneously (on the same day or during the same treatment cycle) as compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the EGFR inhibitor (e.g., erlotinib or cetuximab) is administered after the administration of compound 1 or a pharmaceutically acceptable salt thereof. In some examples, the EGFR inhibitor (e.g., erlotinib or cetuximab) is administered after the administration of compound 1 or a pharmaceutically acceptable salt thereof, or on the same day as the administration of compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, an EGFR inhibitor (e.g., erlotinib or cetuximab) may be administered after or on the same day as the administration of compound 1 or a pharmaceutically acceptable salt thereof. For example, compound 1 or a pharmaceutically acceptable salt thereof may be administered on day 1 of each cycle before the administration of the EGFR inhibitor (e.g., erlotinib or cetuximab) on day 1 of each cycle, and then compound 1 or a pharmaceutically acceptable salt thereof may be administered on the next 20 days QD of the 21-day cycle.

[0126] In preferred embodiments, cetuximab is administered intravenously after compound 1 or a pharmaceutically acceptable salt thereof (e.g., about 120 minutes). If the first infusion is acceptable, the second dose of cetuximab is administered intravenously over 60 ± 10 minutes. In some cases, cetuximab is administered as an intravenous push or bolus.

[0127] KRas G12CMethods for treating lung cancer in patients with mutations are also provided herein, the methods comprising administering to a patient a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine) and an EGFR inhibitor compound selected from the group consisting of erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib (e.g., erlotinib or cetuximab). In one embodiment of such a method, compound 1 is adipine and the EGFR inhibitor compound is erlotinib. In another embodiment of such a method, compound 1 or a pharmaceutically acceptable salt thereof is administered in the QD and amount specified herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, erlotinib is administered in the QD and amount specified herein (e.g., 150 mg). In such a method, compound 1 or a pharmaceutically acceptable salt thereof and the EGFR inhibitor may be administered as described herein. In such a way, lung cancer is KRas G12C It may be NSCLC containing a mutation.

[0128] KRas G12C Methods for treating cancer in patients with CRC containing mutations are also provided herein, the method comprising administering to the patient a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine) and an anti-EGFR antibody as described herein (e.g., cetuximab). In one embodiment of such a method, compound 1 is adipine and the anti-EGFR antibody as described herein is cetuximab. In another embodiment of such a method, compound 1 or a pharmaceutically acceptable salt thereof is administered in the QD as described herein and in the amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, cetuximab is administered at approximately 400 mg / m² on day 1 of the first 21-day cycle. 2 The patient was administered cetuximab in a dose of [amount], followed by approximately 250 mg / m². 2It is administered with cetuximab Q1W. In such a manner, compound 1 or a pharmaceutically acceptable salt thereof and cetuximab may be administered as described herein.

[0129] In another embodiment, KRas G12C A method for treating cancer in patients with CRC containing mutations, the method comprising: (i) administering approximately 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine) in a QD on days 1 to 21 of the first 21-day cycle; and (ii) administering approximately 400 mg / m² on day 1 of the first 21-day cycle. 2 Cetuximab is administered, followed by approximately 250 mg / m². 2 The treatment regimen includes administering cetuximab Q1W to the patient.

[0130] KRas G12C Methods for treating pancreatic cancer in patients with mutations are also provided herein, the methods comprising administering to the patient a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine) and an EGFR inhibitor as described herein (e.g., erlotinib). In one embodiment of such a method, compound 1 is adipine, and the EGFR inhibitor compound as described herein is erlotinib. In another embodiment of such a method, compound 1 or a pharmaceutically acceptable salt thereof is administered in the QD as described herein and in the amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, erlotinib is administered in the QD as described herein, in an amount of about 100 mg or 150 mg. In such a method, compound 1 or a pharmaceutically acceptable salt thereof and erlotinib may be administered as described herein.

[0131] In another embodiment, KRas G12CA method for treating pancreatic cancer, including such cancer, in patients with mutations, the method comprising administering to a patient a treatment regimen comprising (i) administering to the patient in a QD manner about 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine) on days 1 to 21 of the first 21-day cycle, and (ii) administering to the patient in a QD manner 100 mg or 150 mg of erlotinib on days 1 to 21 of the first 21-day cycle.

[0132] In some cases, the treatment regimen includes the administration of one or more additional therapies, which are one or more side effect limiting agents (e.g., drugs intended to reduce the occurrence and / or severity of side effects of the treatment, e.g., anti-nausea agents, corticosteroids (e.g., prednisone or equivalent, e.g., at a dose of 1-2 mg / kg / day), hormone replacement therapy(s)), etc.

[0133] Patients provided herein must be evaluated and KRas as described herein. G12C Confirmed test results for the mutation must be available. In one embodiment, the patient described herein is a patient with KRas for CRC G12C The patient has confirmed test results regarding the mutation. In one such embodiment, the patient has been treated with one or more prior therapies. The patient is diagnosed with NSCLC and KRas G12C Patients described herein whose mutation test results have been confirmed shall not have known associated secondary oncogenic drivers (e.g., in the case of NSCLC: susceptible EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion, RET fusion; or in the case of adenocarcinoma of the colon or rectum: BRAF V600E mutation, ERBB2 amplification). In one such embodiment, the patient has been treated with one or more prior therapies. In one embodiment, such secondary oncogenic drivers are determined using NGS (e.g., an NGS assay by Foundation Medicine, Inc. (FMI)).

[0134] In one embodiment of the method provided herein, in which a patient described herein is treated with a combination therapy including cetuximab, such a patient has experienced disease progression or intolerance to at least one prior chemotherapy regimen (e.g., FOLFOX, FOLFIRI, FOLFOXIRI ± bevacizumab).

[0135] In another embodiment of the method provided herein, if a patient described herein is treated with a combination therapy including erlotinib, such a patient has experienced disease progression or intolerance to at least one prior systemic therapy (e.g., monotherapy or combination therapy with an investigational or approved PD-L1 / PD-1 inhibitor).

[0136] In one embodiment, the patient described herein is KRas G12C They have previously received treatment with specific inhibitors.

[0137] In another embodiment, the patient described herein has not received any treatment with chemotherapy, immunotherapy, or biological therapy as an anti-cancer therapy within 3 weeks prior to administration of the combination therapy described herein, except that: (a) Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (b) If any drug-related toxicity has completely subsided, a kinase inhibitor approved by the regulatory authority may be used up to two weeks prior to administration of the combination therapy described herein; or (c) Treatment with the investigational drug within 3 weeks or 5 half-lives (whichever is shorter) prior to administration of the combination therapy described herein.

[0138] In another embodiment, the patient described herein has not received any radiotherapy (other than palliative radiotherapy for bone metastases and radiotherapy for CNS metastases) as cancer therapy within four weeks prior to the initiation of the combination therapy described herein. In yet another embodiment, the patient described herein has not received any palliative radiotherapy for bone metastases within two weeks prior to the initiation of the combination therapy described herein.

[0139] In another embodiment, the patient described herein has no history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic interstitial pneumonia, or evidence of active interstitial pneumonia on screening chest computed tomography (CT) scans.

[0140] Further provided herein is the use (UL1) of the combination therapy described herein for the treatment of lung cancer, comprising compound 1 or a pharmaceutically acceptable salt thereof and an EGFR inhibitor compound selected from the group consisting of erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib. In one embodiment, the use (UL2) of the combination therapy described herein for the treatment of lung cancer, comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, is provided herein. In such an embodiment, the lung cancer is NSCLC.

[0141] Furthermore, the use of the combination therapy described herein (UL3) for treating lung cancer described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, comprising a drug regimen including (i) administering compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of a first 21-day cycle, and (ii) administering erlotinib in a QD on days 1 to 21 of a first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, erlotinib is administered in an amount of about 150 mg.

[0142] Furthermore, the use of the combination therapy described herein (UL4) for treating lung cancer described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, is provided herein, comprising a drug regimen including (i) administering about 50 to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of the first 21-day cycle, and (ii) administering about 150 mg of erlotinib in a QD on days 1 to 21 of the first 21-day cycle. In one such embodiment, the drug regimen comprises two or more cycles described herein.

[0143] This Specification further provides the use (UL5) of the combination therapy described herein for the manufacture of a medicament for the treatment of lung cancer described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor compound selected from the group consisting of erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib. In one such embodiment, the EGFR inhibitor is erlotinib.

[0144] Furthermore, the use of the combination therapy described herein (UL6) for manufacturing a medicament for treating lung cancer described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, comprising a drug regimen including (i) administering compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of a first 21-day cycle, and (ii) administering erlotinib in a QD on days 1 to 21 of a first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, erlotinib is administered in an amount of about 150 mg.

[0145] Furthermore, this specification provides a use (UL7) of the combination therapy described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, for the manufacture of a medicament for the treatment of lung cancer described herein, comprising a drug regimen including (i) administering about 50 to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of the first 21-day cycle, and (ii) administering about 150 mg of erlotinib in a QD on days 1 to 21 of the first 21-day cycle. In one such embodiment, the drug regimen comprises two or more cycles described herein.

[0146] In such embodiments of the use described herein, lung cancer may be NSCLC. In another such embodiment of the use described herein, the patient described herein is KRas G12C The patient is diagnosed with NSCLC mediated by a mutation.

[0147] Further provided herein are the use of the combination therapy described herein (UC1) for the treatment of CRC as described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and an anti-EGFR antibody selected from the group consisting of cetuximab or panitumumab. In one embodiment, the use of the combination therapy described herein (UC2) for the treatment of CRC as described herein is comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab. In such an embodiment, the CRC is mCRC.

[0148] Furthermore, the use of the combination therapy described herein (UC3) for treating CRC as described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab, wherein (i) compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of the first 21-day cycle, and (ii) approximately 400 mg / m² on day 1 of the 21-day cycle. 2The use of cetuximab, including the administration of cetuximab and a drug regimen comprising the above, is provided herein. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, cetuximab is administered on day 1 of the first 21-day cycle at about 400 mg / m². 2 The dose is administered, followed by cetuximab at approximately 250 mg / m². 2 Administer the amount used in Q1W.

[0149] Furthermore, the use of the combination therapy described herein for the treatment of lung cancer as described herein (UC4), comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab, wherein (i) about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof is administered by QD on days 1 to 21 of the first 21-day cycle, and (ii) about 400 mg / m² is administered on day 1 of the first 21-day cycle. 2 Cetuximab is administered, followed by approximately 250 mg / m². 2 Uses including administering cetuximab Q1W and drug regimens comprising the above are provided herein.

[0150] This specification further provides the use of the combination therapy described herein (UC5) for the manufacture of a medicament for the treatment of CRC described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and an anti-EGFR antibody selected from the group consisting of cetuximab or panitumumab. In one such embodiment, the anti-EGFR antibody is cetuximab.

[0151] In such embodiments of the use described herein, the patient described herein is KRas G12C It is diagnosed as CRC mediated by a mutation.

[0152] Furthermore, the use (UC6) of the combination therapy described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab for manufacturing a medicament for treating CRC described herein, comprising a dosing regimen including: (i) administering compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle; and (ii) administering cetuximab Q1W starting on day 1 of the first 21-day cycle, is provided herein. In such an embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 - 500 mg. In another such embodiment, cetuximab is administered at an amount of about 400 mg / m 2 of cetuximab on day 1 of the first 21-day cycle, followed by administering cetuximab at about 250 mg / m 2 Q1W.

[0153] Furthermore, the use (UC6) of the combination therapy described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab for manufacturing a medicament for treating CRC described herein, comprising a dosing regimen including: (i) administering about 50 - 500 mg of compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle; and (ii) administering about 400 mg / m 2 of cetuximab on day 1 of the first 21-day cycle, followed by administering about 250 mg / m 2 of cetuximab Q1W, is provided herein. In such an embodiment, the dosing regimen includes more than 2 cycles as described herein.

[0154] Furthermore, the use (UP1) of the combination therapy described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib for treating pancreatic cancer described herein is provided herein.

[0155] Furthermore, the use of the combination therapy described herein (UP2) for treating pancreatic cancer described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, comprising a drug regimen including (i) administering compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of a first 21-day cycle, and (ii) administering erlotinib in a QD on days 1 to 21 of a first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, erlotinib is administered in an amount of about 100 mg.

[0156] Furthermore, this specification provides a combination therapy (UP3) described herein for the treatment of pancreatic cancer comprising Compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, comprising a drug regimen including (i) administering about 50 to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof in a QD manner on days 1 to 21 of the first 21-day cycle, and (ii) administering about 100 mg of erlotinib in a QD manner on days 1 to 21 of the first 21-day cycle. In one such embodiment, the drug regimen comprises two or more cycles described herein.

[0157] Furthermore, the use of the combination therapy described herein (UP4), comprising Compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, for the manufacture of a medicament for the treatment of pancreatic cancer described herein, is provided herein.

[0158] Furthermore, the use of the combination therapy described herein (UP5) for manufacturing a medicament for treating pancreatic cancer described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, comprising a dosing regimen including (i) administering compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of a first 21-day cycle, and (ii) administering erlotinib in a QD on days 1 to 21 of a first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, erlotinib is administered in an amount of about 100 mg.

[0159] Furthermore, this specification provides a use (UP6) of the combination therapy described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, for the manufacture of a medicament for the treatment of pancreatic cancer as described herein, comprising a dosing regimen including (i) administering about 50 to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of the first 21-day cycle, and (ii) administering about 100 mg of erlotinib in a QD on days 1 to 21 of the first 21-day cycle. In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0160] The development of combination therapies presents challenges, including, for example, the selection of agents for combination therapies that can lead to improved efficacy while maintaining acceptable toxicity. One particular challenge is the need to identify the gradual toxicity of combinations. In one embodiment of the method described herein, the combination therapy described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof, and erlotinib or cetuximab) is administered in a dosing regimen that includes a time-staggered dosing schedule. In such an embodiment, the patient has a reduction in the number or grade of adverse events (AEs) comparable to that of a control (e.g., SOC therapy, treatment with one of the agents described herein (e.g., compound 1, or erlotinib or cetuximab) alone).

[0161] In the event of an adverse event, it is generally understood that there are four options: (1) continue treatment with any accompanying therapy; (2) adjust the dose of one or more drugs in the drug regimen; (3) temporarily discontinue administration of one or more drugs in the drug regimen; or (4) discontinue administration of one or more drugs in the drug regimen. In one embodiment, the amount of compound 1 is not changed. In another embodiment, the amount of erlotinib administered is not changed. In another embodiment, the amount of cetuximab administered is not changed. In one embodiment, if administration of erlotinib or cetuximab is discontinued, the next administration of compound 1 or a pharmaceutically acceptable salt thereof is given on the same day that administration of erlotinib or cetuximab is resumed. In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered without food (i.e., the patient must not eat at least 2 hours before and 1 hour after administration). In one such embodiment, cetuximab is administered at least 20, 30, 45, or 60 minutes after the administration of compound 1 or a pharmaceutically acceptable salt thereof. In another such embodiment, erlotinib is administered after the administration of compound 1 or a pharmaceutically acceptable salt thereof.

[0162] In one embodiment, the patient described herein experiences gastrointestinal toxicity as grade 2 or lower AE. In such an embodiment, gastrointestinal toxicity is diarrhea, nausea, or vomiting. In another embodiment, the patient described herein experiences phototoxicity. In such an embodiment, the patient should wear sunscreen and protective clothing outdoors.

[0163] In one embodiment, patients described herein who receive combination therapy including cetuximab experience skin reactions, hypomagnesemia, or IRR. In another embodiment, patients described herein who receive combination therapy including erlotinib experience skin toxicity, interstitial lung disease (ILD), liver injury, gastrointestinal (GI) fluid loss, GI perforation, or ocular toxicity.

[0164] Patients described herein may also be administered supplementary therapies including: (a) anticonvulsants or warfarin; (b) oral contraceptives or other possible maintenance therapies; (c) antiemetics and antidiarrheals, provided that such drug therapies should not be administered prophylactically prior to initial treatment with the study drug; (d) analgesics administered in accordance with standard clinical practice; (e) bisphosphonates and denosumab therapy for bone metastases or osteopenia / osteoporosis; or (f) multivitamins, calcium, and vitamin C, D, and E supplements.

[0165] Patients described herein may not concurrently take therapies including (1) potent / moderate CYP3A4 inhibitors (e.g., atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troreandmycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluvoxamine, diltiazem, nefazodone, mibeflazil, verapamil, and grapefruit juice or grapefruit supplements); or (2) potent / moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's wort), and cyproterone).

[0166] In another embodiment, the patients described herein are not administered drugs that reduce gastric acid production, such as proton pump inhibitors or H2 receptor antagonists. In another embodiment, patients administered combination therapy including erlotinib should not have chronic use of anti-angiogenic agents and nonsteroidal anti-inflammatory drugs (NSAIDs).

[0167] In another embodiment, the patient described herein is not administered any of the following therapies: (a) Three weeks prior to administration of the combination therapy described herein or five half-lives, whichever is shorter, or any other investigational therapy during such treatment (excluding Compound 1, or erlotinib or cetuximab); (b) Ancillary therapies intended to treat cancer, whether approved by the FDA or experimental, including chemotherapy, radiotherapy, immunotherapy, biological therapy, herbal therapy, or hormone therapy, except as follows: (i) Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (ii) Hormone replacement therapy or oral contraception; (c) Radiotherapy for clearly progressive disease, excluding new brain metastases in the following systemic response circumstances: Patients who have demonstrated control of systemic disease (defined as having received a clinical benefit [i.e., PR, CR, or SD over ≥3 months]) but who have developed radiation-treated brain metastases may continue therapy with compound 1 during the study until they experience either systemic progression of the disease and / or further progression in the brain (based on the investigator's assessment). (d) Quinidine or other antiarrhythmic agents; or (e) Initiation or increase in dose of hematopoietic colony-stimulating factor (CSF; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; salglamostim, pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) starting 7 days prior to day 1 of the first cycle;

[0168] In one embodiment of such a method, a patient is diagnosed with the cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from a subject. In one embodiment of such a method, the sample is taken before administration of any therapy described herein. In another embodiment of such a method, the sample is taken before administration of at least one drug described herein. In some embodiments, tumor samples may be taken at specified intervals during treatment with the combination therapy described herein in order to evaluate the treatment.

[0169] Tumor or cancer is KRas G12C Determining whether a mutation is present can be done by evaluating the nucleotide sequence encoding the K-Ras protein, by evaluating the amino acid sequence of the K-Ras protein, or by evaluating the characteristics of the proposed K-Ras mutant protein. The sequence of wild-type human K-Ras (e.g., accession number NP203524) is known in the art. In one such embodiment, a sample from a patient described herein is analyzed for KRas using, for example, immunohistochemistry (IHC) or NGS sequencing. G12C Evaluate the mutations.

[0170] By administering the combination therapies described herein, KRas G12C This specification further provides methods for treating transorgan-mediated cancers, including mutations. In one embodiment of such a method, the method includes: (a) KRas in samples taken from patients diagnosed with suspected cancer G12C To measure the presence or absence of mutations, and (b) Administer to the patient an effective amount of compound 1 described herein or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, as described herein.

[0171] In such an embodiment, the EGFR inhibitor is erlotinib or cetuximab. In such an embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 50 to 500 mg. In another such embodiment, erlotinib is administered QD in an amount of about 100 mg or 150 mg. In yet another embodiment, cetuximab is administered at about 400 mg / m 2 on day 1 of the first 21-day cycle, and thereafter cetuximab is administered at about 25 mg / m 2 Q1W.

[0172] Furthermore, a method for treating organ-invasive cancer comprising a KRas G12C mutation, comprising: [[ID=ll]] (a) measuring the presence or absence of a KRas G12C mutation in a sample taken from a patient diagnosed with suspected cancer, and (b) administering to the patient a combination therapy described herein comprising a dosing regimen comprising: (i) administering 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; and (ii) administering 100 or 150 mg of erlotinib QD on days 1 to 21 of the first 21-day cycle.

[0173] Furthermore, a method for treating organ-invasive cancer comprising a KRas G12C mutation, comprising: (a) measuring the presence or absence of a KRas G12C mutation in a sample taken from a patient diagnosed with suspected cancer, and (b) administering to the patient a combination therapy described herein comprising a dosing regimen comprising: (i) administering 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle; (ii) administering about 400 mg / m 2 of cetuximab on day 1 of the first 21-day cycle, and subsequently administering about 2 m 2 g / m of cetuximab Q1W.

[0174] In one embodiment provided herein, a patient is diagnosed with complete response (CR) after treatment with combination therapy according to the method provided herein. In one embodiment provided herein, a patient is diagnosed with partial response (PR) after treatment with combination therapy according to the method provided herein. In one embodiment provided herein, a patient is diagnosed with stable disease (SD) after treatment with combination therapy according to the method provided herein.

[0175] Also provided herein are methods for inhibiting tumor growth or inducing tumor regression in patients as described herein by applying the combination therapies described herein. In one embodiment, a method is provided herein for inhibiting tumor growth in patients having cancer as described herein by administering a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof as described herein and an EGFR inhibitor (e.g., erlotinib or cetuximab) in one or more 21-day cycles as described herein. In one embodiment, a method is provided herein for inhibiting tumor growth in patients having NSCLC, CRC, or pancreatic cancer as described herein by administering a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof as described herein and an EGFR inhibitor (e.g., erlotinib or cetuximab) in one or more 21-day cycles as described herein.

[0176] In one embodiment, a method is provided herein for inducing or improving tumor regression in a patient having the cancer described herein by administering a combination therapy comprising administering compound 1 described herein or a pharmaceutically acceptable salt thereof and an EGFR inhibitor (e.g., erlotinib or cetuximab) in one or more 21-day cycles as described herein. In one embodiment, a method is provided herein for inducing or improving tumor regression in a patient having NSCLC, CRC, or pancreatic cancer as described herein by administering a combination therapy comprising administering compound 1 described herein or a pharmaceutically acceptable salt thereof and an EGFR inhibitor (e.g., erlotinib or cetuximab) in one or more 21-day cycles as described herein. kit

[0177] The combination therapies described herein may be provided as kits comprising one or more of the agents described herein for administration. In one embodiment, the kit comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipinate of compound 1) for administration in combination with an EGFR inhibitor described herein (e.g., erlotinib or cetuximab described herein). In another embodiment, the kit comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipinate of compound 1) packaged together with an EGFR inhibitor described herein (e.g., erlotinib or cetuximab), and the kit comprises separate formulated doses of each agent.

[0178] Furthermore, products or kits comprising Compound 1 or a pharmaceutically acceptable salt thereof (e.g., Compound 1 adipate) and an EGFR inhibitor (e.g., erlotinib or cetuximab) are also provided herein. In some examples, the product further includes a package insert containing instructions for using the EGFR inhibitor (e.g., erlotinib or cetuximab) described herein to treat or delay the progression of a solid tumor (e.g., lung cancer, CRC, or pancreatic cancer as described herein). In one such embodiment, the cancer is NSCLC. In one embodiment, the product further includes a package insert containing instructions for using the EGFR inhibitor (e.g., erlotinib) described herein in combination with Compound 1 or a pharmaceutically acceptable salt thereof (e.g., Compound 1 adipate) to treat or delay the progression of NSCLC in a patient. In one embodiment, the product further includes a package insert containing instructions for using an EGFR inhibitor as specified herein (e.g., erlotinib) in combination with compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) to treat or delay the progression of pancreatic cancer in a patient. In one embodiment, the product further includes a package insert containing instructions for using an EGFR inhibitor as specified herein (e.g., cetuximab) in combination with compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) to treat or delay the progression of CRC in a patient.

[0179] In some examples, the EGFR inhibitors described herein (e.g., erlotinib or cetuximab) and compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) are contained in the same container or in separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. Containers may be formed from a variety of materials such as glass, plastic (e.g., polyvinyl chloride or polyolefin), or metal alloy (e.g., stainless steel or Hastelloy). In some examples, the container holds the formulation, and labels on or associated with the container may indicate instructions for use. The product or kit may further include other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, syringes, and accompanying documentation with instructions for use. In some examples, the product further includes one or more other drugs (e.g., further chemotherapeutic agents or antineoplastic agents). Suitable containers for one or more drugs include, for example, bottles, vials, bags, and syringes.

[0180] Any product or kit described herein may include instructions for administering compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and / or an EGFR inhibitor described herein (e.g., erlotinib or cetuximab) to a patient in accordance with any of the methods described herein. biomarkers

[0181] In one embodiment, KRas is provided by compound 1 or a pharmaceutically acceptable salt thereof. G12C The alkylation of is measured in the patient. In one such embodiment, the measurement is carried out using a sample and KRas provided herein. G12C The alkylation of is tested. In another embodiment, a ctDNA biomarker (e.g., KRas) is obtained from peripheral blood. G12C ) will be evaluated.

[0182] In one embodiment, KRAS / MAPK target genes (e.g., DUSP6, SPRY4), pathway components (e.g., pERK, pS6), and related biomarkers (e.g., Ki67) are regulated by analysis of paired pre- and intra-treatment fresh tumor biopsies. Embodiment

[0183] Several exemplary embodiments of the present invention are provided below.

[0184] Embodiment No. 1: Combination therapy, (a) Compound 1 described herein or a pharmaceutically acceptable salt thereof, (b) EGFR inhibitors, Combination therapy, including

[0185] Embodiment No. 2: The combination therapy according to Embodiment 1, wherein compound 1 is its adipine salt.

[0186] Embodiment No. 3: The combination therapy according to Embodiment 1 or 2, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered via QD on days 1 to 21 of the first 21-day cycle.

[0187] Embodiment No. 4: The combination therapy according to any one of Embodiments 1 to 3, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

[0188] Embodiment No. 5: The combination therapy according to any one of Embodiments 1 to 4, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of approximately 50 mg to 500 mg.

[0189] Embodiment No. 6: The combination therapy according to any one of Embodiments 1 to 5, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg.

[0190] Embodiment No. 7: The combination therapy according to any one of Embodiments 1 to 6, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib or afatinib, or an anti-EGFR antibody.

[0191] Embodiment No. 8: The combination therapy according to any one of Embodiments 1 to 7, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib.

[0192] Embodiment No. 9: The combination therapy according to any one of Embodiments 1 to 8, wherein the EGFR inhibitor is erlotinib.

[0193] Embodiment No. 10: The combination therapy according to Embodiment 9, wherein erlotinib is administered as a QD on days 1 to 21 of the first 21-day cycle.

[0194] Embodiment No. 11: The combination therapy according to any one of Embodiments 1 to 10, wherein the EGFR inhibitor is erlotinib administered in an amount of approximately 100 mg or 150 mg QD.

[0195] Embodiment No. 12: The combination therapy according to Embodiment 11, wherein erlotinib is administered in an amount of approximately 100 mg QD.

[0196] Embodiment No. 13: The combination therapy described in Embodiment 11, wherein erlotinib is administered in an amount of approximately 150 mg QD.

[0197] Embodiment No. 14: The combination therapy according to any one of Embodiments 1 to 7, wherein the EGFR inhibitor is an anti-EGFR antibody comprising panitumumab or cetuximab.

[0198] Embodiment No. 15: The combination therapy according to any one of Embodiments 1 to 7 or 14, wherein the EGFR inhibitor is cetuximab.

[0199] Embodiment No. 16: The combination therapy according to any one of Embodiments 1 to 7 or 14 to 15, wherein the EGFR inhibitor is cetuximab administered in Q1W, which begins on day 1 of the first 21-day cycle.

[0200] Embodiment No. 17: The EGFR inhibitor is administered at a dose of approximately 400 mg / m² on day 1 of the 21-day cycle. 2 In that amount, followed by approximately 250 mg / m² 2 The combination therapy described in any one of Embodiments 1-7 or 14-16, wherein cetuximab is administered in a Q1W dose.

[0201] Embodiment Number 18: KRas G12C A combination therapy according to any one of Embodiments 1 to 13 for use in the treatment of lung cancer including mutations.

[0202] Embodiment No. 19: The combination therapy according to Embodiment 18, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0203] Embodiment No. 20: KRas G12C A combination therapy according to any one of Embodiments 1 to 13 for use in the treatment of pancreatic cancer including mutations.

[0204] Embodiment No. 21: KRas G12C A combination therapy according to any one of Embodiments 1-7 or 14-17 for use in the treatment of colorectal cancer (CRC) including mutations.

[0205] Embodiment No. 22: A combination therapy, (a) Compound 1 described herein or a pharmaceutically acceptable salt thereof, administered by QD on days 1 to 21 of the first 21-day cycle, (b) Erlotinib administered as a QD on days 1 to 21 of the first 21-day cycle, Combination therapy, including

[0206] Embodiment No. 23: The combination therapy according to Embodiment 22, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg, and erlotinib is administered in an amount of about 100 mg or 150 mg.

[0207] Embodiment No. 24: Use in the treatment of lung cancer comprising a KRas G12C mutation, of the combination therapy according to Embodiment 22 or 23.

[0208] Embodiment No. 25: Use in the treatment of pancreatic cancer comprising a KRas G12C mutation, of the combination therapy according to Embodiment 22 or 23.

[0209] Embodiment No. 26: A combination therapy comprising (a) Compound 1 or a pharmaceutically acceptable salt thereof as described herein, administered QD on days 1 to 21 of the first 21-day cycle, and (b) cetuximab, administered Q1W starting on day 1 of the first 21-day cycle. A combination therapy comprising.

[0210] Embodiment No. 27: The combination therapy according to Embodiment 26, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg, and cetuximab is administered at about 400 mg / m 2 on day 1 of the 21-day cycle, and thereafter at about 250 mg / m 2 in a Q1W amount.

[0211] Embodiment No. 28: A method of treating such lung cancer in a patient having lung cancer mediated by a KRas G12C mutation, the method comprising administering an effective amount of a combination therapy comprising (a) Compound 1 or a pharmaceutically acceptable salt thereof as described herein, administered QD on days 1 to 21 of the first 21-day cycle, and (b) an EGFR inhibitor. A method comprising administering.

[0212] Embodiment No. 29: The method according to Embodiment 28, wherein the lung cancer is NSCLC.

[0213] Embodiment No. 30: The method according to Embodiment 28, wherein the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer.

[0214] Embodiment No. 31: The method according to any one of Embodiments 28 to 30, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib.

[0215] Embodiment No. 32: The method according to any one of Embodiments 28 to 31, wherein the EGFR inhibitor is erlotinib.

[0216] Embodiment No. 33: The method according to any one of Embodiments 28 to 32, wherein the EGFR inhibitor is erlotinib administered QD on days 1 to 21 of the first 21-day cycle.

[0217] Embodiment No. 34: The method according to any one of Embodiments 28 to 33, wherein the EGFR inhibitor is erlotinib administered in an amount of about 150 mg QD.

[0218] Embodiment No. 35: A method for treating KRas G12C mutation-mediated CRC in a patient having colorectal cancer (CRC), comprising: (a) Compound 1 described herein or a pharmaceutically acceptable salt thereof administered QD on days 1 to 21 of a first 21-day cycle, and (b) an EGFR inhibitor, administering an effective amount of a combination therapy comprising.

[0219] Embodiment No. 36: The method according to Embodiment 35, wherein the EGFR inhibitor is an anti-EGFR antibody comprising panitumumab or cetuximab.

[0220] Embodiment No. 37: The method according to Embodiment 35 or 36, wherein the EGFR inhibitor is cetuximab.

[0221] Embodiment No. 38: The EGFR inhibitor is administered at a dose of approximately 400 mg / m² on day 1 of the 21-day cycle. 2 In that amount, followed by approximately 250 mg / m² 2 The method according to any one of embodiments 35 to 37, wherein cetuximab is administered in a Q1W dose.

[0222] Embodiment No. 39: KRas G12C A method for treating pancreatic cancer in patients who have mutation-mediated pancreatic cancer, (a) Compound 1 described herein or a pharmaceutically acceptable salt thereof, administered by QD on days 1 to 21 of the first 21-day cycle, (b) EGFR inhibitors, A method comprising administering an effective amount of combination therapy, including [a specific substance].

[0223] Embodiment No. 40: The method according to Embodiment 39, wherein the EGFR inhibitor is erlotinib.

[0224] Embodiment No. 41: The method according to Embodiment 39 or 40, wherein the EGFR inhibitor is erlotinib administered as a QD on days 1 to 21 of the first 21-day cycle.

[0225] Embodiment No. 42: The method according to any one of Embodiments 39 to 41, wherein the EGFR inhibitor is erlotinib administered in an amount of approximately 100 g QD.

[0226] Embodiment No. 43: The method according to any one of Embodiments 28 to 42, wherein compound 1 is its adipine salt.

[0227] Embodiment No. 44: The method according to any one of Embodiments 28 to 43, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

[0228] Embodiment No. 45: The method according to any one of Embodiments 28 to 44, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg.

[0229] Embodiment No. 46: The method according to any one of Embodiments 28 to 45, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg.

[0230] Embodiment No. 47: The method according to any one of Embodiments 28 to 46, wherein the patient is diagnosed as not having a mutation selected from the group consisting of a sensitive EGFR mutation, an ALK rearrangement, a ROS1 rearrangement, a BRAF V600E mutation, an NTRK fusion, and a RET fusion, or a combination thereof.

[0231] Embodiment No. 48: Use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and an EGFR inhibitor for the treatment of lung cancer, CRC, or pancreatic cancer described herein.

[0232] Embodiment No. 49: The use according to Embodiment 48, wherein the cancer is lung cancer or pancreatic cancer, the EGFR inhibitor is erlotinib, and the dosing regimen further comprises (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle, and (ii) administering erlotinib on days 1 to 21 of the first 21-day cycle.

[0233] Embodiment No. 50: The use according to Embodiment 48, wherein the cancer is CRC, the EGFR inhibitor is cetuximab, and the dosing regimen further comprises (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of the first 21-day cycle, and (ii) administering at an amount of about 400 mg / m2 on day 1 of the 21-day cycle and then at an amount of about 250 mg / m2 Q1W.

[0234] Embodiment No. 51: Use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and an EGFR inhibitor for the manufacture of a pharmaceutical product for the treatment of lung cancer, CRC, or pancreatic cancer.

[0235] Embodiment No. 52: The use according to Embodiment 51, wherein the cancer is lung cancer or pancreatic cancer, the EGFR inhibitor is erlotinib, and the drug regimen further comprises (i) administering compound 1 or a pharmaceutically acceptable salt thereof in a QD manner on days 1 to 21 of a first 21-day cycle, and (ii) administering erlotinib on days 1 to 21 of the first 21-day cycle.

[0236] Embodiment No. 53: The use according to Embodiment 51, wherein the cancer is CRC, the EGFR inhibitor is cetuximab, and the drug regimen further comprises (i) administering compound 1 or a pharmaceutically acceptable salt thereof in a QD on days 1 to 21 of a first 21-day cycle, and (ii) administering approximately 400 mg / m2 on day 1 of the 21-day cycle, and thereafter approximately 250 mg / m2 Q1W.

[0237] The following examples are presented as illustrations, not as limitations. [Examples]

[0238] Example 1: Combination of Compound 1 and Erlotinib

[0239] The Carsten rat sarcoma virus oncogene homolog (KRAS) gene encodes a GTPase that plays a central role in mediating cell proliferation and survival signaling. Mutations in KRAS resulting in amino acid substitutions at glycine 12 (G12), glycine 13 (G13), and glutamine 61 (Q61) are common in tumors and are associated with tumorigenesis and the maintenance of invasive tumor growth (Der et al. Nature 1983;304(5926):507-13; Parada et al. Nature 1982;297(5866):474-8; Santos et al. Nature 1982;298(5872):343-7; Taparowsky et al. Nature 1982;300(5894):762-5; Capon et al. Nature 1983;304(5926):507-13). G12C The mutation is common in non-small cell lung cancer (NSCLC), colorectal cancer, and other tumor types (Prior et al. Cancer Res 2012;72(10):2457-67; Vogelestein et al. Science 2013;339(6127):1546-58).

[0240] Compound 1 is KRAS G12C Selectively targeting KRAS G12C It is an oral anticancer agent that provides covalent and irreversible inhibition of KRAS. Compound 1 does not target KRAS, the wild-type form of KRAS, or other mutations in other members of the RAS family. G12C Treatment of positive cells or tumors results in a decrease in KRAS pathway signaling, suppression of cell / tumor cell proliferation, and induction of apoptosis.

[0241] NCI-H2122(KRAS G12CIn an NSCLC xenograft tumor model, the in vivo antitumor efficacy of compound 1 (50 mg / kg, PO, QD) alone or in combination with erlotinib (50 mg / kg, PO, QD) was evaluated. Treatment with compound 1 alone resulted in tumor quiescence (93% tumor growth inhibition (TGI)), while treatment with erlotinib alone resulted in only 48% TGI of tumor growth inhibition. The combination of compound 1 and erlotinib showed improved antitumor efficacy (117% TGI).

[0242] Test materials: Compound 1 (free base) was provided as a solution at a concentration of 8.333 mg / mL (expressed as free base equivalent) in 0.5% (w / v) methylcellulose. Erlotinib (Tarceva®) was provided as a solution at a concentration of 12.5 mg / mL (expressed as free base equivalent) in 7.5% Captisol. All concentrations were calculated based on the average body weight of 25 g of nude mouse strains used in this study. The vehicle control was 0.5% (w / v) methylcellulose and 0.5% (w / v) methylcellulose / 0.2% Tween 80®. The test drugs were stored in a refrigerator set to maintain a temperature range of 4°C to 7°C. All treatment and vehicle control drug solutions were prepared once a week for three weeks.

[0243] Female nude mice, 9-10 weeks old and with an average weight of 24.5g, were obtained from the Charles River Laboratory in Hollister, California. The mice were housed in standard rodent micro-isolate cages and acclimated to the study conditions at least 3 days prior to tumor cell transplantation. Only animals that appeared healthy and showed no obvious abnormalities were used in the study.

[0244] Human non-small lung cancer NCI-H2122 cells were obtained from the American Type Culture Collection (Rockville, Maryland), which carried the G12C oncogenic mutation in K-RAS. The cells were cultured in vitro, harvested during the logarithmic growth phase, and resuspended in Hanks equilibrium salt solution (HBSS) containing Matrigel (BD Biosciences; San Jose, California) in a 1:1 ratio. The cells were then transplanted subcutaneously into the right thorax of 160 nude mice. Each mouse received 10 × 10⁶ cells in a volume of 100 μL. 6 Individual cells were injected. The tumor had an average tumor volume of 150-290 mm². 3 The mice were monitored until the tumor volume was reached. The mice were divided into 10 groups based on tumor volume, with n=10 mice per group. The average tumor volume across all 10 groups was 213 mm at the start of administration. 3 That was the case.

[0245] Mice were administered either a vehicle (150 μL of 0.5% MC and 100 μL of 0.5% MCT), 50 mg / kg of compound 1 (expressed as free-base equivalent), or 50 mg / kg of erlotinib. All treatments were administered daily (QD) orally (PO) over 21 days. Tumor size and mouse body weight were recorded, and the tumor volume was 2000 mm³. 3 When the weight exceeded a certain threshold, or when the weight loss was ≥20% of the starting weight, the mice were immediately euthanized.

[0246] [Table 1]

[0247] Tumor volume was measured in two dimensions (length and width) using an Ultra Cal-IV caliper (Model 54-10-111; Fred V. Fowler Co.; Newton, Massachusetts) and analyzed using Excel, version 14.2.5 (Microsoft Corporation; Redmond, Washington). Tumor volume was calculated using the following formula: Tumor size (mm) 3) = (longer measurement × shorter measurement) 2 ) × 0.5

[0248] An antitumor response was observed, with a partial response (PR) defined as a >50% reduction in tumor volume from the initial volume, and a complete response (CR) defined as a 100% reduction in tumor volume.

[0249] The antitumor effect was evaluated in nude mice with human NCI-H2122 NSCLC xenografts after treatment with compound 1 (50 mg / kg, PO, QD) alone, compared to treatment with erlotinib monotherapy (50 mg / kg, PO, QD) or in combination. Monotherapy resulted in tumor growth inhibition (TGI), with compound 1 achieving a 93% TGI and erlotinib achieving a 48% TGI compared to the vehicle control (see Table 2 and Figure 1). The combination of compound 1 and erlotinib showed improvement in antitumor efficacy, achieving a 117% TGI and a 3 / 10 partial response (PR) (Figure 2).

[0250] [Table 2] CI = Confidence Interval; CR = Complete Response; PR = Partial Response; QD = Once Daily; TI = Tumor Incidence. Vehicle = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose / 0.2% Tween 80 (trademark).

[0251] In the NCI-H2122 human NSCLC xenograft tumor model, a combination antitumor efficacy trial was conducted, and KRAS G12C The inhibitor compound 1 demonstrated suppression of tumor growth (93% TGI, no PR) as a monotherapy. Monotherapy activity with the EGFR inhibitor erlotinib also resulted in tumor growth inhibition (48% TGI, no PR). The combination of compound 1 and erlotinib resulted in improved antitumor efficacy (117% TGI, 3 / 10 PR). These data were presented at KRAS. G12CThis study demonstrates that the combination of the inhibitor compound 1 and erlotinib resulted in improved antitumor activity leading to partial tumor regression in the NCI-H2122 human NSCLC human xenograft tumor model.

[0252] Example 2: Combination of Compound 1 and cetuximab in a PDX CR6256 colorectal cancer xenograft model in female BALB / c nude mice

[0253] The in vivo therapeutic efficacy of compound 1 and cetuximab was preclinically evaluated in the treatment of a subcutaneous PDX CR6256 colon cancer xenograft model in female BALB / c nude mice.

[0254] Female BALB / c nude mice were housed in standard polysulfone IVC cages. The mice were 5-9 weeks old at the time of initial inoculation. Compound 1 was administered as a polypoietic injection (PO) at 30 mg / kg QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0255] Tumor fragments were collected from stock mice and used for inoculation into mice. To induce tumor development, a primary human tumor xenograft model CR6256 tumor fragment (2-3 mm in diameter) was subcutaneously inoculated into the right posterior flank of each mouse. After tumor cell inoculation, animals were monitored daily for morbidity and mortality. During routine monitoring, animals were observed for the effects of tumor growth and treatment on behavior, including motility, food and water consumption, weight gain / loss (weight was measured twice a week after randomization), loss of eye / coat luster (matting), and any other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0256] Tumor volume was measured twice a week after randomization in two dimensions using calipers, and the volume was expressed in mm using the following formula. 3The formula is given as: V = (L × W × W) / 2, where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L). Medication, as well as tumor and body weight measurements, were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

[0257] Tumor Growth Inhibition (TGI): TGI% is an indicator of antitumor activity and is expressed as follows: TGI(%) = 100 × (1 - T / C). T and C are the mean tumor volume (or weight) of the treatment group and the control group, respectively, on a given day.

[0258] The in vivo antitumor effect of Compound 1 (30 mg / kg, orally, once daily) alone or in combination with cetuximab was demonstrated using CR6256 (KRas G12C The efficacy was evaluated in patient-derived colorectal tumor models. Treatment with compound 1 alone resulted in tumor quiescence to regression (108% tumor growth inhibition [TGI]), while cetuximab alone showed moderate to slight tumor growth inhibition (74%). The combination of compound 1 and cetuximab showed improved combination efficacy compared to monotherapy (133%).

[0259] [Table 3]

[0260] Example 3: Combination of compound 1 and cetuximab in the PDX cancer model CR5048 in female NOD-SCID mice.

[0261] The in vivo therapeutic efficacy of compound 1 and cetuximab was preclinically evaluated in the treatment of the PDX cancer model CR5048 in female NOD-SCID mice. The animals had a mean tumor volume of 185.67 mm². 3Animals were randomized on day 0, and administration began on day 1. Compound 1 was administered daily (QD) for 21 days, and cetuximab was administered daily by week (BIW) for 3.5 weeks (7 total doses), both alone and in combination. All animals were sacrificed 8 hours after the final dose (day 21 of the study). Animals were measured twice a week during the study period. At the end of the study, tumors and blood were collected from all animals in the study. Tumors were divided in half, and both halves were rapidly frozen in liquid nitrogen in separate tubes. Blood was collected by cardiac puncture and processed into plasma.

[0262] CR5048(KRas G12C The in vivo antitumor effects of compound 1 (30 mg / kg, orally, once daily) alone or in combination with cetuximab were measured in a colorectal tumor model derived from patient-derived tumors. Treatment with compound 1 alone resulted in tumor growth inhibition (90% tumor growth inhibition [TGI]), while treatment with cetuximab alone showed moderate to mild tumor growth inhibition (59% TGI). The combination of compound 1 and cetuximab showed improved combination efficacy (110%) compared to monotherapy.

[0263] [Table 4]

[0264] Example 4: Combination of Compound 1 and cetuximab in a PDX CR6243 colorectal cancer xenograft model in female BALB / c nude mice

[0265] The in vivo therapeutic efficacy of compound 1 and cetuximab was preclinically evaluated in the treatment of a subcutaneous PDX CR6243 colon cancer xenograft model in female BALB / c nude mice.

[0266] Female BALB / c nude mice were housed in standard polysulfone IVC cages. The mice were 5-9 weeks old at the time of initial inoculation. Compound 1 was administered as a polyoxygenated dose (PO) at 30 mg / kg QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0267] Tumor fragments were collected from stock mice and used for inoculation into mice. To induce tumor development, a primary human tumor xenograft model CR6243 tumor fragment (2-3 mm in diameter) was subcutaneously inoculated into the right posterior flank of each mouse.

[0268] The average tumor size is approximately 192 mm. 3 Randomization was initiated when the target group was reached. After tumor cell inoculation, animals were monitored daily for morbidity and mortality. During routine monitoring, animals were observed for the effects of tumor growth and treatment on behavior, including motility, food and water consumption, weight gain / loss (weight was measured twice weekly after randomization), loss of eye / coat luster (matting), and any other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0269] Tumor volume was measured twice a week after randomization in two dimensions using calipers, and the volume was expressed in mm using the following formula. 3 The formula is given as: V = (L × W × W) / 2, where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L). Medication, as well as tumor and body weight measurements, were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

[0270] Tumor Growth Inhibition (TGI): TGI% is an indicator of antitumor activity and is expressed as follows: TGI(%) = 100 × (1 - T / C). T and C are the mean tumor volume (or weight) of the treatment group and the control group, respectively, on a given day.

[0271] CR6243(KRAS G12CIn vivo antitumor efficacy of compound 1 (30 mg / kg, orally, once daily) alone or in combination with cetuximab in a colorectal tumor model derived from patient-derived tumors. Treatment with compound 1 alone resulted in tumor quiescence to regression (89% tumor growth inhibition [TGI]), while cetuximab alone showed moderate to slight tumor growth inhibition (47% TGI). The combination of compound 1 and cetuximab showed improved combination efficacy (104%) compared to monotherapy.

[0272] [Table 5]

[0273] Example 5: Combination of Compound 1 and cetuximab in a PDX CR6927 colorectal cancer xenograft model in female BALB / c nude mice

[0274] The in vivo therapeutic efficacy of compound 1 and cetuximab was preclinically evaluated in the treatment of a subcutaneous PDX CR6927 colon cancer xenograft model in female BALB / c nude mice.

[0275] Female BALB / c nude mice were housed in standard polysulfone IVC cages. The mice were 5-9 weeks old at the time of initial inoculation. Compound 1 was administered as a polyoxygenated dose (PO) at 30 mg / kg QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0276] Tumor fragments were collected from stock mice and used for inoculation into mice. To induce tumor development, a primary human tumor xenograft model CR6927 tumor fragment (2-3 mm in diameter) was subcutaneously inoculated into the right posterior flank of each mouse.

[0277] The average tumor size is approximately 194 mm. 3Randomization was initiated when the target group was reached. After tumor cell inoculation, animals were monitored daily for morbidity and mortality. During routine monitoring, animals were observed for the effects of tumor growth and treatment on behavior, including motility, food and water consumption, weight gain / loss (weight was measured twice weekly after randomization), loss of eye / coat luster (matting), and any other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0278] Tumor volume was measured twice a week after randomization in two dimensions using calipers, and the volume was expressed in mm using the following formula. 3 The formula is given as: V = (L × W × W) / 2, where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L). Medication, as well as tumor and body weight measurements, were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

[0279] Tumor Growth Inhibition (TGI): TGI% is an indicator of antitumor activity and is expressed as follows: TGI(%) = 100 × (1 - T / C). T and C are the mean tumor volume (or weight) of the treatment group and the control group, respectively, on a given day.

[0280] CR6927(KRAS G12C ) In vivo antitumor efficacy of compound 1 (30 mg / kg, oral, once daily) alone or in combination with cetuximab in a patient-derived colorectal tumor model. Compound 1 as monotherapy and cetuximab as an antitumor agent (29% and 10% tumor growth inhibition [TGI], respectively). The combination of compound 1 and cetuximab resulted in improved combination efficacy (70%) compared to monotherapy. All doses and combinations tested were acceptable based on minimal changes in body weight and overall animal condition.

[0281] [Table 6]

[0282] Example 6: Combination of Compound 1 and cetuximab in a PDX CR2528 colorectal cancer xenograft model in female BALB / c nude mice

[0283] The in vivo therapeutic efficacy of compound 1 and cetuximab was preclinically evaluated in the treatment of a subcutaneous PDX CR2528 colon cancer xenograft model in female BALB / c nude mice.

[0284] Female BALB / c nude mice were housed in standard polysulfone IVC cages. The mice were 8-10 weeks old at the time of initial inoculation. Compound 1 was administered as a polyoxygenated dose (PO) at 30 mg / kg QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0285] Tumor fragments were collected from stock mice and used for inoculation into mice. To induce tumor development, a primary human tumor xenograft model CR2528 tumor fragment (2-3 mm in diameter) was subcutaneously inoculated into the right posterior flank of each mouse.

[0286] The average tumor size is approximately 202 mm. 3 Randomization was initiated when the target group was reached. After tumor cell inoculation, animals were monitored daily for morbidity and mortality. During routine monitoring, animals were observed for the effects of tumor growth and treatment on behavior, including motility, food and water consumption, weight gain / loss (weight was measured twice weekly after randomization), loss of eye / coat luster (matting), and any other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0287] Tumor volume was measured twice a week after randomization in two dimensions using calipers, and the volume was expressed in mm using the following formula. 3The formula is given as: V = (L × W × W) / 2, where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L). Medication, as well as tumor and body weight measurements, were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

[0288] Tumor Growth Inhibition (TGI): TGI% is an indicator of antitumor activity and is expressed as follows: TGI(%) = 100 × (1 - T / C). T and C are the mean tumor volume (or weight) of the treatment group and the control group, respectively, on a given day.

[0289] CR2528(KRAS G12C In vivo antitumor efficacy of compound 1 (30 mg / kg, oral, once daily) alone or in combination with cetuximab in a colorectal patient-derived tumor model. Treatment with compound 1 alone resulted in tumor quiescence (65% tumor growth inhibition [TGI]), while cetuximab alone showed moderate growth inhibition (40% TGI). The combination of compound 1 and cetuximab resulted in improved combination efficacy (117% TGI) compared to monotherapy. All doses and combinations tested were acceptable based on minimal changes in body weight and overall animal condition.

[0290] [Table 7]

[0291] Example 7: Combination of Compound 1 and cetuximab in a PDX CR1451 colorectal cancer xenograft model in female BALB / c nude mice

[0292] The in vivo therapeutic efficacy of compound 1 and cetuximab was preclinically evaluated in the treatment of a subcutaneous PDX CR1451 colon cancer xenograft model in female BALB / c nude mice.

[0293] Female BALB / c nude mice were housed in standard polysulfone IVC cages. The mice were 5-9 weeks old at the time of initial inoculation. Compound 1 was administered as a polyoxygenated dose (PO) at 30 mg / kg QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0294] Tumor fragments were collected from stock mice and used for inoculation into mice. To induce tumor development, a primary human tumor xenograft model CR1451 tumor fragment (2-3 mm in diameter) was subcutaneously inoculated into the right posterior flank of each mouse.

[0295] The average tumor size is approximately 182 mm. 3 Randomization was initiated when the target group was reached. After tumor cell inoculation, animals were monitored daily for morbidity and mortality. During routine monitoring, animals were observed for the effects of tumor growth and treatment on behavior, including motility, food and water consumption, weight gain / loss (weight was measured twice weekly after randomization), loss of eye / coat luster (matting), and any other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal.

[0296] Tumor volume was measured twice a week after randomization in two dimensions using calipers, and the volume was expressed in mm using the following formula. 3 The formula is given as: V = (L × W × W) / 2, where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L). Medication, as well as tumor and body weight measurements, were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

[0297] Tumor Growth Inhibition (TGI): TGI% is an indicator of antitumor activity and is expressed as follows: TGI(%) = 100 × (1 - T / C). T and C are the mean tumor volume (or weight) of the treatment group and the control group, respectively, on a given day.

[0298] CR1451(KRAS G12CIn vivo antitumor efficacy of compound 1 (30 mg / kg, oral, once daily) alone or in combination with cetuximab in a colorectal patient-derived tumor model. Treatment with compound 1 alone resulted in tumor quiescence (64% tumor growth inhibition [TGI]), while cetuximab alone showed delayed growth inhibition (48% TGI). The combination of compound 1 and cetuximab resulted in improved combination efficacy (83% TGI) compared to monotherapy. All doses and combinations tested were acceptable based on minimal changes in body weight and overall animal condition.

[0299] [Table 8]

[0300] Example 8: KRAS is the most frequently mutated oncogene in up to 25% of cancers and is associated with resistance to standard treatment options and overall poor prognosis. While selective inhibitors have been developed as anticancer therapies targeting other nodes of the RAS / MAPK pathway, the KRAS oncoprotein was not considered drug-worthy until the recent discovery of the switch II pocket (Ostrem, et al. Nature 2013;503:548-51). This finding has led to the development of KRAS, specifically KRAS G12C Covalent small molecule inhibitors that target mutations are being evaluated in early clinical development.

[0301] Other KRAS G12C The inhibitor AMG 510 (sotracib) is used in KRAS G12CIt is a small molecule that irreversibly inhibits by locking it in its inactive GDP-bound state. AMG-510 is currently being investigated in ongoing clinical studies. Patients in these studies received prior lines of anticancer therapy for metastatic disease with a median of 3 (range 0-11) before entering the study. Overall, treatment-related adverse events were reported in 56.6% of patients, 11.6% experienced treatment-related grade 3 or 4 events, and 1.6% experienced treatment-related serious adverse events. Grade 3 events occurring in multiple patients included elevated ALT, diarrhea, anemia, elevated AST, and elevated alkaline phosphatase. One patient experienced grade 4 treatment-related elevated ALT, and one patient discontinued AMG 510 due to grade 3 treatment-related elevated ALT and AST. Antitumor activity has been reported, but adverse events associated with AMG-510 exist. The patient demonstrated an objective response, observed in 32.2% of NSCLC patients, with a median duration of response of 10.9 months (ranging from 1.1+ to 13.6). The median progression-free survival (PFS) was reported to be 6.3 months (ranging from 0.0+ to 14.9+) in NSCLC patients (Hong et al. New Eng J Med 2020;383:1207-17).

[0302] MRTX849 is KRAS G12C The mutation-selective small molecule KRAS is being evaluated in clinical studies of patients with progressive solid tumors containing mutations. G12CIt is an inhibitor. Recently, data from a total of 17 patients (including 10 NSCLC patients and 4 CRC patients) were reported, of which 12 patients underwent at least one treatment-related tumor assessment (including 6 NSCLC patients and 4 CRC patients). Most patients had received three or more prior anti-cancer regimens before participating in the study (12 out of 17 patients, 71%). The following treatment-related adverse events were reported in >10% of patients: diarrhea, nausea, elevated AST, vomiting, fatigue, elevated ALT, elevated creatinine, abdominal distension, abdominal pain, elevated ALP, anemia, loss of appetite, dehydration, dry mouth, dysgeusia, dyspnea, QT prolongation, hypomagnesemia, and rash. Grade 3 events included fatigue, loss of appetite, and dyspnea (one patient each). PR-mediated antitumor activity was achieved in 3 out of 6 NSCLC patients and 1 out of 4 CRC patients across all evaluated dose levels (Jaenne et al. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 2019).

[0303] Compound 1.KRAS G12C The specificity of compound 1 against KRAS, along with its mechanism of action, is evident. G12C It is expected to provide potent and irreversible inhibition, enabling a broad therapeutic index that maximizes antitumor activity while minimizing treatment-related toxicity. KRAS G12C Specific therapies targeting positive cancers include KRAS G12C This may provide a more tolerable and effective treatment option for patients with advanced-stage cancer.

[0304] In vitro and in vivo pharmacological studies showed that compound 1 is KRAS G12C It is a very potent and selective covalent inhibitor of KRAS G12C KRAS is better than negative cancer cell lines. G12CIt has been demonstrated that it exhibits selectivity of more than 20,000-fold in inhibiting the proliferation of KRAS-positive cancer cell lines. Mechanism of action studies using compound 1 have shown that, in addition to KRAS target genes such as DUSP6 and SPRY4, downstream MAPK pathway components such as phosphorylated (p)ERK and pS6 are inhibited, thus inhibiting KRAS G12C We have demonstrated that apoptosis induction is observed in positive cancer cell lines. Furthermore, compound 1 has potent monotherapy activity and KRAS G12C It inhibits tumor growth in several nonclinical xenograft models of positive lung tumors. These in vitro and in vivo pharmacological studies have shown that it inhibits locally advanced or metastatic KRAS. G12C We support the use of compound 1 for the treatment of patients with positive solid tumors.

[0305] The results of nonclinical toxicology studies completed to date provide a robust characterization of the toxicity profile of compound 1 and support the administration of compound 1 in patients with cancer. Comprehensive nonclinical toxicity studies were completed to evaluate the oral toxicity, genotoxicity, phototoxicity, and safety pharmacology of compound 1 at potential single and repeated doses. KRAS G12C Since the mutation does not exist in healthy animals, KRAS G12C There are no nonclinical species pharmacologically associated with inhibition.

[0306] Cetuximab is a recombinant human / mouse chimeric monoclonal antibody that specifically binds to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab consists of the Fv region of a mouse anti-EGFR antibody having a human IgG1 heavy chain constant region and a kappa light chain constant region, and has an approximate molecular weight of 152 kDa. Cetuximab is produced in mammalian (mouse myeloma) cell culture. In one embodiment, cetuximab is marketed under the trade name ERBITUX®.

[0307] Cetuximab is approved for the treatment of several different solid tumor types, including metastatic colorectal cancer and head and neck cancer. Erlotinib is approved for the treatment of non-small cell lung cancer (NSCLC), particularly NSCLC tumors with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 substitution mutation (L858R) detected by FDA-approved trials, receiving primary, maintenance, or secondary or higher treatment after progression following at least one prior chemotherapy regimen. Erlotinib is also approved in combination with gemcitabine as a first-line treatment for locally advanced, unresectable, or metastatic pancreatic cancer.

[0308] Early Phase I clinical data from ongoing studies of AMG 510 and MRTX849 as monotherapies are available from KRAS G12C The inhibitors have been shown to be tolerable and to possess promising antitumor activity in patients with metastatic NSCLC and CRC (Janne et al. 2019; Hong et at. New Eng J Med 2020;383:1207-17). However, while this class of inhibitors improves the reported antitumor activity and durability in NSCLC and CRC when used as monotherapy, there remains a significant unmet need, more importantly, to maintain their tolerable safety profile.

[0309] The rationale for combination therapy with EGFR inhibitors. While not bound by any particular theory, based on a mechanistic understanding of the RTK-RAS-MAPK pathway, RTK inhibitors can stimulate KRAS G12C Upstream inhibition is KRAS G12C It is hypothesized that inhibition may be potentially enhanced. The nonclinical study described in Example 1 in cell lines showed that EGFR inhibition by either a small molecule that inhibits wild-type EGFR activity or an anti-EGFR antibody may enhance KRAS G12CThis strategy is supported by demonstrating a synergistic enhancement of inhibition (Lito et al. Science 2016;351:604-8; Canon et al. Nature 2019;575:217-23; Amodio et al. Cancer Disc 2020;10:1129-39; Hallin et al. Cancer Disc 2020;10:54-71). EGFR inhibition leads to KRAS G12C Possible mechanisms that enhance the effect of inhibitors include reducing nucleotide exchange and KRAS G12C To promote the GDP coupling state (Lito et al. 2016), and KRAS G12C This includes reducing the rebound enhancement of RTK signaling upon inhibition (Amodio et al. 2020).

[0310] In in vivo mouse studies combining compound 1 with cetuximab, treatment of mice with CRC PDX using compound 1 and cetuximab reduced tumor growth beyond that seen with compound 1 alone. Nonclinical evidence (see Figures 3-8 and Examples 2-7) shows EGFR inhibition and KRAS in CRC. G12C It shows a synergistic effect with inhibition. The starting dose of cetuximab in combination with compound 1 is 400 mg / m² as an IV infusion over 120 minutes on day 1 in a 21-day cycle. 2 The initial dose is 250 mg / m² as a 60-minute IV infusion weekly. 2 Potential co-toxicities of the drug include gastrointestinal toxicity and elevated liver transaminase levels.

[0311] Multiple KRAS in combination with erlotinib G12CIn positive cell lines, compound 1 combined with erlotinib showed a synergistic effect on inhibiting cell proliferation, along with corresponding reductions in pERK and pS6, which were greater than those observed with compound 1 alone. In in vivo mouse studies, a greater reduction in tumor growth in NSCLC xenografts was achieved with compound 1 and erlotinib compared to compound 1 alone. Nonclinical evidence (see Figures 1 and 2) shows EGFR inhibition and KRAS inhibition in NSCLC. G12C A synergistic effect with inhibition is observed. The starting dose of erlotinib in combination with compound 1 is 150 mg oral QD in a 21-day cycle. Potential co-toxicities of the drug include gastrointestinal toxicity and elevated hepatic transaminase levels.

[0312] Biomarkers. This study aims to predict the response to compound 1, either as a monotherapy or in combination with an EGFR inhibitor (i.e., a predictive biomarker), an early surrogate of activity, and a biomarker associated with progression to a more severe disease state (i.e., a prognostic biomarker), KRAS. G12C Identify and / or evaluate biomarkers that may be associated with acquired tolerance to an inhibitor (e.g., compound 1), susceptibility to adverse events, or lead to improved monitoring or investigation of adverse events (i.e., safety biomarkers), provide evidence of the activity of compound 1 in combination with an EGFR inhibitor (i.e., pharmacodynamic [PD] biomarkers), or enhance knowledge and understanding of disease biology and drug safety. Corresponding biomarker endpoints may include relationships between exploratory biomarkers in blood, plasma, and tumor tissue and safety, PK, activity, or other biomarker endpoints.

[0313] Patients are screened for up to 28 days, followed by the treatment period, and then a safety follow-up period during which they are tracked for safety outcomes during the treatment-specific period after the last dose of the study drug or until they receive another anti-cancer therapy (whichever comes first).

[0314] If, as determined by the principal investigator, there is no unacceptable toxicity or clear disease progression, the patient may continue treatment with compound 1 until the end of the study.

[0315] All patients will be closely monitored for adverse events throughout the study and for the treatment-specific period after the final dose of the study treatment or until the initiation of another anticancer therapy (whichever occurs first). Adverse events will be graded according to NCI CTCAE v5.0.

[0316] The starting dose of compound 1 is 50 mg PO QD. A single-patient dose-escalation cohort will be treated with compound 1 at the escalating dose level.

[0317] Patients with locally advanced, relapsed, or metastatic incurable KRas have progressed or become intolerant to at least one prior systemic therapy, which may include monotherapy or combination therapy. G12C This includes patients with positive tumors (e.g., NSCLC, CRC, or pancreatic cancer). Patients with NSCLC, CRC, or pancreatic cancer are KRas G12C Tests are conducted to identify positive cases.

[0318] KRas from tissue and circulating tumor DNA evaluation G12C Mutation status: Approximately 12% of NSCLC, 4% of CRC, 2% of pancreatic cancer, and many other solid tumors (each with a prevalence of ≤4%) are KRas G12C It has a mutation. Compound 1 is KRas G12C It is a potent and highly selective inhibitor that targets KRAS, but does not target KRAS, the wild-type form of KRAS, or other mutations in other members of the RAS family. Therefore, KRas G12COnly patients with tumors containing the mutation are eligible for the combination therapies described herein. KRAS mutation status may be determined using the FoundationOne® CDx (F1CDx) assay, an FDA-approved broad companion diagnostic (CDx) assay, the FoundationOne® Liquid CDx (F1L CDx) assay, and other FDA-approved (FDA 2020) or well-validated laboratory-developed studies conducted in a Clinical Laboratory Improvement Amendments (CLIA) validated or equivalent laboratory. Previous studies have been conducted on KRas G12C The occurrence of the mutation indicates that it is an initial event (amal-Hanjani et al. N Engl J Med 2017;376:2109-21), and analysis of stored tissue indicates that compound 1 is for the treatment of KRas G12C This suggests it is a viable alternative choice for patients with positive tumors.

[0319] Pharmacodynamic pathway regulation. Compound 1 is KRas G12C By suppressing downstream MAPK signaling through alkylation, KRasG12C is locked into its inactive GDP-bound state. G12C It is an inhibitor. In nonclinical models, compound 1 is used to reduce KRas G12C The level of alkylation and the degree of MAPK pathway suppression correlate with the response to compound 1. Pre- and intra-treatment tumor tissue collection will allow for evaluation of the correlation between MAPK pathway suppression and antitumor activity and compound 1 treatment. The degree of MAPK pathway suppression can be evaluated using RNA analysis of MAPK target genes (e.g., DUSP6, SPRY4) or immunohistochemistry (IHC) analysis of downstream phosphorylation markers (e.g., pERK, pS6). Furthermore, intra-treatment tumor tissue biopsy will allow for evaluation of KRas by compound 1. G12C This may allow for direct assessment of the level of alkylation. Evaluation of these PD biomarkers may provide information for future dose selection.

[0320] Sequencing of genes associated with resistance to compound 1. DNA sequencing technologies such as targeted next-generation sequencing (NGS) and whole-exome sequencing may offer unique opportunities to identify biomarkers of response and / or resistance to compound 1. Sequencing of cancer-related genes may lead to the identification of de novo and acquired resistance mechanisms to compound 1.

[0321] Protein, RNA, and DNA analysis. In addition to protein mutation activation, changes in RNA expression levels or DNA can also modulate the activity of signaling pathways. RNA profiling of tumors allows for unique subtyping of patients enrolled in the study. Analysis of the potential association between subtypes and patient outcomes can identify subpopulations of patients most likely to respond to compound 1.

[0322] Plasma samples for somatic tumor mutation analysis and other biomarkers. There is growing evidence that cell-free DNA obtained from blood samples of patients with cancer contains ctDNA representing the DNA and mutational status of cells within tumors (Diehl et al. 2008; Maheswaran et al. 2008). Assays for detecting cancer-related mutations (e.g., KRAS) from plasma have been validated. The results of these assays may correlate with the mutational status determined from analysis of tumor samples. The use of ctDNA to monitor response to treatment is a very interesting area and could enable early, non-invasive, and quantifiable methods for clinical use to identify specific therapy candidates and monitor the mutational status of cancer over time (Wan et al. Nat Rev Cancer 2017;17:223-38). Analysis of ctDNA collected at various time points during research treatment and after patients have progressed with compound 1 may help identify mechanisms of response resistance and acquired resistance to research treatment.

[0323] Blood samples for next-generation sequencing. Next-generation sequencing (NGS) technology can generate large amounts of sequencing data. Tumor DNA may contain both reported and unreported chromosomal changes due to the tumorigenetic process. To help control sequencing calls in previously unreported genomic changes, blood samples are taken before drug administration to determine whether the changes are somatic.

[0324] Selection Criteria. Patients must meet the following study registration criteria: ● Age ≥ 18 years old; ● Diseases that can be evaluated or measured according to RECIST v1.1; ● Performance status of 0 or 1 in the East Coast Cancer Clinical Trials Group (ECOG) ● Average life expectancy of ≥12 weeks; ● Appropriate hematological and organ function within 14 days prior to the start of the study treatment, as defined below: 〇 Absolute neutrophil count ≥ 1200 / μL; ○ Hemoglobin ≥ 9 g / dL; 〇 Platelet count ≧100,000 / μL; Total bilirubin ≤ 1.5 × ULN; Serum albumin ≥ 2.5 g / dL; ○ AST and ≤2.5×ULN, with the following exceptions: ● Patients with demonstrated liver metastases may have AST and / or ALT ≤ 5.0 × ULN. ○ Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL / min (based on Cockcroft-Gault glomerular filtration rate estimation): (140 - age) × (weight in kg) × (0.85 for women) 72 × (Serum creatinine (mg / dL)) ● For women of childbearing age: Consent to maintain abstinence (refraining from heterosexual intercourse) or to use contraception, and to refrain from donating eggs. ● For men who have not undergone sterilization: Consent to maintain abstinence (refrain from heterosexual intercourse) or to use contraception, and to refrain from donating sperm. ● Confirmation of biomarker eligibility: KRas G12C A valid result from a central blood laboratory demonstrating the presence of the mutation, or from laboratory testing of blood or tumor tissue at any of the facilities (e.g., a validated polymerase chain reaction (PCR)-based assay or NGS assay performed in a CLIA or equivalent accredited laboratory).

[0325] Additional selection criteria: ● Histologically demonstrated locally advanced, recurrent, or metastatic incurable adenocarcinoma of the colon or rectum, without known associated secondary oncogenic drivers (e.g., BRAF V600E mutation, ERBB2 amplification), as determined by FMI NGS assay or by a sponsor-approved, validated PCR-based assay or NGS assay performed in a CLIA-accredited or equivalent laboratory at each institution. Patients with appendiceal tumors are excluded. Patients must have experienced disease progression or intolerance to at least one prior chemotherapy regimen (e.g., FOLFOX, FOLFIRI, FOLFOXIRI ± bevacizumab). ● Histologically demonstrated locally advanced, recurrent, or metastatic incurable NSCLC, without known associated secondary oncogenic drivers (e.g., susceptible EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, NTRK fusions, RET fusions), as determined by FMI NGS assays or by sponsor-approved, validated PCR-based assays or NGS assays performed in CLIA-accredited or equivalent laboratories at each institution. Disease progression or intolerance to at least one prior systemic therapy. This may include monotherapy or combination therapy with investigational or approved PD-L1 / PD-1 inhibitors. ● The patient is KRas G12C Prior treatment with specific inhibitors may be administered.

[0326] General exclusion criteria. Patients who meet any of the following criteria will be excluded: ● Unable to swallow pills or unwilling to swallow them; ● Inability to comply with research and follow-up procedures; ● Malabsorption syndrome or other conditions that interfere with enteral absorption; ● Known, untreated, or active central nervous system (CNS) metastases; ● Patients with a history of treated CNS metastases must meet all of the following criteria: ○ Measurable or evaluable diseases outside the CNS; No history of intracranial hemorrhage or spinal hemorrhage; There is no continued need for corticosteroids as a therapy for CNS metastases, and corticosteroids should be discontinued for ≥2 weeks prior to administration of the drugs described herein, provided there are no ongoing symptoms attributable to CNS metastases; No stereotactic radiotherapy within 7 days prior to day 1 of cycle 1, or no whole-brain radiotherapy within 14 days; ○ No preliminary evidence of progression between completion of therapy directed at the CNS and screening radiographs; ● Pelagic disease or carcinomatous meningitis; ● Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures every other week or more frequently; If the patient has recovered sufficiently from the procedure, is hemodynamically stable, and has symptomatically improved, indwelling pleural or abdominal catheterization may be possible; ● Any active infection that could affect patient safety, or a serious infection requiring intravenous administration of antibiotics within 7 days prior to day 1 of cycle 1; ● A history of clinically significant liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis; ● Known HIV infections; ● Uncontrolled hypercalcemia (ionized calcium >1.5 mmol / L or calcium >12 mg / dL, or corrected serum calcium ≥ ULN), or symptomatic hypercalcemia requiring continuous use of bisphosphonate therapy or denosumab; ● Significant traumatic injury or major surgical treatment within 4 weeks prior to day 1 of cycle 1; ● Patients with a history of chronic diarrhea, short bowel syndrome, major upper gastrointestinal surgery including gastrectomy, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or any active bowel inflammation (including diverticulitis); ● Treatment with immunotherapy or biological therapy, or endocrine therapy within two weeks prior to administration of the drugs described herein: Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); ○ Kinase inhibitors approved by regulatory authorities may be used up to two weeks before the start of research treatment; Treatment with the investigational drug within 3 weeks or 5 half-lives (whichever is shorter) prior to administration of the drug described in this specification. ● Radiotherapy as cancer therapy within 4 weeks prior to administration of the drugs described herein (excluding palliative radiotherapy for bone metastases and radiotherapy for CNS metastases); ● Palliative radiation therapy for bone metastases within two weeks prior to administration of compound 1; ● Adverse events from previous anti-cancer therapies that have not resolved; ● History of other malignant tumors within the five years prior to screening; ● A history of clinically significant cardiovascular dysfunction or active, clinically significant cardiovascular dysfunction, including the following: 〇 A history of stroke or transient ischemic attack within 6 months prior to administration of the drugs described herein; 〇 A history of myocardial infarction within 6 months prior to administration of the drugs described herein; ○ Class III or IV heart disease or congestive heart failure requiring medication, as defined by the New York Cardiology Association. 〇 A history of uncontrolled arrhythmias, ventricular arrhythmias requiring medication, or active ventricular arrhythmias; ○ Coronary heart disease with symptomatic or unstable angina; ○ Congenital long QT syndrome or QT interval > 470 ms corrected using the Friderician formula (QTcF); Current treatments involve drug therapies known to prolong the QT interval; ● Pregnant or breastfeeding, or intending to become pregnant within 6 months of the last dose of compound 1 during the study; or ● A history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic interstitial pneumonia, or evidence of active interstitial pneumonia on a screening chest computed tomography (CT) scan.

[0327] Research and therapeutic formulations, packaging, and handling

[0328] Compound 1 is supplied as active pharmaceutical ingredient (API) powder capsule (PIC) formulations in three strengths: 5 mg, 25 mg, and 100 mg (free base equivalent). Additionally, a film-coated tablet formulation in a 100 mg (free base equivalent) dose strength is also supplied for clinical use. Formulations of Compound 1 should be stored below 86°F (30°C) and protected from moisture.

[0329] To administer Compound 1 at home, a sufficient number of capsules or tablets should be distributed to the patient to last until the next clinic visit or over one cycle. The patient will self-administer Compound 1 as provided herein, except when the patient visits the clinic. Unless otherwise instructed, the patient should take Compound 1 at approximately the same time each day. The patient will be instructed on the number and strength of capsules or tablets to take, according to the assigned dose level and schedule.

[0330] Unless otherwise instructed, Compound 1 should be taken on an empty stomach; that is, food should be avoided at least 2 hours and 1 hour before administration. There are no restrictions on fluid intake. Importantly, the capsule or tablet of Compound 1 should be swallowed completely (without chewing) with at least 240 mL (8 fluid ounces) of water. If a patient misses any dose of Compound 1 or vomits up a capsule or tablet, that dose should be skipped and the patient should be instructed to resume administration with the next scheduled dose. Missed doses should not be supplemented.

[0331] Cetuximab is supplied in commercially available formulations. Cetuximab is administered as a 120-minute intravenous infusion of 400 mg / m² on day 1. 2 The initial dose is administered, followed by 250 mg / m² as a weekly 60-minute IV infusion in a 21-day cycle. 2 It is administered as follows. The maximum infusion rate should not exceed 10 mg / min. Cetuximab should be administered after the administration of compound 1.

[0332] Cetuximab administration should be performed under supervision by trained personnel with immediate access to appropriate equipment and medications to manage potentially serious reactions. Prior to the first infusion, participants must receive premedication with antihistamines and corticosteroids. This premedication is recommended before all subsequent infusions. Close monitoring is required during and for at least one hour after the infusion.

[0333] Erlotinib will be supplied as tablets in strengths of 25 mg, 100 mg, and 150 mg. Erlotinib is administered in PO QDs, starting with 150 mg in 21-day cycles, with a sip of water in between, concurrently with compound 1. All doses of erlotinib should be taken on an empty stomach (i.e., food should be avoided at least 2 hours and 1 hour before administration).

[0334] If erlotinib or cetuximab administration is temporarily suspended due to an adverse event in a given cycle, the next medication cycle should not be started until erlotinib or cetuximab administration can be resumed. Therefore, the current cycle may be extended beyond 21 days, and the patient may continue to receive compound 1. Day 1 of the next cycle should correspond to the point in time when erlotinib or cetuximab administration is resumed.

[0335] Ancillary therapy. Ancillary therapy consists of any drug therapy used by the patient in addition to the drugs described herein (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic therapies, nutritional supplements) from seven days before the first dose of at least one drug described herein until the last dose of at least one drug described herein.

[0336] Permitted therapies: Patients may take (a) anticonvulsants or warfarin; (b) oral contraceptives or other possible maintenance therapies as specified in the eligibility criteria; (c) antiemetics and antidiarrheals should not be administered prophylactically prior to initial treatment with the study drug; (d) analgesics; (e) bisphosphonates and denosumab therapy for bone metastases, osteopenia, or osteoporosis; or multivitamins, calcium, and vitamins C, D, and E supplements may be permitted.

[0337] Therapies requiring caution. Drug therapies given with caution due to effects related to CYP enzymes and compound 1 include, for example, (1) potent / moderate CYP3A4 inhibitors (but not limited to atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troleandmycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluconazole (1) (2) (3) (4) (5) (6) (7) (8) (8) (9) (10) (11) (12) (13) (14) (14) (15) (14) (15) (14) (15) (16) (14) (15) (16) (17) (14) (15) (16) (17) (18) (15) (16) (17) (18) (16) (17) (18) (17) (18) (18) (17) (18) (18) (17) (18) (18) (19

[0338] Coumarin (Coumadin®, warfarin) is strongly blocked during erlotinib therapy. If the patient requires anticoagulation therapy, the use of low molecular weight heparin instead of coumarin is recommended if clinically feasible. If there is no clinically feasible alternative to coumarin, frequent monitoring of INR and prothrombin time is necessary.

[0339] Drugs that reduce gastric acid production, such as proton pump inhibitors or H2 receptor antagonists, have been shown to reduce erlotinib exposure. Therefore, co-administration of these drugs with erlotinib should be avoided. If antacid use is deemed necessary during treatment with erlotinib, they should be taken at least 4 hours or 2 hours before the daily dose of erlotinib.

[0340] Chronic use of anti-angiogenic agents and non-steroidal anti-inflammatory drugs (NSAIDs) is not acceptable in patients receiving erlotinib, as it may increase the risk of GI perforation. Acute use of NSAIDs is acceptable to manage fever or during periods when erlotinib is retained.

[0341] The use of the following concomitant therapies is prohibited during the first administration of the drugs described herein and for at least 7 days prior to administration: ● Investigational therapy within 3 weeks or 5 half-lives (whichever is shorter) prior to the first administration of the drug described herein. ● Ancillary therapies intended to treat cancer, whether approved by the FDA or experimental, including chemotherapy, radiation therapy, immunotherapy, biological therapy, herbal therapy, or hormone therapy, except for the following: Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); ○ Hormone replacement therapy or oral contraception. ● Radiotherapy for clearly progressive disease, excluding new brain metastases in the context of systemic response: Patients who have demonstrated control of systemic disease (defined as having received a clinical benefit [i.e., PR, CR, or SD over ≥3 months]) but who have developed radiation-treated brain metastases may continue therapy with compound 1 during the study until they experience either systemic progression of the disease and / or further progression in the brain (based on the investigator's assessment); ● Quinidine or other antiarrhythmic drugs; ● Initiation or increase in dose of hematopoietic colony-stimulating factors (CSF; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; salglamostim, pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) starting 7 days prior to day 1 of the first cycle.

[0342] Risks associated with Compound 1: Administration of Compound 1 is associated with diarrhea, nausea, vomiting, oral mucosal irritation, minimal to mild transaminase elevation, and phototoxicity.

[0343] Risks associated with cetuximab. Undesirable effects of cetuximab include skin reactions occurring in over 80% of patients, hypomagnesemia occurring in over 10% of patients, and IRRs occurring in over 10% of patients with mild to moderate symptoms and over 1% with severe symptoms. The risk of serious infusion reactions with cetuximab administration may be increased in patients who have been bitten by ticks or have a red meat allergy.

[0344] Risks associated with erlotinib. Erlotinib is associated with the following risks: skin toxicity, interstitial lung disease (ILD), liver injury, gastrointestinal (GI) fluid loss, GI perforation, and ocular toxicity. Current smokers should be advised to quit smoking because their plasma concentrations of erlotinib are lower than those of non-smokers. The degree of reduction is likely to be clinically significant. Potent inducers of CYP3A4 may reduce the efficacy of erlotinib, while potent inhibitors of CYP3A4 may lead to increased toxicity. Erlotinib is a potent inhibitor of CYP1A1, as well as a moderate inhibitor of CYP3A4 and CYP2C8, and a potent inhibitor of glucuronidation by UGT1A1 in vitro. See Erlotinib SmPC for complete drug-drug interaction information.

[0345] Treatment Interruption: If compound 1 is retained for >21 days from the previous study treatment due to toxicity, the study treatment should not be resumed. Compound 1 may be discontinued for up to 21 days due to unexpected concomitant medical events unrelated to the toxicity of the study treatment or disease progression.

[0346] Adverse Events. Adverse events as defined herein refer to any undesirable medical occurrence in a clinical trial subject receiving the drugs described herein in a combination therapy described herein, regardless of the cause. The terms “severe” and “critical” are not synonymous. Severity refers to the intensity of the adverse event (e.g., whether it is assessed as mild, moderate, or severe, or according to the NCI CTCAE), and the event itself may not be relatively medically significant (e.g., severe headache without further findings).

[0347] Adverse events to be monitored include nausea, vomiting, diarrhea, stomatitis, mucositis, hepatitis, or elevated ALT or AST levels, elevated bilirubin or clinical jaundice, systemic lupus erythematosus, nephritis, events suggestive of hypersensitivity, infusion-mediated reactions, CRS, influenza-like illness, and systemic inflammatory response syndrome, atrial fibrillation, myocarditis, pericarditis, vasculitis, myositis, uveitis, retinitis, optic neuritis, autoimmune hemolytic anemia, Stevens-Johnson syndrome, bullous dermatitis, and toxic epidermal necrolysis.

[0348] Throughout this specification and the claims, the words “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense unless otherwise required by context. Embodiments described herein are understood to include embodiments that “consist of” and / or “essentially consist of.”

[0349] Where a range of values ​​is provided, unless otherwise clearly indicated by the context, it should be understood that the upper and lower limits of the range and any other stated or intervening values ​​within that range, up to one-tenth of the lower limit unit, are included herein. The upper and lower limits of these smaller ranges, which can be independently included in smaller ranges, are also included herein, subject to the limits that are specifically excluded in the stated range. If a stated range includes one or both of the limits, the range excluding one or both of those limits is also included herein.

[0350] Many modifications and other embodiments of the inventions described herein will be conceivable to those skilled in the art, benefiting from the teachings presented in the foregoing description and the accompanying drawings. Therefore, it should be understood that the invention should not be limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Certain terms are used herein, but these are used in a general and descriptive sense only and are not intended to be limiting.

Claims

1. Compound 1 KRas, which contains a pharmaceutically acceptable salt thereof. Ｇ１２Ｃ A pharmaceutical product for treating colorectal cancer (CRC) including mutations, A pharmaceutical product used in combination with (i) cetuximab and (ii) FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or FOLFIRI (leucovorin, fluorouracil, and irinotecan).

2. The pharmaceutical product according to claim 1, wherein the chemotherapy is FOLFOX.

3. The pharmaceutical product according to claim 1, wherein the chemotherapy is FOLFIRI.

4. The pharmaceutical product according to any one of claims 1 to 3, wherein cetuximab is administered from day 1 of the first 21-day cycle during Q1W.

5. Cetuximab is administered at approximately 400 mg / m² on day 1 of the aforementioned 21-day cycle. ２ In that amount, followed by approximately 250 mg / m² ２ The pharmaceutical product according to claim 4, administered in the amount of Q1W.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered by QD on days 1 to 21 of a first 21-day cycle.

7. The pharmaceutical product according to any one of claims 1 to 6, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally in the form of a tablet or capsule at QD on days 1 to 21 of a first 21-day cycle.

8. A pharmaceutical product according to any one of claims 1 to 7, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg.

9. The pharmaceutical product according to any one of claims 1 to 8, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 200 mg or 400 mg.

10. A pharmaceutical product according to any one of claims 1 to 9, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 200 mg.

11. A pharmaceutical product according to any one of claims 1 to 9, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg.

12. The pharmaceutical product according to any one of claims 1 to 11, wherein the salt is an adipine salt.

13. The pharmaceutical product according to any one of claims 1 to 12, wherein the patient is receiving treatment with at least one prior or combination therapy.

14. Patient KRas Ｇ１２Ｃ A pharmaceutical product according to any one of claims 1 to 13, which has been previously treated with a specific inhibitor.

15. The patient, KRas Ｇ１２Ｃ A pharmaceutical product according to any one of claims 1 to 14, having a reduction in the level of ctDNA.

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