Methods and compositions comprising a KRAS G12C inhibitor and an EGFR inhibitor for the treatment of solid tumors

Abstract

Provided herein are compositions comprising KRas G12C Combination therapies of inhibitors (e.g., Compound 1) and EGFR inhibitors and methods of using such combination therapies.

Description

[0001] This invention is a divisional application of the invention patent application filed on December 6, 2021, with application number 202180082541.1 and titled "Method and Composition Containing KRASG12C Inhibitor and EGFR Inhibitor for Treating Solid Tumors". Technical Field

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 122,702, filed on December 8, 2020, which is incorporated herein by reference in its entirety and is used for all purposes. Technical Field

[0003] This article provides information including KRas. G12C Combination therapy of inhibitors (e.g., compound 1) and EGFR inhibitors, and methods of using such combination therapy. Background Technology

[0004] Kirsten rat sarcoma virus oncogene homolog (KRAS) is a core component of the RAS / MAPK signaling pathway, an intracellular protein network that transmits extracellular growth factor signals to regulate cell proliferation, differentiation, and survival. Mutations in KRAS can lead to alterations in several amino acids, including glycine 12 (G12), glycine 13, and glutamine 61. These amino acids are commonly found in solid tumors and are associated with tumorigenesis and invasive 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; Taparosky et al., Nature 1982;300:762-5; Capon et al., Nature 1983;304:507-13). Oncogenic KRAS mutations that lead to the conversion from G12 to cysteine ​​(G12C) are common in non-small cell lung cancer (NSCLC) (~12%), colorectal cancer (CRC) (~4%), and other tumor types (≤4%) (Bailey et al., Nature 2016;531:47-52; Campbell et al., NatGenet 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).

[0005] Carrying KRas G12C Mutant advanced tumors (hereinafter referred to as KRas) G12C Positive tumors, including lung cancer (e.g., NSCLC), CRC, and pancreatic cancer, 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, patients with advanced KRas... G12C Patients with positive cancer may receive limited benefit from selected chemotherapy and targeted therapies, thus limiting the effective available treatment options (Roman et al., 2018).

[0006] Therefore, effective therapies and combination therapies are needed for the treatment of cancers, such as those carrying KRas. G12CMutant lung cancer, colorectal cancer, and pancreatic cancer. Summary of the Invention

[0007] This article provides solutions to these and other problems in this field.

[0008] In one aspect, this article provides a combination therapy comprising compound 1 as described herein or a pharmaceutically acceptable salt thereof; and an EGFR inhibitor. In one embodiment, the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib, or an anti-EGFR antibody. In another embodiment, the EGFR inhibitor is erlotinib or cetuximab.

[0009] On the other hand, this article provides a combination therapy comprising compound 1 as described herein or a pharmaceutical salt thereof administered once daily during days 1 to 21 of a first 21-day cycle and erlotinib administered during days 1 to 21 of a first 21-day cycle.

[0010] On the other hand, this article provides a combination therapy comprising compound 1 as described herein or a pharmaceutically acceptable salt thereof administered on days 1 through 21 of the first 21-day cycle (QD) and cetuximab administered on day 1 of the first 21-day cycle (Q1W, once weekly).

[0011] On the other hand, this article provides a treatment for patients suffering from KRas G12C A method for treating such lung cancer in patients with mutation-mediated lung cancer, the method comprising administering an effective dose of a combination therapy comprising compound 1 as described herein or a pharmaceutically acceptable salt thereof, administered via days 1 to 21 of a first 21-day cycle, and an EGFR inhibitor. In one embodiment, the lung cancer is NSCLC.

[0012] On the other hand, this article provides a treatment for patients suffering from KRas G12C A method for treating CRC in patients with mutation-mediated colorectal cancer (CRC) comprising administering an effective dose of combination therapy comprising: compound 1 as described herein or a pharmaceutically acceptable salt thereof, administered on days 1 to 21 of the first 21-day cycle, along with an EGFR inhibitor.

[0013] On the other hand, this article provides a treatment for patients suffering from KRas G12CA method for treating such pancreatic cancer in patients with mutation-mediated pancreatic cancer, comprising administering an effective dose of a combination therapy comprising: compound 1 as described herein or a pharmaceutically acceptable salt thereof, administered on days 1 to 21 of a first 21-day cycle, along with an EGFR inhibitor.

[0014] On the other hand, this article provides the use of combination therapy comprising compound 1 or a pharmaceutical salt thereof and an EGFR inhibitor for the treatment of lung cancer, CRC, or pancreatic cancer as described herein.

[0015] On the other hand, this article provides the use of combination therapy comprising compound 1 or a pharmaceutical salt thereof and an EGFR inhibitor for the manufacture of a medicament for the treatment of lung cancer, CRC, or pancreatic cancer. Attached Figure Description

[0016] Figure 1 illustrates the effects of Compound 1 and erlotinib, alone or in combination, on NCI-H2122 NSCLC tumor xenografts in nude mice. Mediator = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80™. Tumor volumes in the fitted group are depicted after 21 days of QD oral administration of Compound 1 or erlotinib, alone or in combination. Dose levels are expressed as free base equivalents.

[0017] Figure 2 shows individual body weights after treatment with compound 1 or erlotinib alone or in combination in NCI-H2122 NSCLC tumor xenografts in nude mice. QD = once daily (21 times). Mediator = 0.5% (w / v) methylcellulose (150 µL), 0.5% (w / v) methylcellulose / 0.2% Tween 80™ (100 µL) Figure 3 illustrates the effects of compound 1 and cetuximab, alone or in combination, in a CR6256 colorectal xenograft model in nude mice. Mediator = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80™. Tumor volumes in the fitted groups are depicted after 21 days of continuous oral administration (PO), QD (quantitative dose) of compound 1 or IP (intraperitoneal injection), BIW (twice weekly) of cetuximab, alone or in combination. Dose levels are expressed as free base equivalents.

[0018] Figure 4 illustrates the effects of compound 1 and cetuximab, alone or in combination, in a CR5048 colorectal xenograft model in nude mice. Mediator = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80™. Tumor volumes in the fitted groups are depicted after 21 days of continuous oral administration (PO), QD (quantitative dose) of compound 1 or IP (intraperitoneal injection), BIW (twice weekly) of cetuximab, alone or in combination. Dose levels are expressed as free base equivalents.

[0019] Figure 5 illustrates the effects of compound 1 and cetuximab, alone or in combination, in a CR6243 colorectal xenograft model in nude mice. Mediator = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80™. Tumor volumes in the fitted groups are depicted after 21 days of continuous oral administration (PO), QD (quantitative dose) of compound 1 or IP (intraperitoneal injection), BIW (twice weekly) of cetuximab, alone or in combination. Dose levels are expressed as free base equivalents.

[0020] Figure 6 illustrates the effects of compound 1 and cetuximab, alone or in combination, in a CR6927 colorectal xenograft model in nude mice. Mediator = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80™. Tumor volumes in the fitted groups are depicted after 21 days of continuous oral administration (PO), QD (quantitative dose) of compound 1 or IP (intraperitoneal injection), BIW (twice weekly) of cetuximab, alone or in combination. Dose levels are expressed as free base equivalents.

[0021] Figure 7 illustrates the effects of compound 1 and cetuximab, alone or in combination, in a CR2528 colorectal xenograft model in nude mice. Mediator = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80™. Tumor volumes in the fitted groups are depicted after 21 days of continuous oral administration (PO), QD (quantitative dose) of compound 1 or IP (intraperitoneal injection), BIW (twice weekly) of cetuximab, alone or in combination. Dose levels are expressed as free base equivalents.

[0022] Figure 8 illustrates the effects of compound 1 and cetuximab, alone or in combination, in a CR1451 colorectal xenograft model in nude mice. Mediator = 0.5% (w / v) methylcellulose; 0.5% (w / v) methylcellulose, 0.2% Tween 80™. Tumor volumes in the fitted groups are depicted after 21 days of continuous oral administration (PO), QD (quantitative dose) of compound 1 or IP (intraperitoneal injection), BIW (twice weekly) of cetuximab, alone or in combination. Dose levels are expressed as free base equivalents. Detailed Implementation

[0023] definition Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. See, for example: Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY, 2nd edition, J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Methods, apparatus, and materials similar to or equivalent to any of the methods, apparatus, and materials described herein may be used in the practice of this invention.

[0024] The following definitions are provided to aid in understanding certain terms frequently used herein and are not intended to limit the scope of this disclosure. All references cited herein are incorporated herein in their entirety.

[0025] As used herein, unless otherwise stated, the terms “about” and “approximately” when referring to a dose, amount, or weight percentage of an ingredient in a composition or dosage form mean a dose, amount, or weight percentage that is recognized by those skilled in the art to provide an equivalent pharmacological effect to that obtained by the specified dose, amount, or weight percentage. An equivalent dose, amount, or weight percentage may be in the range of 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percentage.

[0026] As used in this article, "KRas" G12C "Inhibitor" refers to a covalent inhibitor that specifically binds to the mutant KRas protein, which contains a Gly to Cys mutation at the position corresponding to residue 12.

[0027] "Compound 1" refers to a compound having the following structure: It has the following chemical name: 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one. In one embodiment, compound 1 is an adipate.

[0028] "Erlotinib" refers to a compound having the following structure: It has the chemical name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. In one embodiment, erlotinib is sold under the trade name TARCEVA®.

[0029] "Gefitinib" refers to a compound having the following structure: It has the chemical name: 4-quinazolinamine N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. In one embodiment, gefitinib is sold under the trade name IRESSA®.

[0030] "Osimertinib" refers to a compound having the following structure: It has the chemical name: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide methanesulfonate. In one embodiment, osimertinib is sold under the trade name TAGRISSO®.

[0031] "Afatinib" refers to a compound having the following structure: It has the chemical name: 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-,(2Z)-2-butenidate (1:2). In one embodiment, afatinib is sold under the trade name GILOTRIF®.

[0032] "Dacomitinib" refers to a compound having the following structure: It has the chemical name: (2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazoline-6-yl}-4-(piperidin-1-yl)but-2-enamide hydrate. In one embodiment, dacomitinib is sold under the trade name VIZIMPRO®.

[0033] The term "pharmaceutical acceptable" means that the molecular entity and composition, when administered to animals (such as, for example, humans) as appropriate, do not produce adverse, allergic, or other adverse reactions.

[0034] The compounds of this invention can be in the form of salts, such as pharmaceutical salts. "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts formed with inorganic and organic acids that retain the bioavailability and properties of the free base and are not biologically or otherwise undesirable. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., and the organic acids can be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid 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, dihydronaphthic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In one embodiment, the salt is formed from adipic acid.

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

[0036] In some embodiments, the salt is selected from hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, hydrogen sulfate, benzenesulfonate, ethanesulfonate, malonate, sinesulfonate, ascorbate, oleate, nicotinate, saccharin, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furonate or 3-furonate), naphthalene disulfonate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethanesulfonate (ethane-1,2-disulfonate). Sulfonates or ethane-1-(sulfonic acid)-2-sulfonates), isothiocyanates (2-hydroxyethyl sulfonates), 2-tris(methyl)benzenesulfonates, 2-naphthalenesulfonates, 2,5-dichlorobenzenesulfonates, D-mandelates, L-mandelates, cinnamates, benzoates, adipates, oxalates, malonates, methylbenzenesulfonates (2-m-benzenesulfonates), naphthalenesulfonates (2-naphthalenesulfonates), camphorsulfonates (camphor-10-sulfonates, e.g., (1S)-(+)-10-camphorsulfonates), glutamates, glutarates, hippurates (2-(benzoylamino)acetate), orotic acid salts, xylene salts (p-xylene-2-sulfonates), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylic acid esters).

[0037] The terms “inhibition” and “reduction”, or any variations thereof, including any measurable reduction or complete inhibition, to achieve the desired result. For example, a reduction of about, at most about, or at least about 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 thereof, may be made, resulting in a reduction in activity compared to normal.

[0038] The terms “EGFR antagonist,” “EGFR inhibitor,” or “EGFR-specific antagonist” are used interchangeably herein and refer to molecules capable of binding to EGFR, reducing EGFR expression levels, or neutralizing, blocking, inhibiting, eliminating, reducing, or interfering with the biological activity of EGFR. EGFR-specific antagonists that can be used in the methods of this invention include compounds provided herein, as well as peptides that specifically bind to EGFR, anti-EGFR antibodies and their antigen-binding fragments, and molecules and derivatives that specifically bind to EGFR thereby isolating it from binding to one or more receptors or ligands. EGFR-specific antagonists also include antagonist variants of EGFR peptides, antisense nucleobase oligomers complementary to at least one segment of a nucleic acid molecule encoding an EGFR peptide; small RNAs complementary to at least one segment of a nucleic acid molecule encoding an EGFR peptide; ribozymes targeting EGFR; peptide bodies targeting EGFR; and EGFR aptamers. Therefore, the term “EGFR activity” specifically includes EGFR-mediated EGFR biological activity. In some embodiments, the EGFR antagonist reduces or inhibits at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of the expression level or biological activity of EGFR.

[0039] "Anti-EGFR antibody" is an EGFR inhibitor as defined herein, and is an antibody that binds to EGFR with sufficient affinity and specificity. In some embodiments, the antibody will have a sufficiently high binding affinity to EGFR; for example, the antibody may have a K+ concentration between 100 nM and 1 pM. d The antibody binds to hEGFR. Antibody affinity can be determined, for example, by surface plasmon resonance-based assays (such as the BIAcore® assay described in PCT application publication number WO2005 / 012359), enzyme-linked immunosorbent assays (ELISA), and competitive assays (such as radioimmunoassay (RIA)).

[0040] In some embodiments, EGFR inhibitors (e.g., compounds described herein or anti-EGFR antibodies described herein) can be used as therapeutic agents to target and interfere with diseases or conditions involving EGFR activity. Furthermore, other biological activity assays can be performed on EGFR inhibitors, for example, to evaluate their effectiveness 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” refers to 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 constant regions of the human IgG1 heavy chain and κ light chain, and has a molecular weight of approximately 152 kDa. Cetuximab is produced in mammalian (mouse myeloma) cell cultures. In one embodiment, cetuximab is sold under the trade name ERBITUX®.

[0042] As used herein, "panitumab" refers to a human IgG2κ monoclonal antibody with a molecular weight of approximately 147 kDa, produced in genetically engineered mammalian (Chinese hamster ovary) cells. Panitumab specifically binds to EGFR on both normal and tumor cells and competitively inhibits the binding of EGFR ligands. In one embodiment, panitumab is sold 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 yet another embodiment, cancer is colorectal cancer (e.g., metastatic CRC). In yet another embodiment, cancer is pancreatic cancer. As used herein, "cancer" refers to cancer with KRas G12C Cancer characterized by mutations.

[0044] As used herein, “treatment” 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, treatment refers to treatment with an effective amount of compound 1 or its pharmaceutically acceptable salt and erlotinib. In another embodiment, treatment refers to treatment with an effective amount of compound 1 or its pharmaceutically acceptable salt and cetuximab. Treatment can be first-line treatment (e.g., the patient may not have previously received treatment or prior systemic therapy), or second-line or subsequent treatment. For example, a patient is considered “treated” if one or more symptoms associated with the cancer described herein are reduced or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), alleviating symptoms caused by the disease, improving the quality of life of a patient with the disease, reducing the dosage of other medications required to treat the disease, and / or prolonging the patient's survival.

[0045] The term "delayed progression" in the context of a disease refers to the postponement, halting, slowing, stabilizing, and / or delaying of the progression of the cancer described herein. Such delay can vary in length depending on the patient's medical history of the cancer and / or the patient to be treated. It will be apparent to those skilled in the art that sufficient or significant delay can effectively encompass prevention, as the patient will not develop cancer.

[0046] In this document, "effective amount" refers to the amount of a therapeutic agent (e.g., an EGFR inhibitor and / or compound 1) described herein that achieves a therapeutic outcome. In some instances, an effective amount of a therapeutic agent or combination of therapeutic agents is the amount of a drug or combination of drugs that achieves the clinical endpoints provided herein. In one embodiment, an effective amount refers to the amount of compound 1 or a pharmaceutically acceptable salt thereof and the amount of erlotinib. In another embodiment, an effective amount refers to the amount of compound 1 or a pharmaceutically acceptable salt thereof and the amount of cetuximab. The effective amount described herein can vary depending on factors such as the patient's disease state, age, sex, and weight, and the ability of the drug to elicit the expected response in the patient. An effective amount is also the amount in which the beneficial effect of treatment outweighs any toxic or adverse effects of treatment. In some embodiments, an effective amount of the drug may have one or more of the following effects: reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing or stopping) the invasion of cancer cells into surrounding organs; inhibiting (i.e., slowing or stopping) tumor metastasis; inhibiting (i.e., slowing or stopping) tumor growth; and / or relieving one or more of the symptoms associated with the disease. An effective amount may be administered once or multiple times. The effective amount of the drug, compound, pharmaceutical composition, or combination therapy described herein may be an amount sufficient to provide direct or indirect treatment.

[0047] The "objective response rate" or "ORR" refers to the percentage of patients who achieve a confirmed complete or partial response within two consecutive periods of ≥ 4 weeks, as determined by investigators according to RECIST v1.1.

[0048] "Duration of Response" or "DOR" refers to the time from the first recorded objective response to disease progression or death from any cause (whichever comes first), as determined by the investigator according to RECIST v1.1.

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

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

[0051] As used in this article, "partial response" and "PR" refer to the persistence of one or more non-target lesions and / or (if applicable) tumor marker levels maintained above normal limits. PR can also refer to a reduction of ≥ 30% in the sum of the diameters of target lesions, the appearance of new lesions in the absence of CR, and clear progression of non-target lesions.

[0052] "Application period" or "cycle" refers to a period of time that includes the application of one or more of the agents described herein (e.g., compound 1 and an EGFR inhibitor) and optional periods of time that do not include the application of one or more of the agents described herein. For example, a cycle may be 21 days in total and include the application of one or more of the agents described herein (e.g., compound 1 and an EGFR inhibitor) on each day of that cycle. In another example, a cycle may be 28 days in total and include 21 days of continuous application of one or more of the agents described herein (e.g., compound 1 and an EGFR inhibitor) and a 7-day rest period. "Rest period" refers to a period of time during which at least one of the agents described herein (e.g., compound 1 and an EGFR inhibitor) is not applied. In one embodiment, a rest period refers to a period of time during which no agents described herein (i.e., compound 1 and an EGFR inhibitor) are applied. In some cases, the rest period provided herein may include the application of another agent that is not compound 1 or an EGFR inhibitor. In such cases, the application of another agent during the rest period should not interfere with or impair the application of the agents described herein. In one case, a cycle as used herein refers to a 21-day cycle without a rest period.

[0053] "Dosing regimen" refers to the administration period described herein, which includes one or more cycles, wherein each cycle may include administration of the drug described herein at different times and in different amounts.

[0054] "QD" means once a day the medication described in this article is administered.

[0055] "BID" means applying the medication described in this article twice a day.

[0056] "Q1W" means applying the medication described in this article once a week.

[0057] "PO" refers to the oral administration of the medication described in this article.

[0058] “IV” means intravenous administration of any of the medications described herein.

[0059] Graded adverse events refer to the severity level determined by NCI CTCAE. In one embodiment, adverse events are graded according to the following table.

[0060] The term "patient" refers to a human patient. Patients can be adults.

[0061] The term "antibody" in this article specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, provided they exhibit the desired biological activity. In one case, the antibody is a full-length monoclonal antibody.

[0062] As used herein, the term IgG “isotype” or “subclass” refers to any subclass of immunoglobulins defined by the chemical and antigenic characteristics of the immunoglobulin constant region.

[0063] Antibodies (immunoglobulins) can be classified into different categories based on the amino acid sequence of their heavy chain constant domains. Immunoglobulins are mainly divided into five classes: IgA, IgD, IgE, IgG, and IgM, and some of them can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, γ, α, γ, and µ, respectively. The subunit structures and three-dimensional conformations of different types of immunoglobulins are well known and are generally described in references such as Abbas et al., *Cellular and Molecular Immunology*, 4th edition (WBSaunders, Co., 2000). Antibodies can be part of a larger fusion molecule formed by the covalent or non-covalent association of the antibody with one or more other proteins or peptides.

[0064] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used interchangeably in this document and refer to an antibody in its essentially complete form, rather than an antibody fragment as defined below. This term refers to an antibody containing the Fc region.

[0065] The term "Fc region" used herein is used to define the C-terminal region of an immunoglobulin heavy chain that comprises at least a portion of a constant region. This term includes both native sequence Fc regions and variant Fc regions. In one aspect, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the C-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore, antibodies produced by host cells by expressing a specific nucleic acid molecule encoding the full-length heavy chain may comprise the full-length heavy chain, or said antibodies may comprise cleaved variants of the full-length heavy chain. This could be the case where the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Therefore, the C-terminal lysine (Lys447) or the C-terminal glycine (Gly446) and lysine (Lys447) of the Fc region may or may not be present. Unless otherwise indicated, the amino acid sequence of the heavy chain including the Fc region is represented herein as lacking a C-terminal lysine (Lys447). In one aspect, a heavy chain including the Fc region as specified herein is included in an antibody disclosed herein, the heavy chain containing an additional C-terminal glycine-lysine dipeptide (G446 and K447). In another aspect, a heavy chain including the Fc region as specified herein is included in an antibody disclosed herein, the heavy chain containing an additional C-terminal glycine residue (G446). In another aspect, a heavy chain including the Fc region as specified herein is included in an antibody disclosed herein, the heavy chain containing an additional C-terminal lysine residue (K447). In one embodiment, the Fc region contains a single amino acid substitution of N297A from the heavy chain. Unless otherwise specified herein, the amino acid residues in the Fc region or constant region are numbered according to the EU numbering system, also known as the EU index, as described herein in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0066] "Naked antibody" refers to an antibody that does not conjugate to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabeled part. Naked antibodies may be present in pharmaceutical compositions.

[0067] An "antibody fragment" comprises a portion of a complete antibody, preferably including its antigen-binding region. - In some cases, the antibody fragments described herein are antigen-binding fragments. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; bisomatic antibodies; 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 population of antibodies, i.e., individual antibodies constituting this population are identical and / or bind to the same epitopes, except for possible variant antibodies (e.g., those containing naturally occurring mutations or generated during the production of the monoclonal antibody formulation, such variants typically exist in small quantities). In contrast to polyclonal antibody formulations, which typically comprise different antibodies targeting different determinants (epitopes), each monoclonal antibody in a monoclonal antibody formulation targets a single determinant on the antigen. Therefore, the modifier "monoclonal" indicates that the antibody is characterized by being obtained from a substantially homogeneous population of antibodies and should not be interpreted as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies according to the invention can be prepared 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 the human immunoglobulin loci.

[0069] As used in this article, the term "hypervariant region" or "HVR" refers to the regions in the antibody variable domain that are hypervariable in sequence and determine antigen binding specificity, such as the "complementarity-determining region" ("CDR").

[0070] Typically, an antibody contains six CDRs; three in the VH region (CDR-H1, CDR-H2, CDR-H3) and three in the VL region (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs in this document include: (a) Hypervariable rings present 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 located at 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 sites present 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 stated, the CDR is determined according to the method described by Kabat et al. (ibid.). Those skilled in the art will understand that the CDR name can also be determined according to the methods described by Chothia (ibid.), McCallum (ibid.), or any other scientifically accepted naming system.

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

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

[0074] When referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain), the Kabat numbering system is typically used (e.g., Kabat et al., Sequences of Proteins of Immunological Interest. 5th ed., U.S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD (1991)). When referring to residues in the constant region of the immunoglobulin heavy chain, the “EU numbering system” or “EU index” is typically used (e.g., the EU index reported by Kabat et al. above). The “EU index described by Kabat” refers to the residue numbering of human IgG1 EU antibodies.

[0075] The term "packaging insert" is used to refer to the instruction leaflet typically included in the commercial packaging of a therapeutic product, which contains information concerning the indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings related to the use of such therapeutic products.

[0076] As used herein, “in combination with” means administering another treatment in addition to the administration of one treatment, for example, including a treatment regimen that includes 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 another treatment before, during, or after the administration of one treatment to a patient.

[0077] A drug administered "concurrently" with one or more other drugs is administered on the same day of treatment with one or more other drugs within the same treatment cycle, and optionally concurrently with one or more other drugs. For example, in cancer treatment administered every 3 weeks, each concurrently administered drug is administered on day 1 of the 3-week cycle.

[0078] Combination therapy This document provides combination therapies (compositions) comprising compound 1 described herein or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and an EGFR inhibitor. In one embodiment, this document provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and gefitinib. In another embodiment, this document provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and osimertinib. In yet another embodiment, this document provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and dacomitinib. In yet another embodiment, this document provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and afatinib. In yet another embodiment, this document provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and panitumumab. In a preferred embodiment, this document provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and erlotinib or cetuximab. In another preferred embodiment, the combination therapy includes erlotinib. In yet another such embodiment, the combination therapy includes cetuximab.

[0079] This document further provides a combination therapy (composition) comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an EGFR inhibitor compound (e.g., gefitinib, erlotinib, osimertinib, dacomitinib, or afatinib). In one such embodiment, the EGFR inhibitor is erlotinib.

[0080] This document further provides a combination therapy (composition) comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-EGFR antibody (e.g., panitumumab or cetuximab). In one such embodiment, the anti-EGFR antibody is cetuximab.

[0081] In one aspect, this article provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and an EGFR inhibitor (e.g., erlotinib or cetuximab). In one embodiment, the combination therapy described herein can be used to treat KRas-containing... G12CCertain solid tumors with mutations. In one such embodiment, combination therapy can be used to treat KRas-containing tumors. G12C Some solid tumors with mutations in which EGFR inhibitors are not approved for use.

[0082] In one embodiment, the combination therapy described herein can be used to treat conditions containing KRas as described herein. G12C Certain types of lung cancer with mutations. In one such embodiment, the lung cancer is one containing KRas. G12C Mutant non-small cell lung cancer (NSCLC).

[0083] In another embodiment, the combination therapy described herein can be used to treat KRas-containing... G12C Mutant colorectal cancer. In one such embodiment, the methods described herein can be used to treat KRas-containing colorectal cancer. G12C Combination therapy for mutated colorectal cancer is 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 includes FOLFIRI (i.e., administration of leucovorin, fluorouracil, and irinotecan). In another such embodiment, the additional agent includes FOLFOX (i.e., administration of leucovorin, fluorouracil, and oxaliplatin).

[0084] In another embodiment, the combination therapy described herein can be used to treat KRas-containing... G12C Mutated pancreatic cancer. In one such embodiment, the methods described herein can be used to treat KRas-containing pancreatic cancer. G12C Combination therapy for mutated pancreatic cancer is administered in combination with one or more additional agents. In one such embodiment, the additional agent includes gemcitabine.

[0085] In one aspect, this article provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof administered via QD on days 1 through 21 of a first 21-day cycle, and an EGFR inhibitor (e.g., erlotinib or cetuximab). In such embodiments, the combination therapy can be used to treat patients as described herein who contain KRas. G12C Mutated solid tumors (e.g., lung cancer, colorectal cancer, pancreatic cancer).

[0086] In one respect, this article provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof administered during QDs from day 1 to day 21 of the first 21-day cycle, and erlotinib administered during QDs from day 1 to day 21 of the first cycle.

[0087] On the other hand, this article provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof administered on days 1 through 21 of a first 21-day cycle and cetuximab administered on day 1 of the first 21-day cycle (QD) at Q1W.

[0088] In one embodiment of the combination therapy described herein, compound 1 or its pharmaceutical salt is administered in a fixed dose once daily. In one embodiment, it is administered orally (PO), wherein compound 1 or its pharmaceutical salt is formulated as a tablet or capsule. In such an embodiment, compound 1 or its pharmaceutical salt is formulated (and administered) as a film-coated tablet.

[0089] In one embodiment of the combination therapy described herein, compound 1 or its pharmaceutically acceptable salt is administered in doses of 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 300 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 The compound is administered in doses of up to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 150 mg, or 50 mg to 100 mg QD. In another embodiment, compound 1 or its pharmaceutically acceptable salt is administered in doses of about 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 its pharmaceutically acceptable salt is administered in doses 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 its pharmaceutically acceptable salt is administered in doses of about 300 to 600 mg. In another such embodiment, compound 1 or its pharmaceutically acceptable salt is administered in doses of about 400 mg. In a preferred embodiment, compound 1 of the combination therapy described herein is administered in the form of adipate. In such embodiments, the amount of compound 1 or its pharmaceutical salt is applied relative to the amount in the form of free base.

[0090] In one embodiment of the combination therapy described herein, an EGFR inhibitor is administered according to the package insert.

[0091] In one embodiment, the combination therapy described herein comprises erlotinib, wherein erlotinib is administered in amounts of about 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 an amount of about 100 mg. In another embodiment, erlotinib is administered in an amount of about 150 mg.

[0092] In one embodiment, erlotinib is administered as a component of the combination therapy described herein at a dose of 150 mg QD. In another embodiment, erlotinib is administered as a component of the combination therapy described herein at a dose of 100 mg QD. In such embodiments, erlotinib may be administered in combination with compound 1 or a pharmaceutically acceptable salt thereof in a dosing regimen comprising administering each agent QD over a 21-day cycle. In one such embodiment, erlotinib is administered concurrently 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 or 50 mg.

[0093] In another embodiment, the combination therapy described herein includes cetuximab, wherein cetuximab is administered at a dose of approximately 200 to 400 mg / m². 2 The dosage is as follows. In one embodiment, cetuximab is administered as the first / initial dose at approximately 400 mg / m². 2 The dosage was administered. In another embodiment, cetuximab was administered at approximately 250 mg / m². 2 The dosage is as follows. In one such embodiment, cetuximab is administered at approximately 400 mg / m² on day 1 of the first 21-day cycle. 2 The dosage was applied, and in the first 21-day cycle at 250 mg / m². 2 The amount Q1W is applied.

[0094] This article also provides a combination therapy comprising compound 1 or its pharmaceutical salt and gefitinib, wherein gefitinib is administered at a dose of 250 mg QD for each 21-day cycle.

[0095] This article further provides a combination therapy comprising compound 1 or its pharmaceutical salt and osimertinib, wherein osimertinib is administered at a dose of 80 mg QD for each 21-day cycle.

[0096] This article further provides a combination therapy comprising compound 1 or its pharmaceutical salt and dacomitinib, wherein dacomitinib is administered at a dose of 45 mg QD for each 21-day cycle.

[0097] This article further provides a combination therapy comprising compound 1 or its pharmaceutical salt and afatinib, wherein afatinib is administered at a dose of 40 mg QD for each 21-day cycle.

[0098] This article further provides a combination therapy comprising compound 1 or its pharmaceutical salt and panitumumab, wherein panitumumab is administered at a dose of 6 mg / kg Q2W (once every two weeks) for each 21-day cycle.

[0099] In a preferred embodiment, the combination therapy described herein comprises compound 1 or a pharmaceutically acceptable salt thereof administered via QD as described herein, and erlotinib, wherein erlotinib is administered to the patient at a dose of approximately 150 mg QD. In another preferred embodiment, the combination therapy described herein comprises compound 1 or a pharmaceutically acceptable salt thereof administered via QD as described herein, and cetuximab, wherein cetuximab is administered at a dose of approximately 400 mg / m² on day 1 of the first 21-day cycle. 2 Administered at a dose of 250 mg / m² during the first 21-day cycle. 2 Q1W application.

[0100] In one embodiment, the combination therapy described herein is used to treat KRas-containing... G12C Mutant lung cancer. In one such embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) 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., compound 1 adipic acid salt) and erlotinib, wherein the combination therapy is used to treat lung cancer containing KRas as described herein. G12C Mutant lung cancer. In one embodiment, the combination therapy described herein is used to treat lung cancer containing KRas. G12C The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-EGFR antibody (e.g., panitumumab). In this embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In another embodiment, the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. The lung cancer may be stage I or stage II. In one embodiment, the lung cancer is stage III or stage IV.

[0101] In another embodiment, it can be used to treat KRas-containing... G12C A combination therapy for mutated lung cancer, wherein the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipicate) and erlotinib, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD on days 1 to 21 of a first 21-day cycle, and erlotinib is administered QD on days 1 to 21 of a first 21-day cycle. In a preferred embodiment, the lung cancer is NSCLC (e.g., metastatic NSCLC).

[0102] In another embodiment, it can be used to treat KRas-containing... G12C A combination therapy for mutated lung cancer, wherein the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and erlotinib, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD at a dose of about 50 mg to 500 mg on days 1 to 21 of a first 21-day cycle, and erlotinib is administered QD at a dose of about 150 mg on days 1 to 21 of a first 21-day cycle. In a preferred embodiment, the lung cancer is NSCLC. In one embodiment, erlotinib is administered according to a packaging insert.

[0103] In yet another embodiment is the combination therapy described herein, which can be used to treat KRas-containing... G12C Mutated CRC. In one particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-EGFR antibody selected from cetuximab or panitumumab, wherein the combination therapy is for the treatment of KRas-containing CRC as described herein. G12C Mutated CRC. In a preferred embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and cetuximab, wherein the combination therapy is used to treat KRas-containing CRC as described herein. G12C Mutant CRC. In one such embodiment, the CRC is metastatic CRC (mCRC). In one embodiment, the combination therapy is used to contain KRas G12C First-line treatment for mutated CRC. In another embodiment, combination therapy is used with KRas-containing... G12C Second-line treatment for mutated CRC. In one such embodiment, the patient has previously developed the disease and has previously been treated with KRas. G12C Inhibitor therapy.

[0104] In such embodiments, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and cetuximab, and can be used to treat patients containing KRas. G12CPatients with mutated CRC, as described in this article, can also receive the FOLFIRI regimen or irinotecan.

[0105] In such embodiments, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-EGFR antibody (e.g., panitumumab), and can be used to treat patients containing KRas. G12C Patients with mutated CRC, as described in this article, can also receive the FOLFOX regimen.

[0106] In another embodiment, the combination therapy can be used to treat KRas-containing [treatments / treatments]. G12C The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and cetuximab, wherein compound 1 is administered via QD on days 1 through 21 of the first 21-day cycle, and cetuximab is administered on day 1 of the first 21-day cycle at approximately 400 mg / m². 2 Administer at the prescribed dose, and during the first 21-day cycle at 250 mg / m². 2 The amount Q1W is applied. In a preferred embodiment, the CRC is a transfer CRC (mCRC).

[0107] In another embodiment, the combination therapy can be used to treat KRas-containing [treatments / treatments]. G12C The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and cetuximab, wherein compound 1 is administered QD at a dose of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and cetuximab is administered QD at approximately 400 mg / m² on day 1 of the first 21-day cycle. 2 Administer at the prescribed dose, and during the first 21-day cycle at 250 mg / m². 2 The dosage Q1W is administered. In a preferred embodiment, the CRC is a transfer CRC (mCRC). In one embodiment, cetuximab is administered according to the packaging insert.

[0108] In one embodiment, the combination therapy described herein is used to treat KRas-containing... G12C Mutated pancreatic cancer. In one particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and erlotinib, wherein the combination therapy is used to treat pancreatic cancer containing KRas as described herein. G12C Mutant pancreatic cancer.

[0109] In one such embodiment, the combination therapy comprises compound 1 or a pharmaceutical salt thereof (e.g., compound 1 adipate), wherein compound 1 is administered via QD on days 1 to 21 of the first 21-day cycle, and erlotinib is administered via QD on days 1 to 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., compound 1 adipate), wherein compound 1 is administered QD at a dose of about 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and erlotinib is administered QD at a dose of 100 mg or 150 mg on days 1 to 21 of the first 21-day cycle. In one such embodiment, erlotinib is administered QD at a dose of about 150 mg as described herein. In another such embodiment, erlotinib is administered QD at a dose of about 100 mg as described herein. In one embodiment, erlotinib is administered according to a package insert.

[0111] Treatment This article also provides treatment for patients with KRas, as described herein. G12C A method for treating such solid tumors in patients with mutated solid tumors (e.g., lung cancer, CRC, or pancreatic cancer). One embodiment is a treatment for patients with KRas-containing solid tumors. G12C A method for treating such solid tumors in patients with mutated lung cancer, CRC, or pancreatic cancer, comprising administering to the patient an effective amount of a combination therapy comprising compound 1 described herein or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and an EGFR inhibitor (e.g., a group of EGFR inhibitor compounds selected from erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib, or an anti-EGFR antibody comprising panitumumab or cetuximab). In one embodiment, this is a treatment for patients with KRas-containing... G12C A method for treating such solid tumors in patients with mutated lung cancer, CRC, or pancreatic cancer, the method comprising administering to the patient an effective amount of a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and erlotinib or cetuximab.

[0112] On the one hand, this article provides a treatment for patients with KRas G12CA method for treating such lung cancer in patients with mutated lung cancer, comprising administering to the patient an effective amount of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and an EGFR inhibitor compound selected from the group consisting of erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib. In one aspect, this article provides a treatment for patients with lung cancer caused by KRas... G12C A method for treating such lung cancer in patients with mutation-mediated lung cancer, comprising administering an effective amount of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and erlotinib.

[0113] In one embodiment of the method 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 still another embodiment, the lung cancer is adenoma, carcinoid tumor, or 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] This article also provides a treatment for patients with KRas-containing diseases. G12C A method for treating such cancer in patients with mutated NSCLC, wherein the method comprises administering to the patient an effective amount of the combination therapy as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle; and (ii) administering an effective amount of erlotinib on days 1 to 21 of a first 21-day cycle. In one embodiment of the method provided herein, the method is used to treat adenocarcinoma. In one embodiment of the method provided herein, the method comprises two or more cycles. In one such embodiment, the method is used to treat first-line NSCLC.

[0115] This article also provides a treatment for patients with KRas-containing diseases. G12C A method for treating this type of cancer in patients with mutated NSCLC, wherein the method comprises administering to the patient an effective amount of a combination therapy as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administering approximately 150 mg of erlotinib on days 1 to 21 of the first 21-day cycle.

[0116] On the other hand, this article provides a treatment for patients with CRC containing KRas G12C A method for treating mutated CRC, comprising administering to a patient an effective amount of a combination therapy comprising compound 1 described herein or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-EGFR antibody (e.g., panitumumab or cetuximab). In another embodiment of the method provided herein, a treatment for patients with CRC comprising KRas... G12C A method for treating mutated CRC, comprising administering to a patient an effective amount of a combination therapy containing compound 1 or a pharmaceutical salt thereof (e.g., compound 1 adipate) and cetuximab.

[0117] This article also provides a treatment for patients with KRas-containing diseases. G12C A method for treating this type of cancer in patients with mutated CRC, wherein the method comprises administering to the patient an effective amount of a combination therapy as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of a first 21-day cycle; and (ii) administering an effective amount of cetuximab on day 1 of a first 21-day cycle, Q1W. In one such embodiment, 250 or 400 mg / m² 2 As described herein, in one embodiment of the method provided herein, the method includes two or more cycles.

[0118] This article also provides a treatment for patients with KRas-containing diseases. G12C A method for treating this type of cancer in patients with mutated CRC, wherein the method comprises administering to the patient an effective amount of a combination therapy as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administering approximately 400 mg / m² thereafter on day 1 of the first 21-day cycle. 2 Cetuximab, administered at approximately 250 mg / m² every 1 week. 2 Cetuximab.

[0119] In this type of treatment containing KRas G12C In one embodiment of a method for treating mutated CRC, such a method further includes administering an effective amount of FOLFIRI or irinotecan, as described herein, to the patient.

[0120] This article also provides a treatment for patients with pancreatic cancer containing KRas. G12CA method for treating mutated pancreatic cancer, comprising administering to a patient an effective amount of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and erlotinib.

[0121] In another embodiment, for a treatment of patients with KRas G12C A method for treating such cancer in patients with mutated pancreatic cancer, wherein the method comprises administering to the patient an effective amount of a combination therapy as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle; and (ii) administering an effective amount of erlotinib 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 its pharmaceutical salt is used in doses of about 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 300 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 The compound is administered in doses of up to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 150 mg, or 50 mg to 100 mg QD. In another embodiment, compound 1 or its pharmaceutical salt is administered in doses of about 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 its pharmaceutical salt is administered in doses 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 its pharmaceutical salt is administered in doses of about 300 to 600 mg. In another such embodiment, compound 1 or its pharmaceutical salt is administered in doses of about 400 mg. In a preferred embodiment, compound 1 of the combination therapy described herein is administered in the form of an adipic acid salt. In such embodiments, the amount of compound 1 or its pharmaceutical salt is administered relative to the amount in the free base form.

[0123] The methods provided herein may include administering the combination therapy described herein as part of a dosing regimen. In one such embodiment, the dosing regimen includes one or more cycles. In another embodiment, the dosing regimen includes at least two cycles. In yet another embodiment, the dosing regimen includes two to three cycles. In another aspect provided herein, the dosing regimen includes 2, 3, 4, 5, 6, 8, 10, 12, 16, 18, 20, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles. In yet another embodiment, the dosing regimen includes about 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18, 2-12, or 2-6 cycles. In one embodiment, the dosing regimen includes administering the combination therapy as described herein for any number of cycles until the expected response (e.g., PFS, OS, ORR, and / or DOR) is achieved (e.g., an increase in PFS, OS, ORR, and / or DOR compared to the control group described herein). In another embodiment, the dosing regimen includes administering the combination therapy as described herein for any number of cycles until toxicity occurs or the patient experiences one or more adverse events (AEs) that prevent further administration. In yet another embodiment, the dosing regimen includes administering the combination therapy as described herein for any number of cycles until disease progression.

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

[0125] In some 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) with compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, an EGFR inhibitor (e.g., erlotinib or cetuximab) is administered after the administration of compound 1 or a pharmaceutically acceptable salt thereof. In some cases, an EGFR inhibitor (e.g., erlotinib or cetuximab) is administered both after the administration of compound 1 or a pharmaceutically acceptable salt thereof and on the same day. In one embodiment, an EGFR inhibitor (e.g., erlotinib or cetuximab) may be administered on the same day after the administration of compound 1 or a pharmaceutically acceptable salt thereof. For example, compound 1 or its pharmaceutically acceptable salt may be administered on day 1 of each cycle before administering an EGFR inhibitor (e.g., erlotinib or cetuximab), wherein compound 1 or its pharmaceutically acceptable salt is then administered QD for the next 20 days of a 21-day cycle.

[0126] In a preferred embodiment, cetuximab is administered intravenously after compound 1 or its pharmaceutically acceptable salt (e.g., about 120 minutes). If the first infusion is tolerated, a second intravenous (IV) administration of cetuximab is given within 60 minutes ± 10 minutes. In some instances, cetuximab is administered as an intravenous bolus or pill.

[0127] This article also provides treatment for patients with KRas. G12C Methods for treating such cancer in patients with mutated lung cancer, wherein the method comprises administering to the patient a treatment regimen containing an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipic acid salt) 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 an adipic acid salt and the EGFR inhibitor compound is erlotinib. In another embodiment of such a method, compound 1 or a pharmaceutically acceptable salt thereof is administered QD as described herein and in the amount described herein (e.g., 50 mg–500 mg). In another embodiment of such a method, erlotinib is administered QD as described herein and in the amount described 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 method, the lung cancer may be containing KRas G12C Mutant NSCLC.

[0128] This article also provides treatment for patients with KRas. G12C Methods for treating this type of cancer in patients with mutated CRC, wherein the method comprises administering to the patient a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipic acid salt) and an anti-EGFR antibody (e.g., cetuximab) as described herein. In one embodiment of such a method, compound 1 is adipic acid salt, 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 QD as described herein, and at the amount described herein (e.g., 50 mg–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 dosage of cetuximab was administered, followed by approximately 250 mg / m² every 1 week. 2 Cetuximab. In such methods, compound 1 or its pharmaceutically acceptable salt and cetuximab may be administered as described herein.

[0129] In another embodiment, for a treatment of patients with KRas G12C A method for treating this type of cancer in patients with mutated CRC, wherein the method comprises administering to the patient a combination therapy comprising a treatment regimen as described herein, the treatment regimen comprising: (i) administering approximately 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate) via 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, administered at approximately 250 mg / m² every 1 week thereafter. 2 Cetuximab.

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

[0131] In another embodiment, a treatment is provided for patients suffering from KRas-containing... G12C A method for treating such cancer in patients with mutated pancreatic cancer, wherein the method comprises administering a treatment regimen to the patient comprising (i) administering approximately 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate) to the patient via QD during days 1 to 21 of the first 21-day cycle and (ii) administering 100 mg or 150 mg of erlotinib to the patient via QD during 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, wherein the additional therapies are one or more side effect limiters (e.g., agents designed to reduce the occurrence and / or severity of treatment side effects, such as antinausea agents, corticosteroids (e.g., prednisone or equivalents, e.g., at a dose of 1 to 2 mg / kg / day), hormone replacement drugs, etc.).

[0133] The patients described in this article must be evaluated and have KRas as described in this article. G12C Confirmatory test results for mutation. In one embodiment, the patient described herein has KRas for CRC. G12C Confirmatory test results for the mutation. In one such embodiment, the patient has previously been treated with one or more prior therapies. The diagnosis described herein is NSCLC with KRas-specific mutations. G12C Patients with confirmatory mutation test results must not have a known secondary oncogenic driver (e.g., for NSCLC: sensitized EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion, RET fusion; or for adenocarcinoma of the colon or rectum: BRAF V600E mutation, ERBB2 amplification). In one such embodiment, the patient has previously been treated with one or more prior therapies. In one embodiment, such secondary oncogenic drivers are determined using NGS (e.g., by Foundation Medicine, Inc. (FMI) NGS assay).

[0134] In one embodiment of the method provided herein, the patients described herein are treated with a combination therapy comprising cetuximab, such patients have experienced disease progression or are intolerant to at least one prior chemotherapy regimen (e.g., FOLFOX, FOLFIRI, FOLFOXIRI ± bevacizumab).

[0135] In another embodiment of the method provided herein, the patients described herein are treated with a combination therapy containing erlotinib, such patients have experienced disease progression or are intolerant to at least one prior systemic therapy (e.g., a single agent or a combination therapy with an investigational or approved PD-L1 / PD-1 inhibitor).

[0136] In one embodiment, the patient described herein has received KRas G12C Prior treatment with specific inhibitors.

[0137] In another embodiment, the patients described herein have not received chemotherapy, immunotherapy, or biological therapy as anticancer treatment within 3 weeks prior to administration of the combination therapy described herein, or have not received endocrine therapy as anticancer treatment within 2 weeks prior to administration of the combination therapy described herein, except in the following circumstances: (a) Hormone therapy for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer) using gonadotropin-releasing hormone (GnRH) agonists or antagonists; (b) Regulatoryly approved kinase inhibitors may be used up to two weeks prior to administration of the combination therapy described herein, provided that any drug-related toxicities have been completely resolved; or (c) Treatment with the study agent within 3 weeks or 5 half-lives prior to administration of the combination therapy described herein, whichever is shorter.

[0138] In another embodiment, the patients described herein did not receive radiation therapy as cancer treatment (except for palliative radiation to bone metastases and radiation to CNS metastases as described above) within 4 weeks prior to initiating the combination therapy described herein. In yet another embodiment, the patients described herein did not receive palliative radiation to bone metastases within 2 weeks prior to initiating the combination therapy described herein.

[0139] In another embodiment, the patient described herein does not have a history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia, or evidence of active pneumonia on a chest computed tomography (CT) scan.

[0140] This document further provides the use (UL1) of the combination therapy 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 embodiment, the use (UL2) is provided for the treatment of lung cancer as described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib. In one such embodiment, the lung cancer is NSCLC.

[0141] This document further provides the use (UL3) of the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib for the treatment of lung cancer as described herein, the combination therapy comprising a dosing regimen comprising: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of a first 21-day cycle; and (ii) administration of erlotinib on days 1 through 21 of the 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] This document further provides the use (UL4) of the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib for the treatment of lung cancer as described herein, the combination therapy comprising a dosing regimen comprising: (i) administration of about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof during QD on days 1 to 21 of a first 21-day cycle; and (ii) administration of about 150 mg of erlotinib during QD on days 1 to 21 of a first 21-day cycle. In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0143] This document further provides the use (UL5) of the combination therapy 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] This document further provides the use (UL6) of the combination therapy described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib in the manufacture of a medicament for the treatment of lung cancer as described herein, the combination therapy comprising a dosing regimen comprising: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of a first 21-day cycle; and (ii) administration of erlotinib on days 1 through 21 of the first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg. In another such embodiment, erlotinib is administered in an amount of about 150 mg.

[0145] This document further provides the use (UL7) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, in the manufacture of a medicament for the treatment of lung cancer as described herein, the combination therapy comprising a dosing regimen comprising: (i) administration of about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof during QDs from day 1 to day 21 of a first 21-day cycle; and (ii) administration of about 150 mg of erlotinib during QDs from day 1 to day 21 of a first 21-day cycle. In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0146] In such embodiments of the uses described herein, lung cancer may be NSCLC. In another such embodiment of the uses described herein, the patient described herein is diagnosed with KRas G12C Mutation-mediated NSCLC.

[0147] This document further provides the use of the combination therapy 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, for the treatment of CRC as described herein (UC1). In one embodiment, the use of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof, and cetuximab, for the treatment of CRC as described herein (UC2). In one such embodiment, the CRC is mCRC.

[0148] This article further provides the use (UC3) of the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab for the treatment of CRC as described herein, the combination therapy comprising a dosing regimen comprising: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle; and (ii) administration of approximately 400 mg / m² on day 1 of the first 21-day cycle.2 Cetuximab. In one such embodiment, compound 1 or its pharmaceutically acceptable salt 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 a dose of about 400 mg / m². 2 Administered at the indicated dose, followed by approximately 250 mg / m². 2 The dosage of cetuximab was Q1W.

[0149] This article further provides the use of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab, for the treatment of lung cancer as described herein (UC4), the combination therapy comprising a dosing regimen comprising: (i) administering approximately 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof 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, administered at approximately 250 mg / m² every 1 week thereafter. 2 Cetuximab.

[0150] This document further provides the use (UC5) of the combination therapy described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and an anti-EGFR antibody in the manufacture of a medicament for the treatment of CRC as described herein, wherein the anti-EGFR antibody is 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 uses described herein, the patient described herein is diagnosed with KRas G12C Mutation-mediated CRC.

[0152] This document further provides the use (UC6) of the combination therapy described herein comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab in the manufacture of a medicament for the treatment of CRC as described herein, the combination therapy comprising a dosing regimen comprising: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of a first 21-day cycle (QD); and (ii) administration of cetuximab on day 1 of a first 21-day cycle (Q1W). 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 a first 21-day cycle at an amount of about 400 mg / m² thereafter. 2 The dosage of cetuximab is approximately 250 mg / m². 2 The dosage of cetuximab was Q1W.

[0153] This document further provides the use (UC6) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab, in the manufacture of a medicament for the treatment of CRC as described herein, the combination therapy comprising a dosing regimen comprising: (i) administering approximately 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof 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, subsequently administered at approximately 250 mg / m² every 1 week. 2 Cetuximab. In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0154] This article further provides the use of the combination therapy described herein, comprising compound 1 or its pharmaceutical salt and erlotinib, for the treatment of pancreatic cancer as described herein (UP1).

[0155] This document further provides the use (UP2) of the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib for the treatment of pancreatic cancer as described herein, the combination therapy comprising a dosing regimen comprising: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle; and (ii) administration of erlotinib on days 1 to 21 of the first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg. In another such embodiment, erlotinib is administered in an amount of about 100 mg.

[0156] This document further provides the use of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, for the treatment of pancreatic cancer as described herein (UP3), the combination therapy comprising a dosing regimen comprising: (i) administration of about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof during days 1 to 21 of a first 21-day cycle; and (ii) administration of about 100 mg of erlotinib during days 1 to 21 of a first 21-day cycle. In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0157] This article further provides the use of the combination therapy described herein, comprising compound 1 or a pharmaceutical salt thereof and erlotinib, in the manufacture of a medicament for the treatment of pancreatic cancer as described herein (UP4).

[0158] This document further provides the use (UP5) of the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib in the manufacture of a medicament for the treatment of pancreatic cancer as described herein, the combination therapy comprising a dosing regimen comprising: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of a first 21-day cycle; and (ii) administration of erlotinib on days 1 through 21 of the first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg. In another such embodiment, erlotinib is administered in an amount of about 100 mg.

[0159] This document further provides the use (UP6) of the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib in the manufacture of a medicament for the treatment of pancreatic cancer as described herein, the combination therapy comprising a dosing regimen comprising: (i) administration of about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof during days 1 to 21 of a first 21-day cycle; and (ii) administration of about 100 mg of erlotinib during days 1 to 21 of a 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 improve efficacy while maintaining acceptable toxicity. A particular challenge is the need to differentiate the incremental toxicity of the combination. In one embodiment of the methods described herein, the combination therapy described herein (e.g., compound 1 or its pharmaceutically acceptable salt and erlotinib or cetuximab) is administered with a dosing regimen that includes staggered dosing times. In one such embodiment, patients have a reduced number or grade of adverse events (AEs) compared to a control (e.g., SOC therapy, treated with a single agent described herein (e.g., compound 1 or erlotinib or cetuximab)).

[0161] As is generally known, in the event of an adverse event, there are four options: (1) to continue the original treatment with optional concomitant therapy; (2) to adjust the dosage of one or more agents in the dosing regimen; (3) to suspend the administration of one or more agents in the dosing regimen; or (4) to discontinue the administration of one or more agents in the dosing 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, in the event of an interruption of erlotinib administration, the next administration of compound 1 or its saponin occurs on the same day as the resumption of erlotinib or cetuximab administration. In one embodiment, compound 1 or its saponin is administered without food (i.e., the patient should not eat for at least 2 hours before administration and at least 1 hour after administration). In one such embodiment, cetuximab is administered at least 20, 30, 45, or 60 minutes after administration of compound 1 or its saponin. In another such embodiment, erlotinib is administered after the administration of compound 1 or its pharmaceutical salt.

[0162] In one embodiment, the patient described herein experienced gastrointestinal toxicity, with an adverse event (AE) grade of less than or equal to 2. In one such embodiment, gastrointestinal toxicity is diarrhea, nausea, or vomiting. In another embodiment, the patient described herein experienced phototoxicity. In such embodiments, the patient should apply sunscreen and wear protective clothing when outdoors.

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

[0164] Patients described in this article may also receive concomitant therapies, including: (a) antiepileptic drugs or warfarin; (b) oral contraceptives or other permitted maintenance therapies; (c) antiemetics and antidiarrheals, provided that such drugs are not administered prophylactically prior to initial treatment with the investigational drug; (d) analgesics administered according to standard clinical practice; (e) bisphosphonates and denosumab for bone metastases or osteopenia / osteoporosis; or (f) multivitamins, calcium, and vitamin C, D, and E supplements.

[0165] Patients described in this article must not receive concurrent treatment with any of the following: (1) strong / moderate CYP3A4 inhibitors (e.g., atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, acetomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivatan, fluvoxamine, diltiazem, nefazodone, mibeladil, verapamil, and grapefruit juice or grapefruit supplement) or (2) strong / moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, travirline, modafinil, hypericin (St. John's wort), and cyproterone acetate.

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

[0167] In another embodiment, the patient described herein did not receive any of the following treatments: (a) Any other investigational therapy (excluding compound 1 or erlotinib or cetuximab) that occurred 3 weeks or five half-lives (whichever is shorter) prior to or during the administration of the combination therapy described herein. (b) Companion therapies intended to treat cancer, whether FDA-approved or experimental, including chemotherapy, radiation therapy, immunotherapy, biotherapy, traditional Chinese medicine, or hormone therapy, except in the following cases: (i) Hormone therapy for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer) using gonadotropin-releasing hormone (GnRH) agonists or antagonists; (ii) Hormone replacement therapy or oral contraceptives; (c) Radiotherapy for clearly progressive disease, except for new brain metastases in the presence of a systemic response: Patients whose systemic disease has been demonstrated to be under control (defined as having achieved clinical benefit [i.e., PR, CR or SD lasting ≥3 months]) but who have developed brain metastases that are available for radiotherapy will be allowed to continue receiving therapy using compound 1 during the study period until they experience systemic progression of their disease and / or further progression of the brain (based on investigator assessment).

[0168] (d) Quinidine or other antiarrhythmic agents; or (e) Start or increase the dose of hematopoietic colony-stimulating factors (CSF; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; saxaglastine, pegfilgrastim, erythropoietin, dabepostine and thrombopoietin) 7 days before day 1 of cycle 1; In one embodiment of such a method, the patient is diagnosed with the cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is collected prior to the administration of any of the therapies described herein. In another such embodiment, the sample is collected prior to the administration of at least one of the agents described herein. In some embodiments, tumor samples may be collected at specific time intervals during treatment with the combination therapies described herein to evaluate the treatment.

[0169] Whether a tumor or cancer contains KRas can be determined by evaluating the nucleotide sequence encoding the K-Ras protein, evaluating the amino acid sequence of the K-Ras protein, or evaluating the characteristics of a hypothetical K-Ras mutant protein. G12C Mutations. Wild-type human K-Ras sequences (e.g., accession number NP203524) are known in the art. In one such embodiment, KRas from samples from the patients described herein are evaluated using, for example, immunohistochemistry (IHC) or NGS sequencing. G12C mutation.

[0170] This article further provides a treatment for KRas-containing diseases by administering combination therapies as described herein. G12C A method for detecting mutated tumors that are not known to be cancerous. In one embodiment of such a method, the method includes: (a) Determine the presence of KRas in samples taken from patients suspected of having cancer. G12C Mutation; and (b) Administer to the patient a combination therapy as described herein, comprising an effective amount of compound 1 or a pharmaceutical salt thereof and an EGFR inhibitor as described herein.

[0171] In one such embodiment, the EGFR inhibitor is erlotinib or cetuximab. In one such embodiment, compound 1 or its pharmaceutically acceptable salt is administered at a dose of about 50 to 500 mg QD. In another such embodiment, erlotinib is administered at a dose of about 100 mg or 150 mg QD. In yet another such embodiment, cetuximab is administered at a dose of about 400 mg / m² on day 1 of the first 21-day cycle. 2 Administered at the indicated dose, followed by approximately 250 mg / m². 2 The dosage of cetuximab was Q1W.

[0172] This article further provides information on treatments involving KRas. G12C A method for identifying mutated tumors as cancerous, wherein the method includes: (a) Determine the presence of KRas in samples taken from patients suspected of having cancer. G12C Mutation; and (b) Administering to the patient the combination therapy as described herein, comprising a dosing regimen comprising: (i) administering 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administering 100 or 150 mg of erlotinib on days 1 to 21 of the first 21-day cycle.

[0173] This article further provides information on treatments involving KRas. G12C A method for identifying mutated tumors as cancerous, wherein the method includes: (a) Determine the presence of KRas in samples taken from patients suspected of having cancer. G12C Mutation; and (b) Administering to the patient the combination therapy as described herein, comprising a dosing regimen comprising: (i) administering 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof 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, administered at approximately 250 mg / m² every 1 week. 2 Cetuximab.

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

[0175] This document also provides methods for inhibiting tumor growth or achieving tumor regression in patients described herein, achieved through the administration of combination therapies described herein. In one embodiment provided herein, a method for inhibiting tumor growth in a patient with cancer as described herein is provided, comprising administering a combination therapy containing compound 1 or a pharmaceutically acceptable salt thereof and an EGFR inhibitor (e.g., erlotinib or cetuximab) over one or more 21-day cycles described herein. In another embodiment provided herein, a method for inhibiting tumor growth in a patient with NSCLC, CRC, or pancreatic cancer as described herein is provided, comprising administering a combination therapy containing compound 1 or a pharmaceutically acceptable salt thereof and an EGFR inhibitor (e.g., erlotinib or cetuximab) over one or more 21-day cycles described herein.

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

[0177] Reagent test kit The combination therapies described herein may be provided in the form of a kit containing one or more of the pharmaceutical agents described herein for administration. In one embodiment, the kit includes compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) for administration in combination with an EGFR inhibitor as described herein (e.g., erlotinib or cetuximab). In another embodiment, the kit includes compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) packaged together with an EGFR inhibitor as described herein (e.g., erlotinib or cetuximab), wherein the kit contains individually formulated doses of each pharmaceutical agent.

[0178] This document also provides articles or kits comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and an EGFR inhibitor described herein (e.g., erlotinib or cetuximab). In some cases, the articles further comprise a packaging insert containing instructions on using an EGFR inhibitor described herein (e.g., erlotinib or cetuximab) 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 articles further comprise a packaging insert containing instructions on using a combination of an EGFR inhibitor described herein (e.g., erlotinib) with compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) to treat or delay the progression of a patient's NSCLC. In one embodiment, the articles further comprise a packaging insert containing instructions on using a combination of an EGFR inhibitor described herein (e.g., erlotinib) with compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) to treat or delay the progression of a patient's pancreatic cancer. In one embodiment, the article of manufacture further includes a packaging insert containing instructions for treating or delaying the progression of CRC in a patient using a combination of the EGFR inhibitor described herein (e.g., cetuximab) with compound 1 or a pharmaceutical salt thereof (e.g., compound 1 adipate).

[0179] In some cases, the EGFR inhibitors described herein (e.g., erlotinib or cetuximab) and compound 1 or its pharmaceutically acceptable salts (e.g., compound 1 adipate) are in the same container or separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. Containers can be formed from a variety of materials, such as glass, plastics (e.g., polyvinyl chloride or polyolefins), or metal alloys (e.g., stainless steel or Hastelloy). In some cases, the container contains the formulation, and a label on or associated with the container may indicate instructions for use. The product or kit may also include other materials desired from a commercial and user perspective, including additional buffers, diluents, filters, needles, syringes, and packaging inserts with instructions for use. In some cases, the product further includes one or more other pharmaceutical agents (e.g., additional chemotherapeutic agents and antitumor agents). Suitable containers for one or more agents 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 adipate) and / or an EGFR inhibitor described herein (e.g., erlotinib or cetuximab) to a patient according to any of the methods described herein.

[0181] biomarkers In one embodiment, the effect of compound 1 or its pharmaceutical salt on KRas is measured in a patient. G12C Alkylation. In one such embodiment, samples were used to measure and test the KRas provided herein. G12C Alkylation. In another embodiment, ctDNA biomarkers (e.g., KRas) from peripheral blood are alkylated. G12C An evaluation will be conducted.

[0182] In one embodiment, regulation of KRAS / MAPK target genes (e.g., DUSP6, SPRY4), pathway components (e.g., pERK, pS6), and related biomarkers (e.g., Ki67) is performed by analyzing paired pre-treatment and in-treatment fresh tumor biopsies.

[0183] Example The following provides some exemplary embodiments of the present invention.

[0184] Example No. 1: A combination therapy comprising: (a) Compound 1 as described herein or its pharmaceutical salt; and (b) EGFR inhibitors.

[0185] Example No. 2: Combination therapy example 1, wherein compound 1 is its adipic acid salt.

[0186] Example No. 3: The combination according to Example 1 or 2, wherein compound 1 or its pharmaceutical salt is administered on days 1 to 21 of the first 21-day cycle.

[0187] Example No. 4: The combination therapy according to any one of Examples 1-3, wherein compound 1 or its pharmaceutical salt is administered orally as a tablet or capsule.

[0188] Example No. 5: The combination therapy according to any one of Examples 1-4, wherein compound 1 or its pharmaceutical salt is administered in an amount of about 50 mg to 500 mg.

[0189] Example No. 6: The combination therapy according to any one of Examples 1 to 5, wherein compound 1 or its pharmaceutical salt 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] Example No. 7: The combination therapy according to any one of Examples 1 to 6, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib or an anti-EGFR antibody.

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

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

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

[0194] Example No. 11: The combination therapy according to any one of Examples 1 to 10, wherein the EGFR inhibitor is erlotinib administered QD at a dose of about 100 mg or 150 mg.

[0195] Example No. 12: The combination therapy according to Example 11, wherein erlotinib is administered at a dose of about 100 mg QD.

[0196] Example No. 13: The combination therapy according to Example 11, wherein erlotinib is administered at a dose of approximately 150 mg QD.

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

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

[0199] Example No. 16: A combination therapy according to any one of Examples 1 to 7 or 14 to 15, wherein the EGFR inhibitor is cetuximab, which is administered Q1W starting on day 1 of the first 21-day cycle.

[0200] Example No. 17: A combination therapy according to any one of Examples 1 to 7 or 14 to 16, wherein the EGFR inhibitor is cetuximab, administered at approximately 400 mg / m² on day 1 of a 21-day cycle.2 Administered at a dose of approximately 250 mg / m². 2 The amount Q1W is applied.

[0201] Example No. 18: A combination therapy according to any one of Examples 1 to 13, used to treat KRas G12C Mutant lung cancer.

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

[0203] Example No. 20: A combination therapy according to any one of Examples 1 to 13, used to treat KRas-containing... G12C Mutant pancreatic cancer.

[0204] Example No. 21: A combination therapy according to any one of Examples 1 to 7 or 14 to 17, for treating KRas-containing... G12C Mutant colorectal cancer (CRC).

[0205] Example No. 22: A combination therapy comprising: (a) Compound 1 or its pharmaceutically acceptable salt as described herein, administered via QD on days 1 through 21 of the first 21-day cycle; and (b) Erlotinib, administered via QD on days 1 through 21 of the first 21-day cycle.

[0206] Example No. 23: The combination therapy according to Example 22, wherein compound 1 or its pharmaceutical salt 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] Example No. 24: The combination therapy according to any one of Examples 22 or 23 is used to treat KRas-containing... G12C Uses of mutated lung cancer.

[0208] Example No. 25: The combination therapy according to any one of Examples 22 or 23 is used to treat KRas-containing... G12C Uses of mutated pancreatic cancer.

[0209] Example No. 26: A combination therapy comprising: (a) Compound 1 or its pharmaceutically acceptable salt as described herein, administered via QD on days 1 through 21 of the first 21-day cycle; and (b) Cetuximab, administered on day 1 of the first 21-day cycle, Q1W.

[0210] Example No. 27: The combination therapy according to Example 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 on day 1 of the 21-day cycle at about 400 mg / m². 2 Administered at a dose of approximately 250 mg / m². 2 The amount Q1W is applied.

[0211] Example No. 28: A treatment for patients suffering from KRas G12C A method for treating this type of lung cancer in patients with mutation-mediated lung cancer, the method comprising administering an effective dose of a combination therapy, the combination therapy comprising: (a) Compound 1 or its pharmaceutically acceptable salt as described herein, administered via QD on days 1 through 21 of the first 21-day cycle; and (b) EGFR inhibitors.

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

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

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

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

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

[0217] Example No. 34: The method according to any one of Examples 28 to 33, wherein the EGFR inhibitor is erlotinib administered in a dose of about 150 mg QD.

[0218] Example No. 35: A treatment for patients suffering from KRas G12CA method for treating CRC in patients with mutation-mediated colorectal cancer (CRC) that involves administering an effective dose of a combination therapy comprising: (a) Compound 1 or its pharmaceutically acceptable salt as described herein, administered via QD on days 1 through 21 of the first 21-day cycle; and (b) EGFR inhibitors.

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

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

[0221] Example No. 38: The method according to any one of Examples 35 to 37, wherein the EGFR inhibitor is cetuximab, administered at approximately 400 mg / m² on day 1 of a 21-day cycle. 2 Administered at a dose of approximately 250 mg / m², and thereafter at a dose of approximately 250 mg / m². 2 The amount Q1W is applied.

[0222] Example No. 39: A treatment for patients suffering from KRas G12C A method for treating this type of pancreatic cancer in patients with mutation-mediated pancreatic cancer, the method comprising administering an effective dose of a combination therapy comprising: (a) Compound 1 or its pharmaceutically acceptable salt as described herein, administered via QD on days 1 through 21 of the first 21-day cycle; and (b) EGFR inhibitors.

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

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

[0225] Example No. 42: The method according to any one of Examples 39 to 41, wherein the EGFR inhibitor is erlotinib administered in a dose of about 100 mg QD.

[0226] Example No. 43: The method according to any one of Examples 28-42, wherein compound 1 is its adipic acid salt.

[0227] Example No. 44: The method according to any one of Examples 28-43, wherein compound 1 or its pharmaceutical salt is administered orally as a tablet or capsule.

[0228] Example No. 45: The method according to any one of Examples 28-44, wherein compound 1 or its pharmaceutical salt is applied in an amount of about 50 mg to 500 mg.

[0229] Example No. 46: The method according to any one of Examples 28 to 45, wherein compound 1 or its pharmaceutical salt is applied in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg.

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

[0231] Example No. 48: Use of a combination therapy comprising compound 1 or a pharmaceutical salt thereof and an EGFR inhibitor for the treatment of lung cancer, CRC or pancreatic cancer as described herein.

[0232] Example No. 49: The use according to Example 48, wherein the cancer is lung cancer or pancreatic cancer, and the EGFR inhibitor is erlotinib, and further includes a dosing regimen comprising: (i) administering compound 1 or a pharmaceutical salt thereof 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] Example No. 50: The use according to Example 48, wherein the cancer is CRC and the EGFR inhibitor is cetuximab, and further includes a dosing regimen comprising: (i) administering compound 1 or a pharmaceutical salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administering it on day 1 of the 21-day cycle at an amount of about 400 mg / m2, and thereafter at an amount of about 250 mg / m2 on Q1W.

[0234] Example No. 51: Use of a combination therapy comprising compound 1 or a pharmaceutical salt thereof and an EGFR inhibitor in the manufacture of a medicament for the treatment of lung cancer, CRC, or pancreatic cancer.

[0235] Example No. 52: The use according to Example 51, wherein the cancer is lung cancer or pancreatic cancer, and the EGFR inhibitor is erlotinib, and further includes a dosing regimen comprising: (i) administering compound 1 or a pharmaceutical salt thereof 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.

[0236] Example No. 53: According to the use described in Example 51, wherein the cancer is CRC and the EGFR inhibitor is cetuximab, and further comprising a dosing regimen comprising: (i) administering compound 1 or a pharmaceutical salt thereof on days 1 to 21 of a first 21-day cycle; and (ii) administering it on day 1 of a 21-day cycle at an amount of about 400 mg / m2, and thereafter at an amount of about 250 mg / m2 on Q1W.

[0237] The following examples are provided for illustrative purposes only and not for limitation.

[0238] Example Example 1: The combination of compound 1 and erlotinib The Kirsten rat sarcoma virus oncogene homolog (KRAS) gene encodes a GTPase that plays a central role in mediating cell growth and survival signaling. Mutations in KRAS resulting in the substitution of glycine 12 (G12), glycine 13 (G13), and glutamine 61 (Q61) amino acids 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; Taparosky et al., Nature 1982;300(5894):762-5; Capon et al., Nature 1983;304(5926):507-13). KRAS G12CMutations are prevalent 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).

[0239] Compound 1 is an oral anticancer therapeutic agent that selectively targets KRAS. G12C This led to KRAS G12C Covalent and irreversible inhibition. Compound 1 does not target other mutations in KRAS, wild-type KRAS, or other members of the RAS family. Treatment of KRAS with compound 1 G12C Positive cells or tumors can lead to reduced KRAS pathway signaling, inhibited cell / tumor cell growth, and induced apoptosis.

[0240] Compound 1 (50 mg / kg, PO, QD) alone or in combination with erlotinib (50 mg / kg, PO, QD) was identified in NCI-H2122 (KRAS) G12C In vivo antitumor efficacy in an NSCLC xenograft tumor model. Single-agent treatment with compound 1 resulted in tumor stasis (93% tumor growth inhibition (TGI)), while single-agent treatment with erlotinib resulted in tumor growth inhibition with only 48% TGI. Improved antitumor efficacy was observed using the combination of compound 1 and erlotinib (117% TGI).

[0241] Test materials. Compound 1 (free base) was provided as a 0.5% (w / v) methylcellulose solution at a concentration of 8.333 mg / mL (expressed as free base equivalent). Erlotinib (Tarceva™) was provided as a solution in 7.5% Captisol at a concentration of 12.5 mg / mL (expressed as free base equivalent). All concentrations were calculated based on the average weight of 25 g of the nude mouse strain used in this study. The mediator controls were 0.5% (w / v) methylcellulose and 0.5% (w / v) methylcellulose / 0.2% Tween 80™. Test reagents were stored in a refrigerator set to maintain a temperature range of 4°C to 7°C. All treatment and mediator control dosing solutions were prepared weekly for three weeks.

[0242] Female nude mice aged 9 to 10 weeks were obtained from Charles River Laboratory (Hollister, CA), with an average weight of 24.5 g. Mice were housed in standard rodent miniature isolation cages and acclimatized to research conditions for at least 3 days prior to tumor cell implantation. Only animals that appeared healthy and without obvious abnormalities were used for the study.

[0243] Human non-small cell lung cancer NCI-H2122 cells were obtained from the American Type Culture Collection (Rockville, MD) and possessed the G12C oncogenic mutation in K-RAS. Cells were cultured in vitro, harvested during the logarithmic growth phase, and resuspended 1:1 in Hank balanced salt solution (HBSS) containing Matrigel (BD Biosciences; San Jose, CA). The cells were then subcutaneously implanted into the right flank of 160 nude mice. Each mouse was injected with 10 × 10⁻⁶ cells. 6 100 μL of cells were collected. Tumors were monitored until they reached 150 to 290 mm. 3 The average tumor volume was determined. Mice were divided into six groups of n = 10 mice each based on tumor volume. At the start of administration, the average tumor volume across all six groups was 213 mm. 3 .

[0244] Mice were administered the mediator (150 µL 0.5% MC and 100 µL 0.5% MCT), 50 mg / kg of compound 1 (expressed as free base equivalent), or 50 mg / kg of erlotinib. All treatments were administered orally (PO) daily via force-feeding for 21 days. Tumor size and mouse weight were recorded, and mice were identified when the tumor volume exceeded 2000 mm. 3 Mice were euthanized immediately if their weight decreased to ≥20% of their initial weight.

[0245] Table 1: Research Design

[0246] 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, MA) and analyzed using Excel version 14.2.5 (Microsoft Corporation; Redmond WA). Tumor volume was calculated using the following formula: Tumor size (mm)3 = (longer measurement value × shorter measurement value) 2 ) ×0.5 Note the anti-tumor response, where partial response (PR) is defined as a reduction of >50% in tumor volume from the initial tumor volume, and complete response (CR) is defined as a reduction of 100% in tumor volume.

[0247] The antitumor efficacy of compound 1 (50 mg / kg, PO, QD) was evaluated in nude mice with human NCI-H2122 NSCLC xenografts after treatment with compound 1 alone (50 mg / kg, PO, QD), compared to or when in combination with compound 1. Monotherapy resulted in tumor growth inhibition (TGI), with compound 1 causing a 93% TGI and erlotinib a 48% TGI compared to the mediator control (see Table 2 and Figure 1). The combination of compound 1 and erlotinib was observed to improve antitumor efficacy, resulting in a 117% TGI and 3 / 10 partial responses (PR) (Figure 2).

[0248] Table 2: Antitumor activity of compound 1 and erlotinib, alone or in combination, in nude mice with human NCI-H2122 NSCLC xenograft tumors.

[0249] A combined antitumor efficacy study was conducted in the NCI-H2122 human NSCLC xenograft tumor model, demonstrating the efficacy of KRAS. G12C Inhibitor compound 1, as a single agent, inhibited tumor growth (93% TGI, no PR). The single-agent activity of the EGFR inhibitor erlotinib also resulted in tumor growth inhibition (48% TGI, no PR). The combination of compound 1 and erlotinib improved antitumor efficacy (117% TGI, 3 / 10 PR). These data suggest that KRAS... G12C The combination of the inhibitor, compound 1, with erlotinib resulted in enhanced antitumor activity, leading to partial tumor regression in the NCI-H2122 human NSCLC xenograft tumor model.

[0250] Example 2: Combination of compound 1 and cetuximab in a PDX CR6256 colon cancer xenograft model in female BALB / c nude mice.

[0251] In the treatment of a female BALB / c nude mouse subcutaneous PDX CR6256 colon cancer xenograft model, the in vivo therapeutic efficacy combination of compound 1 and cetuximab was preclinically evaluated.

[0252] Female BALB / c nude mice were housed in standard polysulfone IVC cages. Mice were 5 to 9 weeks old at initial vaccination. Compound 1 was administered at 30 mg / kg PO QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0253] Tumor fragments from reserve mice were harvested and used for inoculation. A primary human tumor xenograft model CR6256 tumor fragment (2-3 mm in diameter) was subcutaneously inoculated into the right posterior abdomen of each mouse to promote tumor development. Morbidity and mortality were assessed daily after tumor cell inoculation. During routine monitoring, animals were examined for any effects of tumor growth and treatment on behavior, such as activity level, food and water consumption, weight gain / loss (measured twice weekly after randomization), eye / hair dulling, and any other abnormalities. Individual animal mortality and observed clinical signs were documented in detail.

[0254] Tumor volume was measured twice weekly in two dimensions using calipers after randomization, and the volume was expressed in mm using the following formula. 3 In units: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). Drug administration and tumor and body weight measurements were performed in a laminar flow hood. Study Director was used. TM The software (version 3.1.399.19) measures body weight and tumor volume.

[0255] Tumor growth inhibition (TGI): TGI% is an indicator of antitumor activity, expressed as: TGI (%) = 100 x (1-T / C). T and C are the mean tumor volume (or weight) in the treatment group and control group, respectively, at a given date.

[0256] In CR6256 (KRas G12C The in vivo antitumor efficacy of compound 1 (30 mg / kg, orally, once daily) alone or in combination with cetuximab was evaluated in colorectal tumor models derived from patients. Single-agent treatment with compound 1 resulted in tumor stasis to regression (108% tumor growth inhibition [TGI]), while single-agent cetuximab showed moderate to mild tumor growth inhibition (74%). The combination of compound 1 and cetuximab showed improved combination efficacy relative to single-agent treatment (133%).

[0257] Table 3: Antitumor activity of compound 1 and cetuximab, alone or in combination, in a nude mouse xenograft model derived from CR6256 colorectal patients.

[0258] Example 3: Combination of compound 1 and cetuximab in CR5048, a PDX cancer model in female NOD-SCID mice.

[0259] In the treatment of the PDX cancer model CR5048 in female NOD-SCID mice, the in vivo efficacy of compound 1 and cetuximab was preclinically evaluated. When the mean tumor volume reached 185.67 mm... 3 Animals were randomized on day 0 and administered cetuximab on day 1. Animals were given cetuximab, alone or in combination with BIWx 3.5 weeks (7 total doses), for 21 consecutive days (QD). All animals were terminated 8 hours after their last dose (day 21 of the study). Animals were measured twice weekly during the study period. At the end of the study, tumors and blood were collected from all study animals. Tumors were split in half, and both halves were rapidly frozen in liquid nitrogen in separate tubes. Blood was collected via cardiac puncture and processed into plasma.

[0260] In CR5048 (KRas G12C The in vivo antitumor efficacy of compound 1 (30 mg / kg, orally, once daily) alone or in combination with cetuximab was measured in colorectal tumor models. Single-agent treatment with compound 1 resulted in tumor growth inhibition (90% TGI), while single-agent cetuximab treatment showed moderate to mild tumor growth inhibition (59% TGI). The combination of compound 1 and cetuximab showed improved combination efficacy relative to single-agent treatment (110%).

[0261] Table 4: Antitumor activity of compound 1 and cetuximab, alone or in combination, in a nude mouse xenograft model derived from CR5048 colorectal patients.

[0262] Example 4: Combination of compound 1 and cetuximab in a PDX CR6243 colon cancer xenograft model in female BALB / c nude mice In the treatment of a female BALB / c nude mouse subcutaneous PDX CR6243 colon cancer xenograft model, the in vivo therapeutic efficacy combination of compound 1 and cetuximab was preclinically evaluated.

[0263] Female BALB / c nude mice were housed in standard polysulfone IVC cages. Mice were 5 to 9 weeks old at initial vaccination. Compound 1 was administered at 30 mg / kg PO QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0264] Tumor fragments from reserve mice were harvested and used for inoculation. A primary human tumor xenograft model CR6243 tumor fragment (2 to 3 mm in diameter) was subcutaneously injected into the right posterior abdomen of each mouse to promote tumor development. When the average tumor size reaches approximately 192 mm 3 Randomization begins immediately. Morbidity and mortality are assessed daily after tumor cell inoculation. During routine monitoring, animals are examined for any effects of tumor growth and treatment on behavior, such as activity level, food and water consumption, weight gain / loss (measured twice weekly after randomization), eye / hair dullness, and any other abnormalities. Individual animal mortality and observed clinical signs are documented in detail.

[0265] Tumor volume was measured twice weekly in two dimensions using calipers after randomization, and the volume was expressed in mm using the following formula. 3 In units: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). Drug administration and tumor and body weight measurements were performed in a laminar flow hood. Study Director was used. TM The software (version 3.1.399.19) measures body weight and tumor volume.

[0266] Tumor growth inhibition (TGI): TGI% is an indicator of antitumor activity, expressed as: TGI (%) = 100 x (1-T / C). T and C are the mean tumor volume (or weight) in the treatment group and control group, respectively, at a given date.

[0267] In CR6243 (KRAS) G12C The in vivo antitumor efficacy of compound 1 (30 mg / kg, orally, once daily) alone or in combination with cetuximab in colorectal tumor models. Single-agent treatment with compound 1 resulted in tumor stasis to regression (89% tumor growth inhibition [TGI]), while single-agent cetuximab showed moderate to mild tumor growth inhibition (47% TGI). The combination of compound 1 and cetuximab showed improved combination efficacy relative to single-agent treatment (104%).

[0268] Table 5: Antitumor activity of compound 1 and cetuximab, alone or in combination, in a nude mouse xenograft model derived from CR6243 colorectal patients.

[0269] Example 5: Combination of compound 1 and cetuximab in a PDX CR6927 xenograft model of colorectal cancer in female BALB / c nude mice In the treatment of a female BALB / c nude mouse subcutaneous PDX CR6927 colon cancer xenograft model, the in vivo therapeutic efficacy combination of compound 1 and cetuximab was preclinically evaluated.

[0270] Female BALB / c nude mice were housed in standard polysulfone IVC cages. Mice were 5 to 9 weeks old at initial vaccination. Compound 1 was administered at 30 mg / kg PO QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0271] Tumor fragments from reserve mice were harvested and used for inoculation. A primary human tumor xenograft model CR6927 tumor fragment (2 to 3 mm in diameter) was subcutaneously injected into the right posterior abdomen of each mouse to promote tumor development. When the average tumor size reaches approximately 194 mm 3 Randomization begins immediately. Morbidity and mortality are assessed daily after tumor cell inoculation. During routine monitoring, animals are examined for any effects of tumor growth and treatment on behavior, such as activity level, food and water consumption, weight gain / loss (measured twice weekly after randomization), eye / hair dullness, and any other abnormalities. Individual animal mortality and observed clinical signs are documented in detail.

[0272] Tumor volume was measured twice weekly in two dimensions using calipers after randomization, and the volume was expressed in mm using the following formula. 3 In units: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). Drug administration and tumor and body weight measurements were performed in a laminar flow hood. Study Director was used. TM The software (version 3.1.399.19) measures body weight and tumor volume.

[0273] Tumor growth inhibition (TGI): TGI% is an indicator of antitumor activity, expressed as: TGI (%) = 100 x (1-T / C). T and C are the mean tumor volume (or weight) in the treatment group and control group, respectively, at a given date.

[0274] In CR6927 (KRAS) G12C In vivo antitumor efficacy of compound 1 (30 mg / kg, orally, once daily) alone or in combination with cetuximab in a colorectal tumor model. Single-agent compound 1 and cetuximab showed antitumor activity (29% and 10% tumor growth inhibition [TGI], respectively). Combination of compound 1 with cetuximab resulted in improved combination efficacy (70%) relative to single-agent administration. All doses and combinations tested were tolerable based on minimal changes in body weight and overall animal condition.

[0275] Table 6: Antitumor activity of compound 1 and cetuximab, alone or in combination, in a nude mouse xenograft model derived from CR6927 colorectal patients.

[0276] Example 6: Combination of compound 1 and cetuximab in a PDX CR2528 xenograft model of colorectal cancer in female BALB / c nude mice In the treatment of a female BALB / c nude mouse subcutaneous PDX CR2528 colon cancer xenograft model, the in vivo therapeutic efficacy combination of compound 1 and cetuximab was preclinically evaluated.

[0277] Female BALB / c nude mice were housed in standard polysulfone IVC cages. Mice were 8 to 10 weeks old at initial vaccination. Compound 1 was administered at 30 mg / kg PO QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0278] Tumor fragments from reserve mice were harvested and used for inoculation. A primary human tumor xenograft model CR2528 tumor fragment (2 to 3 mm in diameter) was subcutaneously injected into the right posterior abdomen of each mouse to promote tumor development. When the average tumor size reaches approximately 202 mm 3Randomization begins immediately. Morbidity and mortality are assessed daily after tumor cell inoculation. During routine monitoring, animals are examined for any effects of tumor growth and treatment on behavior, such as activity level, food and water consumption, weight gain / loss (measured twice weekly after randomization), eye / hair dullness, and any other abnormalities. Individual animal mortality and observed clinical signs are documented in detail.

[0279] Tumor volume was measured twice weekly in two dimensions using calipers after randomization, and the volume was expressed in mm using the following formula. 3 In units: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). Drug administration and tumor and body weight measurements were performed in a laminar flow hood. Study Director was used. TM The software (version 3.1.399.19) measures body weight and tumor volume.

[0280] Tumor growth inhibition (TGI): TGI% is an indicator of antitumor activity, expressed as: TGI (%) = 100 x (1-T / C). T and C are the mean tumor volume (or weight) in the treatment group and control group, respectively, at a given date.

[0281] In CR2528 (KRAS) G12C In vivo antitumor efficacy of compound 1 (30 mg / kg, orally, once daily) alone or in combination with cetuximab in colorectal tumor models. Single-agent treatment with compound 1 resulted in tumor stasis (65% tumor growth inhibition [TGI]), while single-agent cetuximab showed moderate tumor growth inhibition (40% TGI). Combination of compound 1 with cetuximab resulted in improved combination efficacy relative to single-agent treatment (117% TGI). All doses and combinations tested were tolerable, based on minimal changes in body weight and overall animal condition.

[0282] Table 7: Antitumor activity of compound 1 and cetuximab, alone or in combination, in a nude mouse xenograft model derived from CR2528 colorectal patients.

[0283] Example 7: Combination of compound 1 and cetuximab in a PDX CR1451 xenograft model of colorectal cancer in female BALB / c nude mice In the treatment of a female BALB / c nude mouse subcutaneous PDX CR1451 colon cancer xenograft model, the in vivo therapeutic efficacy combination of compound 1 and cetuximab was preclinically evaluated.

[0284] Female BALB / c nude mice were housed in standard polysulfone IVC cages. Mice were 5 to 9 weeks old at initial vaccination. Compound 1 was administered at 30 mg / kg PO QD for 21 days. Cetuximab was administered intraperitoneally (IP) at 20 mg / kg BIW for 3 weeks.

[0285] Tumor fragments from reserve mice were harvested and used for inoculation. A primary human tumor xenograft model CR1451 tumor fragment (2 to 3 mm in diameter) was subcutaneously injected into the right posterior abdomen of each mouse to promote tumor development.

[0286] When the average tumor size reaches approximately 182 mm 3 Randomization begins immediately. Morbidity and mortality are assessed daily after tumor cell inoculation. During routine monitoring, animals are examined for any effects of tumor growth and treatment on behavior, such as activity level, food and water consumption, weight gain / loss (measured twice weekly after randomization), eye / hair dullness, and any other abnormalities. Individual animal mortality and observed clinical signs are documented in detail.

[0287] Tumor volume was measured twice weekly in two dimensions using calipers after randomization, and the volume was expressed in mm using the following formula. 3 In units: V = (L x W x W) / 2, where V is the tumor volume, L is the tumor length (the longest tumor dimension), and W is the tumor width (the longest tumor dimension perpendicular to L). Drug administration and tumor and body weight measurements were performed in a laminar flow hood. Study Director was used. TM The software (version 3.1.399.19) measures body weight and tumor volume.

[0288] Tumor growth inhibition (TGI): TGI% is an indicator of antitumor activity, expressed as: TGI (%) = 100 x (1-T / C). T and C are the mean tumor volume (or weight) in the treatment group and control group, respectively, at a given date.

[0289] In CR1451 (KRAS) G12CIn vivo antitumor efficacy of compound 1 (30 mg / kg, orally, once daily) alone or in combination with cetuximab in colorectal tumor models. Single-agent treatment with compound 1 resulted in tumor stasis to regression (64% tumor growth inhibition [TGI]), while single-agent cetuximab showed the slowest tumor growth inhibition (48% TGI). Combination of compound 1 with cetuximab resulted in improved combination efficacy relative to single-agent treatment (83% TGI). All doses and combinations tested were tolerable, based on minimal changes in body weight and overall animal condition.

[0290] Table 8: Antitumor activity of compound 1 and cetuximab, administered alone or in combination, in a nude mouse xenograft model of CR1451 colorectal patient.

[0291] Example 8: KRAS is the most frequently mutated oncogene in up to 25% of cancers and is associated with resistance to selected standard-of-care therapies and poor overall prognosis. Although selective inhibitors have been developed as anticancer therapies to target other nodes in the RAS / MAPK pathway, the KRAS oncoprotein was considered untreatable until the recent discovery of the Switch II pocket (Ostrem, et al., Nature 2013;503:548-51). With this discovery, the aim is to target KRAS, and specifically KRAS. G12C Mutant covalent small molecule inhibitors are being evaluated in early clinical development.

[0292] Other KRAS G12C Inhibitor. AMG 510 (Sotorasibu) is a drug produced by KRAS... G12CAMG-510 is a small molecule that is irreversibly inhibited by locking it in its inactive GDP-binding state. It is currently being investigated in ongoing clinical studies. Patients in those studies had received a median of 3 (range, 0 to 11) prior to enrollment in the study for a previous line of anticancer therapy for metastatic disease. Overall, 56.6% of patients reported treatment-related adverse events; 11.6% experienced treatment-related grade 3 or 4 events, and 1.6% experienced treatment-related serious adverse events. Grade 3 events occurring in more than one patient included elevated ALT, diarrhea, anemia, elevated AST, and elevated alkaline phosphatase. One patient experienced a grade 4 treatment-related ALT elevation, and one patient discontinued AMG-510 due to grade 3 treatment-related ALT and AST elevations. While antitumor activity has been reported, adverse events associated with AMG-510 have been observed. In 32.2% of NSCLC patients, confirmed objective responses were achieved, and the median duration of response was 10.9 months (range, 1.1+ to 13.6). The median progression-free survival (PFS) for NSCLC patients has been reported to be 6.3 months (range, 0.0+ to 14.9+) (Hong et al., New Eng J Med 2020;383:1207-17).

[0293] MRTX849 is a mutant-selective small molecule KRAS. G12C Inhibitors, which are currently being studied in a study with KRAS G12CThis study evaluated patients with advanced solid tumors exhibiting mutations. Data from a total of 17 patients (10 with NSCLC and 4 with CRC) were recently reported, of whom 12 had undergone at least one in-treatment tumor evaluation (6 with NSCLC and 4 with CRC). Most patients had received three or more prior anticancer regimens prior to enrollment (12 of the 17 patients, 71%). >10% of patients reported the following treatment-related adverse events: diarrhea, nausea, elevated AST, vomiting, fatigue, elevated ALT, elevated creatinine, abdominal distension, abdominal pain, elevated ALP, anemia, decreased appetite, dehydration, dry mouth, dysgeusia, dyspnea, QT prolongation, hypomagnesemia, and rash. Grade 3 events included fatigue, decreased appetite, and dyspnea (1 patient each). Of all the dose levels evaluated, 3 out of 6 NSCLC patients and 1 out of 4 CRC patients achieved PR antitumor activity (Jänne et al., AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 2019).

[0294] Compound 1. Compound 1 against KRAS G12C The specificity and mechanism of action of KRAS lead to the G12C Effective and irreversible inhibition, with the potential to achieve a broad therapeutic index, maximizing antitumor activity while minimizing treatment-related toxicities. Targeting KRAS G12C Specific therapies for KRAS-positive cancers may be available. G12C This provides more tolerable and effective treatment options for patients with advanced cancer.

[0295] In vitro and in vivo pharmacological studies have shown that compound 1 is a KRAS G12C Highly effective and selective covalent inhibitors, exhibiting efficacy against KRAS. G12C The selectivity of growth inhibition of positive cancer cell lines is against KRAS. G12C The negative cancer cell lines showed an effect more than 20,000 times greater. Mechanism-of-action studies of compound 1 showed that, in addition to KRAS target genes (such as DUSP6 and SPRY4), downstream MAPK pathway components (such as phosphorylated (p)ERK and pS6) were also inhibited and in KRAS... G12C Apoptosis induction was observed in positive cancer cell lines. Furthermore, compound 1 exhibits potent single-agent activity and is effective in KRAS. G12CCompound 1 inhibits tumor growth in numerous nonclinical xenograft models of positive lung tumors. These in vitro and in vivo pharmacological studies support the use of compound 1 for the treatment of patients with locally advanced or metastatic KRAS. G12C Patients with positive solid tumors.

[0296] The results of the non-clinical toxicology studies completed to date provide a robust characterization of the toxicity profile of Compound 1 and support its administration in cancer patients. Comprehensive non-clinical toxicity studies were completed to evaluate the potential single- and repeated-dose oral toxicities, genotoxicities, phototoxicities, and safety pharmacology of Compound 1. (Due to KRAS) G12C The mutation is not present in healthy animals, therefore there is no KRAS. G12C Inhibitory pharmacologically relevant non-clinical species.

[0297] 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 containing constant regions of the human IgG1 heavy chain and κ light chain, with a molecular weight of approximately 152 kDa. Cetuximab is produced in mammalian (mouse myeloma) cell cultures. In one embodiment, cetuximab is sold under the trade name ERBITUX®.

[0298] Cetuximab is approved for the treatment of various types of solid tumors, including metastatic colorectal and head and neck cancers. Erlotinib is approved for the treatment of non-small cell lung cancer (NSCLC), particularly NSCLC tumors with epidermal growth factor receptor (EGFR) deletions (EGFR) or exon 21 (L858R) substitution mutations (as detected by an FDA-approved test) following progression after at least one prior chemotherapy regimen, as first-line, maintenance, or second-line or more treatment. Erlotinib is also approved in combination with gemcitabine for first-line treatment of locally advanced, unresectable, or metastatic pancreatic cancer.

[0299] Early Phase I clinical data from ongoing studies of AMG 510 and MRTX849 as monotherapy suggest that KRAS... G12C Inhibitors are well-tolerated and exhibit good antitumor activity in patients with metastatic NSCLC and CRC (Janne et al., 2019; Hong et al., New Eng J Med 2020;383:1207-17). However, a significant unmet need remains for the use of such inhibitors as single agents in NSCLC and CRC to improve the reported antitumor activity and durability in these patients, while importantly maintaining their tolerable safety profile.

[0300] The basic principle of combination therapy with EGFR inhibitors: Unbound by any particular theory and based on the mechanistic understanding of the RTK-RAS-MAPK pathway, it has been hypothesized that RTK inhibitors inhibit KRAS. G12C Upstream may potentially enhance KRAS G12C Inhibition. This strategy is supported in non-clinical studies in cell lines, as described in Example 1, because EGFR inhibition with small molecules or anti-EGFR antibodies that inhibit wild-type EGFR activity has been shown to synergistically enhance KRAS. G12C 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 enhances KRAS. G12C Possible mechanisms of inhibitory effects include reducing nucleotide exchanges to support KRAS. G12C GDP combined with state (Lito et al., 2016) and reduced RTK signal in KRAS G12C The rebound effect is enhanced under the inhibition (Amodio et al., 2020).

[0301] In combination with cetuximab. In in vivo mouse studies, treatment with the combination of compound 1 and cetuximab in mice with CRC PDX reduced tumor growth, exceeding what was seen with compound 1 alone. Non-clinical evidence (see Figures 3-8 and Examples 2-7) shows EGFR inhibition and KRAS G12C Inhibit synergistic effects in CRC. The starting dose of cetuximab in combination with compound 1 will be 400 mg / m² over a 21-day cycle. 2 The initial dose was administered via IV infusion over 120 minutes on day 1, followed by weekly doses of 250 mg / m². 2 Intravenous infusion over 60 minutes. Potential overlapping toxicities of the drug include gastrointestinal toxicity and elevated liver transaminases.

[0302] Combined with erlotinib. In multiple KRAS G12CIn positive cell lines, the combination of compound 1 and erlotinib showed a synergistic effect in inhibiting cell growth and a corresponding reduction in pERK and pS6, which was greater than that seen when compound 1 was used alone. In in vivo mouse studies, the use of compound 1 and erlotinib reduced tumor growth in NSCLC xenografts to a greater extent than when compound 1 was used alone. Non-clinical evidence (see Figure 1 and...) Figure 2 ) shows EGFR inhibition and KRAS G12C Inhibit synergistic effects in NSCLC. The starting dose of erlotinib in combination with compound 1 is 150 mg PO QD, over a 21-day cycle. Potential overlapping toxicities of the agents include gastrointestinal toxicity and elevated liver transaminases.

[0303] Biomarkers. This study will identify and / or evaluate biomarkers that predict response to compound 1 as a single agent or in combination with an EGFR inhibitor (i.e., predictive biomarkers), are early alternatives to activity, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), and are correlated with KRAS. G12C Acquired resistance to an inhibitor (e.g., compound 1) is associated with susceptibility to adverse events or may lead to improved adverse event monitoring or investigation (i.e., safety biomarkers), may provide evidence of the activity of compound 1 in combination with an EGFR inhibitor (i.e., pharmacodynamic [PD] biomarkers), or may increase knowledge and understanding of disease biology and drug safety. Relevant biomarker endpoints include the relationship between exploratory biomarkers in blood, plasma, and tumor tissue and safety, PK, activity, or other biomarker endpoints.

[0304] Patients will be screened for up to 28 days, followed by a treatment period and a safety follow-up period. During this period, patients' safety outcomes will be followed up until the treatment-specific period after their last dose of the study drug or until they receive another anticancer therapy, whichever comes first.

[0305] In the absence of unacceptable toxicity and clear disease progression as determined by the investigators, patients may continue treatment with compound 1.

[0306] Adverse events will be closely monitored in all patients throughout the study and during the treatment-specific period following the last dose of study treatment or until the initiation of another anticancer therapy (whichever occurs first). Adverse events will be graded according to NCI CTCAE v5.0.

[0307] The starting dose of compound 1 will be 50 mg, PO QD. The single-patient dose escalation cohort will be treated at escalating dose levels of compound 1.

[0308] Patients include those with locally advanced, recurrent, or metastatic, incurable KRas. G12C Patients with positive tumors (e.g., NSCLC, CRC, or pancreatic cancer) who have disease progression or are intolerant to at least one prior systemic therapy (which may include single-agent or combination therapy). KRas will be screened in patients with NSCLC, CRC, or pancreatic cancer. G12C Positive.

[0309] KRas from tissue and circulating tumor DNA assessment 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%) carry KRas. G12C Mutation. Compound 1 is a potent and highly selective inhibitor that targets KRas. G12C However, it does not target KRAS, wild-type KRAS, or other mutations in other members of the RAS family. Therefore, it only targets KRAS carriers. G12C Only patients with mutated tumors are eligible to receive the combination therapy described in this article. KRAS mutation status can be determined using FoundationOne. ® CDx (F1CDx) assay (FDA-approved broad companion diagnostic (CDx) assay), FoundationOne ® LiquidCDx (F1L CDx) assays and other FDA-approved (FDA 2020) or fully validated laboratory-developed tests performed in clinical laboratory improvement act amends (CLIA) accredited or equivalent laboratories. Previous studies have shown that KRas G12C The occurrence of the mutation was an early event (Jamal-Hanjani et al., N Engl J Med 2017;376:2109-21), indicating that the analysis of the archived organization was for selecting KRas. G12C A suitable alternative to compound 1 treatment for patients with positive tumors.

[0310] Pharmacodynamic pathway regulation. Compound 1 is KRas G12C Inhibitors, which are mediated by KRas G12CAlkylation inhibits downstream MAPK signaling, thereby locking it in its inactive GDP-binding state. In non-clinical models, compound 1 inhibits KRas... G12C The level of alkylation and the extent of MAPK pathway inhibition are correlated with the response to compound 1. Pre- and post-treatment tumor tissue collection will allow for the assessment of the correlation between MAPK pathway inhibition and antitumor activity and compound 1 treatment. The extent of MAPK pathway inhibition can be assessed using RNA analysis of MAPK target genes (e.g., DUSP6, SPRY4) or immunohistochemical (IHC) analysis of phosphorylated downstream markers (e.g., pERK, pS6). Furthermore, post-treatment tumor tissue biopsy allows for direct assessment of the effect of compound 1 on KRas... G12C The level of alkylation. Evaluation of these PD biomarkers may inform future dosage selection.

[0311] Sequencing of genes associated with resistance to compound 1. DNA sequencing technologies, such as targeted next-generation sequencing (NGS) and whole-exome sequencing, can provide unique opportunities to identify biomarkers of response to 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.

[0312] Protein, RNA, and DNA analysis. Besides protein mutation activation, alterations in RNA expression levels or DNA can also modulate the activity of signal transduction pathways. RNA profiling of tumors will allow for intrinsic subtyping of patients participating in the study. Analyzing the potential associations between subtypes and patient outcomes can identify the patient subgroups most likely to respond to compound 1.

[0313] Plasma samples are used for somatic tumor mutation analysis and other biomarkers. Increasing evidence suggests that cell-free DNA obtained from blood samples of cancer patients contains ctDNA, which represents the DNA and mutational status of tumor cells (Diehl et al., 2008; Maheswaran et al., 2008). Assays for detecting cancer-related mutations (e.g., KRAS) in plasma have been validated. The results of these assays may correlate with the mutational status identified by tumor sample analysis. Monitoring response to treatment using ctDNA is an area of ​​great interest and could allow for early, non-invasive, and quantifiable methods in a clinical setting to identify candidates for specific therapies and monitor the mutational status of cancer over time (Wan et al., Nat Rev Cancer 2017;17:223-38). Analyzing ctDNA collected at different times during study treatment and after progression following compound 1 treatment may help identify response mechanisms to study treatments and acquired resistance.

[0314] Blood samples are used for next-generation sequencing. Next-generation sequencing (NGS) technology can generate large amounts of sequencing data. Due to the tumorigenesis process, tumor DNA may contain both reported and unreported chromosomal alterations. To help control sequencing calls for previously unreported genomic alterations, blood samples are collected before drug administration to determine whether the alterations are somatic.

[0315] Inclusion criteria. Patients must meet the following criteria for study inclusion: ● Age ≥ 18 years old; ● Diseases that are assessable or measurable according to RECIST v1.1; ● Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1; ● Life expectancy ≥ 12 weeks; ● Sufficient blood and organ function must be present for 14 days prior to the start of the treatment study, as defined below: o Absolute neutrophil count ≥ 1200 / µL; o Hemoglobin ≥ 9 g / dL; o Platelet count ≥ 100,000 / µL; o Total bilirubin ≤ 1.5 × ULN; o Serum albumin ≥ 2.5 g / dL; o AST and ALT ≤ 2.5 × ULN, except in the following cases: ■ Patients with a history of liver metastases may have AST and / or ALT ≤ 5.0 × ULN.

[0316] o Based on Cockcroft-Gault glomerular filtration rate estimation, serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL / min: (140 - age) × (weight in kg) × (0.85 if female) 72 × (serum creatinine, in mg / dL) ● For women of childbearing age: agree to abstain from sex (avoid heterosexual intercourse) or use contraception, and agree not to donate eggs; ● For men who have not undergone surgical sterilization: agree to abstain from sex (avoid heterosexual intercourse) or use contraception, and agree not to donate sperm; ● Confirmation of biomarker eligibility: Valid results from central blood testing or local blood or tumor tissue testing, recorded in KRas. G12C The presence of mutations (e.g., by validated polymerase chain reaction (PCR)-based assays or NGS assays performed in CLIA or equivalent certified laboratories).

[0317] Additional inclusion criteria ● Histologically documented locally advanced, recurrent, or metastatic incurable colorectal adenocarcinoma without known concomitant secondary oncogenic drivers (e.g., BRAF V600E mutation, ERBB2 amplification) as determined by FMI NGS assay or by sponsor-approved empirical PCR-based or NGS assay performed in a locally CLIA-certified or equivalent laboratory.

[0318] Patients with appendiceal tumors were excluded. The patient must have experienced disease progression or be intolerant to at least one prior chemotherapy regimen (e.g., FOLFOX, FOLFIRI, FOLFOXIRI ± bevacizumab). ● Histologically documented locally advanced, recurrent, or metastatic incurable NSCLC without known concomitant secondary oncogenic drivers (e.g., sensitized EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, NTRK fusions, RET fusions), as determined by FMI NGS assays or by sponsor-approved empirical PCR-based or NGS assays performed in a locally CLIA-certified or equivalent laboratory.

[0319] o Disease progression or intolerance to at least one prior systemic therapy. This may include single-agent therapy or combination therapy with an investigational or approved PD-L1 / PD-1 inhibitor.

[0320] ● The patient may have received KRas G12C Prior treatment with specific inhibitors.

[0321] General exclusion criteria. Patients meeting any of the following criteria will be excluded: ● Unable or unwilling to swallow pills; ● Unable to adhere to research and follow-up procedures; ● Malabsorption syndrome or other conditions that interfere with intestinal absorption; ● Known and untreated or active central nervous system (CNS) metastases; ● Patients with a history of treated CNS metastases, provided they meet all of the following criteria: o Measurable or assessable diseases outside the CNS; o No history of intracranial hemorrhage or spinal cord hemorrhage; o There is no ongoing requirement to use corticosteroids to treat CNS metastases, corticosteroids were discontinued ≥2 weeks prior to administration of the medication described herein, and there are no persistent symptoms due to CNS metastases; o No stereotactic radiation was administered within 7 days prior to Day 1 of Cycle 1, or no whole-brain radiation was administered within 14 days prior to Day 1 of Cycle 1. There is no clinical evidence of interim progress between completing CNS-targeted therapy and screening imaging studies; ● Piarrhea or carcinomatous meningitis; ● Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage procedures (every two weeks or more); o If the patient has fully recovered from surgery, is hemodynamically stable, and has improved symptoms, then pleural or peritoneal catheter placement may be permitted; ● Any active infection that may affect patient safety, or a serious infection requiring IV antibiotics, within 7 days prior to Day 1 of Cycle 1; ● A clinically significant history of liver disease, including viral hepatitis or other types of hepatitis, current alcoholism, or cirrhosis; ● Known HIV infection; ● Uncontrolled hypercalcemia (>1.5 mmol / L ionized calcium or calcium >12 mg / dL or corrected serum calcium ≥ ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab; ● Significant injury or major surgery within 4 weeks prior to Day 1 of Cycle 1; ● Patients with chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery (including gastrectomy), a history of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or any active bowel inflammation (including diverticulitis); ● Treatment with chemotherapy, immunotherapy, or biological therapy as an anticancer therapy within 3 weeks prior to administration of the drugs described herein, or treatment with endocrine therapy as an anticancer therapy within 2 weeks prior to administration of the drugs described herein, except in the following circumstances: Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers such as prostate cancer, endometrial cancer, and hormone receptor-positive breast cancer. o Regulatoryly approved kinase inhibitors may be used up to two weeks before the start of study treatment; o Treat with the study drug within 3 weeks or 5 half-lives prior to administration of the drug described herein, whichever is shorter.

[0322] ● Radiation therapy (except for palliative radiation for bone metastases and radiation for CNS metastases) should be administered within 4 weeks prior to the administration of the drugs described herein as a cancer treatment. ● Palliative radiation therapy for bone metastases within 2 weeks prior to the initiation of compound 1 administration; ● Unresolved adverse events from previous anticancer therapies; ● History of other malignant tumors within 5 years prior to screening; ● A history of clinically significant cardiovascular dysfunction or active clinically significant cardiovascular dysfunction, including: o A history of stroke or transient ischemic attack within 6 months prior to administration of the medication described herein; o A history of myocardial infarction within 6 months prior to administration of the medication described herein; o New York Heart Association class III or IV heart disease or congestive heart failure requiring medication o Uncontrolled arrhythmia, a history of ventricular arrhythmia requiring medication, or active ventricular arrhythmia; o Coronary artery disease with symptomatic or unstable angina; o Congenital long QT syndrome or QT interval (QTcF) > 470 ms corrected by the Fridericia formula; Currently, treatment is being carried out using drugs known to prolong the QT interval. ● Pregnant or breastfeeding, or planning to become pregnant during the study period or within 6 months after the last dose of compound 1; or ● A history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced lung inflammation, or idiopathic lung inflammation, or evidence of active lung inflammation on a chest computed tomography (CT) scan; Research on therapeutic formulations, packaging, and processing.

[0323] Compound 1 will be supplied as an active pharmaceutical ingredient (API) powder / capsule (PIC) formulation 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) strength will also be supplied for clinical use. Compound 1 should be stored at or below 86°F (30°C) and protected from moisture.

[0324] For the dosage of Compound 1 to be administered at home, the patient should be given an adequate number of capsules or tablets to continue until the next visit or to maintain a cycle. The patient will administer Compound 1 as described herein at home unless the patient visits a clinic. Unless otherwise instructed, the patient should take Compound 1 at approximately the same time each day. The number and strength of capsules or tablets to be taken will be instructed according to the dosage level and schedule specified by the patient.

[0325] Unless otherwise instructed, Compound 1 should be taken on an empty stomach, meaning that food should be avoided for at least 2 hours before and 1 hour after the dose. There are no restrictions on fluid intake. Importantly, the Compound 1 capsules or tablets should be swallowed whole (without chewing) with at least 240 mL (8 fluid ounces) of water. If a patient misses any dose of Compound 1 or spits out a capsule or tablet, the patient should be instructed to skip that dose and resume administration at the next scheduled dose. Missed doses will not be made up.

[0326] Cetuximab will be available in a commercially available formulation. Cetuximab will be available at a dose of 400 mg / m². 2 The initial dose was administered via intravenous infusion over 120 minutes on day 1, followed by weekly doses of 250 mg / m². 2 Administer intravenously over 60 minutes, for a period of 21 days. The maximum infusion rate should not exceed 10 mg / min. Cetuximab should be administered after compound 1.

[0327] Cetuximab administration will be conducted in a monitored environment with immediate access to trained personnel and adequate equipment and medication to manage potential serious reactions. Participants must receive a prophylactic antihistamine and corticosteroid prior to the first infusion. It is recommended that such a prophylactic be administered before all subsequent infusions. Close monitoring is required during the infusion and for at least one hour after completion. Erlotinib will be available in tablet form in 25 mg, 100 mg, and 150 mg strengths. Erlotinib will be administered in 150 mg doses over a 21-day cycle, concurrently with compound 1, via a PO QD, with small sips of water in between. All doses of erlotinib should be taken on an empty stomach (i.e., avoid eating for at least 2 hours before and 1 hour after dose administration).

[0328] If erlotinib or cetuximab is discontinued due to an adverse event during a given cycle, the next dosing cycle should not begin until erlotinib or cetuximab can be resumed. Therefore, the current cycle may be extended by more than 21 days, and the patient may continue receiving compound 1. Day 1 of the next cycle should correspond to the point at which erlotinib or cetuximab is resumed.

[0329] Companion therapy. Companion therapy consists of any medications other than those described herein used by the patient from 7 days prior to the first administration of at least one of the medications described herein until the last administration of at least one of the medications described herein. These medications may include prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, and nutritional supplements.

[0330] Permitted therapies. Patients may take (a) antiepileptic drugs or warfarin; (b) oral contraceptives or other permitted maintenance therapies as specified in the eligibility criteria; (c) antiemetics and antidiarrheals should not be administered prophylactically prior to initial treatment with the investigational drug; (d) analgesics; (e) bisphosphonates and denosumab for bone metastases, osteopenia, or osteoporosis; or multivitamins, calcium, and vitamin C, D, and E supplements are permitted.

[0331] Prophylactic therapy. Medications given prophylactically due to effects related to CYP enzymes and compound 1 include, for example: (1) strong / moderate CYP3A4 inhibitors, including but not limited to: atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, acetomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivatan, fluvoxamine, diltiazem, nefazodone, mibeladil, verapamil, and grapefruit juice or grapefruit supplement; (2) strong / moderate CYP3A4 inducers, including but not limited to: rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, travirline, modafinil, hypericin (St. John's wort), and cyproterone acetate. Full-dose oral or parenteral anticoagulants for therapeutic purposes may be used provided that the INR and / or aPTT are within therapeutic limits (according to institutional standards) for 14 days prior to administration of any of the medications described herein and the patient has been receiving a stable dose of anticoagulant for ≥ 1 week prior to the initiation of study treatment. The list of medications is not intended to be exhaustive.

[0332] Strongly oppose the use of coumarin during erlotinib therapy. ® (Warfarin). If the patient requires anticoagulation therapy, low molecular weight heparin is recommended as an alternative to coumarin, where clinically feasible. If no clinically feasible coumarin alternative is available, INR and prothrombin time must be monitored frequently.

[0333] Medications that reduce stomach acid production, such as proton pump inhibitors or H2 receptor antagonists, have been shown to reduce erlotinib exposure. Therefore, co-administration of these medications with erlotinib should be avoided. If antacids are deemed necessary during erlotinib treatment, they should be taken at least 4 hours before or 2 hours after daily erlotinib administration.

[0334] Patients receiving erlotinib are not permitted to use anti-angiogenic agents and nonsteroidal anti-inflammatory drugs (NSAIDs) for extended periods, as these may increase the risk of GI perforation. Acute use of NSAIDs is permitted to control fever or during periods when erlotinib is discontinued.

[0335] Contraindicated therapies. The following concomitant therapies are contraindicated during and for at least 7 days prior to the first administration of the medication described herein: ● Investigational therapy within 3 weeks or five half-lives prior to the first administration of the drug described herein, whichever is shorter; ● Companion therapies intended to treat cancer, whether FDA-approved or experimental, including chemotherapy, radiation therapy, immunotherapy, biotherapy, traditional Chinese medicine, or hormone therapy, except in the following cases: Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers such as prostate cancer, endometrial cancer, and hormone receptor-positive breast cancer. Hormone replacement therapy or oral contraceptives.

[0336] ● For radiotherapy of clearly progressive disease, except for new brain metastases in the event of a systemic response: Patients whose systemic disease has been demonstrated to be under control (defined as having achieved clinical benefit [i.e., PR, CR, or SD lasting ≥ 3 months]) but who have developed brain metastases that are available for radiotherapy will be allowed to continue receiving therapy using compound 1 during the study period until they experience systemic progression of their disease and / or further progression of the brain (based on investigator assessment).

[0337] ● Quinidine or other antiarrhythmic drugs; ● Start or increase the dose of hematopoietic colony-stimulating factors (CSF; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; saxaglastine, pegfilgrastim, erythropoietin, dabepostine, and thrombopoietin) 7 days before day 1 of cycle 1. Risks associated with Compound 1. Administration of Compound 1 has been associated with diarrhea, nausea, vomiting, oral mucosal irritation, minimal to mild elevation of transaminases, and phototoxicity.

[0338] Risks associated with cetuximab. Adverse reactions to cetuximab include skin reactions in over 80% of patients, hypomagnesemia in over 10% of patients, mild to moderate symptoms in over 10% of patients, and an IRR of severe symptoms in over 1% of patients. Patients who have been bitten by ticks or have a red meat allergy may have an increased risk of serious infusion reactions when given cetuximab.

[0339] 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, as smokers have lower plasma concentrations of erlotinib compared to non-smokers. The degree of reduction may be clinically significant. Strong inducers of CYP3A4 may reduce the efficacy of erlotinib, while strong inhibitors of CYP3A4 may lead to increased toxicity. Erlotinib is a strong inhibitor of CYP1A1, a moderate inhibitor of CYP3A4 and CYP2C8, and a strong inhibitor of in vitro UGT1A1 glucuronidation. Please refer to Erlotinib SmPC for complete drug interaction information.

[0340] Treatment interruption. If the toxicity of Compound 1 persists for >21 days from the start of the previous study treatment, the study treatment should not be restarted. Compound 1 may be suspended for up to 21 days in the event of an unexpected medical complication unrelated to the toxicity of the study treatment or disease progression.

[0341] Adverse events. As defined herein, an adverse event refers to any unfortunate medical event in a clinical study subject who received the drug described herein in combination therapy, regardless of causal attribution. The terms “serious” and “critical” are not synonyms. Severity refers to the intensity of the adverse event (e.g., graded as mild, moderate, or severe, or according to NCICTCAE); the event itself may have relatively minor medical significance (such as severe headache without any further findings)

[0342] Adverse events to be monitored include nausea, vomiting, diarrhea, stomatitis, mucositis, hepatitis or elevated ALT or AST, elevated bilirubin or clinical jaundice, systemic lupus erythematosus, nephritis, events suggesting anaphylaxis, 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, Stephen Johnson syndrome, bullous dermatitis, and toxic epidermal necrolysis.

[0343] In this specification and claims, unless the context otherwise requires, the words “comprising,” “including,” and “containing” are used in a non-exclusive sense. It should be understood that the embodiments described herein include “consisting of the embodiments” and / or “substantially consisting of the embodiments.”

[0344] If a range of values ​​is provided, it should be understood that every intermediate value between the upper and lower limits of that range (to one-tenth of the unit of the lower limit, unless the context explicitly specifies otherwise), as well as any other specified value or intermediate value within the specified range, is included herein. The upper and lower limits of these smaller ranges may be independently included within that smaller range and are also included herein, based on any explicitly excluded limit value within the specified range. Where a specified range includes one or two limits, this document also includes ranges that exclude one or both of those included limits.

[0345] Many variations and other embodiments of the invention set forth herein will come to mind for those skilled in the art, taking advantage of the teachings presented in the foregoing description and the accompanying drawings. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed, and that variations and other embodiments are intended to be included within the scope of the appended claims. Although specific terminology is used herein, it is used only in a general and descriptive sense and not for limiting purposes.

Claims

1. A combination therapy comprising: (a) Compound 1 Or its medicinal salt; and (b) EGFR inhibitors.

2. The combination therapy according to claim 1, wherein compound 1 is its adipic acid salt.

3. The combination according to claim 1 or 2, wherein compound 1 or its pharmaceutical salt is administered on days 1 to 21 of the first 21-day cycle.

4. The combination therapy according to any one of claims 1 to 3, wherein compound 1 or its pharmaceutical salt is administered orally in tablet or capsule form.

5. The combination therapy according to any one of claims 1 to 4, wherein compound 1 or its pharmaceutical salt is administered in an amount of about 50 mg to 500 mg.

6. The combination therapy according to any one of claims 1 to 5, wherein compound 1 or its pharmaceutical salt is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg.

7. The combination therapy according to any one of claims 1 to 6, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib, or an anti-EGFR antibody.

8. The combination therapy according to any one of claims 1 to 7, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib.

9. The combination therapy according to any one of claims 1 to 8, wherein the EGFR inhibitor is erlotinib.

10. The combination therapy of claim 9, wherein erlotinib is administered on days 1 to 21 of the first 21-day cycle.

11. The combination therapy according to any one of claims 1 to 10, wherein the EGFR inhibitor is erlotinib administered in a dose of about 100 mg or 150 mg QD.

12. The combination therapy according to claim 11, wherein erlotinib is administered in a dose of about 100 mg QD.

13. The combination therapy according to claim 11, wherein erlotinib is administered in a dose of about 150 mg QD.

14. The combination therapy according to any one of claims 1 to 7, wherein the EGFR inhibitor is an anti-EGFR antibody comprising panitumumab or cetuximab.

15. The combination therapy according to any one of claims 1 to 7 or 14, wherein the EGFR inhibitor is cetuximab.

16. The combination therapy according to any one of claims 1 to 7 or 14 to 15, wherein the EGFR inhibitor is cetuximab administered Q1W starting from day 1 of the first 21-day cycle.

17. The combination therapy according to any one of claims 1 to 7 or 14 to 16, wherein the EGFR inhibitor is cetuximab administered on day 1 of the 21-day cycle at an amount of about 400 mg / m² and thereafter at an amount of about 250 mg / m² Q1W.

18. The combination therapy according to any one of claims 1 to 13, for treating KRas-containing... G12C Mutant lung cancer.

19. The combination therapy of claim 18, wherein the lung cancer is non-small cell lung cancer (NSCLC).

20. The combination therapy according to any one of claims 1 to 13, for treating KRas-containing... G12C Mutant pancreatic cancer.

21. The combination therapy according to any one of claims 1 to 7 or 14 to 17, for treating KRas-containing... G12C Mutant colorectal cancer (CRC).

22. A combination therapy comprising: (a) Compound 1 Or its medicinal salt, administered via QD on days 1 to 21 of the first 21-day cycle; (b) Erlotinib, administered on days 1 through 21 of the first 21-day cycle.

23. The combination therapy according to claim 22, wherein compound 1 or a pharmaceutical 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.

24. The combination therapy according to any one of claims 22 or 23, for treating KRas-containing... G12C Mutant lung cancer.

25. The combination therapy according to any one of claims 22 or 23, for treating KRas-containing... G12C Mutant pancreatic cancer.

26. A combination therapy comprising: (a) Compound 1 Or its medicinal salt, administered via QD on days 1 to 21 of the first 21-day cycle; (b) Cetuximab, administered on day 1 of the first 21-day cycle, Q1W.

27. The combination therapy according to claim 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 on day 1 of the 21-day cycle in an amount of about 400 mg / m² and thereafter in an amount of about 250 mg / m² Q1W.

28. A treatment for patients suffering from KRas G12C A method for treating this type of lung cancer in patients with mutation-mediated lung cancer, the method comprising administering an effective dose of a combination therapy, the combination therapy comprising: (a) Compound 1 ， Or its medicinal salt, administered via QD on days 1 to 21 of the first 21-day cycle; and (b) EGFR inhibitors.

29. The method of claim 28, wherein the lung cancer is NSCLC.

30. The method of claim 28, wherein the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer.

31. The method according to any one of claims 28 to 30, wherein the EGFR inhibitor is erlotinib, gefitinib, osimertinib, dacomitinib, or afatinib.

32. The method according to any one of claims 28 to 31, wherein the EGFR inhibitor is erlotinib.

33. The method according to any one of claims 28 to 32, wherein the EGFR inhibitor is erlotinib administered on days 1 to 21 of the first 21-day cycle.

34. The method according to any one of claims 28 to 33, wherein the EGFR inhibitor is erlotinib administered in a dose of about 150 mg QD.

35. A treatment for patients suffering from KRas G12C A method for treating such CRC in patients with mutation-mediated colorectal cancer (CRC), the method comprising administering an effective dose of a combination therapy, the combination therapy comprising: (a) Compound 1 ， Or its medicinal salt, administered via QD on days 1 to 21 of the first 21-day cycle; and (b) EGFR inhibitors.

36. The method of claim 35, wherein the EGFR inhibitor is an anti-EGFR antibody comprising panitumumab or cetuximab.

37. The method of claim 35 or 36, wherein the EGFR inhibitor is cetuximab.

38. The method according to any one of claims 35 to 37, wherein the EGFR inhibitor is cetuximab administered on day 1 of the 21-day cycle at an amount of about 400 mg / m² and thereafter at an amount of about 250 mg / m² Q1W.

39. A treatment for patients suffering from KRas G12C A method for treating such pancreatic cancer in patients with mutation-mediated pancreatic cancer, the method comprising administering an effective dose of a combination therapy, the combination therapy comprising: (a) Compound 1 ， Or its medicinal salt, administered via QD on days 1 to 21 of the first 21-day cycle; and (b) EGFR inhibitors.

40. The method of claim 39, wherein the EGFR inhibitor is erlotinib.

41. The method of claim 39 or 40, wherein the EGFR inhibitor is erlotinib administered on days 1 to 21 of the first 21-day cycle.

42. The method according to any one of claims 39 to 41, wherein the EGFR inhibitor is erlotinib administered in a dose of about 100 mg QD.

43. The method according to any one of claims 28 to 42, wherein compound 1 is its adipate.

44. The method according to any one of claims 28 to 43, wherein compound 1 or a pharmaceutical salt thereof is administered orally in tablet or capsule form.

45. The method according to any one of claims 28 to 44, wherein compound 1 or its pharmaceutical salt is administered in an amount of about 50 mg to 500 mg.

46. ​​The method according to any one of claims 28 to 45, wherein compound 1 or its pharmaceutical salt is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mg.

47. The method according to any one of claims 28 to 46, wherein the patient is diagnosed as not having a mutation selected from the group consisting of: sensitized EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, NTRK fusions and RET fusions, or combinations thereof.

48. Use of a combination therapy comprising compound 1 or a pharmaceutical salt thereof and an EGFR inhibitor for the treatment of lung cancer, CRC, or pancreatic cancer as described herein.

49. The use according to claim 48, wherein the cancer is lung cancer or pancreatic cancer, and the EGFR inhibitor is erlotinib, and further comprising a dosing regimen comprising: (i) Administer compound 1 or its pharmaceutical salt on days 1 through 21 of the first 21-day cycle; (ii) Administer erlotinib on days 1 through 21 of the first 21-day cycle.

50. The use according to claim 48, wherein the cancer is CRC, and the EGFR inhibitor is cetuximab, and further comprising a dosing regimen comprising: (i) Administer compound 1 or its pharmaceutical salt on days 1 through 21 of the first 21-day cycle; (ii) Administered on day 1 of the 21-day cycle at a dose of approximately 400 mg / m², and thereafter at a dose of approximately 250 mg / m² (Q1W).

51. Use of a combination therapy comprising compound 1 or a pharmaceutical salt thereof and an EGFR inhibitor in the manufacture of a medicament for the treatment of lung cancer, CRC, or pancreatic cancer.

52. The use according to claim 51, wherein the cancer is lung cancer or pancreatic cancer, and the EGFR inhibitor is erlotinib, and further comprising a dosing regimen comprising: (i) Administer compound 1 or its pharmaceutical salt on days 1 through 21 of the first 21-day cycle; (ii) Administer erlotinib on days 1 through 21 of the first 21-day cycle.

53. The use according to claim 51, wherein the cancer is CRC, and the EGFR inhibitor is cetuximab, and further comprising a dosing regimen comprising: (i) Administer compound 1 or its pharmaceutical salt on days 1 through 21 of the first 21-day cycle; (ii) Administered on day 1 of the 21-day cycle at a dose of approximately 400 mg / m², and thereafter at a dose of approximately 250 mg / m² (Q1W).

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