Methods and compositions comprising krasg12c inhibitor and EGFR inhibitor for treating solid tumors

Abstract

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

Description

Technical Field

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

[0002] Technical Field KRas G12C Combinations therapies comprising a KRas inhibitor (e.g., Compound 1) and an EGFR inhibitor, and methods of using such combination therapies are provided herein.

Background Art

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

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

[0005] Therefore, there is a need for effective therapies and combination therapies for treating cancers such as lung cancer, colorectal cancer, and pancreatic cancer with KRas G12C mutations.

Summary of the Invention

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

[0007] In one aspect, provided herein is a combination therapy comprising Compound 1 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 one embodiment, the EGFR inhibitor is erlotinib or cetuximab.

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

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

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

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

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

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

[0014] In another aspect, provided herein is the use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and an EGFR inhibitor for the manufacture of a medicament for the treatment of lung cancer, CRC or pancreatic cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0015]

Figure 1

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DETAILED DESCRIPTION OF THE INVENTION

[0023] Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For example, see Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). In the practice of this invention, any method, apparatus, and material similar or equivalent to those described herein can be used.

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

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

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

[0027] “Compound 1” has the structure: TIFF2025093924000002.tif49170 and has the chemical name 1 - ((S)-4 - ((R)-7-(6 - amino - 4 - methyl - 3-(trifluoromethyl)pyridin - 2 - yl)-6 - chloro - 8 - fluoro - 2 - (((S)-1 - methylpyrrolidin - 2 - yl)methoxy)quinazolin - 4 - yl)-3 - methylpiperazin - 1 - yl)prop - 2 - en - 1 - one. In one embodiment, Compound 1 is the adipate salt.

[0028] “Erlotinib” has the structure: TIFF2025093924000003.tif29170 and has the chemical name: N-(3 - ethynylphenyl)-6,7 - bis(2 - methoxyethoxy)-4 - quinazolinamine. In one embodiment, erlotinib is commercially available under the trade name TARCEVA®.

[0029] "Gefitinib" has the structure: TIFF2025093924000004.tif30170 and has the chemical name: 4 - quinazolinamine N-(3 - chloro - 4 - fluorophenyl)-7 - methoxy - 6 - [3-(4 - morpholinyl)propoxy]. In one embodiment, gefitinib is commercially available under the trade name IRESSA®.

[0030] "Osimertinib" has the structure: TIFF2025093924000005.tif37170 and 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 mesylate salt. In one embodiment, osimertinib is commercially available under the trade name TAGRISSO®.

[0031] "Afatinib" has the structure: TIFF2025093924000006.tif45170 and has the chemical name: 2 - butenamide, N - [4 - [(3 - 4 - fluorophenyl)amino]-7 - [[(3S)-tetrahydro - 3 - furanyl]oxy]-6 - quinazolinyl]-4-(dimethylamino)-,(2E)-,(2Z)-2 - butenedioate(1:2). In one embodiment, afatinib is commercially available under the trade name GILOTRIF®.

[0032] "Dacomitinib" has the structure: TIFF2025093924000007.tif34170 and has the chemical name: (2E)-N-{4 - [(3 - chloro - 4 - fluorophenyl)amino]-7 - methoxyquinazolin - 6 - yl}-4-(piperidin - 1 - yl)but - 2 - enamide monohydrate. In one embodiment, dacomitinib is commercially available under the trade name VIZIMPRO®.

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

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

[0035] Examples of "pharmaceutically acceptable basic addition salts" include salts derived from inorganic bases such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Specific basic addition salts are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples of salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines including basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Specific organic non-toxic bases 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, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, phthalate (e.g., 2-phthalate or 3-phthalate), napadisylate (naphthalene-1,5-disulfonate, or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate, or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, edisylate, malonate, mesitylate (2-mesitylenesulfonate), naphthylate (2-naphthalenesulfonate), camsylate (camphor 10-sulfonate, e.g., (1S)-(+)-10-camphor-sulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0037] The terms "inhibit" and "reduce / decrease," or any variations of these terms, include any measurable reduction / decrease or complete inhibition to achieve the desired result. For example, about, up to 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 a decrease of any of these range variables, a decrease in activity compared to normal may exist.

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

[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 certain embodiments, the antibody has a sufficiently high binding affinity for EGFR; for example, the antibody can bind to hEGFR at a K d value of 100 nM to 1 pM. Antibody affinity can be determined, for example, by surface plasmon resonance-based assays (such as BIAcore® assays as described in PCT Publication No. WO2005 / 012359), enzyme-linked immunosorbent assays (ELISA), and competitive assays (such as radioimmunoassays (RIA)).

[0040] In certain embodiments, an EGFR inhibitor (e.g., a compound described herein, or an anti-EGFR antibody described herein) can be used as a therapeutic agent in targeting and interfering with a disease or condition in which EGFR activity is involved. Also, an EGFR inhibitor can be subjected to other biological activity assays, for example, to evaluate its effectiveness as a therapeutic agent. Such assays are known in the art and, in the case of anti-EGFR antibodies, depend on the target antigen and the intended use of the antibody. In one embodiment, the anti-EGFR antibody is a monoclonal antibody. In another embodiment, the anti-EGFR antibody is a recombinant humanized anti-EGFR monoclonal antibody.

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

[0042] As used herein, "panitumumab" refers to a human IgG2 kappa monoclonal antibody having an approximate molecular weight of 147 kDa, produced in genetically engineered mammalian (Chinese hamster ovary) cells. Panitumumab specifically binds to EGFR on both normal and tumor cells and competitively inhibits the binding of ligands to EGFR. In one embodiment, panitumumab is commercially available under the trade name VECTIBIX (registered trademark).

[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, the cancer is lung cancer. In another embodiment, the cancer is NSCLC. In another embodiment, the cancer is colorectal cancer (e.g., metastatic CRC). In another embodiment, the cancer is pancreatic cancer. As used herein, "cancer" refers to cancer characterized by having a G12C KRas mutation.

[0044] As used herein, "treating" includes treatment with an effective amount of a therapeutic agent (e.g., an EGFR inhibitor or Compound 1) or a combination of therapeutic agents (e.g., an EGFR inhibitor and Compound 1). In one embodiment, treating refers to treatment with an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and erlotinib. In one embodiment, treating refers to treatment with an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, and cetuximab. Treatment can be first-line treatment (e.g., the patient may not have been previously treated or has not received prior systemic therapy) or second-line treatment or subsequent treatment. For example, "treatment" is successful when one or more symptoms associated with the cancer described herein, including but not limited to, reduction (or destruction) of cancerous cell growth, alleviation of symptoms due to the disease, improvement in the quality of life of those suffering from the disease, reduction in the dosage of other drug therapies required for treatment of the disease, and / or prolongation of the patient's survival period, are alleviated or eliminated.

[0045] The term "delaying the progression" of a disease refers to delaying, preventing, retarding, slowing, stabilizing, and / or postponing the onset of the cancer described herein. This delay can be of various durations depending on the cancer being treated herein and / or the patient's medical history. As will be apparent to those skilled in the art, a sufficient or significant delay can effectively encompass prevention in the sense that the patient does not develop cancer.

[0046] As used herein, "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 result. In some examples, the effective amount of a therapeutic agent or combination of therapeutic agents is the amount of the agent or combination of agents that achieves a clinical endpoint provided herein. In one embodiment, the effective amount refers to the amount of Compound 1 or a pharmaceutically acceptable salt thereof and the amount of erlotinib. In one embodiment, the effective amount refers to the amount of Compound 1 or a pharmaceutically acceptable salt thereof and the amount of cetuximab. The effective amount herein may vary depending on factors such as the patient's disease state, age, gender, and weight, as well as the ability of the agent to elicit the desired response in the patient. The effective amount is also one in which the therapeutically beneficial effect exceeds any toxic or detrimental effect of the treatment. In some embodiments, the effective amount of the drug reduces the number of cancer cells, reduces tumor size, inhibits (i.e., delays or stops) the invasion of cancer cells into peripheral organs, inhibits (i.e., delays or stops) tumor metastasis, inhibits (i.e., delays or stops) tumor growth, and / or has the effect of reducing one or more of the symptoms associated with the disease. The effective amount can be administered in one or more administrations. The effective amount of a drug, compound, pharmaceutical composition, or combination therapy described herein can be an amount sufficient to directly or indirectly achieve a therapeutic treatment.

[0047] "Objective response rate" or "ORR" refers to the proportion of patients in whom a complete response or partial response has been confirmed at two consecutive opportunities separated by ≧ 4 weeks, as determined by the investigator in charge of the clinical trial in accordance with RECIST v1.1.

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

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

[0050] As used herein, "complete response" and "CR" refer to the disappearance of all target lesions and, where applicable, normalization of tumor marker levels.

[0051] As used herein, "partial response" and "PR" refer to the persistence of one or more non-target lesions and / or, where applicable, maintenance above the normal limits of tumor marker levels. PR may also refer to a ≧30% decrease in the sum of the diameters of target lesions in the absence of CR, new lesions, and clear progression in non-target lesions.

[0052] "Treatment period" or "cycle" refers to a period that includes administration of one or more agents described herein (e.g., Compound 1 and an EGFR inhibitor), and any period that does not include administration of one or more agents described herein. For example, a cycle can be a total of 21 days and include administration of one or more agents described herein (e.g., Compound 1 and an EGFR inhibitor) on each day of the cycle. In another example, a cycle can be a total of 28 days and include administration of one or more agents described herein (e.g., Compound 1 and an EGFR inhibitor) over a 21-day period and a 7-day drug-free period. "Drug-free period" refers to a period during which at least one of the agents described herein (i.e., Compound 1 and an EGFR inhibitor) is not administered. In one embodiment, the drug-free period refers to a period during which none of the agents described herein (i.e., Compound 1 and an EGFR inhibitor) are administered. The drug-free periods provided herein can optionally include administration of another agent that is not Compound 1 or an EGFR inhibitor. In such cases, administration of another agent during the drug-free period should not interfere with or be detrimental to the administration of the agents described herein. In one example, a cycle as used herein refers to a 21-day cycle without a drug-free period.

[0053] "Dosing regimen" refers to the period of administration of the agents described herein, including one or more cycles, where each cycle can include administration of the agents described herein at different times or in different amounts.

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

[0055] "BID" refers to administering the agent described herein twice daily.

[0056] "Q1W" refers to administering the agent described herein once weekly.

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

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

[0059] Grading of adverse events refers to the severity grading scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table. TIFF2025093924000008.tif56170

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

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

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

[0063] Depending on the amino acid sequence of the constant domains of those heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, γ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known and are generally described, e.g., in Abbas et al. Cellular and Mol. Immunology, 4th ed. (W.B. Saunders, Co., 2000). An antibody can be part of a larger fusion molecule formed by a 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 herein to refer to an antibody in its substantially intact form that is not an antibody fragment as described below. This term refers to an antibody that includes the Fc region.

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

[0066] "Naked antibody" refers to an antibody that is not bound to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabel. A naked antibody may be present in a pharmaceutical composition.

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

[0068] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a collection of substantially homogeneous antibodies, i.e., the individual antibodies that make up the collection are identical and / or bind the same epitope, except for possible variant antibodies that may be present in minor amounts, including, for example, naturally occurring mutations or mutations arising during the production of a monoclonal antibody preparation. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous collection of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be made by a variety of techniques including, but not limited to, the hybridoma method, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals that include all or part of the human immunoglobulin loci.

[0069] As used herein, the terms "hypervariable region" or "HVR" refer to each region of an antibody variable domain that is hypervariable in sequence and that determines antigen-binding specificity, e.g., each of the "complementarity determining regions" (CDRs).

[0070] Generally, an antibody contains six CDRs, three in VH (CDR-H1, CDR-H2, CDR-H3) and three in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include the following: (a) Hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987); (b) CDRs present 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 contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)).

[0071] Unless otherwise specified, CDRs are determined according to Kabat et al. above. Those skilled in the art will understand that CDR designations can be determined according to the above Chothia, the above MacCallum, or any other scientifically approved nomenclature system.

[0072] "Framework" or "FR" refers to variable domain residues other than complementarity determining regions (CDRs). The FRs of a variable domain generally consist of four FR domains: FR1, FR2, FR3, and FR4. Thus, CDR and FR sequences generally occur in the following order in VH (or VL): FR1-CDR-H1 (CDR-L1)-FR2-CDR-H2 (CDR-L2)-FR3-CDR-H3 (CDR-L3)-FR4.

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

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

[0075] The term "package insert" is used to refer to the instructions customarily included in the commercial package of a therapeutic product that contain information regarding indications, usage, dosage, administration, combination therapy, contraindications and / or warnings regarding the use of such therapeutic product.

[0076] As used herein, "in combination with" refers to administering one mode of treatment in addition to a treatment regimen that includes the administration of another mode of treatment, e.g., an EGFR inhibitor (e.g., erlotinib or cetuximab) and Compound 1 or a pharmaceutically acceptable salt thereof as described herein. Thus, "in combination with" refers to the administration of one mode of treatment before, during, or after the administration of another mode of treatment to a patient.

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

[0078] A combination therapy (composition) is provided herein that comprises Compound 1 or a pharmaceutically acceptable salt thereof (e.g., Compound 1 adipate) and an EGFR inhibitor described herein. In one embodiment, a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate of Compound 1) and gefitinib is provided herein. In another embodiment, a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate of Compound 1) and osimertinib is provided herein. In another embodiment, a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate of Compound 1) and dacomitinib is provided herein. In yet another embodiment, a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate of Compound 1) and afatinib is provided herein. In yet another embodiment, a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate of Compound 1) and panitumumab is provided herein. In a preferred embodiment, a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate of Compound 1) and erlotinib or cetuximab is provided herein. In another preferred embodiment, the combination therapy comprises erlotinib. In another such embodiment, the combination therapy comprises cetuximab.

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

[0080] Further provided herein is 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 such an embodiment, the anti-EGFR antibody is cetuximab.

[0081] In one aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof (e.g., Compound 1 adipate) and an EGFR inhibitor (e.g., erlotinib or cetuximab). In one embodiment, the combination therapy described herein is useful for the treatment of certain solid tumors comprising a KRas G12C mutation. In such an embodiment, the combination therapy is useful for the treatment of certain solid tumors comprising a KRas G12C mutation, where the EGFR inhibitor is not approved for administration in such tumors.

[0082] In one embodiment, the combination therapy described herein is useful for the treatment of certain types of lung cancer described herein comprising a KRas G12C mutation. In such an embodiment, the lung cancer is non-small cell lung cancer (NSCLC) comprising a KRas G12C mutation.

[0083] In another embodiment, the combination therapy described herein is useful for the treatment of colorectal cancer comprising a KRas G12C mutation. In such an embodiment, the combination therapy described herein that is useful for the treatment of colorectal cancer comprising a KRas G12C mutation 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 comprises FOLFIRI (i.e., administration of leucovorin, fluorouracil, and irinotecan). In another such embodiment, the additional agent comprises FOLFOX (i.e., administration of leucovorin, fluorouracil, and oxaliplatin).

[0084] In another embodiment, the combination therapy described herein is useful for the treatment of pancreatic cancer comprising a KRas G12C mutation. In such an embodiment, the combination therapy described herein that is useful for the treatment of pancreatic cancer comprising a KRas G12C mutation is administered in combination with one or more additional agents. In such an embodiment, the additional agent comprises gemcitabine.

[0085] In one aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof administered QD on days 1 to 21 of a first 21-day cycle and an EGFR inhibitor (e.g., erlotinib or cetuximab). In such embodiments, the combination therapy is useful for the treatment of solid tumors (e.g., lung cancer, colorectal cancer, pancreatic cancer) comprising the KRas G12C mutation described herein.

[0086] In one aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof administered QD on days 1 to 21 of a first 21-day cycle and erlotinib administered QD on days 1 to 21 of the first cycle.

[0087] In another aspect, provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof administered QD on days 1 to 21 of a first 21-day cycle and cetuximab administered Q1W starting on day 1 of the first 21-day cycle.

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

[0089] In one embodiment of the combination therapy described herein, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount 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 to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 150 mg, or 50 mg to 100 mg. In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount 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 a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In such an embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 300 - 600 mg. In another such embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg. In a preferred embodiment, Compound 1 of the combination therapy described herein is administered as the adipate salt. In such an embodiment, the amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered as the amount relative to the free base form.

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

[0091] In one embodiment, the combination therapy described herein includes erlotinib, and erlotinib is administered in an amount 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 in an amount of 150 mg QD. In another embodiment, erlotinib is administered as a component of the combination therapy described herein in an amount of 100 mg QD. In such embodiments, erlotinib can be administered in combination with Compound 1 or a pharmaceutically acceptable salt thereof in a dosing regimen that includes administration of each agent QD in a 21-day cycle. In such one embodiment, erlotinib is administered with water between doses simultaneously with Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, the amount of erlotinib administered in the combination therapy described herein can be reduced. In one embodiment, the amount of erlotinib is reduced in increments of 25 mg or 50 mg.

[0093] In another embodiment, the combination therapy described herein includes cetuximab, and cetuximab is administered in an amount of about 200 - 400 mg / m 2 In one embodiment, cetuximab is administered as a first dose / initial dose in an amount of about 400 mg / m 2 In another embodiment, cetuximab is administered in an amount of about 250 mg / m 2 In such one embodiment, cetuximab is administered in an amount of about 400 mg / m 2 on day 1 of the first 21-day cycle and 250 mg / m 2 Q1W for the first 21-day cycle.

[0094] Also provided herein is a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and gefitinib, and gefitinib is administered in an amount of 250 mg QD for each 21-day cycle.

[0095] A combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and osimertinib is further provided herein, and osimertinib is administered in an amount of 80 mg QD for each 21-day cycle.

[0096] A combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and dacomitinib is further provided herein, and dacomitinib is administered in an amount of 45 mg QD for each 21-day cycle.

[0097] A combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and afatinib is still further provided herein, and afatinib is administered in an amount of 40 mg QD for each 21-day cycle.

[0098] A combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and panitumumab is still further provided herein, and panitumumab is administered in an amount of 6 mg / kg Q2W for each 21-day cycle.

[0099] In a preferred embodiment, the combination therapy described herein comprises Compound 1 or a pharmaceutically acceptable salt thereof described herein administered QD and erlotinib, and erlotinib is administered to a patient at a dose of about 150 mg QD. In another preferred embodiment, the combination therapy described herein comprises Compound 1 or a pharmaceutically acceptable salt thereof described herein administered QD and cetuximab, and cetuximab is about 400 mg / m on day 1 of the first 21-day cycle 2 in an amount of, 250 mg / m on day 1 of the first 21-day cycle 2 administered Q1W.

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

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

[0102] In yet another embodiment, KRas G12CA combination therapy useful for the treatment of lung cancer containing a mutation, said combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (for example, the adipate salt of compound 1), wherein compound 1 is administered QD in an amount of about 50 mg to 500 mg per day from day 1 to day 21 of the first 21-day cycle, and erlotinib is administered QD in an amount of about 150 mg per day from day 1 to day 21 of the first 21-day cycle. In a preferred embodiment, the lung cancer is NSCLC. In one embodiment, erlotinib is administered in accordance with the package insert.

[0103] In yet another embodiment, KRas G12C The combination therapy described herein useful for the treatment of CRC containing a mutation. In a particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (for example, the adipate salt of compound 1) and an anti-EGFR antibody selected from cetuximab or panitumumab, and the combination therapy is for treating CRC containing the KRas G12C mutation described herein. In a preferred embodiment, it is a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (for example, the adipate salt of compound 1) and cetuximab, and the combination therapy is for treating CRC containing the KRas G12C mutation described herein. In such an embodiment, the CRC is metastatic CRC (mCRC). In one embodiment, the combination therapy is for the first-line treatment of CRC containing the KRas G12C mutation. In another embodiment, the combination therapy is for the second-line treatment of CRC containing the KRas G12C mutation. In such an embodiment, the patient has a disease that has previously progressed and was previously treated with a KRas G12C inhibitor.

[0104] In an embodiment where the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (for example, the adipate salt of compound 1) and cetuximab and is useful for treating CRC containing the KRas G12C mutation, the patient described herein may be administered the FOLFIRI regimen or irinotecan.

[0105] The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (for example, the adipate salt of compound 1) and an anti-EGFR antibody (for example, panitumumab), and in such embodiments useful for treating CRC containing a KRas G12C mutation, a FOLFOX regimen may be administered to the patients described herein.

[0106] In another embodiment, it is a combination therapy useful for treating CRC containing a KRas G12C mutation. The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (for example, the adipate salt of compound 1). Compound 1 is administered QD from day 1 to day 21 of the first 21-day cycle, and cetuximab is administered at about 400 mg / m 2 in an amount of 250 mg / m on day 1 of the first 21-day cycle 2 and administered Q1W. In a preferred embodiment, the CRC is metastatic CRC (mCRC).

[0107] In another embodiment, it is a combination therapy useful for treating CRC containing a KRas G12C mutation. The combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (for example, the adipate salt of compound 1). Compound 1 is administered QD in an amount of about 50 mg to 500 mg from day 1 to day 21 of the first 21-day cycle, and cetuximab is administered at about 400 mg / m 2 in an amount of 250 mg / m on day 1 of the first 21-day cycle 2 and administered Q1W. In a preferred embodiment, the CRC is metastatic CRC (mCRC). In one embodiment, cetuximab is administered according to the package insert.

[0108] In one embodiment, the combination therapy described herein is used for treating pancreatic cancer containing a KRas G12C mutation. In a specific embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (for example, the adipate salt of compound 1) and erlotinib, and the combination therapy is the KRas described hereinG12C It is for treating pancreatic cancer with mutations.

[0109] In such an embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., the adipate salt of compound 1), and compound 1 is administered QD from day 1 to day 21 of the first 21-day cycle, and erlotinib is administered QD from day 1 to day 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., the adipate salt of compound 1), and compound 1 is administered QD in an amount of about 50 mg to 500 mg from day 1 to day 21 of the first 21-day cycle, and erlotinib is administered QD in an amount of 100 mg or 150 mg from day 1 to day 21 of the first 21-day cycle. In such an embodiment, erlotinib is administered in an amount of about 150 mg QD as described herein. In another such embodiment, erlotinib is administered in an amount of about 100 mg QD as described herein. In one embodiment, erlotinib is administered according to the accompanying document. Treatment method

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

[0112] In one embodiment, KRas G12C A method of treating such lung cancer in a patient having lung cancer comprising a mutation, 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., the adipate salt of compound 1) and an EGFR inhibitor compound selected from the group consisting of erlotinib, gefitinib, osimertinib, dacomitinib or afatinib. In one embodiment, KRas G12C A method of treating such lung cancer in a patient having lung cancer mediated by a mutation, 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 adipate salt) and erlotinib.

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

[0114] Also, KRas G12CA method of treating such cancer in a patient having NSCLC comprising a mutation, the method comprising administering to the patient an effective amount of a combination therapy described herein, the combination therapy comprising a dosing regimen that includes: (i) administering QD from day 1 to day 21 of a first 21-day cycle an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof; and (ii) administering QD from day 1 to day 21 of the first 21-day cycle an effective amount of erlotinib. In one embodiment of the method provided herein, the method is for treating adenocarcinoma. In one embodiment of the method provided herein, the method includes two or more cycles. In such an embodiment, the method is for treating first-choice NSCLC.

[0115] Also, in a patient having NSCLC with a KRas G12C A method of treating such cancer in a patient having NSCLC comprising a mutation, the method comprising administering to the patient an effective amount of a combination therapy described herein, the combination therapy comprising a dosing regimen that includes: (i) administering QD from day 1 to day 21 of a first 21-day cycle 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof; and (ii) administering QD from day 1 to day 21 of the first 21-day cycle about 150 mg / kg of erlotinib.

[0116] In another aspect, a method of treating CRC having a KRas G12C mutation in a patient having CRC, 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 adipate) and an anti-EGFR antibody described herein (e.g., panitumumab or cetuximab). In another embodiment of the above method, a method of treating CRC having a KRas G12C mutation in a patient having CRC, 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 adipate) and cetuximab.

[0117] Also, in a KRas G12CA method of treating such cancer in a patient having CRC with a mutation, comprising administering a QD dose of 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 cetuximab Q1W starting on day 1 of the first 21-day cycle, the method comprising administering to the patient an effective amount of the combination therapy described herein, including a dosing regimen. In one such embodiment, 250 or 400 mg / m described herein 2 In one embodiment of the method provided herein, the method includes more than one cycle.

[0118] Also, KRas G12C A method of treating such cancer in a patient having CRC with a mutation, comprising (i) administering 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD on days 1 to 21 of a first 21-day cycle, and (ii) administering cetuximab at about 400 mg / m 2 on day 1 of the first 21-day cycle, followed by administering cetuximab at about 250 mg / m 2 Q1W, the method comprising administering an effective amount of the combination therapy described herein, including a dosing regimen.

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

[0120] Also, KRas G12C A method of treating pancreatic cancer in a patient having pancreatic cancer with a KRas mutation, 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 adipate) described herein and erlotinib.

[0121] In another embodiment, KRas G12CA method of treating pancreatic cancer comprising a mutation in a patient, the method comprising administering to the patient an effective amount of a combination therapy described herein, the dosing regimen comprising: (i) administering a QD dose of 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 a QD dose of an effective amount of erlotinib on days 1 to 21 of the first 21-day cycle. In one such embodiment, erlotinib is administered in an amount of about 100 mg or 150 mg as described herein. In one embodiment, erlotinib is administered in an amount of 100 mg. In another such embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg as described herein.

[0122] In one embodiment of the method described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount 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 to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 150 mg, or 50 mg to 100 mg. In another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount 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 a pharmaceutically acceptable salt thereof is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg. In such an embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 300 - 600 mg. In another such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 400 mg. In a preferred embodiment, compound 1 of the combination therapy described herein is administered as the adipate salt. In such an embodiment, the amount of compound 1 or a pharmaceutically acceptable salt thereof is administered as the amount relative to the free base form.

[0123] The methods provided herein may include administration of the combination therapies described herein as part of a dosing regimen. In such an embodiment, the dosing regimen includes one or more cycles. In another embodiment, the dosing regimen includes at least two cycles. In another embodiment, the dosing regimen includes two to three cycles. In another aspect, the dosing regimens provided herein include two, three, four, five, six, eight, ten, twelve, sixteen, eighteen, twenty, twenty-four, thirty, thirty-six, forty-two, forty-eight, fifty-four, sixty, sixty-six, or seventy-two cycles. In yet another embodiment, the dosing regimen includes from about two to seventy-two, two to sixty-six, two to sixty, two to fifty-four, two to forty-eight, two to forty-two, two to thirty-six, two to thirty, two to twenty-four, two to eighteen, two to twelve, or two to six cycles. In one embodiment, the dosing regimen includes administration of any number of cycles of the combination therapies described herein until a desired response (e.g., PFS, OS, ORR, and / or DOR) reaches a desired outcome (e.g., an increase in PFS, OS, ORR, and / or DOR as compared to a control described herein). In another embodiment, the dosing regimen includes administration of any number of cycles of the combination therapies described herein until toxicity develops or the patient experiences one or more adverse events (AEs) that otherwise prevent further administration. In yet another embodiment, the dosing regimen includes administration of any number of cycles of the combination therapies described herein until disease progression.

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

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

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

[0127] KRas G12CAlso provided herein is a method of treating such cancer in a patient having lung cancer comprising a mutation, the method comprising administering to the patient a treatment regimen comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate) 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 method, Compound 1 is adipate and the EGFR inhibitor compound is erlotinib. In another embodiment of such method, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD as described herein and in an amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such method, erlotinib is administered QD as described herein and in an amount as described herein (e.g., 150 mg). In such method, Compound 1 or a pharmaceutically acceptable salt thereof and the EGFR inhibitor may be administered as described herein. In such method, the lung cancer may be NSCLC G12C comprising a KRas

[0128] mutation. G12C Also provided herein is a method of treating such cancer in a patient having CRC comprising a KRas mutation, the method comprising administering to the patient a treatment regimen comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate) and an anti-EGFR antibody as described herein (e.g., cetuximab). In one embodiment of such method, Compound 1 is adipate and the anti-EGFR antibody as described herein is cetuximab. In another embodiment of such method, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD as described herein and in an amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such method, cetuximab is administered at a dose of about 400 mg / m 2 on day 1 of the first 21-day cycle, followed by about 250 mg / m 2It is administered with cetuximab Q1W. In such a method, compound 1 or a pharmaceutically acceptable salt thereof and cetuximab can be administered as described herein.

[0129] In another embodiment, KRas G12C A method of treating such cancer in a patient having CRC with a KRas 2 mutation, the method comprising (i) administering about 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate) QD on days 1 to 21 during a first 21-day cycle, and (ii) administering about 400 mg / m 2 of cetuximab on day 1 of the first 21-day cycle, followed by administering about 250 mg / m 2 of cetuximab Q1W, comprising administering a treatment regimen to the patient.

[0130] KRas G12C Also provided herein is a method of treating such cancer in a patient having pancreatic cancer with a KRas G12C mutation, the method comprising administering to the patient a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate), and an EGFR inhibitor (e.g., erlotinib) as described herein. In one embodiment of such a method, compound 1 is adipate and the EGFR inhibitor compound 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 the amounts described herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, erlotinib is administered QD as described herein in an amount of about 100 mg or 150 mg. In such a method, compound 1 or a pharmaceutically acceptable salt thereof and erlotinib can be administered as described herein.

[0131] In another embodiment, KRas G12CA method of treating pancreatic cancer, including such cancer, in a patient having a mutation, the method comprising administering to the patient QD from day 1 to day 21 during a first 21-day cycle: (i) about 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipate), and (ii) administering to the patient QD from day 1 to day 21 during the first 21-day cycle 100 mg or 150 mg of erlotinib, comprising administering to the patient a treatment regimen.

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

[0133] The patients provided herein must be evaluated and must have confirmed test results for the KRas G12C mutations described herein. In one embodiment, the patients described herein have confirmed test results for KRas G12C mutations for CRC. In such an embodiment, the patient has been treated with one or more prior therapies. A patient diagnosed with NSCLC and having confirmed test results for KRas G12C mutations described herein should not have a known accompanying second oncogenic driver (e.g., in the case of NSCLC: sensitive EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, NTRK fusions, RET fusions; or in the case of adenocarcinoma of the colon or rectum: BRAF V600E mutations, ERBB2 amplifications). In such an embodiment, the patient has been treated with one or more prior therapies. In one embodiment, such a second oncogenic driver is determined using NGS (e.g., NGS assay by Foundation Medicine, Inc. (FMI)).

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

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

[0136] In one embodiment, a patient described herein has G12C received prior treatment with a specific inhibitor of KRas.

[0137] In another embodiment, a patient described herein has not received chemotherapy, immunotherapy, or biologic therapy as an anticancer therapy within 3 weeks prior to administration of the combination therapy described herein, or endocrine therapy within 2 weeks prior to administration of the combination therapy described herein, except for: (a) Hormonal therapy with a gonadotropin-releasing hormone (GnRH) agonist or antagonist for an endocrine-sensitive cancer (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (b) A kinase inhibitor approved by a regulatory authority may be used up to 2 weeks prior to administration of the combination therapy described herein if any drug-related toxicity has completely resolved; or (c) Treatment with an investigational drug within 3 weeks or 5 half-lives (whichever is shorter) prior to administration of the combination therapy described herein.

[0138] In another embodiment, the patient described herein has not received radiation therapy (other than palliative radiation for bone metastases and radiation for CNS metastases as described above) as a cancer therapy within 4 weeks prior to the start of administration of the combination therapy described herein. In yet another embodiment, the patient described herein has not received palliative radiation for bone metastases within 2 weeks prior to the administration of 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 pneumonitis, or idiopathic interstitial pneumonia, or evidence of active interstitial pneumonia on screening chest computed tomography (CT) scan.

[0140] The present specification 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, for the treatment of lung cancer described herein. In one embodiment, the present specification provides the use (UL2) of the combination therapy described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, for the treatment of lung cancer described herein. In such an embodiment, the lung cancer is NSCLC.

[0141] Furthermore, the present specification provides the use (UL3) of the combination therapy described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, for treating lung cancer described herein, the use comprising a dosing regimen comprising: (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of a first 21-day cycle; and (ii) administering erlotinib QD from day 1 to day 21 of the first 21-day cycle. In such an embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 - 500 mg. In another such embodiment, erlotinib is administered in an amount of about 150 mg.

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

[0143] Further provided herein is the use (UL5) 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 for the manufacture of a medicament for treating lung cancer described herein. In such an embodiment, the EGFR inhibitor is erlotinib.

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

[0145] Furthermore, provided herein is the use (UL7) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, for manufacturing a medicament for treating lung cancer as described herein, the use comprising a dosing regimen including: (i) administering about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle; and (ii) administering about 150 mg of erlotinib QD from day 1 to day 21 of the first 21-day cycle. In such an embodiment, the dosing regimen includes two or more cycles as described herein.

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

[0147] Further provided herein is the use (UC1) 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 treating CRC as described herein. In one embodiment, it is the use (UC2) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab, for treating CRC as described herein. In such an embodiment, the CRC is mCRC.

[0148] Furthermore, provided herein is the use (UC3) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and cetuximab, for treating CRC as described herein, the use comprising: (i) administering compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle; and (ii) administering about 400 mg / m on day 1 of a 21-day cycle 2Administration of cetuximab, and a dosing regimen comprising the same are provided herein. In such an 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 at about 400 mg / m 2 on Day 1 of the first 21-day cycle, followed by cetuximab at about 250 mg / m 2 administered Q1W.

[0149] Furthermore, provided herein is the use (UC4) of the combination therapy described herein for the treatment of lung cancer, comprising Compound 1 or a pharmaceutically acceptable salt thereof and cetuximab, wherein (i) about 50 to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered QD from Day 1 to Day 21 of the first 21-day cycle, and (ii) about 400 mg / m 2 of cetuximab is administered on Day 1 of the first 21-day cycle, followed by about 250 mg / m 2 of cetuximab administered Q1W. A dosing regimen comprising the same is provided herein.

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

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

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

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

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

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

[0156] Furthermore, provided herein is the use (UP3) of the combination therapy described herein comprising Compound 1 or a pharmaceutically acceptable salt thereof for treating pancreatic cancer described herein and erlotinib, the dosing regimen comprising: (i) administering about 50-500 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle; and (ii) administering about 100 mg of erlotinib QD from day 1 to day 21 of the first 21-day cycle. In such an embodiment, the dosing regimen comprises more than 2 cycles as described herein.

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

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

[0159] Further provided herein is the use (UP6) of the combination therapy described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and erlotinib, for manufacturing a medicament for treating pancreatic cancer, the use comprising a dosing regimen including: (i) administering about 50 to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle; and (ii) administering about 100 mg of erlotinib QD from day 1 to day 21 of the first 21-day cycle. In such an embodiment, the dosing regimen includes two or more cycles as described herein.

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

[0161] When an adverse event occurs, it is generally understood that there are the following four options: (1) continue treatment as is using any adjunctive therapy; (2) adjust the dosage of one or more drugs in the dosing regimen; (3) temporarily interrupt the administration of one or more drugs in the dosing regimen; or (4) discontinue the administration of one or more drugs 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, when the administration of erlotinib or cetuximab is interrupted, the next administration of Compound 1 or a pharmaceutically acceptable salt thereof is carried out on the same day that the administration of erlotinib or cetuximab is resumed. In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered without food (i.e., the patient must not eat for at least 2 hours before and 1 hour after administration). In such an embodiment, the administration of cetuximab is at least 20, 30, 45, or 60 minutes after the administration of Compound 1 or a pharmaceutically acceptable salt thereof. In another such embodiment, the administration of erlotinib is after the administration of Compound 1 or a pharmaceutically acceptable salt thereof.

[0162] In one embodiment, the patients described herein who are administered a combination therapy comprising cetuximab experience skin reactions, hypomagnesemia, or IRR. In another embodiment, the patients described herein who are administered a combination therapy comprising erlotinib experience skin toxicity, interstitial lung disease (ILD), liver injury, gastrointestinal (GI) fluid loss, GI perforation, or ocular toxicity.

[0163] In one embodiment, the patients described herein experience gastrointestinal toxicity as a grade 2 or lower AE. In such an embodiment, the gastrointestinal toxicity is diarrhea, nausea, or vomiting. In another embodiment, the patients described herein experience phototoxicity. In such an embodiment, the patient should wear sunscreen and protective clothing outdoors.

[0164] Patients described in this specification may also be administered concomitant therapies including the following: (a) antispasmodics or warfarin; (b) oral contraceptives or other possible maintenance therapies; (c) antiemetics and antidiarrheals, provided that such pharmacotherapy should not be prophylactically administered prior to the first treatment with the investigational drug; (d) analgesics administered according to standard clinical practice; (e) bisphosphonate and denosumab therapies for bone metastases or osteopenia / osteoporosis; or (f) multivitamins, calcium, and vitamin C, D, and E supplements.

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

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

[0167] In another embodiment, patients described in this specification are not administered any of the following therapies: (a) Either 3 weeks before administration of the combination therapy described herein or the shorter of 5 half-lives, whichever is shorter, or any other investigational therapy during such treatment (excluding Compound 1, or erlotinib or cetuximab); (b) Concomitant therapies intended for the treatment of cancer, whether FDA-approved or experimental, including chemotherapy, radiation therapy, immunotherapy, biological therapy, herbal therapy, or hormonal therapy, except for: (i) Hormonal therapy using a gonadotropin-releasing hormone (GnRH) agonist or antagonist for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (ii) Hormone replacement therapy or oral contraception; (c) Radiation therapy for definite progressive disease, except for new brain metastases in the context of the following systemic response situations: Patients who have shown control of systemic disease (defined as having received a clinical benefit [i.e., PR, CR, or SD for ≥ 3 months]) but have developed brain metastases treatable by radiation therapy may continue to receive therapy with Compound 1 during the study until they experience either systemic progression of the disease and / or further progression in the brain (based on the evaluation of the study responsible physician). (d) Quinidine or other antiarrhythmic agents; or (e) Initiation or dose increase of hematopoietic colony-stimulating factor (CSF; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; sargramostim, pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) starting 7 days before Day 1 of the first cycle;

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

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

[0170] Further provided herein is a method of treating an organ-invasive cancer containing a KRas G12C mutation by administering the combination therapy described herein. In one embodiment of such a method, the method comprises: (a) measuring the presence or absence of a KRas G12C mutation in a sample taken from a patient diagnosed with suspected cancer, and (b) administering to the patient a combination therapy described herein comprising an effective amount of Compound 1 described herein or a pharmaceutically acceptable salt thereof and an EGFR inhibitor.

[0171] In such an embodiment, the EGFR inhibitor is erlotinib or cetuximab. In such an embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is administered QD in an amount of about 50 to 500 mg. In another such embodiment, erlotinib is administered QD in an amount of about 100 mg or 150 mg. In yet another embodiment, cetuximab is administered on day 1 of the first 21-day cycle in an amount of about 400 mg / m 2 and then cetuximab is administered Q1W in an amount of about 250 mg / m 2 .

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

[0173] Furthermore, a method for treating organ-invasive cancer comprising a KRas G12C mutation, comprising: (a) measuring the presence or absence of a KRas G12C mutation in a sample taken from a patient diagnosed with suspected cancer; and (b) administering to the patient the combination therapy described herein comprising a dosing regimen comprising (i) administering 50 mg to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof QD from days 1 to 21 of the first 21-day cycle; (ii) administering about 400 mg / m 2 of cetuximab on day 1 of the first 21-day cycle, followed by administering about 250 mg / m 2 of cetuximab Q1W.

[0174] In one embodiment of the invention provided herein, a patient is diagnosed with CR after treatment with combination therapy by the method provided herein. In one embodiment of the invention provided herein, a patient is diagnosed with PR after treatment with combination therapy by the method provided herein. In one embodiment of the invention provided herein, a patient is diagnosed with SD after treatment with combination therapy by the method provided herein.

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

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

[0177] The combination therapy described herein can be provided as a kit comprising one or more of the agents described herein for administration. In one embodiment, the kit comprises Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the adipate salt of Compound 1) for administration in combination with an EGFR inhibitor described herein (e.g., erlotinib or cetuximab described herein). In another embodiment, the kit comprises Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the adipate salt of Compound 1) packaged together with an EGFR inhibitor described herein (e.g., erlotinib or cetuximab), and the kit comprises separately formulated dosages of each agent.

[0178] Also provided herein are articles of manufacture or kits comprising Compound 1 described herein or a pharmaceutically acceptable salt thereof (e.g., Compound 1 adipate) and an EGFR inhibitor (e.g., erlotinib or cetuximab). In some examples, the article of manufacture further comprises a package insert including instructions for using the EGFR inhibitor described herein (e.g., erlotinib or cetuximab) for treating a solid tumor (e.g., lung cancer, CRC, or pancreatic cancer described herein) or delaying its progression. In such an embodiment, the cancer is NSCLC. In one embodiment, the article of manufacture further comprises a package insert including instructions for using the EGFR inhibitor described herein (e.g., erlotinib) in combination with Compound 1 or a pharmaceutically acceptable salt thereof (e.g., Compound 1 adipate) for treating NSCLC or delaying its progression in a patient. In one embodiment, the article of manufacture further comprises a package insert including instructions for using the EGFR inhibitor described herein (e.g., erlotinib) in combination with Compound 1 or a pharmaceutically acceptable salt thereof (e.g., Compound 1 adipate) for treating pancreatic cancer or delaying its progression in a patient. In one embodiment, the article of manufacture further comprises a package insert including instructions for using the EGFR inhibitor described herein (e.g., cetuximab) in combination with Compound 1 or a pharmaceutically acceptable salt thereof (e.g., Compound 1 adipate) for treating CRC or delaying its progression in a patient.

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

[0180] Any manufactured product or kit described herein can 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. Biomarker

[0181] In one embodiment, alkylation of KRas by Compound 1 or a pharmaceutically acceptable salt thereof G12C is measured in a patient. In such an embodiment, the measurement is performed using a sample and tested for alkylation of KRas G12C provided herein. In another embodiment, evaluation of a ctDNA biomarker (e.g., KRas G12C ) from peripheral blood is performed.

[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 on-treatment fresh tumor biopsies. Embodiment

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

[0184] Embodiment No. 1: A combination therapy comprising: (a) Compound 1 described herein or a pharmaceutically acceptable salt thereof, and (b) An EGFR inhibitor. The combination therapy.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0200] Embodiment No. 17: The combination therapy according to any one of Embodiments 1 to 7 or 14 to 16, wherein the EGFR inhibitor is cetuximab administered in an amount of about 400 mg / m 2 on the first day of the 21-day cycle, and then in an amount of about 250 mg / m 2 Q1W.

[0201] Embodiment No. 18: The combination therapy according to any one of Embodiments 1 to 13 for use in the treatment of lung cancer comprising a KRas G12C mutation.

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

[0203] Embodiment No. 20: The combination therapy according to any one of Embodiments 1 to 13 for use in the treatment of pancreatic cancer comprising a KRas G12C mutation.

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

[0205] Embodiment No. 22: A combination therapy comprising: (a) Compound 1 described herein or a pharmaceutically acceptable salt thereof administered QD from day 1 to day 21 of the first 21-day cycle, and (b) erlotinib administered QD from day 1 to day 21 of the first 21-day cycle.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0221] Embodiment No. 38: The EGFR inhibitor is administered in an amount of about 400 mg / m on the first day of the 21-day cycle, and then in an amount of about 250 mg / m 2 Q1W, and is cetuximab, according to any one of Embodiments 35 to 37. 2 The method according to any one of Embodiments 35 to 37, which is cetuximab administered in an amount of Q1W.

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

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

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

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

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

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

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

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

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

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

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

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

[0234] Use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and an EGFR inhibitor for the manufacture of a medicament for treating lung cancer, CRC or pancreatic cancer.

[0235] Embodiment No. 52: The cancer is lung cancer or pancreatic cancer, the EGFR inhibitor is erlotinib, and it further includes a dosing regimen comprising (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle, and (ii) administering erlotinib from day 1 to day 21 of the first 21-day cycle. The use according to Embodiment 51.

[0236] Embodiment No. 53: The cancer is CRC, the EGFR inhibitor is cetuximab, and it further includes a dosing regimen comprising (i) administering Compound 1 or a pharmaceutically acceptable salt thereof QD from day 1 to day 21 of the first 21-day cycle, and (ii) administering it in an amount of about 400 mg / m2 on day 1 of the 21-day cycle and then in an amount of about 250 mg / m2 Q1W. The use according to Embodiment 51.

[0237] The following examples are presented by way of illustration and not limitation.

Example

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

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

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

[0241] NCI-H2122 (KRAS G12C)In an NSCLC xenograft tumor model, the in vivo antitumor efficacy of Compound 1 (50 mg / kg, PO, QD) alone or in combination with erlotinib (50 mg / kg, PO, QD) was evaluated. Treatment with single-agent Compound 1 resulted in tumor stasis (93% tumor growth inhibition (TGI)), while single-agent treatment with erlotinib resulted in only 48% TGI tumor growth inhibition. An improvement in antitumor effect (117% TGI) was observed with the combination of Compound 1 and erlotinib.

[0242] Test materials. Compound 1 (free base) was provided as a solution at a concentration of 8.333 mg / mL (expressed as free base equivalent) in 0.5% (w / v) methylcellulose. Erlotinib (Tarceva (trademark)) was provided as a solution at a concentration of 12.5 mg / mL (expressed as free base equivalent) in 7.5% Captisol. All concentrations were calculated based on the average body weight of 25 g of the nude mouse strain used in this study. The vehicle controls were 0.5% (w / v) methylcellulose and 0.5% (w / v) methylcellulose / 0.2% Tween 80 (trademark). The test agents were stored in a refrigerator set to maintain a temperature range of 4°C to 7°C. All treatment and vehicle control dosing solutions were prepared once a week for 3 weeks.

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

[0244] Human non-small cell lung cancer NCI-H2122 cells were obtained from the American Type Culture Collection (Rockville, Maryland), which had a G12C oncogenic mutation in K-RAS. The cells were cultured in vitro, harvested during the logarithmic growth phase, and resuspended in Hank's balanced salt solution (HBSS) containing Matrigel (BD Biosciences; San Jose, California) at a 1:1 ratio. Then, the cells were transplanted subcutaneously into the right chest of 160 nude mice. Each mouse was injected with 10 × 10 6 cells at a volume of 100 μL. Tumors were monitored until the average tumor volume reached 150 - 290 mm 3 . The mice were assigned to 10 groups based on tumor volume, with n = 10 mice per group. The average tumor volume across all 10 groups was 213 mm 3 at the start of dosing.

[0245] The mice were given vehicle (150 μL of 0.5% MC and 100 μL of 0.5% MCT), 50 mg / kg of Compound 1 (expressed as the free-base equivalent), or 50 mg / kg of erlotinib. All treatments were administered orally (PO) daily (QD) by forced oral gavage over 21 days. Tumor size and mouse body weight were recorded, and the mice were euthanized immediately when the tumor volume exceeded 2000 mm 3 or when the weight loss was ≥ 20% of the starting weight.

[0246]

Table 1

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

[0248] Antitumor responses were observed, and partial response (PR) was defined as a > 50% decrease from the initial tumor volume, and complete response (CR) was defined as a 100% decrease in tumor volume.

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

[0250]

Table 2

[0251] In the NCI-H2122 human NSCLC xenograft tumor model, a combined antitumor efficacy study was conducted, and it was demonstrated that compound 1, a KRAS G12C inhibitor, suppressed tumor growth (93% TGI, no PR) as a single agent. Single-agent activity with the EGFR inhibitor erlotinib also resulted in tumor growth inhibition (48% TGI, no PR). The combination of compound 1 and erlotinib resulted in an improvement in the antitumor effect (117% TGI, 3 / 10 PR). These data indicate that KRAS G12CIt is demonstrated that the combination of compound 1, an inhibitor, and erlotinib results in an improvement in antitumor activity leading to partial tumor regression in the NCI-H2122 human NSCLC human xenograft tumor model.

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

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

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

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

[0256] Tumor volume was measured twice a week after being randomly measured two-dimensionally using calipers, and the volume was measured in mm using the following formula 3Represented by: V = (L × W × W) / 2, where V is the tumor volume, L is the tumor length (longest tumor dimension), and W is the tumor width (longest tumor dimension perpendicular to L). Drug administration and measurement of the tumor and body weight were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

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

[0258] The in vivo antitumor effect of compound 1 (30 mg / kg, oral, once a day) alone or in combination with cetuximab was evaluated in a CR6256 (KRas G12C ) colorectal patient-derived tumor model. Treatment with compound 1 alone resulted in tumor stasis to regression (108% tumor growth inhibition [TGI]), while single-agent cetuximab showed moderate to slight tumor growth inhibition (74%). The combination of compound 1 and cetuximab showed improved combination efficacy (133%) compared to the single agents.

[0259]

Table 3

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

[0261] The in vivo treatment efficacy combination of compound 1 and cetuximab was preclinically evaluated in the treatment of the PDX cancer model CR5048 in female NOD-SCID mice. The animals had an average tumor volume of 185.67 mm 3On day 0 when the tumors reached a certain size, they were randomized, and administration was initiated on day 1. The animals were dosed with compound 1 daily (QD) for 21 days and cetuximab BIW × 3.5 weeks (total of 7 doses), either alone or in combination. All animals were sacrificed 8 hours after the final dose (day 21 of the study). During the study period, the animals were measured twice a week. At the end of the study, tumors and blood were collected from all animals during the study. The tumors were cut in half, and both pieces were snap-frozen in liquid nitrogen in separate tubes. Blood was collected by cardiac puncture and processed into plasma.

[0262] CR5048 (KRas G12C ) The in vivo antitumor efficacy of compound 1 (30 mg / kg, oral, once daily) alone or in combination with cetuximab was measured in a CR5048 (KRas

[0263]

Table 4

[0264] Example 4: Combination of Compound 1 and Cetuximab in a PDX CR6243 Colorectal Cancer Xenograft Model in Female BALB / c Nude Mice

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

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

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

[0268] When the average tumor size reached approximately 192 mm 3 randomization was initiated. After tumor cell inoculation, animals were checked daily for morbidity and mortality. During routine monitoring, animals were checked for the effects of tumor growth and treatment on behavior such as motility, food and water consumption, weight gain / loss (weight was measured twice a week after randomization), loss of shine of eyes / hair (matting), and any other abnormalities. For each individual animal, mortality and observed clinical signs were recorded in detail.

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

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

[0271] CR6243 (KRAS G12C) In vivo antitumor efficacy of compound 1 (30 mg / kg, oral, once daily) alone or in combination with cetuximab in a tumor model derived from colorectal cancer patients. Treatment with compound 1 alone resulted in tumor stasis and regression (89% tumor growth inhibition [TGI]), while treatment with cetuximab alone showed moderate to slight tumor growth inhibition (47% TGI). The combination of compound 1 and cetuximab showed improved combined efficacy (104%) compared to the single agents.

[0272]

Table 5

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

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

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

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

[0277] The average tumor size was approximately 194 mm 3Randomization was initiated when [the specified condition] was reached. After tumor cell inoculation, animals were checked daily for morbidity and mortality. During routine monitoring, animals were checked for the effects of tumor growth and treatment on behavior such as motility, food and water consumption, weight gain / loss (weight was measured twice a week after randomization), loss of gloss on eyes / hair (matting), and any other abnormalities. For each individual animal, mortality and observed clinical signs were recorded in detail.

[0278] After randomizing the tumor volume two-dimensionally using calipers, it was measured twice a week, and the volume was expressed in mm 3 using the following formula: V = (L × W × 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). Dosing and measurement of tumor and weight were performed on a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

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

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

[0281]

Table 6

[0282] Example 6: Combination of Compound 1 and Cetuximab in a PDX CR2528 Colorectal Cancer Xenograft Model in Female BALB / c Nude Mice

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

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

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

[0286] Randomization was initiated when the average tumor size reached approximately 202 mm 3 After tumor cell inoculation, animals were checked daily for morbidity and mortality. During routine monitoring, animals were checked for the effects of tumor growth and treatment on behavior such as motility, food and water consumption, weight gain / loss (weight was measured twice a week after randomization), loss of shine of eyes / hair (matting), and any other abnormalities. For each individual animal, mortality and observed clinical signs were recorded in detail.

[0287] Tumor volume was measured twice a week after two - dimensional randomization using calipers, and the volume was calculated in mm using the following formula 3Represented by: V = (L × W × 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). Dosing and measurement of the tumor and body weight were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

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

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

[0290]

Table 7

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

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

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

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

[0295] Randomization was initiated when the average tumor size reached approximately 182 mm 3 After tumor cell inoculation, animals were checked daily for morbidity and mortality. During routine monitoring, animals were checked for the effects of tumor growth and treatment on behavior such as motility, food and water consumption, weight gain / loss (weight was measured twice a week after randomization), loss of shine of eyes / hair (matting), and any other abnormalities. For each individual animal, mortality and observed clinical signs were recorded in detail.

[0296] After randomizing two - dimensionally using calipers, tumor volume was measured twice a week and the volume was expressed in mm 3 as follows: V=(L×W×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). Dosing, as well as tumor and weight measurements, were performed in a clean bench. Body weight and tumor volume were measured using Study Director™ software (version 3.1.399.19).

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

[0298] CR1451 (KRAS G12C) In vivo antitumor efficacy of compound 1 (30 mg / kg, oral, once daily) alone or in combination with cetuximab in a tumor model derived from colorectal cancer patients. Treatment with compound 1 alone resulted in tumor stasis (64% tumor growth inhibition [TGI]), while single-agent cetuximab showed a delay in growth inhibition (48% TGI). The combination of compound 1 and cetuximab resulted in improved combination efficacy (83% TGI) compared to the single agents. All doses and combinations tested were tolerated based on minimal changes in body weight and overall animal symptoms.

[0299]

Table 8

[0300] Example 8: KRAS is the most frequently mutated oncogene in up to 25% of cancers and is associated with resistance to standard treatment options and poor overall prognosis. Selective inhibitors have been developed as anticancer therapies targeting other nodes of the RAS / MAPK pathway, but the KRAS oncoprotein was considered undruggable until the recent discovery of the switch II pocket (Ostrem, et al. Nature 2013;503:548-51). This finding has led to the evaluation of covalent small molecule inhibitors targeting KRAS, specifically KRAS G12C mutations, in early clinical development.

[0301] Other KRAS G12C inhibitor, AMG 510 (sotorasib), is a KRAS G12Cis a small molecule that irreversibly inhibits by locking it in its inactive GDP-bound state. AMG-510 is currently being investigated in ongoing clinical trials. Patients in these trials had received a median of 3 (range 0-11) prior lines of anticancer therapy for metastatic disease before entering the study. Overall, treatment-related adverse events were reported in 56.6% of patients, 11.6% of patients experienced treatment-related grade 3 or 4 events, and 1.6% of patients experienced treatment-related serious adverse events. Grade 3 events occurring in multiple patients included increased ALT, diarrhea, anemia, increased AST, and increased alkaline phosphatase. One patient experienced a grade 4 treatment-related increase in ALT, and one patient discontinued AMG 510 due to grade 3 treatment-related increases in ALT and AST. Antitumor activity has been reported, but there are adverse events associated with AMG-510. Patients had an objective response confirmed in 32.2% of NSCLC patients, and the median duration of response was 10.9 months (range 1.1+ to 13.6) in patients. The median PFS was reported to be 6.3 months (range 0.0+ to 14.9+) in NSCLC patients (Hong et al. New Eng J Med 2020;383:1207-17).

[0302] MRTX849 is a mutant-selective small molecule KRAS G12C being evaluated in a clinical study of patients with progressive solid tumors having the KRAS G12CIt is an inhibitor. Recently, data from a total of 17 patients (including 10 NSCLC patients and 4 CRC patients) were reported, and among them, 12 patients received tumor evaluations during at least one treatment (including 6 NSCLC patients and 4 CRC patients). Most patients had received more than 3 prior anticancer regimens before study enrollment (12 out of 17 patients, 71%). The following treatment-related adverse events were reported in >10% of patients: diarrhea, nausea, increased AST, vomiting, fatigue, increased ALT, increased creatinine, abdominal distension, abdominal pain, increased ALP, anemia, loss of appetite, dehydration, thirst, dysgeusia, dyspnea, QT prolongation, hypomagnesemia, and rash. Grade 3 events included fatigue, loss of appetite, and dyspnea (1 patient each). Antitumor activity by PR was achieved in 3 out of 6 NSCLC patients and 1 out of 4 CRC patients across all dose levels evaluated (Jaenne et al. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 2019).

[0303] Compound 1. KRAS G12C The specificity of Compound 1 for, along with its mechanism of action, KRAS G12C is expected to result in a potent and irreversible inhibition of KRAS, enabling a broad therapeutic index that maximizes antitumor activity while minimizing treatment-related toxicity. For specific therapies targeting KRAS G12C positive cancers, it may provide a more tolerable and effective treatment option for patients with advanced cancers bearing KRAS G12C .

[0304] In vitro and in vivo pharmacological studies have shown that Compound 1 is a very potent and selective covalent inhibitor of KRAS, with a higher affinity for KRAS G12C than for KRAS G12C negative cancer cell lines G12CIt has been demonstrated to exhibit selectivity exceeding 20,000-fold in the inhibition of the growth of positive cancer cell lines. The mechanism of action study using 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 inhibited, and KRAS G12C It has been demonstrated that apoptosis induction is observed in positive cancer cell lines. Furthermore, Compound 1 has potent single-agent activity and KRAS G12C Inhibits tumor growth in several non-clinical 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 positive solid tumors.

[0305] The results of non-clinical toxicology studies completed to date provide a robust characterization of the toxicity profile of Compound 1 and support the administration of Compound 1 to cancer patients. Comprehensive non-clinical toxicity studies were completed to evaluate the potential single-dose and repeated-dose oral toxicity, genotoxicity, phototoxicity, and safety pharmacology of Compound 1. Since KRAS G12C mutations do not exist in healthy animals, there are no non-clinical species pharmacologically relevant to KRAS G12C inhibition.

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

[0307] Cetuximab is approved for the treatment of several different solid tumor types, including metastatic colorectal and head and neck cancers. Erlotinib is approved for the treatment of non-small cell lung cancer (NSCLC), specifically NSCLC tumors with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 substitution mutations (L858R) detected by FDA-approved tests that receive first-line, maintenance or second-line, or more treatment after progression following at least one prior chemotherapy regimen. Erlotinib is also approved for first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer in combination with gemcitabine.

[0308] Initial Phase I clinical data from ongoing studies of AMG 510 and MRTX849 as single agents have shown that KRAS G12C inhibitors are tolerable and have promising antitumor activity in patients with metastatic NSCLC and CRC (Janne et al. 2019; Hong et at. New Eng J Med 2020;383:1207-17). However, there remains a large unmet need to improve the antitumor activity and durability reported in NSCLC and CRC while using inhibitors of this class as single agents and, more importantly, to maintain their tolerable safety profiles.

[0309] Rationale for combination therapy with EGFR inhibitors. Without being bound by any particular theory, based on the mechanistic understanding of the RTK-RAS-MAPK pathway, inhibition upstream of KRAS G12C by RTK inhibitors is hypothesized to potentially enhance KRAS G12C inhibition. The non-clinical studies described in Example 1 in cell lines show that EGFR inhibition by either a small molecule or an anti-EGFR antibody that inhibits the activity of wild-type EGFR results in KRAS G12CThis strategy is supported by demonstrating a synergistic enhancement of inhibition (Lito et al. Science 2016;351:604-8; Canon et al. Nature 2019;575:217-23; Amodio et al. Cancer Disc 2020;10:1129-39; Hallin et al. Cancer Disc 2020;10:54-71). Mechanisms by which EGFR inhibition may enhance the effect of KRAS G12C inhibitors include reducing nucleotide exchange to promote the GDP-bound state of KRAS G12C (Lito et al. 2016), and reducing the rebound enhancement of RTK signaling upon KRAS G12C inhibition (Amodio et al. 2020).

[0310] In in vivo mouse studies with the combination of cetuximab, treatment of mice with CRC PDX using the combination of compound 1 and cetuximab reduced tumor growth beyond that seen with compound 1 alone. Preclinical evidence (see Figures 3-8 and Examples 2-7) demonstrates a synergistic effect between EGFR inhibition and KRAS G12C inhibition in CRC. The starting dose of cetuximab in combination with compound 1 was 400 mg / m 2 as a 120-minute IV infusion on day 1 in a 21-day cycle, followed by 250 mg / m 2 as a 60-minute IV infusion weekly. Potential overlapping toxicities of the agents include gastrointestinal toxicity and elevated liver transaminases.

[0311] In combination with erlotinib Multiple KRAS G12CIn the positive cell line, compound 1 in combination with erlotinib showed a synergistic effect on the inhibition of cell proliferation, along with a corresponding decrease in pERK and pS6 that was greater than the effect seen with compound 1 alone. In in vivo mouse studies, a greater decrease in tumor growth of NSCLC xenografts was achieved with compound 1 and erlotinib compared to compound 1 alone. Preclinical evidence (see Figures 1 and 2) shows a synergistic effect between EGFR inhibition and KRAS G12C inhibition in NSCLC. The starting dose of erlotinib in combination with compound 1 will be 150 mg oral QD in a 21-day cycle. Potential overlapping toxicities of the agents include gastrointestinal toxicity and elevated liver transaminases.

[0312] Biomarkers. This study identifies and / or evaluates biomarkers that can predict response to compound 1 as a single agent or in combination with an EGFR inhibitor (i.e., predictive biomarkers), early surrogates of activity, related to progression to a more severe disease state (i.e., prognostic biomarkers), related to the development of acquired resistance to a KRAS G12C inhibitor (e.g., compound 1), related to susceptibility to the occurrence of adverse events, or that can lead to an improvement in the monitoring or investigation of adverse events (i.e., safety biomarkers), provide evidence of the activity of compound 1 in combination with an EGFR inhibitor (i.e., pharmacodynamic [PD] biomarkers), or enhance knowledge and understanding of disease biology and drug safety. Corresponding biomarker endpoints include exploratory biomarkers in blood, plasma, and tumor tissue and the relationships between safety, PK, activity, or other biomarker endpoints.

[0313] Patients are screened over a safety follow-up period during which they are followed for safety outcomes over a maximum period of 28 days, followed by the treatment period, and the treatment-specific period until after the last dose of the study drug or until receipt of another anticancer therapy (whichever occurs first).

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

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

[0316] The starting dose of Compound 1 will be 50 mg PO QD. Treat single patient dose-escalation cohorts with escalating doses of Compound 1.

[0317] Patients include those with locally advanced, recurrent or metastatic incurable KRas G12C positive tumors (e.g., NSCLC, CRC or pancreatic cancer) with disease progression or intolerance to at least one prior systemic therapy, which may include monotherapy or combination therapy. Patients with NSCLC, CRC, or pancreatic cancer are screened for KRas G12C positivity.

[0318] KRas G12C mutation status from tissue and circulating tumor DNA evaluations. Approximately 12% of NSCLC, 4% of CRC, 2% of pancreatic cancer, and many other solid tumors (each with a prevalence of ≤ 4%) have KRas G12C mutations. Compound 1 is a potent and highly selective inhibitor that targets KRas G12C but does not target other mutations in KRAS, the wild-type form of KRAS, or other members of the RAS family. Thus, KRas G12COnly patients with tumors having a mutation are eligible for administration of the combination therapy described herein. The status of the KRAS mutation may be determined using the FoundationOne® CDx (F1CDx) assay, the US Food and Drug Administration (FDA)-approved Broad companion diagnostic (CDx) assay, the FoundationOne® Liquid CDx (F1L CDx) assay, and other FDA-approved (FDA 2020) or well-validated laboratory-developed tests performed in a laboratory validated by the Clinical Laboratory Improvement Amendments (CLIA) or equivalently certified. Previous studies have shown that the occurrence of the KRas G12C mutation is an early event (amal-Hanjani et al. N Engl J Med 2017;376:2109-21), and analysis of archival tissue has been suggested to be a sufficient alternative for selection of patients with KRas G12C positive tumors.

[0319] Pharmacodynamic pathway modulation. Compound 1 is a KRas G12C inhibitor that locks KRasG12C in its inactive GDP-bound state by suppressing downstream MAPK signaling through alkylation of KRas G12C . In non-clinical models, the level of KRas G12C alkylation and the degree of MAPK pathway suppression by Compound 1 correlate with the response to Compound 1. Collection of tumor tissue before and during treatment will enable evaluation of the correlation between MAPK pathway suppression and anti-tumor activity and Compound 1 treatment. The degree of MAPK pathway suppression can be evaluated using RNA analysis of MAPK target genes (e.g., DUSP6, SPRY4) or immunohistochemical (IHC) analysis of phosphorylated downstream markers (e.g., pERK, pS6). Furthermore, on-treatment tumor tissue biopsies may enable direct assessment of the level of KRas G12C alkylation by Compound 1. Evaluation of these PD biomarkers may provide information for future dose selection.

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

[0321] Protein, RNA, and DNA analysis. In addition to the mutational activation of proteins, changes in RNA expression levels or DNA may also regulate the activity of signaling pathways. Tumor RNA profiling enables the unique subtyping of patients enrolled in the study. Analysis of the potential association between subtypes and patient outcomes may identify the subpopulation of patients most likely to respond to Compound 1.

[0322] Somatic tumor mutation analysis and plasma samples for other biomarkers. There is increasing evidence that cell-free DNA obtained from blood specimens of patients with cancer contains circulating tumor DNA (ctDNA) that represents the DNA and mutational status of cells within the tumor (Diehl et al. 2008; Maheswaran et al. 2008). Assays for detecting cancer-related mutations (e.g., KRAS) from plasma have been validated. The results of these assays may correlate with the mutational status determined from the analysis of tumor specimens. The use of ctDNA to monitor response to treatment is a very interesting area and may enable an early non-invasive and quantifiable method for identifying candidates for specific therapies and monitoring the mutational status of cancer over time for use in the clinical setting (Wan et al. Nat Rev Cancer 2017;17:223-38). Analysis of ctDNA collected at various time points during investigational treatment and after the patient has progressed on Compound 1 may help identify mechanisms of response resistance and acquired resistance to investigational treatment.

[0323] Blood Sample for Next-Generation Sequencing. Next-generation sequencing (NGS) technology can generate large amounts of sequencing data. Tumor DNA can include both reported and unreported chromosomal changes due to the tumorigenesis process. To assist in controlling sequencing calls for previously unreported genomic changes, a pre-dose blood sample is collected to determine whether the changes are somatic.

[0324] Selection Criteria. Patients must meet the following study enrollment criteria: ● Age ≥ 18 years; ● Disease evaluable or measurable by RECIST v1.1; ● An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 ● A life expectancy of ≥ 12 weeks; ● Appropriate hematologic and organ function within 14 days before the start of study treatment, as defined below: 〇 Absolute neutrophil count ≥ 1200 / μL; 〇 Hemoglobin ≥ 9 g / dL; 〇 Platelet count ≥ 100,000 / μL; 〇 Total bilirubin ≤ 1.5 × ULN; 〇 Serum albumin ≥ 2.5 g / dL; 〇 AST and ≤ 2.5 × ULN, with the following exceptions: ● Patients with proven liver metastases may have AST and / or ALT ≤ 5.0 × ULN. 〇 Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL / min (based on the estimated glomerular filtration rate by Cockcroft-Gault): (140 - age) × (weight in kg) × (0.85 for females) 72 × (serum creatinine (mg / dL)) ● In the case of women of childbearing potential: agreement to maintain abstinence (refrain from heterosexual intercourse) or use contraceptive methods and refrain from egg donation. ● For men who have not had a sterilization operation: Agreement to maintain abstinence (refrain from heterosexual intercourse), or use contraception, and refrain from sperm donation. ● Confirmation of biomarker eligibility: KRas G12C Either a central laboratory test of blood to demonstrate the presence of the mutation, or a valid result from either a central laboratory test of blood or a test at each facility of blood or tumor tissue (e.g., a validated polymerase chain reaction (PCR)-based assay or NGS assay performed in a CLIA or equivalent-certified laboratory).

[0325] Additional selection criteria: ● Histologically proven, locally advanced, recurrent or metastatic incurable adenocarcinoma of the colon or rectum without a known concomitant second oncogenic driver (e.g., BRAF V600E mutation, ERBB2 amplification) as determined by the FMI NGS assay or a validated PCR-based assay or NGS assay approved by the sponsor and performed in a CLIA-certified or equivalent-certified laboratory at each facility. 〇 Patients with appendiceal tumors are excluded. 〇 Patients must not have experienced disease progression or intolerance to at least one prior chemotherapy regimen (e.g., FOLFOX, FOLFIRI, FOLFOXIRI ± bevacizumab). ● Histologically proven, locally advanced, recurrent or metastatic incurable NSCLC without a known concomitant second oncogenic driver (e.g., sensitive EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion, RET fusion) as determined by the FMI NGS assay or a validated PCR-based assay or NGS assay approved by the sponsor and performed in a CLIA-certified or equivalent-certified laboratory at each facility. 〇 Disease progression or intolerance to at least one prior systemic therapy. This may include monotherapy or combination therapy with a PD-L1 / PD-1 inhibitor during the trial or after approval. ● Patients may have received prior treatment with a KRas G12C specific inhibitor.

[0326] General exclusion criteria. Patients who meet any of the following criteria are excluded: ● Unable or unwilling to swallow tablets; ● Unable to comply with the study and follow-up procedures; ● Malabsorption syndrome or other conditions that interfere with enteral absorption; ● Known and untreated or active central nervous system (CNS) metastases; ● Patients with a history of treated CNS metastases are eligible provided they meet all of the following criteria: 〇 Measurable or evaluable disease outside the CNS; 〇 No history of intracranial or spinal cord hemorrhage; 〇 No ongoing need for corticosteroids as therapy for CNS metastases, corticosteroids have been discontinued ≥ 2 weeks prior to administration of the agents described herein, and there are no ongoing symptoms attributable to CNS metastases; 〇 No stereotactic radiation within 7 days prior to Day 1 of Cycle 1 or no whole brain radiation within 14 days; 〇 No evidence of interim progression between completion of therapy directed to the CNS and screening radiographic examinations; ● Leptomeningeal disease or carcinomatous meningitis; ● Uncontrolled pleural effusion, pericardial fluid accumulation, or ascites requiring recurrent drainage procedures every other week or more frequently; 〇 An indwelling thoracic or abdominal catheter may be possible if the patient has recovered sufficiently from the procedure, is hemodynamically stable, and has symptomatic improvement; ● Any active infectious disease that may affect patient safety or severe infection requiring intravenous antibiotic administration within 7 days prior to Day 1 of Cycle 1; ● History of clinically significant liver disease including viral or other hepatitis, current alcohol abuse, 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 continuous use of bisphosphonate therapy or denosumab; ● Significant traumatic injury or major surgical treatment within 4 weeks prior to Day 1 of Cycle 1; ● Patients with a history of chronic diarrhea, short bowel syndrome or major upper gastrointestinal surgery including gastrectomy, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or any active intestinal inflammation (including diverticulitis); ● Immunotherapy or biologic therapy, or treatment with endocrine therapy within 2 weeks prior to administration of the agent described herein: 〇 Hormonal therapy using a gonadotropin-releasing hormone (GnRH) agonist or antagonist for hormone-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); 〇 Kinase inhibitors approved by the regulatory authorities may be used up to 2 weeks prior to the start of the investigational treatment; 〇 Treatment with an investigational drug within 3 weeks or 5 half-lives (whichever is shorter) prior to administration of the agent described herein. ● Radiation therapy as a cancer treatment within 4 weeks prior to administration of the agent described herein (except palliative radiation for bone metastases and radiation for CNS metastases); ● Palliative radiation for bone metastases within 2 weeks prior to administration of Compound 1; ● Adverse events from previous anticancer therapy that have not resolved; ● History of other malignancies within 5 years prior to screening; ● History of clinically significant cardiovascular insufficiency or active clinically severe cardiovascular insufficiency, including: 〇 History of stroke or transient ischemic attack within 6 months prior to administration of the agent described herein; 〇 History of myocardial infarction within 6 months prior to administration of the agent described herein; 〇 New York Heart Association class III or IV heart disease or congestive heart failure requiring drug therapy 〇 Uncontrolled arrhythmia, history of requiring drug therapy, or active ventricular arrhythmia; 〇 Coronary heart disease with symptomatic or unstable angina; 〇 Congenital long QT syndrome corrected using the Fridericia formula (QTcF) or QT interval > 470 ms; 〇 Current treatment with drug therapy known to prolong the QT interval; ● Pregnant or lactating, or intending to become pregnant during the study or within 6 months after the last dose of Compound 1; or ● History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic interstitial pneumonia, or evidence of active interstitial pneumonia on screening chest computed tomography (CT) scan

[0327] Study treatment formulation, packaging, and handling

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

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

[0330] Unless otherwise indicated, Compound 1 should be taken on an empty stomach, i.e., food should be avoided at least 2 hours before and 1 hour after dosing. There is no restriction on fluid intake. Importantly, the capsules or tablets of Compound 1 should be swallowed whole (without chewing) with a minimum of 240 mL (8 fluid ounces) of water. If a patient misses any dose of Compound 1 or vomits the capsule or tablet, the patient should be instructed to skip that dose and resume dosing at the next scheduled dose. Missed doses should not be replenished.

[0331] Cetuximab is supplied as a commercially available formulation. Cetuximab is administered as an initial dose of 400 mg / m 2 by 120-minute IV infusion on Day 1, followed by 250 mg / m 2 by 60-minute IV infusion weekly in 21-day cycles. The maximum infusion rate should not exceed 10 mg / min. Cetuximab should be administered after the administration of Compound 1.

[0332] The administration of cetuximab is performed in a monitored setting with trained personnel and appropriate equipment and medications readily available to manage potentially severe reactions. Prior to the first infusion, participants must receive premedication with an antihistamine and a corticosteroid. This premedication is recommended prior to all subsequent infusions. Close monitoring is required during and for at least 1 hour after the infusion.

[0333] Erlotinib will be supplied as tablets in strengths of 25 mg, 100 mg, and 150 mg. Erlotinib is initiated at 150 mg and administered PO QD in 21-day cycles, during which time it is taken with a sip of water and concomitantly with Compound 1. All doses of erlotinib should be taken on an empty stomach (i.e., food should be avoided at least 2 hours before and 1 hour after dosing).

[0334] If the administration of erlotinib or cetuximab is temporarily discontinued due to an adverse event during a given cycle, the next dosing cycle must not be initiated until erlotinib or cetuximab administration can be resumed. Therefore, the current cycle may be extended beyond 21 days, and the patient may continue to receive Compound 1. The first day of the next cycle must correspond to the time point at which erlotinib or cetuximab administration is resumed.

[0335] Concomitant Therapy. Concomitant therapy consists of any pharmacotherapy (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal therapies or homeopathic therapies, nutritional supplements) used by the patient in addition to the drugs described herein from 7 days prior to the first administration of at least one of the drugs described herein until the last administration of at least one of the drugs described herein.

[0336] Permitted Therapies. The patient may take (a) anticonvulsants or warfarin; (b) oral contraceptives or other possible maintenance therapies as specified by the eligibility criteria; (c) antiemetics and antidiarrheals should not be prophylactically administered prior to the first treatment with the investigational drug; (d) analgesics; (e) bisphosphonate and denosumab therapies for bone metastases or osteopenia or osteoporosis; or multivitamins, calcium, and vitamin C, D, and E supplements may be permitted.

[0337] Therapies requiring attention. As drug therapies to be administered with care due to the effects related to CYP enzymes and Compound 1, for example, (1) strong / moderate CYP3A4 inhibitors (including, but not limited to, atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troleandomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluvoxamine, diltiazem, nefazodone, mibefradil, verapamil, and grapefruit juice or grapefruit supplements); (2) strong / moderate CYP3A4 inducers (including, but not limited to, rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's wort), and cyproterone). The use of oral anticoagulants or parenteral anticoagulants at full doses for therapeutic purposes, provided that the INR and / or aPTT are within the therapeutic limit (according to the facility's criteria) within 14 days before the administration of any of the agents described herein, and the patient has been taking a stable dose of anticoagulants for ≥1 week before the start of the study treatment. The list of drug therapies is not intended to be comprehensive.

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

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

[0340] Patients receiving erlotinib are at increased risk of GI perforation, so chronic use of anti-angiogenic agents and non-steroidal anti-inflammatory drugs (NSAIDs) is not permitted. Acute use of NSAIDs is permitted for managing fever or during the period that erlotinib is being held.

[0341] Prohibited Therapies The use of the following concomitant therapies is prohibited for at least 7 days before and during the first administration of the agents described herein: ● Investigational therapies within 3 weeks or 5 half-lives (whichever is shorter) prior to the first administration of the agents described herein ● Concomitant therapies intended for the treatment of cancer, whether FDA-approved or experimental, including chemotherapy, radiation therapy, immunotherapy, biologic therapy, herbal therapy, or hormonal therapy, except for: 〇 Hormonal therapy with gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); 〇 Hormone replacement therapy or oral contraception. ● Radiation therapy for definite progressive disease, except for new brain metastases in the setting of a systemic response: Patients who have demonstrated control of systemic disease (defined as having received a clinical benefit [i.e., PR, CR, or SD for ≥ 3 months]) and who develop brain metastases treatable by radiation may continue to receive therapy with Compound 1 during the study until they experience either systemic progression of the disease and / or further progression in the brain (based on the assessment of the study responsible physician); ● Quinidine or other antiarrhythmic drugs; ● Initiation or dose increase of hematopoietic colony-stimulating factors (CSFs; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; sargramostim, pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) starting 7 days before Day 1 of the first cycle

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

[0343] Risks associated with cetuximab. The undesirable effects of cetuximab include skin reactions occurring in more than 80% of patients, hypomagnesemia occurring in more than 10% of patients, and IRR occurring in mild to moderate symptoms in more than 10% of patients and severe symptoms in more than 1% of patients. The risk of severe infusion reactions due to cetuximab administration may increase in patients who have been bitten by a mite or have a red meat allergy.

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

[0345] Treatment interruption. If Compound 1 has been withheld from previous study treatment for > 21 days due to toxicity, study treatment should not be restarted. Compound 1 can be stopped for a maximum of 21 days due to unexpected concurrent medical events not related to toxicity or disease progression of the study treatment.

[0346] Adverse event. An adverse event as defined in this specification refers to any unfavorable medical occurrence in a clinical trial subject administered with the agent described in this specification in the combination therapy described in this specification, regardless of the attribution of the cause. The terms "severe" and "serious" are not synonyms. Severity refers to the intensity of the adverse event (e.g., evaluated as mild, moderate, or severe, or in accordance with NCI CTCAE), and the event itself may not be relatively medically significant (such as severe headache without further findings).

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

[0348] Throughout this specification and the claims, the phrase "comprise, comprises, and comprising" is used in a non-exclusive sense unless the context requires otherwise. It is understood that the embodiments described in this specification include embodiments "consisting of" and / or "consisting essentially of".

[0349] When a range of values is provided, unless the context clearly indicates otherwise, each intervening value between the upper and lower limits of the range and any other stated value or intervening value within the stated range, to one-tenth of the unit of the lower limit, is to be understood as being included in this specification. The upper and lower limits of these smaller ranges that can be independently included in smaller ranges (rangers) are also included in this specification, subject to the specifically excluded limit values in the stated range. When one or both of the limit values are included in the stated range, ranges excluding either or both of those included limit values are also included in this specification.

[0350] Many modifications and other embodiments of the inventions described herein will come to mind to those skilled in the relevant arts having the benefit of the teachings presented in the foregoing description and the related drawings. Accordingly, it is to be understood that the inventions are not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. (a) Compound 1 or a pharma- ceutically acceptable salt thereof; (b) an EGFR inhibitor; Combination therapy, including

2. 2. The combination therapy of claim 1, wherein compound 1 is an adipate salt thereof.

3. 3. The combination therapy of claim 1 or 2, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered QD on days 1-21 of a first 21-day cycle.

4. The combination therapy of any one of claims 1 to 3, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered orally as a tablet or capsule.

5. The combination therapy of any one of claims 1 to 4, wherein compound 1 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg.

6. The combination therapy of any one of claims 1 to 5, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg.

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

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

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

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

12. 12. The combination therapy of claim 11, wherein erlotinib is administered in an amount of about 100 mg QD.

13. 12. The combination therapy of claim 11, wherein erlotinib is administered in an amount of about 150 mg QD.

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

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

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

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

18. KRas Ｇ１２Ｃ 14. The combination therapy of any one of claims 1 to 13 for use in the treatment of lung cancer comprising a mutation.

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

20. KRas Ｇ１２Ｃ 14. A combination therapy according to any one of claims 1 to 13 for use in the treatment of pancreatic cancer comprising a mutation.

21. KRas Ｇ１２Ｃ 20. The combination therapy of any one of claims 1 to 7 or 14 to 17 for use in the treatment of mutation-containing colorectal cancer (CRC).

22. (a) Compound 1 administered QD on days 1-21 of a first 21-day cycle or a pharma- ceutically acceptable salt thereof; (b) erlotinib administered QD on days 1 to 21 of said first 21-day cycle; and Combination therapy, including

23. 23. The combination therapy of claim 22, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 50 mg to 500 mg, and erlotinib is administered in an amount of about 100 mg or 150 mg.

24. KRas Ｇ１２Ｃ 24. The combination therapy of claim 22 or 23 for use in the treatment of a lung cancer that comprises a mutation.

25. KRas Ｇ１２Ｃ 24. The combination therapy of claim 22 or 23 for use in the treatment of a mutation-containing pancreatic cancer.

26. (a) Compound 1 administered QD on days 1-21 of a first 21-day cycle or a pharma- ceutically acceptable salt thereof; (b) cetuximab administered Q1W starting on day 1 of the first 21-day cycle; and Combination therapy, including

27. 27. The combination therapy of claim 26, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 50 mg to 500 mg, and cetuximab is administered in an amount of about 400 mg / m2 on day 1 of said 21 day cycle and about 250 mg / m2 Q1W thereafter.

28. KRas Ｇ１２Ｃ 1. A method of treating a mutation-mediated lung cancer in a patient having such lung cancer, comprising: (a) Compound 1 administered QD on days 1-21 of a first 21-day cycle or a pharma- ceutically acceptable salt thereof; (b) an EGFR inhibitor; The method comprises administering an effective amount of a combination therapy comprising:

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

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

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

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

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

34. 34. The method of any one of claims 28-33, wherein the EGFR inhibitor is erlotinib administered in an amount of about 150 mg QD.

35. KRas in patients with colorectal cancer (CRC) Ｇ１２Ｃ 1. A method of treating mutation-mediated CRC, comprising: (a) Compound 1 administered QD on days 1-21 of a first 21-day cycle or a pharma- ceutically acceptable salt thereof; (b) an EGFR inhibitor; The method comprises administering an effective amount of a combination therapy comprising:

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

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

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

39. KRas Ｇ１２Ｃ 1. A method of treating mutation-mediated pancreatic cancer in a patient having such cancer, comprising: (a) Compound 1 administered QD on days 1-21 of a first 21-day cycle or a pharma- ceutically acceptable salt thereof (b) an EGFR inhibitor; and The method comprises administering an effective amount of a combination therapy comprising:

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

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

42. 42. The method of any one of claims 39-41, wherein the EGFR inhibitor is erlotinib administered in an amount of about 100 mg QD.

43. 43. The method of any one of claims 28 to 42, wherein compound 1 is an adipate salt thereof.

44. 44. The method of any one of claims 28 to 43, wherein Compound 1 or a pharma- ceutically acceptable salt thereof is administered orally as a tablet or capsule.

45. 45. The method of any one of claims 28 to 44, wherein compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 50 mg to 500 mg.

46. 46. ​​The method of any one of claims 28-45, wherein Compound 1, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg.

47. 47. The method of any one of claims 28 to 46, wherein the patient is diagnosed as not having a mutation selected from the group consisting of a susceptible EGFR mutation, an ALK rearrangement, a ROS1 rearrangement, a BRAF V600E mutation, an NTRK fusion, and a RET fusion, or a combination thereof.

48. The use of a combination therapy comprising Compound 1, or a pharma- ceutically acceptable salt thereof, and an EGFR inhibitor for the treatment of lung cancer, CRC, or pancreatic cancer as described herein.

49. 49. The use of claim 48, wherein the cancer is lung cancer or pancreatic cancer, the EGFR inhibitor is erlotinib, and further comprising a dosing regimen comprising: (i) administering compound 1, or a pharmaceutically acceptable salt thereof, QD on days 1-21 of a first 21 day cycle; and (ii) administering erlotinib on days 1-21 of the first 21 day cycle.

50. 49. The use of claim 48, wherein the cancer is CRC and the EGFR inhibitor is cetuximab, and further comprising a dosing regimen comprising: (i) administering compound 1, or a pharmaceutically acceptable salt thereof, QD on days 1 to 21 of a first 21 day cycle; and (ii) administering compound 1 in an amount of about 400 mg / m2 on day 1 of the 21 day cycle, thereafter in an amount of about 250 mg / m2 Q1W.

51. 23. Use of a combination therapy comprising Compound 1, or a pharma- ceutically acceptable salt thereof, and an EGFR inhibitor for the manufacture of a medicament for treating lung cancer, CRC, or pancreatic cancer.

52. 52. The use of claim 51 , wherein the cancer is lung cancer or pancreatic cancer, the EGFR inhibitor is erlotinib, and further comprising a dosing regimen comprising: (i) administering compound 1, or a pharmaceutically acceptable salt thereof, QD on days 1-21 of a first 21 day cycle; and (ii) administering erlotinib on days 1-21 of the first 21 day cycle.

53. 52. The use of claim 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 pharmaceutically acceptable salt thereof, QD on days 1 to 21 of a first 21 day cycle; and (ii) administering compound 1 in an amount of about 400 mg / m2 on day 1 of the 21 day cycle, thereafter in an amount of about 250 mg / m2 Q1W.

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