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

Abstract

KRas G12C This provides a means for treating cancers with mutations. [Solution] KRas G12C Provided hereby are combination therapies comprising an inhibitor (e.g., compound 1 represented by the following structural formula or a pharmaceutically acceptable salt thereof) and a VEGF antagonist (e.g., bevacizumab), and methods for using such combination therapy. TIFF2026082807000014.tif49170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 113,609, filed on 13 November 2020, which is incorporated herein by reference in its entirety for all purposes.

[0002] Field of Invention KRas G12C This specification provides combination therapies comprising an inhibitor (e.g., compound 1) and a VEGF antagonist (e.g., bevacizumab), and methods for using such combination therapy. [Background technology]

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

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

[0005] Therefore, KRas G12C Effective treatments and combination therapies are needed to treat cancers such as lung cancer, colorectal cancer, hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, ovarian cancer, and pancreatic cancer that have mutations. [Overview of the project]

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

[0007] In one embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof as described herein and an anti-VEGF antibody is provided herein.

[0008] In one such embodiment, the anti-VEGF antibody is bevacizumab. In another such embodiment, compound 1 is its adipine salt. In yet another such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1-21 of the first 21-day cycle, and bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle. In yet another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1-21 of the first 21-day cycle in an amount of about 50 mg-500 mg, and bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle in an amount of about 5-20 mg / kg. In one such embodiment, bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle in an amount of 15 mg / kg.

[0009] In another aspect, KRas G12CA method of 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 and an anti-VEGF antibody is provided herein.

[0010] In another aspect, KRas in a patient having such lung cancer G12C A method of treating mutation-mediated colorectal cancer in a patient having such colorectal cancer, the method comprising administering an effective amount of a combination therapy comprising Compound 1 described herein or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody is provided herein.

[0011] In another aspect, KRas in a patient having such lung cancer G12C A method of treating mutation-mediated pancreatic cancer in a patient having 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 and an anti-VEGF antibody is provided herein.

[0012] In another aspect, KRas in a patient having such lung cancer G12C A method of treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer mediated by mutation in a patient having such lung cancer, the method comprising administering an effective amount of a combination therapy comprising Compound 1 described herein or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody is provided herein.

[0013] In such embodiments of the present method, the anti-VEGF antibody is bevacizumab. In another such embodiment of the present method, compound 1 is its adipine salt. In yet another such embodiment of the present method, compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1-21 of the first 21-day cycle, and bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle. In yet another embodiment of the present method, compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1-21 of the first 21-day cycle in an amount of about 50 mg-500 mg, and bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle in an amount of about 5-20 mg / kg. In one such embodiment of the present method, bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle in an amount of 15 mg / kg.

[0014] In another embodiment, the present invention provides a method for treating a patient having NSCLC, CRC, or pancreatic cancer, comprising administering to the patient a therapeutic regimen comprising an effective amount of Compound 1 described herein or a pharmaceutically acceptable salt thereof and an effective amount of an anti-VEGF antibody (e.g., bevacizumab).

[0015] In another embodiment, the use of a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab for the treatment of lung cancer, CRC, or pancreatic cancer as described herein is provided herein.

[0016] In yet another embodiment, the use of a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab for the manufacture of a medicament for the treatment of lung cancer, CRC, or pancreatic cancer is provided herein. [Brief explanation of the drawing]

[0017] [Figure 1]Figure 1 shows the effects of compound 1 (adipate) administered at 50 mg / kg alone and in combination with an anti-VEGF antibody in nude mouse NCI-H2122 NSCLC tumor xenografts. Vehicle = 0.5% (w / v) methylcellulose. Individual tumor volume data are shown for vehicle / anti-VEGF antibody control (upper left panel), anti-VEGF antibody (lower left panel), compound 1 (upper right panel), and compound 1 + anti-VEGF antibody (lower right panel). Each group (n=10) was administered for 21 days. Dose levels are expressed as free base equivalents.

[0018] [Figure 2] Figure 2 shows the tumor volume of NCI-H2122 NSCLC tumor-bearing nude mice treated with compound 1 as an adipinate administered alone or in combination with an anti-VEGF antibody. Vehicle = 0.5% (w / v) methylcellulose; isotype anti-gD control antibody. Group-matched tumor volume is shown after oral administration of compound 1 over 21 days, either alone with QD or in combination with an anti-VEGF antibody administered with BIW. Dose levels are expressed as free base equivalents. [Modes for carrying out the invention]

[0019] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains. See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, apparatus, and materials similar to or equivalent to those described herein may be used in carrying out this invention.

[0020] The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of this disclosure. All references mentioned herein are invoked by reference in their entirety.

[0021] Where used herein, unless otherwise specified, the terms “about” and “approximately” refer to a dose, volume, or weight percentage of an ingredient in a composition or dosage form, meaning a dose, volume, or weight percentage recognized by those skilled in the art to provide an equivalent pharmacological effect to that obtained from a specified dose, volume, or weight percentage. An equivalent dose, volume, or weight percentage may be within the range of 30%, 20%, 15%, 10%, 5%, 1%, or less than the specified dose, volume, or weight percentage.

[0022] When used herein, "KRas G12C The term "inhibitor" refers to a covalent inhibitor that specifically binds to mutant KRas proteins containing a mutation from Gly to Cys at the position corresponding to residue 12.

[0023] Compound 1 has the following structure: TIFF2026082807000002.tif49170 The chemical name is 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidine-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazine-1-yl)propa-2-en-1-one. In one embodiment, compound 1 is an adipine salt.

[0024] The term "pharmaceutically acceptable" refers to molecular elements and compositions that, when administered appropriately to animals, such as humans, do not produce adverse reactions, allergic reactions, or other side effects.

[0025] The compounds of the present invention may also be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. "Pharmacologically acceptable acid addition salt" means a salt that is formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, or phosphoric acid, which retains the biological efficacy and properties of the free base and is biologically or otherwise desirable. The organic acid can be selected from the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid categories of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In one embodiment, the salt is formed with adipic acid.

[0026] The term "pharmaceutically acceptable base addition salts" includes salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Specific base addition salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples of pharmaceutically acceptable salts derived from organic non-toxic bases include primary, secondary, and tertiary amines, naturally occurring substituted amines, cyclic amines, and substituted amines containing basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and salts of polyamine resins. Specific examples of organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0027] In some embodiments, the salt is hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipine, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, phloate (e.g., 2-phloate or 3-phloate), napadisylate (naphthalene-1,5-disulfonate, or naphthalene-1(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonic acid Salt, or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethyl sulfonate), 2-mesitylene sulfonate, 2-naphthalene sulfonate, 2,5-dichlorobenzene sulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipine, esylate, malonate, mesicylate (2-mesitylene sulfonate), napsylate (2-na Selected from phthalene sulfonates, cansylates (camphor 10-sulfonates, e.g., (1S)-(+)-10-camphor-sulfonates), glutamates, glutarates, hippuric acid (2-(benzoylamino)acetate), orotinates, xylates (p-xylene-2-sulfonates), and pamoates (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylates).

[0028] The terms “inhibit” and “reduce,” or any variation thereof, include any measurable reduction or complete inhibition to achieve the desired result. For example, there may be a reduction in the variable, a decrease in activity compared to normal, by about, at most about, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range of these variables.

[0029] The term “vascular endothelial growth factor” or “VEGF” refers to vascular endothelial growth factor protein A, as exemplified by Swiss Prot accession number P15692, Gene ID (NCBI): 7422. The term “VEGF” encompasses the protein having the amino acid sequence of Swiss Prot accession number P15692, Gene ID (NCBI): 7422, as well as its homologs and isoforms. The term “VEGF” also encompasses known isoforms of VEGF, e.g., splice isoforms, e.g., VEGF 111 , VEGF 121 , VEGF 145 , VEGF 165 , VEGF 189 , and VEGF 206 , as well as their naturally occurring alleles and processed forms (VEGF) 165This includes human vascular endothelial growth factor (containing 110 amino acids) produced by plasmin cleavage, which are described in Ferrara Mol. Biol. Cell. 21:687, 2010; Leung et al., Science, 246:1306, 1989; and Houck et al., Mol. Endocrin., 5:1806, 1991. The term "VEGF" also refers to VEGF derived from non-human species such as mice, rats, or primates. VEGF derived from specific species may be indicated by terms such as hVEGF for human VEGF and mVEGF for mouse VEGF. The term "VEGF" also refers to a polypeptide cleavage form containing amino acids 8-109 or 1-109 of human vascular endothelial growth factor, which is 165 amino acids. Any reference to any such form of VEGF is, in this application, for example, "VEGF 109 "VEGF(8~109)", "VEGF(1~109)", or "VEGF 165 It can be identified by "[...]". The amino acid positions of "cleaved" native VEGF are numbered as shown in the native VEGF sequence. For example, amino acid position 17 (methionine) in cleaved native VEGF is also position 17 (methionine) in native VEGF. Cleaved native VEGF has binding affinity to KDR and Flt-1 receptors comparable to that of native VEGF. As used herein, the term "VEGF variant" refers to a VEGF polypeptide containing one or more amino acid mutations in the native VEGF sequence. Optionally, one or more amino acid mutations may include amino acid substitutions. For the purpose of concisely representing VEGF variants as described herein, note that the numbers refer to the positions of amino acid residues along the amino acid sequence of the putative native VEGF (provided in Leung et al., (see above) and Houck et al., (see above)). Unless otherwise specified herein, the term "VEGF" refers to VEGF-A.

[0030] The terms "VEGF antagonist" or "VEGF-specific antagonist" refer to molecules that can bind to VEGF, reduce VEGF expression levels, or neutralize, block, inhibit, suppress, reduce, or interfere with the biological activity of VEGF (including, but not limited to, VEGF binding to one or more VEGF receptors, VEGF signaling, and VEGF-mediated angiogenesis, as well as endothelial cell survival or proliferation). For example, molecules that can neutralize, block, inhibit, suppress, reduce, or interfere with the biological activity of VEGF may exert their effects by binding to one or more VEGF receptors (VEGFRs) (e.g., VEGFR1, VEGFR2, VEGFR3, membrane-bound VEGF receptors (mbVEGFRs), or soluble VEGF receptors (sVEGFRs)). VEGF-specific antagonists useful in the method of the present invention include polypeptides that specifically bind to VEGF, anti-VEGF antibodies and their antigen-binding fragments, receptor molecules and derivatives that specifically bind to VEGF and thereby block binding to one or more receptors, fusion proteins (e.g., VEGF-Trap (Regeneron)), and VEGF 121- Peregrine is an example. Other VEGF-specific antagonists include antagonist variants of VEGF polypeptides, antisense nucleic acid base oligomers complementary to at least a fragment of the nucleic acid molecule encoding the VEGF polypeptide, small RNAs complementary to at least a fragment of the nucleic acid molecule encoding the VEGF polypeptide, ribozymes targeting VEGF, peptide bodies for VEGF, and VEGF aptamers. Other VEGF antagonists include polypeptides that bind to VEGFR, anti-VEGFR antibodies, and their antigen-binding fragments, as well as derivatives or fusion proteins that bind to VEGFR and thereby block, inhibit, suppress, reduce, or interfere with the biological activity of VEGF (e.g., VEGF signaling). Other VEGF-specific antagonists include non-peptide small molecules that can bind to VEGF or VEGFR and block, inhibit, suppress, reduce, or interfere with the biological activity of VEGF. Therefore, the term "VEGF activity" specifically includes the VEGF-mediated biological activity of VEGF. In certain embodiments, VEGF antagonists reduce or inhibit the expression level or biological activity of VEGF by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the VEGF inhibited by the VEGF-specific antagonist is VEGF(8-109), VEGF(1-109), or VEGF 165 That is the case.

[0031] An "anti-VEGF antibody" is an antibody that binds to VEGF with sufficient affinity and specificity. In certain embodiments, the antibody has a sufficiently high binding affinity to VEGF, for example, the antibody has a K2-1pM d It can bind to hVEGF at a certain value. Antibody affinity can be determined by, for example, surface plasmon resonance assays (such as the BIAcore® assay described in PCT application publication WO2005 / 012359), enzyme-linked immunosorbent assays (ELISA), and competitive assays (e.g., radioimmunoassays (RIA)).

[0032] In certain embodiments, anti-VEGF antibodies may be used as therapeutic agents when targeting and interfering with diseases or conditions involving VEGF activity. Antibodies may also be subjected to other biological activity assays, for example, to evaluate their efficacy as therapeutic agents. Such assays are known in the art and depend on the target antigen and intended use of the antibody. Examples include HUVEC inhibition assays, tumor cell growth inhibition assays (e.g., those described in International Publication No. 89 / 06692), antibody-dependent cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) assays (U.S. Patent No. 5,500,362), and agonist activity or hematopoietic assays (see International Publication No. 95 / 27062). Anti-VEGF antibodies typically do not bind to other VEGF homologs such as VEGF-B or VEGF-C, nor to other growth factors such as PIGF, PDGF, or bFGF. In one embodiment, the anti-VEGF antibody is a monoclonal antibody that binds to the same epitope as monoclonal anti-VEGF antibody A4.6.1 produced by hybridoma ATCC HB 10709. In another embodiment, the anti-VEGF antibody is a recombinant humanized anti-VEGF monoclonal antibody produced according to Presta et al. (Cancer Res. 57:4593-4599, 1997), including but not limited to the antibody known as bevacizumab (BV, AVASTIN®).

[0033] Bevacizumab, also known as "rhuMAb VEGF" and "BV," and marketed under the trademark names "AVASTIN®," "Zirabev®," and "Mvasi®," is a recombinant humanized anti-VEGF monoclonal antibody produced according to Presta et al. (Cancer Res. 57:4593-4599, 1997).

[0034] Bevacizumab contains a mutant human IgG1 framework region and antigen-binding complementarity-determining region derived from mouse anti-hVEGF monoclonal antibody A.4.6.1, which blocks the binding of human VEGF to its receptor. Approximately 93% of the amino acid sequence of bevacizumab, including the majority of the framework region, is derived from human IgG1, and approximately 7% of the sequence is derived from mouse antibody A4.6.1. Bevacizumab has a molecular weight of approximately 149,000 daltons and is glycosylated. Bevacizumab and other humanized anti-VEGF antibodies are further described in U.S. Patent No. 6,884,879, issued on 26 February 2005, the entire disclosure of which is expressly incorporated herein by reference. Additional preferred antibodies include the G6 or B20 series antibodies (e.g., G6-31, B20-4.1) described in International Publication No. 2005 / 012359 of the PCT application. For additional preferred antibodies, see U.S. Patent Nos. 7,060,269, 6,582,959, 6,703,020, 6,054,297, International Publication Nos. 98 / 45332, 96 / 30046, 94 / 10202, European Patent No. 0666868B1, U.S. Patent Application Publication Nos. 2006009360, 20050186208, 20030206899, 20030190317, 20030203409, and 20050112126, and Popkov et al., (Journal of Immunological Methods 288:149-164, 2004). Other preferred antibodies include those containing residues F17, M18, D19, Y21, Y25, Q89, 191, K101, E103, and C104, or antibodies containing residues F17, Y21, Q22, Y25, D63, 183, and Q89, which bind to functional epitopes on human VEGF. Bevacizumab is approved for the treatment of several different solid tumor types, including metastatic colorectal cancer, advanced NSCLC, metastatic breast cancer, advanced renal cell carcinoma, ovarian cancer, cervical cancer, unresectable or metastatic hepatocellular carcinoma, and recurrent glioblastoma.

[0035] The term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. In one embodiment, cancer is lung cancer. In another embodiment, cancer is NSCLC. In another embodiment, cancer is colorectal cancer (e.g., metastatic CRC). In another embodiment, cancer is pancreatic cancer. In yet another embodiment, cancer is hepatocellular carcinoma (e.g., unresectable or metastatic). In another embodiment, cancer is breast cancer (e.g., metastatic breast cancer "mBC"). In yet another embodiment, cancer is renal cell carcinoma (e.g., advanced renal cell carcinoma). In another embodiment, cancer is ovarian cancer. In yet another embodiment, cancer is endometrial cancer. As used herein, "cancer" means KRas G12C This refers to cancer characterized by the presence of mutations.

[0036] As used herein, “to treat” includes treatment with an effective dose of a therapeutic agent (e.g., bevacizumab or compound 1) or a combination of therapeutic agents (e.g., bevacizumab and compound 1). Treatment may be first-line treatment (e.g., the patient may not have been treated previously or has not received prior systemic treatment), second-line treatment, or subsequent treatment. “Treatment” is successful if, for example, the patient is reduced in number (or destroyed) of cancer cells, alleviated in number of symptoms associated with the disease, improved quality of life for the person with the disease, reduced dose of other drug treatments required for the treatment of the disease, and / or extended survival of the patient.

[0037] The term “delay in disease progression” refers to delaying, preventing, slowing, postponing, stabilizing, and / or postponing the onset of the cancers described herein. This delay may vary in length depending on the cancer being treated and / or the patient’s medical history. As will be apparent to those skilled in the art, a sufficient or significant delay may substantially encompass prevention in that the patient does not develop cancer.

[0038] In this specification, “effective dose” refers to the amount of the therapeutic agent described herein (e.g., bevacizumab and / or compound 1) that achieves a therapeutic outcome. In some examples, an effective dose of the therapeutic agent or combination of therapeutic agents is the amount of the agent or combination of agents that achieves the clinical endpoint provided herein. The effective dose as described herein may vary depending on factors such as the patient’s disease state, age, sex, and weight, as well as the agent’s ability to induce the desired response in the patient. The effective dose is also the amount in which the therapeutically beneficial effects outweigh any toxic or adverse effects of the treatment. In some embodiments, an effective dose of the agent may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., delaying or stopping) the invasion of cancer cells into peripheral organs, inhibiting (i.e., delaying or stopping) tumor metastasis, inhibiting (i.e., delaying or stopping) tumor growth, and / or alleviating one or more of the symptoms associated with the disease. An effective dose may be administered in one or more doses. The effective amounts of drugs, compounds, pharmaceutical compositions, or combination therapies described herein may be sufficient to achieve therapeutic treatment directly or indirectly.

[0039] "Objective response rate" or "ORR" refers to the percentage of patients who achieved complete or partial remission in two consecutive opportunities separated by ≥4 weeks, as determined by the principal investigator in accordance with RECIST v1.1.

[0040] The "response period" or "DOR" refers to the time from the first occurrence of a recorded objective response to the earlier of the following dates: disease progression as determined by the principal investigator in accordance with RECIST v1.1, or death from any cause.

[0041] "Progression-free survival" or "PFS" refers to the time from enrollment to the earlier of the date of the first recorded disease progression or death from any cause, as determined by the principal investigator using RECIST v1.1.

[0042] As used herein, “complete response” and “CR” refer to the disappearance of all target lesions and (if applicable) the normalization of tumor marker levels.

[0043] As used herein, “partial response” and “PR” refer to the persistence and / or (where applicable) maintenance of tumor marker levels above the normal limit in one or more non-target lesions. PR may also refer to CR, a reduction of ≥30% in the sum of the diameters of target lesions in the absence of new lesions and apparent progression in non-target lesions.

[0044] "Administration period" or "cycle" means a period including the administration of one or more of the drugs described herein (e.g., Compound 1 and bevacizumab), and any period not including the administration of one or more of the drugs described herein. For example, a cycle may be 21 days in total, with each day of the cycle including the administration of one or more of the drugs described herein (e.g., Compound 1 and bevacizumab). In another example, a cycle may be 28 days in total, including the administration of one or more of the drugs described herein (e.g., Compound 1 and bevacizumab) over a 21-day period and a 7-day rest period. "Rest period" means a period during which at least one of the drugs described herein (i.e., Compound 1 and bevacizumab) is not administered. In one embodiment, a rest period means a period during which none of the drugs described herein (i.e., Compound 1 and bevacizumab) is administered. The rest periods provided herein may, in some cases, include the administration of another drug other than Compound 1 or bevacizumab. In such cases, the administration of another drug during the drug-free period should not interfere with or disadvantage the administration of the drug described herein. For example, the term "cycle" as used herein refers to a 21-day cycle without a drug-free period.

[0045] "Medication regimen" means a period of administration of the drugs described herein, comprising one or more cycles, each cycle of which may include administration of the drugs described herein at different times or in different amounts.

[0046] "QD" refers to administering the drug described herein once daily.

[0047] "BID" refers to administering the drug described herein twice a day.

[0048] "Q3W" refers to the administration of the medication described herein once every three weeks.

[0049] "PO" refers to oral administration of the drugs described herein.

[0050] "IV" refers to the intravenous administration of any of the drugs described herein.

[0051] A graded adverse event refers to a graded severity scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table. TIFF2026082807000003.tif45170

[0052] The term "patient" refers to a human patient. The patient may be an adult.

[0053] In this specification, the term "antibody" specifically includes monoclonal antibodies (such as full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, insofar as they exhibit the desired biological activity. In one example, the antibody is a full-length monoclonal antibody.

[0054] As used herein, the terms IgG “isotype” or “subclass” mean any of the subclasses of immunoglobulins defined by the chemical and antigenic properties of their constant regions.

[0055] Depending on the amino acid sequence of the constant domains of their heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five main classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, γ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and are generally described, for example, in Abbas et al., Cellular and Mol. Immunology, 4th ed. (WBSaunders, Co., 2000). Antibodies may be part of a larger fusion molecule formed by the covalent or non-covalent association of an antibody with one or more other proteins or peptides.

[0056] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein synonymously to refer to an antibody in its substantially intact form, not to the antibody fragments described below. This term refers to an antibody containing an Fc region.

[0057] The term “Fc region” is used herein to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more amino acids, particularly one or two, from the C-terminus of the heavy chain. Thus, by expression of a particular nucleic acid molecule encoding a full-length heavy chain, antibodies produced by host cells may contain the full-length heavy chain or a cleaved variant of the full-length heavy chain. This may occur when the last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Therefore, the C-terminal lysine (Lys447), or C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present. The amino acid sequence of the heavy chain containing the Fc region is shown herein without the C-terminal lysine (Lys447) unless otherwise indicated. In one embodiment, the heavy chain containing the Fc region as specified herein, as contained in the antibody disclosed herein, includes an additional C-terminal glycine-lysine dipeptide (G446 and K447). In one embodiment, the heavy chain containing the Fc region as specified herein, as contained in the antibody disclosed herein, includes an additional C-terminal glycine residue (G446). In one embodiment, the heavy chain containing the Fc region as specified herein, as contained in the antibody disclosed herein, includes an additional C-terminal lysine residue (K447). In one embodiment, the Fc region includes the single amino acid substitution N297A of the heavy chain. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system (also known as the EU index), as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0058] A "naked antibody" refers to an antibody that is not conjugated with a heterogeneous portion (e.g., a cytotoxic portion) or a radioactive label. Naked antibodies may be present in a pharmaceutical composition.

[0059] An "antibody fragment" preferably comprises a portion of an intact antibody, including its antigen-binding region. In some examples, the antibody fragments described herein are antigen-binding fragments. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFvs), and multispecific antibodies formed from antibody fragments.

[0060] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies constituting the population are identical and / or bind to the same epitope, with the exception of possible variant antibodies, such as naturally occurring mutations or variants that occur during the production of the monoclonal antibody preparation and are usually present in small amounts. In contrast to polyclonal antibody preparations, which typically contain various antibodies against various determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is against a single determinant on an antigen. Therefore, the modifier “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous collection of antibodies and should not be interpreted as requiring antibody production by any particular method. For example, monoclonal antibodies used in accordance with the present invention may be produced by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of a human immunoglobulin locus.

[0061] As used herein, the terms “hypervariable region” or “HVR” mean each of the regions of the antibody variable domain that are hypervariable within the sequence and determine antigen-binding specificity, such as “complementarity-determining regions” (CDRs).

[0062] Generally, an antibody contains six CDRs, three located in the VH (CDR-H1, CDR-H2, CDR-H3) and three located in the VL (CDR-L1, CDR-L2, CDR-L3). Examples of CDRs used herein include: (a) Hypervariable loops formed at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987); (b) CDRs present in amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) Antigen contact occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J.Mol.Biol.262:732-745 (1996)).

[0063] Unless otherwise specified, the CDR will be determined in accordance with Kabat et al. above. Those skilled in the art will understand that the notation of the CDR may be determined in accordance with Chothia above, McCallum above, or any other scientifically recognized nomenclature system.

[0064] "Framework" or "FR" refers to variable domain residues other than the complementarity-determining region (CDR). The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the CDR and FR sequences generally appear in VH (or VL) in the following sequence: FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR-L3)-FR4.

[0065] The terms “Kabat-like variable domain residue numbering” or “Kabat-like amino acid position numbering,” and their variations, refer to the numbering system used in the heavy-chain or light-chain variable domains of antibody edits as described by Kabat et al. (see above). Using this numbering scheme, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to the shortening or insertion of FR or HVR in the variable domain. For example, a heavy-chain variable domain may contain a single amino acid insertion after H2 residue 52 (Kabat-like residue 52a) and a residue inserted after heavy-chain FR residue 82 (e.g., Kabat-like residues 82a, 82b, and 82c). The Kabat numbering of residues can be determined for a given antibody by the alignment of homologous regions between the antibody sequence and the “standard” Kabat-numbered sequence.

[0066] The Kabat numbering system is generally used to refer to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU numbering system" or "EU index" is generally used when referring to residues in the constant region of the immunoglobulin heavy chain (e.g., the EU index reported by Kabat et al. (see above)). "EU index as in Kabat" refers to the residue numbering of human IgG1 EU antibodies.

[0067] The term “package insert” is used to refer to the instructions that are customarily included in the market packaging of a therapeutic product, including information relating to indications, usage, dosage, administration, combination therapy, contraindications, and / or warnings for the use of such therapeutic product.

[0068] As used herein, “in combination with” means administering one treatment regimen in addition to another treatment regimen, for example, the administration of a VEGF antagonist described herein (e.g., bevacizumab) and compound 1 or a pharmaceutically acceptable salt thereof. Thus, “in combination with” means administering one treatment regimen before, during, or after administration of the other treatment regimen to the patient.

[0069] Drugs administered "concurrently" with one or more other drugs are administered on the same treatment day as the other drugs, and at the same time as the other drugs, if necessary, within the same treatment cycle. For example, in cancer therapy administered every three weeks, each drug administered concurrently is given on day 1 of the three-week cycle.

[0070] Combination therapy A combination therapy (composition) comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and an anti-VEGF antagonist described herein is provided herein. Furthermore, a combination therapy (composition) comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and an anti-VEGF antibody (e.g., bevacizumab) is provided herein.

[0071] Various anti-VEGF antibodies are intended and described herein. In some examples, the anti-VEGF antibody is a monoclonal antibody. In some examples, the anti-VEGF antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some examples, the anti-VEGF is a humanized antibody. In some examples, the anti-VEGF is a human antibody. In one embodiment, the anti-VEGF is bevacizumab (e.g., AVASTIN®, ZIRABEV® (bevacizumab-bvzr), or MVASI® (bevacizumab-awwb)).

[0072] In one embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and bevacizumab is provided herein. In one embodiment, the combination therapy described herein is KRas G12C It is useful for treating certain solid tumors, including those with mutations. In one embodiment, the combination therapy described herein is used for KRas G12C It is useful for treating certain types of lung cancer described herein, including mutations. In one such embodiment, lung cancer is KRas G12C This is non-small cell lung cancer (NSCLC) containing mutations. In another embodiment, the combination therapy described herein is KRas G12C It is useful for treating colorectal cancer including mutations. In another embodiment, the combination therapy described herein is used for KRas G12C It is useful in treating pancreatic cancer, including mutated cancers.

[0073] In another embodiment, the combination therapy described herein is KRas G12CIt is useful for treating hepatocellular carcinoma including mutations. In another embodiment, the combination therapy described herein is KRas G12C It is useful for treating breast cancer including mutations. In another embodiment, the combination therapy described herein is KRas G12C It is useful for treating renal cell carcinoma including mutations. In another embodiment, the combination therapy described herein is used for KRas G12C It is useful for treating endometrial cancer including mutations. In another embodiment, the combination therapy described herein is used for KRas G12C It is useful in treating ovarian cancer, including mutated cancers.

[0074] In one embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof administered as a QD on days 1 to 21 of a first 21-day cycle, and an anti-VEGF antibody is provided herein. In such embodiments, the combination therapy is KRas as described herein. G12C It is useful in treating solid tumors containing mutations (e.g., lung cancer, colorectal cancer, pancreatic cancer).

[0075] In one embodiment, a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof administered as a QD on days 1 to 21 of a first 21-day cycle, and bevacizumab administered as a Q3W on day 1 of the first 21-day cycle, is provided herein.

[0076] In one embodiment of the combination therapy described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered as a fixed-dose QD (quick dose). In one embodiment, administration is oral (PO), and compound 1 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In such an embodiment, compound 1 or a pharmaceutically acceptable salt thereof is formulated (and administered) as a film-coated tablet.

[0077] In one embodiment of the combination therapy described herein, compound 1 or a pharmaceutically acceptable salt thereof is present in amounts of approximately 5 mg to 600 mg, 5 mg to 500 mg, 5 mg to 400 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 600 mg, 25 mg to 500 mg, and 25 mg to In another embodiment, compound 1 or a pharmaceutically acceptable fluctuating salt thereof is administered in amounts of approximately 5 mg, 25 mg, 50 mg, 100 mg, 25 mg, 25 mg, 25 mg, 25 mg, 25 mg, 100 mg, 25 mg, 50 mg, 50 mg, 600 mg, 50 mg, 50 mg, 400 mg, 50 mg, 300 mg, 50 mg, 250 mg, 50 mg, 200 mg, 50 mg, 150 mg, or 50 mg. In yet another embodiment, compound 1 or a pharmaceutically acceptable fluctuating salt thereof is administered in amounts of approximately 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg. In yet another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts of about 50 mg, 100 mg, or 400 mg. In a preferred embodiment, compound 1 of the combination therapy described herein is administered as an adipine. In such embodiments, the amount of compound 1 or a pharmaceutically acceptable salt thereof is administered relative to the free base form. In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in BID in amounts described herein (e.g., 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg).

[0078] In one embodiment of the combination therapy described herein, the anti-VEGF antibody is administered according to the package insert. In a preferred embodiment, the anti-VEGF antibody is bevacizumab. In such an embodiment, bevacizumab is administered at a fixed dose of 15 mg / kg according to the package insert. In such an embodiment, bevacizumab is administered over 90 minutes ± 15 minutes.

[0079] As a general suggestion, the effective dose of an anti-VEGF antibody (e.g., bevacizumab) administered to a human is within the range of approximately 1 to 50 mg per kg of body weight, regardless of whether it is administered as a single or multiple dose.

[0080] In some exemplary embodiments, the anti-VEGF antibody is administered in doses of approximately 1 to approximately 45 mg / kg, approximately 1 to approximately 40 mg / kg, approximately 1 to approximately 35 mg / kg, approximately 1 to approximately 30 mg / kg, approximately 1 to approximately 25 mg / kg, approximately 1 to approximately 20 mg / kg, approximately 1 to approximately 15 mg / kg, approximately 1 to approximately 10 mg / kg, approximately 1 to approximately 5 mg / kg, or approximately 5 to approximately 15 mg / kg, for example, daily, weekly, every two weeks, every three weeks, or every four weeks. In one such embodiment, the anti-VEGF antibody is administered in doses of approximately 5 mg / kg to approximately 15 mg / kg every two weeks or every three weeks. In another embodiment, the anti-VEGF antibody is administered in doses of approximately 10 mg / kg to approximately 20 mg / kg every two weeks or every three weeks.

[0081] In one embodiment, the anti-VEGF antibody is administered at a dose of approximately 15 mg / kg every three weeks (Q3W). In another embodiment, the anti-VEGF antibody is administered at a dose of approximately 10 mg / kg every two weeks (Q2W). In such embodiments, the anti-VEGF antibody is bevacizumab.

[0082] In a preferred embodiment, the combination therapy described herein comprises compound 1 or a pharmaceutically acceptable salt thereof administered via QD, and bevacizumab, which is administered intravenously to the patient at a dose of approximately 15 mg / kg Q3W.

[0083] In one embodiment, the combination therapy described herein is KRas G12C It is used to treat lung cancer including mutations. In a particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and bevacizumab, and the combination therapy is as described herein for KRas G12CThis invention is for treating lung cancer, including mutations. In one such embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In another such embodiment, the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer. The lung cancer may be stage I or II. In one embodiment, the lung cancer may be stage III or IV.

[0084] In another aspect, KRas G12C Provided herein are combination therapies useful for treating lung cancer including mutations, comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab. In one such embodiment, the lung cancer is NSCLC.

[0085] In yet another aspect, KRas G12C A combination therapy useful for treating lung cancer including mutations is provided herein, comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD on days 1-21 of the first 21-day cycle, and bevacizumab is administered Q3W on day 1 of the first 21-day cycle. In a preferred embodiment, the lung cancer is NSCLC.

[0086] In yet another aspect, KRas G12C A combination therapy useful for the treatment of lung cancer including mutations is provided herein, comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in a QD dose of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered in a Q3W dose of approximately 15 mg / kg on day 1 of the first 21-day cycle. In one preferred embodiment, the lung cancer is NSCLC. In one embodiment, bevacizumab is administered according to the prescribing information.

[0087] The combinations described herein are KRas G12CIn such embodiments useful for treating lung cancer including mutations, the combination therapy may further include administration of one or both of carboplatin and paclitaxel.

[0088] In one embodiment, the combination therapy described herein is KRas G12C Used to treat CRCs including mutations. In a particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and bevacizumab, and the combination therapy is used for KRas as described herein. G12C This is for treating CRCs containing mutations. In one such embodiment, the CRC is metastatic CRC (mCRC). In one embodiment, the combination therapy is KRas G12C This is for first-line use treatment of CRCs including mutations. In another embodiment, combination therapy is KRas G12C This is for the second-line treatment of CRC including mutations. In one such embodiment, the patient has previously progressed from a disease that had bevacizumab as first-line therapy.

[0089] In yet another aspect, KRas G12C A combination therapy useful for treating CRC including mutations is provided herein, comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipine), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD at a dose of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered Q3W at a dose of approximately 15 mg / kg on day 1 of the first 21-day cycle.

[0090] Combination therapy is KRas G12C In such embodiments useful for treating CRCs including mutations, such combination therapy may further include the administration of fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin-based chemotherapy.

[0091] In one embodiment, the combination therapy described herein is KRas G12CIt is used to treat pancreatic cancer including mutations. In one particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and bevacizumab, and the combination therapy is as described herein for KRas G12C It is intended to treat pancreatic cancer, including mutated cancers.

[0092] In yet another aspect, KRas G12C A combination therapy useful for the treatment of mutated pancreatic cancer is provided herein, comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-21 of the first 21-day cycle (QD), and bevacizumab is administered on day 1 of the first 21-day cycle (Q3W).

[0093] In yet another aspect, KRas G12C A combination therapy useful for the treatment of pancreatic cancer including mutations is provided herein, comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipine), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in a QD of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered in a Q3W of approximately 5 to 20 mg / kg on day 1 of the first 21-day cycle. In one such embodiment, bevacizumab is administered in a Q3W of approximately 15 mg / kg as described herein. In one embodiment, bevacizumab is administered according to the prescribing information.

[0094] In yet another aspect, KRas G12CThis specification provides combination therapies useful for the treatment of hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, including mutations, comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in a QD dose of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered in a Q3W dose of approximately 5 to 20 mg / kg on day 1 of the first 21-day cycle. In one such embodiment, bevacizumab is administered in a Q3W dose of approximately 15 mg / kg as described herein. In one embodiment, bevacizumab is administered according to the prescribing information.

[0095] Treatment method KRas as described herein G12C In patients with solid tumors containing mutations (e.g., lung cancer, CRC, pancreatic cancer, hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer), methods for treating such solid tumors are also provided herein. In one embodiment, KRas G12C A method for treating a solid tumor in a patient having lung cancer, CRC, pancreatic cancer, hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, including mutations, comprising administering to the patient an effective dose of combination therapy comprising compound 1 described herein or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and an anti-VEGF antibody (e.g., bevacizumab).

[0096] In one embodiment, KRas G12C A method for treating lung cancer in a patient having a mutation is provided herein, comprising administering to the patient an effective dose of combination therapy comprising compound 1 described herein or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and an anti-VEGF antibody. In one embodiment, KRas G12C This specification provides a method for treating lung cancer in a patient having mutation-mediated lung cancer, comprising administering to the patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab.

[0097] In one embodiment of the method provided herein, the lung cancer is non-small cell lung cancer (NSCLC). In such an embodiment, the anti-VEGF antibody is bevacizumab. In another embodiment of the method 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 yet another such embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is small cell lung cancer. In yet another embodiment, the lung cancer is an adenoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer may be stage III or stage IV lung cancer.

[0098] Also, KRas G12C Also provided herein is a method for treating NSCLC in patients having mutations, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) a QD administration 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) a Q3W administration of an effective amount of bevacizumab on day 1 of a first 21-day cycle. In one embodiment of the method provided herein, the method is for treating adenocarcinoma. In one embodiment of the method provided herein, the method comprises two or more cycles. In such one embodiment, the method is for treating first-line NSCLC.

[0099] Also, KRas G12C A method for treating NSCLC in patients with mutations is provided herein, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) a QD administration of 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle, and (ii) a Q3W administration of approximately 5 to 20 mg / kg of bevacizumab on day 1 of the first 21-day cycle.

[0100] KRas as described herein G12C In one embodiment of a method for treating lung cancer including mutations, the method further comprises administering an effective amount of carboplatin and paclitaxel, or both, to the patient.

[0101] In another embodiment, KRas in patients with CRC G12C A method for treating CRC including mutations is provided herein, comprising administering to a patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-VEGF antibody as described herein. Another embodiment of the method provided herein is a method for treating CRC, comprising administering to a patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab.

[0102] Also, KRas G12C Also provided herein is a method for treating cancer in patients having CRC including mutations, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) a QD administration 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) a Q3W administration of an effective amount of bevacizumab on day 1 of a first 21-day cycle. In one such embodiment, bevacizumab is administered in an amount of about 5 to 20 mg / kg as described herein. In another such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg as described herein. In one embodiment, bevacizumab is administered in an amount of 15 mg / kg.

[0103] KRas G12C In one embodiment of such a method for treating CRC including mutations, such a method further comprises administering to the patient chemotherapy based on an effective amount of fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin.

[0104] Also, KRasG12C A method for treating pancreatic cancer in a patient having a mutation is provided herein, comprising administering to the patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-VEGF antibody. Another embodiment of the method provided herein is a method for treating pancreatic cancer, comprising administering to the patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab.

[0105] In another embodiment, KRas G12C A method for treating pancreatic cancer, including mutations, in a patient, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) a QD administration 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) a Q3W administration of an effective amount of bevacizumab on day 1 of a first 21-day cycle. In one such embodiment, bevacizumab is administered in an amount of about 5 mg / kg to 20 mg / kg as described herein. In one embodiment, bevacizumab is administered in an amount of 15 mg / kg. 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.

[0106] Also, KRas G12CA method for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer in patients having a mutation is provided herein, comprising administering to the patient an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-VEGF antibody. Another embodiment of the method provided herein is a method for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer in patients having such cancer, comprising administering an effective dose of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab.

[0107] In another embodiment, KRas G12C A method for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, including mutations, in a patient, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) a QD administration 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) a Q3W administration of an effective amount of bevacizumab on day 1 of a first 21-day cycle. In one such embodiment, bevacizumab is administered in an amount of about 10 mg to 20 mg as described herein. In one embodiment, bevacizumab is administered in an amount of 15 mg / kg. 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.

[0108] In one embodiment of the method described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered as a fixed-dose QD dose. In one embodiment, administration is oral (PO), and compound 1 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof is available in doses of 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, 2 In another embodiment, compound 1 or a pharmaceutically acceptable ABLE salt thereof is administered in amounts of approximately 5 mg, 25 mg, 50 mg, 100 mg, 25 mg, 150 mg, 25 mg, 100 mg, 25 mg, 50 mg, 600 mg, 50 mg, 500 mg, 400 mg, 50 mg, 300 mg, 250 mg, 200 mg, 150 mg, or 50 mg to 100 mg. In yet another embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in amounts of about 50 mg, 100 mg, or 400 mg. In a preferred embodiment, compound 1 or a pharmaceutically acceptable salt thereof of the combination therapy described herein is administered as an adipine. In such embodiments, the amount of compound 1 or a pharmaceutically acceptable salt thereof is administered relative to the free base form.

[0109] In one embodiment of the method described herein, bevacizumab is administered in doses of about 1 to about 45 mg / kg, about 1 to about 40 mg / kg, about 1 to about 35 mg / kg, about 1 to about 30 mg / kg, about 1 to about 25 mg / kg, about 1 to about 20 mg / kg, about 1 to about 15 mg / kg, about 1 to about 10 mg / kg, about 1 to about 5 mg / kg, or about 5 to about 15 mg / kg, for example, daily, weekly, every two weeks, every three weeks, or every four weeks. In one such embodiment, bevacizumab is administered in doses of about 5 mg / kg to about 15 mg / kg every two weeks or every three weeks. In another such embodiment, bevacizumab is administered in doses of about 10 mg / kg to about 20 mg / kg every two weeks or every three weeks.

[0110] In one embodiment of the method described herein, bevacizumab is administered at a dose of approximately 15 mg / kg every three weeks (Q3W). In another embodiment, bevacizumab is administered at a dose of approximately 10 mg / kg every two weeks (Q2W).

[0111] Also, KRas G12C Also provided herein is a method for treating NSCLC in patients having mutations, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof in an amount of about 50 mg to 500 mg QD on days 1 to 21 of a first 21-day cycle, and (ii) administering an effective amount of bevacizumab in an amount of 15 mg / kg on day 1 of a first 21-day cycle Q3W. In one embodiment of the method provided herein, the method is for use in treating adenocarcinoma.

[0112] Also, KRas G12CAlso provided herein is a method for treating cancer in patients having a CRC including a mutation, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof in an amount of about 50 mg to 500 mg QD on days 1 to 21 of the first 21-day cycle, and (ii) administering an effective amount of bevacizumab in an amount of 15 mg / kg on day 1 of the first 21-day cycle Q3W.

[0113] Also, KRas G12C Also provided herein is a method for treating a patient having pancreatic cancer including mutations, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof in a dose of approximately 50 mg to 500 mg QD on days 1 to 21 of the first 21-day cycle, and (ii) administering an effective amount of bevacizumab in a dose of 15 mg / kg on day 1 of the first 21-day cycle, with a dose of Q3W.

[0114] Also, KRas G12C Also provided herein is a method for treating a patient having hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, including mutations, comprising administering to the patient an effective amount of the combination therapy described herein, comprising a drug regimen including (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof in a dose of approximately 50 mg to 500 mg QD on days 1 to 21 of the first 21-day cycle, and (ii) administering an effective amount of bevacizumab in a dose of 15 mg / kg Q3W on day 1 of the first 21-day cycle.

[0115] The methods provided herein may include the administration of the combination therapies described herein as part of a drug regimen. In one such embodiment, the drug regimen comprises one or more cycles. In another embodiment, the drug regimen comprises at least two cycles. In yet another embodiment, drug regimens comprising 2, 3, 4, 5, 6, 8, 10, 12, 16, 18, 20, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles are provided herein. In yet another embodiment, the drug regimen comprises about 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18, 2-12, or 2-6 cycles. In one embodiment, the drug regimen comprises administering the combination therapy described herein for any number of cycles until a desired response (e.g., PFS, OS, ORR, and / or DOR) is achieved (e.g., PFS, OS, ORR, and / or DOR are increased compared to the control described herein). In another embodiment, the drug regimen comprises administering the combination therapy described herein for any number of cycles until toxicity occurs or the patient experiences one or more adverse events (AEs) that otherwise prevent further administration. In yet another embodiment, the drug regimen comprises administering the combination therapy described herein for any number of cycles until disease progression.

[0116] In one embodiment of the method described herein, a patient is given 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 ~5 doses, 3~50 doses, 3~45 doses, 3~40 doses, 3~35 doses, 3~30 doses, 3~25 doses, 3~20 doses, 3~15 doses, 3~10 doses, 3~5 doses, 4~50 doses, 4~4 5 doses, 4~40 doses, 4~35 doses, 4~30 doses, 4~25 doses, 4~20 doses, 4~15 doses, 4~10 doses, 4~5 doses, 5~50 doses, 5~45 doses, 5~40 doses, 5~35 Amount, 5-30 doses, 5-25 doses, 5-20 doses, 5-15 doses, 5-10 doses, 10-50 doses, 10-45 doses, 10-40 doses, 10-35 doses, 10-30 doses, 10-25 doses , 10~20 doses, 10~15 doses, 15~50 doses, 15~45 doses, 15~40 doses, 15~35 doses, 15~30 doses, 15~25 doses, 15~20 doses, 20~50 doses, 20~4 Administer bevacizumab in doses of 5, 20-40, 20-35, 20-30, 20-25, 25-50, 25-45, 25-40, 25-35, 25-30, 30-50, 30-45, 30-40, 30-35, 35-50, 35-45, 35-40, 40-50, 40-45, or 45-50. In one preferred embodiment, the dose is administered intravenously.

[0117] In certain embodiments, the therapeutic agents of the combination therapy described herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof, and bevacizumab) may be administered in any suitable manner known in the Art. For example, bevacizumab may be administered sequentially (on different days) or simultaneously (on the same day or during the same therapeutic cycle) as Compound 1 or a pharmaceutically acceptable salt thereof. In one embodiment, bevacizumab is administered after the administration of Compound 1 or a pharmaceutically acceptable salt thereof. In some examples, bevacizumab may be administered after the administration of Compound 1, or a pharmaceutically acceptable salt thereof may be administered on the same day. In one embodiment, bevacizumab may be administered after the administration of Compound 1 or a pharmaceutically acceptable salt thereof on the same day. For example, Compound 1 or a pharmaceutically acceptable salt thereof may be administered on day 1 of each cycle before bevacizumab is administered on day 1 of each cycle, and then Compound 1 or a pharmaceutically acceptable salt thereof may be administered on a QD basis for the next 20 days of a 21-day cycle.

[0118] In preferred embodiments, bevacizumab is administered intravenously after compound 1 or a pharmaceutically acceptable salt thereof (e.g., about 60 minutes). In one example, bevacizumab may be administered intravenously over 90 ± 15 minutes. If the first infusion is acceptable, the second dose of bevacizumab is administered intravenously over 60 ± 10 minutes. If a 60-minute infusion is acceptable, all subsequent infusions may be delivered over 30 ± 10 minutes. In some examples, bevacizumab is administered as an intravenous push or bolus.

[0119] KRas G12CMethods for treating lung cancer including mutations in patients with such cancer are also provided herein, the method comprising administering to the patient a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine) and an anti-VEGF antibody as described herein (e.g., bevacizumab). In one embodiment of such a method, compound 1 is adipine and the anti-VEGF antibody as described herein is bevacizumab. In another embodiment of such a method, compound 1 or a pharmaceutically acceptable salt thereof is administered in the QD and amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, bevacizumab is administered in the Q3W and amount as described herein (e.g., 5 to 20 mg / kg). In such a method, compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab may be administered as described herein. In such a method, lung cancer is KRas G12C It may be NSCLC containing a mutation.

[0120] KRas G12C Methods for treating CRCs containing mutations in patients with such cancers are also provided herein, the methods comprising administering to the patient a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine) and an anti-VEGF antibody as described herein (e.g., bevacizumab). In one embodiment of such a method, compound 1 is adipine and the anti-VEGF antibody as described herein is bevacizumab. In another embodiment of such a method, compound 1 or a pharmaceutically acceptable salt thereof is administered in the QD and amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, bevacizumab is administered in the Q3W and amount as described herein (e.g., 5 to 20 mg / kg). In such a method, compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab may be administered as described herein.

[0121] KRas G12CMethods for treating pancreatic cancer, including mutations, in patients with such cancer are also provided herein, the method comprising administering to the patient a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine) and an anti-VEGF antibody as described herein (e.g., bevacizumab). In one embodiment of such a method, compound 1 is adipine and the anti-VEGF antibody as described herein is bevacizumab. In another embodiment of such a method, compound 1 or a pharmaceutically acceptable salt thereof is administered in the QD and amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, bevacizumab is administered in the Q3W and amount as described herein (e.g., 5 to 20 mg / kg). In such a method, compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab may be administered as described herein.

[0122] KRas G12C Methods for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer in patients with mutations are also provided herein, the methods comprising administering to the patient a therapeutic regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipine) and an anti-VEGF antibody as described herein (e.g., bevacizumab). In one embodiment of such a method, compound 1 is adipine and the anti-VEGF antibody as described herein is bevacizumab. In another embodiment of such a method, compound 1 or a pharmaceutically acceptable salt thereof is administered in the QD and amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, bevacizumab is administered in the Q3W and amount as described herein (e.g., 5 to 20 mg / kg). In such a method, compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab may be administered as described herein.

[0123] In some cases, a treatment regimen includes the administration of one or more additional therapies, which may be one or more side effect limiting agents (e.g., drugs intended to reduce the occurrence and / or severity of side effects of the treatment, e.g., anti-nausea agents, corticosteroids (e.g., prednisone or equivalent, e.g., at a dose of 1-2 mg / kg / day), hormone replacement therapy(s)), etc.

[0124] Patients provided herein must be evaluated and KRas as described herein. G12C Confirmed test results for mutations must be available. Patients described herein diagnosed with NSCLC must not have known associated secondary oncogenic drivers (e.g., in the case of NSCLC: susceptible EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion, RET fusion; or in the case of adenocarcinoma of the colon or rectum: BRAF V600E mutation, ERBB2 amplification). In one embodiment, such secondary oncogenic drivers are determined using NGS (e.g., an NGS assay by Foundation Medicine, Inc. (FMI)).

[0125] In one embodiment, the patient described herein does not have known, untreated, or active central nervous system (CNS) metastases (which are either progressive or require anticonvulsants or corticosteroids for symptomatic treatment). If such a patient has a history of treated CNS metastases, the patient may be treated using the methods described herein, and such a patient has: (1) measurable or evaluable extra-CNS disease; (2) no history of intracranial or spinal hemorrhage; and (3) no ongoing need for corticosteroids as treatment for CNS metastases, and corticosteroids are not administered in combination with the combination therapy described herein. ≧ (4) Treatment was discontinued two weeks prior, and there are no ongoing symptoms attributable to CNS metastases; (5) No stereotactic radiotherapy was administered within 7 days prior to day 1 of cycle 1 as described herein, or whole-brain radiotherapy was administered within 14 days; (6) There is no evidence of preliminary progression between the completion of treatment for CNS and screening radiological examinations.

[0126] In one embodiment, the patient described herein is KRas G12C They have previously received treatment with specific inhibitors.

[0127] In another embodiment, the patient described herein has not received chemotherapy, immunotherapy, or biological therapy as an anti-cancer therapy within 3 weeks prior to administration of the combination therapy described herein, except that: (a) Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (b) If any drug-related toxicity has completely subsided, a kinase inhibitor approved by the regulatory authority may be used up to two weeks prior to administration of the combination therapy described herein; or (c) Treatment with the investigational drug within 3 weeks or 5 half-lives, whichever is shorter, prior to administration of the combination therapy described herein.

[0128] In another embodiment, the patient described herein has not received any radiotherapy (other than palliative radiotherapy for bone metastases and radiotherapy for CNS metastases) as cancer therapy within four weeks prior to the initiation of the combination therapy described herein. In yet another embodiment, the patient described herein has not received any palliative radiotherapy for bone metastases within two weeks prior to the initiation of the combination therapy described herein.

[0129] In another embodiment, the patient described herein is not poorly controlled in terms of hypertension (e.g., systolic >150 mmHg or diastolic >100 mmHg). In another embodiment, the patient described herein has no history or evidence of a genetic bleeding diathesis or coagulation disorder with a risk of bleeding. In another embodiment, the patient described herein has no current or recent (e.g., <10 days prior to the start of the study treatment) use of aspirin (>325 mg / day) or clopidogrel (>75 mg / day). In yet another embodiment, the patient described herein has no history of thrombotic disorders within the last six months prior to the start of the study treatment. In another embodiment, the patient described herein does not have 2+ or higher proteinuria on a dipstick urine test during screening or at the evaluation on day 1 of the scheduled cycle 1, and should undergo a 24-hour urine collection, demonstrating ≤1 g of protein in 24 hours prior to administration of the anti-VEGF antibody described herein (e.g., bevacizumab).

[0130] In one embodiment, the patient described herein does not have a severe non-healing wound, active ulcer, or untreated fracture. In another embodiment, the patient described herein does not have a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within six months prior to administration of the anti-VEGF antibody described herein (e.g., bevacizumab). In yet another embodiment, the patient described herein does not have pulmonary hemorrhage / hemoptysis (more than half a teaspoon of red blood cells) within one month prior to administration of the anti-VEGF antibody described herein, e.g., bevacizumab. In yet another embodiment, the patient described herein does not have clear tumor infiltration into the thoracic great vessels or clear cavitation of pulmonary lesions as observed on imaging.

[0131] Furthermore, the use of the combination therapy described herein (UL1) comprising Compound 1 or a pharmaceutically acceptable salt thereof for treating lung cancer as described herein and bevacizumab is provided herein. In one embodiment, the use of the combination therapy described herein (UL2) comprising Compound 1 or a pharmaceutically acceptable salt thereof for treating NSCLC as described herein and bevacizumab is provided herein.

[0132] Furthermore, the use of the combination therapy described herein (UL3) for treating lung cancer described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, comprising a drug regimen including (i) administering compound 1 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 21 of a first 21-day cycle, and (ii) administering bevacizumab as a Q3W on day 1 of a first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 to 20 mg / kg.

[0133] Furthermore, the use of the combination therapy described herein (UL4) for treating lung cancer, comprising Compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, is provided herein, comprising a drug regimen including (i) administering about 50 to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 21 of the first 21-day cycle, and (ii) administering about 15 mg / kg of bevacizumab as a Q3W on day 1 of the first 21-day cycle. In one such embodiment, the drug regimen comprises two or more cycles as described herein.

[0134] Furthermore, the use of the combination therapy described herein, comprising Compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the manufacture of a medicament for the treatment of lung cancer described herein (UL5) is provided herein.

[0135] Furthermore, the use of the combination therapy described herein (UL6) for manufacturing a medicament for treating lung cancer described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, comprising a drug regimen including (i) a QD administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle, and (ii) a Q3W administration of bevacizumab on day 1 of a first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 to 20 mg / kg.

[0136] Furthermore, provided herein are the use of the combination therapy described herein (UL7) for manufacturing a medicament for treating lung cancer described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, the combination therapy comprising a drug regimen including (i) administering about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 21 of the first 21-day cycle, and (ii) administering about 15 mg / kg of bevacizumab as a Q3W on day 1 of the first 21-day cycle. In one such embodiment, the drug regimen comprises two or more cycles as described herein.

[0137] In such embodiments of the use described herein, lung cancer may be NSCLC. In another such embodiment of the use described herein, the patient described herein is KRas G12C The patient is diagnosed with NSCLC mediated by a mutation.

[0138] Furthermore, the use of the combination therapy described herein (UC1) for treating CRC described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, is provided herein.

[0139] Furthermore, the use of the combination therapy described herein (UC2) for treating CRC described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, comprising a drug regimen including (i) a QD administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle, and (ii) a Q3W administration of bevacizumab on day 1 of the first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 to 20 mg / kg.

[0140] Furthermore, the use of the combination therapy described herein (UC3) for treating CRC described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, is provided herein, comprising a drug regimen including (i) administering about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 21 of the first 21-day cycle, and (ii) administering about 15 mg / kg of bevacizumab as a Q3W on day 1 of the first 21-day cycle. In one such embodiment, the drug regimen comprises two or more cycles as described herein.

[0141] Furthermore, the use of the combination therapy described herein (UC4), comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the manufacture of a medicament for treating CRC described herein, is provided herein.

[0142] Furthermore, the use of the combination therapy described herein (UC5) for manufacturing a medicament for treating CRC described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, comprising a drug regimen including (i) a QD administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle, and (ii) a Q3W administration of bevacizumab on day 1 of a first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 to 20 mg / kg.

[0143] Furthermore, provided herein are the use of the combination therapy described herein (UC6) for manufacturing a medicament for treating CRC described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, the combination therapy comprising a drug regimen including (i) administering about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 21 of the first 21-day cycle, and (ii) administering about 15 mg / kg of bevacizumab as a Q3W on day 1 of the first 21-day cycle. In one such embodiment, the drug regimen comprises two or more cycles as described herein.

[0144] Furthermore, the use of the combination therapy described herein (UP1), comprising Compound 1 or a pharmaceutically acceptable salt thereof for the treatment of pancreatic cancer as described herein, and bevacizumab, is provided herein.

[0145] Furthermore, the use of the combination therapy described herein (UP2) for treating pancreatic cancer, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, comprising a drug regimen including (i) a QD administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle, and (ii) a Q3W administration of bevacizumab on day 1 of a first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 to 20 mg / kg.

[0146] Furthermore, the use of the combination therapy described herein (UP3) for treating pancreatic cancer, comprising Compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, is provided herein, comprising a drug regimen including (i) administering about 50 to 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 21 of the first 21-day cycle, and (ii) administering about 15 mg / kg of bevacizumab as a Q3W on day 1 of the first 21-day cycle. In one such embodiment, the drug regimen comprises two or more cycles as described herein.

[0147] Furthermore, the use of the combination therapy described herein (UP4), comprising Compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the manufacture of a medicament for the treatment of pancreatic cancer described herein, is provided herein.

[0148] Furthermore, the use of the combination therapy described herein (UP5) for manufacturing a medicament for treating pancreatic cancer described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, comprising a drug regimen including (i) a QD administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle, and (ii) a Q3W administration of bevacizumab on day 1 of a first 21-day cycle. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 to 20 mg / kg.

[0149] Furthermore, provided herein are the use of the combination therapy described herein (UP6) for manufacturing a medicament for treating pancreatic cancer described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, the combination therapy comprising a drug regimen including (i) administering about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 21 of the first 21-day cycle, and (ii) administering about 15 mg / kg of bevacizumab as a Q3W on day 1 of the first 21-day cycle. In one such embodiment, the drug regimen comprises two or more cycles as described herein.

[0150] Furthermore, the use of the combination therapy described herein (UA1), comprising Compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the treatment of hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer as described herein, is provided herein.

[0151] Furthermore, the use of the combination therapy described herein (UA2) for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer as described herein, comprising a drug regimen including (i) administering compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle as a QD, and (ii) administering bevacizumab on day 1 of a first 21-day cycle as a Q3W. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 to 20 mg / kg.

[0152] Furthermore, the use of the combination therapy described herein (UA3) for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer as described herein, comprising a drug regimen including (i) administering about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle as a QD, and (ii) administering about 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle as a Q3W. In one such embodiment, the drug regimen comprises two or more cycles as described herein.

[0153] Furthermore, the use of the combination therapy described herein (UA4), comprising Compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the manufacture of a medicament for the treatment of hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer as described herein, is provided herein.

[0154] Furthermore, the use of the combination therapy described herein (UA5) for manufacturing a medicament for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer as described herein, comprising a drug regimen including (i) administering compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle as a QD, and (ii) administering bevacizumab on day 1 of a first 21-day cycle as a Q3W. In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 to 500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 to 20 mg / kg.

[0155] Furthermore, provided herein are the use of the combination therapy described herein (UA6) for manufacturing a medicament for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer as described herein, comprising a drug regimen including (i) administering about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of a first 21-day cycle as a QD, and (ii) administering about 15 mg / kg of bevacizumab on day 1 of a first 21-day cycle as a Q3W. In one such embodiment, the drug regimen comprises two or more cycles as described herein.

[0156] The development of combination therapies presents challenges, including, for example, the selection of agents for combination therapies that can lead to improved efficacy while maintaining acceptable toxicity. One particular challenge is the need to identify the gradual toxicity of combinations. In one embodiment of the method described herein, the combination therapy described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab) is administered in a dosing regimen that includes a time-staggered dosing schedule. In such an embodiment, the patient has a reduction in the number or grade of adverse events (AEs) comparable to that of a control (e.g., SOC therapy, treatment with one of the agents described herein (e.g., compound 1 or a pharmaceutically acceptable salt thereof, or bevacizumab) alone).

[0157] In the event of an adverse event, it is generally understood that there are four options: (1) continue treatment with any combination therapy; (2) adjust the dose of one or more drugs in the drug regimen; (3) temporarily discontinue administration of one or more drugs in the drug regimen; or (4) discontinue administration of one or more drugs in the drug regimen. In one embodiment, the amount of compound 1 or a pharmaceutically acceptable salt thereof is not changed. In another embodiment, the amount of bevacizumab administered is not changed. In one embodiment, if administration of bevacizumab is interrupted, the next administration of compound 1 or a pharmaceutically acceptable salt thereof is given on the same day that administration of bevacizumab is resumed. In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered without food (i.e., the patient must not eat at least 2 hours before and 1 hour after administration).

[0158] In one embodiment, the patient described herein experiences gastrointestinal toxicity as an AE of grade 2 or less. In such an embodiment, the gastrointestinal toxicity is diarrhea, nausea, or vomiting. In another embodiment, the patient described herein experiences phototoxicity. In such an embodiment, the patient should wear sunscreen and protective clothing outdoors.

[0159] Patients described herein may also be administered combination therapies including: (a) anticonvulsants or warfarin; (b) oral contraceptives or other possible maintenance therapies; (c) antiemetics and antidiarrheals, provided that such therapies should not be administered prophylactically prior to initial treatment with the study drug; (d) analgesics administered in accordance with standard clinical practice; (e) bisphosphonates and denosumab therapy for bone metastases or osteopenia / osteoporosis; or (f) multivitamins, calcium, and vitamins C, D, and E supplements.

[0160] Patients described herein may not simultaneously take treatments including (1) potent / moderate CYP3A4 inhibitors (e.g., atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troreandmycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluvoxamine, diltiazem, nefazodone, mibeflazil, verapamil, and grapefruit juice or grapefruit supplements), or (2) potent / moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's wort), and cyproterone).

[0161] In another embodiment, the patient described herein is not administered any of the following therapies: (a) Three weeks prior to administration of the combination therapy described herein or five half-lives, whichever is shorter, or any other investigational therapy during such treatment (excluding Compound 1 or a pharmaceutically acceptable salt thereof, or bevacizumab); (b) Combination therapies intended to treat cancer, whether approved by the FDA or experimental, including chemotherapy, radiotherapy, immunotherapy, biological therapy, herbal therapy, or hormone therapy, except as follows: (i) Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (ii) Hormone replacement therapy or oral contraceptives; (c) Radiotherapy for clearly progressive disease, excluding new brain metastases in the following systemic response situations: patients who have shown control of systemic disease (clinical benefit [i.e., ≧ Patients who have received a PR, CR, or SD over a three-month period, but who have developed radiation-treated brain metastases, may continue treatment with compound 1 or a pharmaceutically acceptable salt thereof during the study until they experience either systemic progression of the disease and / or further progression in the brain (based on the investigator's assessment). (d) Quinidine or other antiarrhythmic agents; or (e) Initiation or increase in dose of hematopoietic colony-stimulating factor (CSF; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; salglamostim, pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) starting 7 days prior to day 1 of the first cycle.

[0162] In one embodiment of such a method, a patient is diagnosed with the cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from a subject. In one embodiment of such a method, the sample is taken before administration of any treatment described herein. In another embodiment of such a method, the sample is taken before administration of at least one drug described herein. In some embodiments, tumor samples may be taken at specified intervals during treatment with the combination therapy described herein in order to evaluate the treatment.

[0163] Tumor or cancer is KRas G12CWhether or not a mutation is present can be determined by evaluating the nucleotide sequence encoding the K-Ras protein, by evaluating the amino acid sequence of the K-Ras protein, or by evaluating the characteristics of the predicted K-Ras mutant protein. The sequence of wild-type human K-Ras (e.g., accession number NP 203524) is known in the art. In one such embodiment, a sample from a patient described herein is analyzed for KRas using, for example, immunohistochemistry (IHC) or NGS sequencing. G12C Evaluate the mutations.

[0164] By administering the combination therapies described herein, KRas G12C This specification further provides methods for treating transorgan cancers, including mutations. In one embodiment of such a method, the method includes: (a) KRas in samples taken from patients diagnosed with suspected cancer G12C To measure the presence or absence of mutations, and (b) Administer to the patient the combination therapy described herein comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab.

[0165] In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD in an amount of about 50–500 mg. In another such embodiment, bevacizumab is administered as a Q3W in an amount of about 5–20 mg / kg.

[0166] Furthermore, KRas G12C A method for treating organ-wide cancers, including mutations, (a) KRas in samples taken from patients diagnosed with suspected cancer G12C To measure the presence or absence of mutations, and (b) A method is provided herein that includes administering to a patient a combination therapy described herein, comprising a drug regimen comprising (i) a QD dose of 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle, and (ii) a Q3W dose of 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle.

[0167] In one embodiment provided herein, a patient is diagnosed with complete response (CR) after treatment with combination therapy according to the method provided herein. In one embodiment provided herein, a patient is diagnosed with partial response (PR) after treatment with combination therapy according to the method provided herein. In one embodiment provided herein, a patient is diagnosed with stable disease (SD) after treatment with combination therapy according to the method provided herein.

[0168] Also provided herein are methods for inhibiting tumor growth or inducing tumor regression in patients as described herein by applying the combination therapies described herein. In one embodiment, a method is provided herein for inhibiting tumor growth in patients having cancer as described herein by administering a combination therapy comprising administering compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab in one or more 21-day cycles as described herein. In one embodiment, a method is provided herein for inhibiting tumor growth in patients having NSCLC, CRC, or pancreatic cancer as described herein by administering a combination therapy comprising administering compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab in one or more 21-day cycles as described herein.

[0169] In one embodiment, a method for inducing or improving tumor regression in a patient having the cancer described herein by administering a combination therapy comprising administering compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab in one or more 21-day cycles as described herein. In one embodiment, a method for inducing or improving tumor regression in a patient having NSCLC, CRC, or pancreatic cancer as described herein by administering a combination therapy comprising administering compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab in one or more 21-day cycles as described herein.

[0170] kit The combination therapies described herein may be provided as kits comprising one or more of the agents described herein for administration. In one embodiment, the kit comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) for administration in combination with bevacizumab as described herein. In another embodiment, the kit comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) packaged together with bevacizumab, and the kit comprises separate formulated doses of each agent.

[0171] Furthermore, products or kits comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and an anti-VEGF antibody (e.g., bevacizumab) are also provided herein. In some examples, the product further includes a package insert containing instructions for using the anti-VEGF antibody to treat or delay the progression of a solid tumor (e.g., lung cancer, CRC, or pancreatic cancer as described herein). In one such embodiment, the cancer is NSCLC. In one embodiment, the product further includes a package insert containing instructions for using bevacizumab in combination with compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) to treat or delay the progression of a patient's NSCLC.

[0172] In some examples, an anti-VEGF antibody (e.g., bevacizumab) and compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) are contained in the same container or in separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. Containers may be made from a variety of materials such as glass, plastic (e.g., polyvinyl chloride or polyolefin), or metal alloy (e.g., stainless steel or Hastelloy). In some examples, the container holds the formulation, and labels on or associated with the container may indicate instructions for use. The product or kit may further include other materials desirable from a commercial and user perspective, such as other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some examples, the product further includes one or more other drugs (e.g., additional chemotherapeutic agents or antineoplastic agents). Suitable containers for one or more drugs include, for example, bottles, vials, bags, and syringes.

[0173] Any manufactured product or kit described herein may include instructions for administering compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipinate) and / or an anti-VEGF antibody (e.g., bevacizumab) to a patient in accordance with any method described herein.

[0174] biomarkers In one embodiment, KRas is provided by compound 1 or a pharmaceutically acceptable salt thereof. G12C The alkylation of is measured in the patient. In one such embodiment, the measurement is carried out using a sample and KRas provided herein. G12C The alkylation of is tested. In another embodiment, a ctDNA biomarker (e.g., KRas) is obtained from peripheral blood. G12C ) will be evaluated.

[0175] In one embodiment, KRAS / MAPK target genes (e.g., DUSP6, SPRY4), pathway components (e.g., pERK, pS6), and related biomarkers (e.g., Ki67) are regulated by analyzing paired fresh tumor biopsies taken before and during treatment.

[0176] Embodiment Several exemplary embodiments of the present invention are provided below.

[0177] Embodiment 1: (a) Compound 1 TIFF2026082807000004.tif49170 or a pharmaceutically acceptable salt thereof, (b) Combination therapy including an anti-VEGF antibody.

[0178] Embodiment 2: The combination therapy according to Embodiment 1 or 2, wherein the anti-VEGF antibody is bevacizumab.

[0179] Embodiment 3: The combination therapy according to either Embodiment 1 or Embodiment 2, wherein compound 1 is its adipine salt.

[0180] Embodiment 4: The combination therapy according to any one of Embodiments 1 to 3, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of a first 21-day cycle, and bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle.

[0181] Embodiment 5: The combination therapy according to any one of Embodiments 1 to 4, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

[0182] Embodiment 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 50 mg to 500 mg.

[0183] Embodiment 7: The combination therapy according to any one of Embodiments 1 to 6, wherein 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.

[0184] Embodiment 8: The combination therapy according to any one of Embodiments 2 to 7, wherein bevacizumab is administered Q3W in an amount of about 5 to 20 mg / kg.

[0185] Embodiment 9: The combination therapy according to Embodiment 5, wherein bevacizumab is administered Q3W in an amount of about 10 to 20 mg / kg.

[0186] Embodiment 10: The combination therapy according to any one of Embodiments 2 to 9, wherein bevacizumab is administered intravenously to a patient at a dose of about 15 mg / kg Q3W.

[0187] Embodiment 11: The combination therapy according to any one of Embodiments 1 to 10 for use in lung cancer containing a KRas G12C mutation.

[0188] Embodiment 12: The combination therapy according to Embodiment 11, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0189] Embodiment 13: The combination therapy according to any one of Embodiments 1 to 10 for use in colorectal cancer (CRC) containing a KRas G12C mutation.

[0190] Embodiment 14: The combination therapy according to any one of Embodiments 1 to 10 for use in pancreatic cancer containing a KRas G12C mutation.

[0191] Embodiment 15: The combination therapy according to any one of Embodiments 1 to 10 for use in hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer containing a KRas G12C mutation.

[0192] Embodiment 16: (a) Compound 1 or a pharmaceutically acceptable salt thereof administered QD on days 1 to 21 of the first 21-day cycle, and (b) Bevacizumab administered Q3W on day 1 of the first 21-day cycle comprising a combination therapy.

[0193] Embodiment 17: The combination therapy according to Embodiment 16, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD in amounts of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered as a Q3W in amounts of approximately 15 mg / kg on day 1 of the first 21-day cycle.

[0194] Embodiment 18: KRas G12C A method for treating lung cancer in patients who have lung cancer mediated by mutations, (a) Compound 1 or a pharmaceutically acceptable salt thereof, (b) A method comprising administering an effective amount of combination therapy comprising an anti-VEGF antibody.

[0195] Embodiment 19: The combination therapy according to any one of Embodiment 18, wherein the lung cancer is NSCLC.

[0196] Embodiment 20: The combination therapy according to any one of Embodiments 18, wherein the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer.

[0197] Embodiment 21: In patients with colorectal cancer (CRC), KRas G12C A method for treating mutation-mediated CRC, (a) Compound 1 or a pharmaceutically acceptable salt thereof, (b) A method comprising administering an effective amount of combination therapy comprising an anti-VEGF antibody.

[0198] Embodiment 22: In a patient with such lung cancer, KRas G12C A method for treating pancreatic cancer mediated by mutations, (a) Compound 1 or a pharmaceutically acceptable salt thereof, (b) A method comprising administering an effective dose of combination therapy, including an anti-VEGF antibody.

[0199] Embodiment 23: KRas G12CA method for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer in patients who have such cancers mediated by mutations, (a) Compound 1 or a pharmaceutically acceptable salt thereof, (b) A method comprising administering an effective dose of combination therapy, including an anti-VEGF antibody.

[0200] Embodiment 24: The method according to any one of Embodiments 18 to 23, wherein the anti-VEGF antibody is bevacizumab.

[0201] Embodiment 25: The method according to any one of Embodiments 18 to 24, wherein compound 1 is its adipine salt.

[0202] Embodiment 26: The method according to any one of Embodiments 18 to 25, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of a first 21-day cycle, and bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle.

[0203] Embodiment 27: The method according to any one of Embodiments 18 to 26, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

[0204] Embodiment 28: The method according to any one of Embodiments 18 to 27, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg.

[0205] Embodiment 29: The method according to any one of Embodiments 18 to 28, wherein 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.

[0206] Embodiment 30: The method according to any one of Embodiments 18 to 29, wherein bevacizumab is administered in a dose of approximately 5 to 20 mg / kg in Q3W.

[0207] Embodiment 31: The method according to any one of Embodiments 18 to 30, wherein bevacizumab is administered in a dose of approximately 10 to 20 mg / kg in Q3W.

[0208] Embodiment 32: The method according to any one of Embodiments 18 to 31, wherein bevacizumab is administered intravenously to the patient at a dose of approximately 15 mg / kg in Q3W.

[0209] Embodiment 33: KRas G12C A method for treating such cancer in patients with NSCLC containing mutations, (a) Compound 1 or a pharmaceutically acceptable salt thereof, which is QD compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle, (b) A method comprising administering to the patient an effective dose of combination therapy comprising bevacizumab administered Q3W on day 1 of the first 21-day cycle.

[0210] Embodiment 34: (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD in doses of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle. (b) The method according to Embodiment 33, wherein bevacizumab is administered in a dose of 5-20 mg / kg on day 1 of the first 21-day cycle in Q3W.

[0211] Embodiment 35: The method according to any one of Embodiments 18 to 34, wherein bevacizumab is administered after administration of compound 1 or a pharmaceutically acceptable salt thereof.

[0212] Embodiment 36: A method for treating NSCLC, CRC, or pancreatic cancer in a patient, comprising administering to the patient a therapeutic regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof and an effective amount of an anti-VEGF antibody.

[0213] Embodiment 37: The method according to Embodiment 32, wherein compound 1 is an adipine salt.

[0214] Embodiment 38: The method according to Embodiment 32 or Embodiment 33, wherein the anti-VEGF is bevacizumab.

[0215] Embodiment 39: (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD in doses of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle. (b) The method according to any one of embodiments 36 to 38, wherein bevacizumab is administered in a dose of 5 to 20 mg / kg on day 1 of the first 21-day cycle in Q3W.

[0216] Embodiment 40: The method according to any one of Embodiments 18 to 39, wherein the patient is diagnosed as not having a mutation selected from the group consisting of susceptible EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, NTRK fusions, and RET fusions, or combinations thereof.

[0217] Embodiment 41: Use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab for the treatment of lung cancer, CRC, or pancreatic cancer as described herein.

[0218] Embodiment 42: The use according to Embodiment 41, further comprising a drug regimen comprising (i) administering compound 1 or a pharmaceutically acceptable salt thereof as a QD dose on days 1 to 21 of the first 21-day cycle, and (ii) administering bevacizumab as a Q3W dose on day 1 of the first 21-day cycle.

[0219] Embodiment 43: The use according to Embodiment 41 or Embodiment 42, further comprising (i) administering approximately 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof as a QD dose on days 1 to 21 of the first 21-day cycle, and (ii) administering approximately 5 to 20 mg / kg of bevacizumab as a Q3W dose on day 1 of the first 21-day cycle.

[0220] Embodiment 44: Use of a combination therapy comprising Compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab for the manufacture of a pharmaceutical product for the treatment of lung cancer, CRC, or pancreatic cancer.

[0221] Embodiment 45: The use according to Embodiment 44, further comprising (i) administering compound 1 or a pharmaceutically acceptable salt thereof as a QD dose on days 1 to 21 of the first 21-day cycle, and (ii) administering bevacizumab as a Q3W dose on day 1 of the first 21-day cycle.

[0222] Embodiment 46: The use according to Embodiment 44 or Embodiment 45, further comprising (i) administering about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof as a QD dose on days 1 to 21 of a first 21-day cycle, and (ii) administering about 5 to 20 mg / kg of bevacizumab as a Q3W dose on day 1 of the first 21-day cycle. In such an embodiment, the drug regimen comprises two or more cycles as described herein.

[0223] Embodiment 47: KRas by compound 1 or a pharmaceutically acceptable salt thereof G12C The method according to any one of Embodiments 18 to 40 or the use according to any one of Embodiments 41 to 46, wherein the alkylation of is measured in the patient.

[0224] The following examples are presented as illustrations, not as limitations. [Examples]

[0225] Example 1: Preclinical study

[0226] 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 the maintenance of aggressive tumor growth (Der et al. Proc Natl Acad Sci U S A 1982;79(11):3637-40; 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). Compound 1 is an oral anticancer therapeutic agent that selectively targets KRAS G12C and covalently and irreversibly inhibits KRAS G12C . For the examples described herein, Compound 1 shall refer to the adipate salt of Compound 1 unless otherwise specified. Compound 1 does not target other mutations in KRAS, wild-type forms of KRAS, or other members of the RAS family. Treatment of KRAS G12C positive cells or tumors with Compound 1 results in a decrease in KRAS pathway signaling, inhibition of cell / tumor cell proliferation, and induction of apoptosis. Constitutive RAS signaling in tumors alters the tumor microenvironment in multiple ways, including the induction of multiple angiogenic and immunosuppressive cytokines such as VEGF, IL-6, IL-8, GCSF, and GM-CSF. Therefore, a combination strategy that targets tumor-specific KRAS-mediated proliferation and survival signaling in combination with an agent that effectively targets the supportive tumor stromal pathway is of great therapeutic interest.

[0227] NCI-H2122(KRAS G12C The in vivo antitumor efficacy of compound 1 (50 mg / kg, PO, QD), either alone or in combination with anti-VEGF, was evaluated in an NSCLC xenograft tumor model. Treatment with compound 1 alone resulted in tumor quiescence (98% tumor growth inhibition (TGI)), while treatment with anti-VEGF alone showed slow growth inhibition (70% TGI). These studies demonstrate that the combination of compound 1 and anti-VEGF resulted in an early improvement in the initial tumor response and increased antitumor activity (102% TGI) compared with compound 1 alone. All doses and combinations tested were acceptable based on minimal changes in body weight and overall animal condition.

[0228] Compound 1 (adipate) was a solution at a concentration of 11.5 mg / mL in 0.5% (w / v) methylcellulose. Anti-VEGFA B20.4.1.1 (Mu anti-VEGFA B20.4.1.1; hereinafter referred to as anti-VEGF) was a solution in histidine buffer (20 nM histidine acetate, 240 nM sucrose, 0.02% Tween 20 (trademark), pH 5.5). The oral administration vehicle control was 0.5% (w / v) methylcellulose. Anti-gD isotype control (Hu anti-gD 5B6; hereinafter referred to as isotype control) was a solution in physiological saline.

[0229] Female nude mice, 9-10 weeks old with an average weight of 26.0g, were obtained from the Charles River Laboratory in Hollister, California. The mice were housed in standard rodent micro-isolate cages and acclimated to the study conditions at least 3 days prior to tumor cell transplantation. Only animals that appeared healthy and showed no obvious abnormalities were used in the study.

[0230] Human non-small lung cancer NCI-H2122 cells were obtained from the American Type Culture Collection (Rockville, Maryland) and harbored 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. Subsequently, the cells were transplanted subcutaneously into the right chest of 60 nude mice. Each mouse was injected with 10×10 6 cells at a volume of 100 μL. Tumors were monitored until they reached an average tumor volume of 115 - 228 mm 3 . The mice were divided into four groups of n = 10 mice per group based on tumor volume. The average tumor volume across all four groups was 146 mm 3 at the start of dosing.

[0231] Mice were given vehicle (100 μL of 0.5% MC) or 50 mg / kg of Compound 1 (expressed as the free base equivalent). The MC vehicle and Compound 1 were administered orally (PO) daily (QD) by gavage in a volume of 100 μL for 21 days. The isotope control and anti-VEGF antibody were administered intravenously (IV) at 10 mg / kg for the first dose and then intraperitoneally (IP) at 5 mg / kg twice a week (BIW) for subsequent doses.

[0232] Tumor size and mouse body weight were recorded twice a week throughout the course of the study. When the tumor volume exceeded 2000 mm 3 , or when the weight loss was 20% of their starting weight, the mice were immediately euthanized. ≧

[0233]

Table 1

[0234] All concentrations were calculated based on the average body weight of 23 g of the nude mouse strain used in this study.

[0235] Tumor volume was measured in two dimensions (length and width) using an Ultra Cal-IV caliper (Model 54-10-111; Fred V. Fowler Co.; Newton, Massachusetts) and analyzed using Excel, version 14.2.5 (Microsoft Corporation; Redmond, Washington). Tumor volume was calculated using the following formula: Tumor size (mm) 3 ) = (longer measurement × shorter measurement) 2 ) × 0.5

[0236] An antitumor response was observed, with a partial response (PR) defined as a >50% reduction from the initial tumor volume and a complete response (CR) defined as a 100% reduction in tumor volume.

[0237] The animals' weight was measured using an Adventure Pro AV812 scale (Ohaus Corporation; Pinebrook, New Jersey). The rate of weight change was calculated using the following formula: Weight change (%) = [(Current weight / Initial weight) - 1) × 100]

[0238] This approach used a generalized additive mixed model (GAMM) to analyze transformed tumor volume over time, addressing both repeated measures from the same study subjects and moderate dropout before the end of the study (Lin et al. Wiley Online Library; 1999; 61: 381-400 and Liang Biometrical Journal. Wiley Online Library; 2005; 47: 358-68). Since tumors generally exhibit exponential growth, tumor volumes were subjected to a natural logarithmic transformation before analysis.

[0239] Efficacy estimates were obtained by calculating the percentage difference between the daily mean baseline-adjusted AUCs of the relevant groups fitted to the original (i.e., untransformed) scale over a common period.

[0240] A generalized additive mixed model (GAMM) was also used to analyze live body weight (i.e., grams) over time. After fitting the data, live body weight data at each time point from all individual animals and all group fits were normalized and replotted separately in two different ways: 1) normalized to the baseline weight and reported as the percentage resulting in % body weight change, and 2) normalized to the maximum weight to date and reported as the percentage resulting in % body weight loss.

[0241] The antitumor effect of compound 1 (50 mg / kg, PO, QD) alone was evaluated in nude mice carrying human NCI-H2122 NSCLC xenografts, compared to monotherapy with anti-VEGF (10 mg / kg, IV, initial dose, followed by 5 mg / kg, IP, BIW). Monotherapy resulted in tumor growth inhibition (TGI). Compared to the vehicle control, compound 1 resulted in a 98% TGI with a partial response (PR) of 2 / 10, while anti-VEGF resulted in a 70% TGI with a PR of 0 / 10. In comparison, the combination of compound 1 and anti-VEGF resulted in more consistent antitumor efficacy within the first week of treatment, with only 2 / 10 mice showing an increase in tumor volume compared to 5 / 10 in the compound 1 group and 9 / 10 in the anti-VEGF group. The improvement in antitumor effect compared to monotherapy with compound 1 was 102% TGI with a PR of 1 / 10 (see Figures 1 and 2).

[0242] [Table 2]

[0243] In a study of the combined antitumor efficacy in the NCI-H2122 human NSCLC xenograft tumor model, compound 1 and anti-VEGF demonstrated that they suppressed tumor growth (98% TGI and 70% TGI, respectively) as monotherapy. The combination of compound 1 and anti-VEGF induced an antitumor response, with 80% (8 / 10) mice showing a reduction in initial tumor size compared to 50% (5 / 10) of mice in the compound 1 group and 10% (1 / 10) of mice in the anti-VEGF control group. The antitumor activity of the compound 1 and anti-VEGF combination showed an improvement in antitumor effect (102% TGI) compared to compound 1 alone (98% TGI). These data demonstrate that the combination of compound 1 and anti-VEGF is well-tolerated and improves the initial tumor response and overall antitumor activity in the NCI-H2122 human NSCLC xenograft tumor model.

[0244] Example 2:

[0245] KRAS is the most frequently mutated oncogene in up to 25% of cancers and is associated with resistance to standard treatment options and an overall poor prognosis. While selective inhibitors have been developed as anticancer therapies targeting other nodes of the RAS / MAPK pathway, the KRAS oncoprotein was not considered drug-worthy until the recent discovery of the switch II pocket (Ostrem, et al. Nature 2013;503:548-51). This finding has led to the development of KRAS, specifically KRAS G12C Covalent small molecule inhibitors that target mutations are being evaluated in early clinical development.

[0246] Other KRAS G12C inhibitors The AMG 510 (Sotrasiv) is KRAS G12CIt is a small molecule that irreversibly inhibits by locking it in an inactive GDP-bound state. AMG-510 is currently being investigated in ongoing clinical studies. Patients in these studies received prior lines of anticancer therapy for metastatic disease with a median of 3 (range 0 to 11) before entering the study. Overall, treatment-related adverse events were reported in 56.6% of patients, 11.6% experienced treatment-related grade 3 or 4 events, and 1.6% experienced treatment-related serious adverse events. Grade 3 events occurring in multiple patients included elevated ALT, diarrhea, anemia, elevated AST, and elevated alkaline phosphatase. One patient experienced grade 4 treatment-related elevated ALT, and one patient discontinued AMG 510 due to grade 3 treatment-related elevated ALT and AST. Antitumor activity has been reported, but adverse events associated with AMG-510 exist. The patient demonstrated an objective response, observed in 32.2% of NSCLC patients, with a median duration of response of 10.9 months (ranging from 1.1+ to 13.6). The median progression-free survival (PFS) was reported to be 6.3 months (ranging from 0.0+ to 14.9+) in NSCLC patients (Hong et al. New Eng J Med 2020;383:1207-17).

[0247] MRTX849 is KRAS G12C The mutation-selective small molecule KRAS is being evaluated in clinical studies of patients with progressive solid tumors containing mutations. G12CIt is an inhibitor. Recently, data from a total of 17 patients (including 10 NSCLC patients and 4 CRC patients) were reported, of which 12 patients underwent tumor evaluation during at least one treatment (including 6 NSCLC patients and 4 CRC patients). Most patients had received three or more prior anti-cancer regimens before participating in the study (12 out of 17 patients, 71%). The following treatment-related adverse events were reported in >10% of patients: diarrhea, nausea, elevated AST, vomiting, fatigue, elevated ALT, elevated creatinine, abdominal distension, abdominal pain, elevated ALP, anemia, loss of appetite, dehydration, dry mouth, dysgeusia, dyspnea, QT prolongation, hypomagnesemia, and rash. Grade 3 events included fatigue, loss of appetite, and dyspnea (one patient each). PR-mediated antitumor activity was achieved in 3 out of 6 NSCLC patients and 1 out of 4 CRC patients across all evaluated dose levels (Janne et al. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 2019).

[0248] compound 1 KRAS G12C The specificity of compound 1 against KRAS, along with its mechanism of action, G12C It is expected to provide potent and irreversible inhibition, enabling a broad therapeutic index that maximizes antitumor activity while minimizing treatment-related toxicity. KRAS G12C Specific treatments for positive cancers include KRAS G12C This may provide a more tolerable and effective treatment option for patients with advanced-stage cancer.

[0249] In vitro and in vivo pharmacological studies showed that compound 1 is KRAS G12C It is a very potent and selective covalent inhibitor of KRAS G12C KRAS is better than negative cancer cell lines. G12CIt has been demonstrated to exhibit selectivity exceeding 20,000-fold in growth inhibition against 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 It 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.

[0250] 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. An extensive non-clinical toxicity study was 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.

[0251] Bevacizumab is a recombinant humanized IgG1 monoclonal antibody specifically directed against vascular endothelial growth factor (VEGF), which recognizes all isoforms of VEGF. Bevacizumab contains human framework regions and mouse complementarity-determining regions. Bevacizumab can exert a direct anti-angiogenic effect by binding to the tumor environment and removing VEGF from the tumor environment. Additional anti-tumor activity may be derived from its effects on the tumor vasculature, interstitial pressure, and vascular permeability, providing enhanced delivery of chemotherapy to tumor cells (Jain, Nat Med 2001;7:987-9).

[0252] Bevacizumab is approved for the treatment of several different solid tumor types, including metastatic colorectal cancer, advanced NSCLC, unresectable or metastatic hepatocellular carcinoma, metastatic breast cancer, advanced renal cell carcinoma, ovarian cancer, and recurrent glioblastoma.

[0253] Early Phase I clinical data from ongoing studies of AMG 510 and MRTX849 as monotherapies are available from KRAS G12C The inhibitors have been shown to be tolerable and to possess promising antitumor activity in patients with metastatic NSCLC and CRC (Janne et al. 2019; Hong et at. New Eng J Med 2020;383:1207-17). However, there remains a significant unmet need to improve the antitumor activity and durability reported in NSCLC and CRC using this class of inhibitors as monotherapy while maintaining their tolerable safety profiles in key respects.

[0254] Theoretical basis for combination therapy with bevacizumab The role of increased VEGF expression and poor prognosis has been reported in most solid tumors (Zhan et al. J Thorac Oncol 2009;4:1094-103; Gentzler et al. Curr Treat Options Oncol 2013;14:595-609). Elevated VEGF mRNA levels were detected in tumor cell lines expressing mutant KRAS, but gene disruption of the mutant KRAS allele in human colon cancer cells resulted in decreased VEGF secretion (Rak et al. N Eng J Med 2016;375:1823-33).

[0255] The VEGF pathway also plays a crucial role in enabling and maintaining the immunosuppressive tumor microenvironment through several mechanisms. For example, VEGF-A has been shown to induce FasL expression on endothelial cells, which has the ability to kill effector CD8+ T cells but not T-reg cells. Administration of anti-VEGF-A attenuated tumor endothelial FasL expression, resulting in a significant increase in the influx of tumor-rejecting CD8+ to FoxP3+ T cells, which is FasL-dependent and led to CD8-dependent suppression of tumor growth (Motz et al. 2014). In contrast, bevacizumab can restore and / or maintain the antigen-presenting ability of dendritic cells, resulting in enhanced T cell infiltration in tumors (Oelkrug and Ramage Clin Exp Immunol 2014;178:1-8;Wallin et al. Nat Commun 2016;7:12624). In addition to increased T cell transport to tumors (Manning et al. Clin Cancer Res 2007;13:3951-9), several publications have shown that anti-VEGF therapy can also reduce the frequency of myeloid-derived suppressor cells, decrease the production of inhibitory cytokines, and reduce the expression of inhibitory checkpoints on tumor CD8+ T cells (Roland et al. PLOS One 2009;4:e7669; Voron et al. J Exp Med 2015;212:139-48). Therefore, the immunomodulatory effects of bevacizumab are expected to increase CD8-positive T cell recruitment and mitigate intratumoral immunosuppression.

[0256] KRAS G12C Given the growing evidence suggesting that both inhibition and VEGF inhibition have immunomodulatory effects that can reduce intratumor immunosuppression and increase T cell infiltration, KRAS G12C There is scientific evidence to support combining inhibition with VEGF blockade.

[0257] In in vivo studies, the combination of compound 1 with anti-VEGF monoclonal antibody therapy resulted in an increased initial tumor response and improved overall antitumor efficacy compared to compound 1 alone.

[0258] Compound 1 is a progressive or transmissible KRAS G12C - To be investigated in combination with bevacizumab in patients with positive solid tumors. The dose of bevacizumab in combination with compound 1 will be 15 mg / kg IV on day 1 of each 21-day cycle. Potential co-toxicities include gastrointestinal toxicity, which is expected to be monitorable and manageable with supportive care and potential dose adjustments.

[0259] This study will evaluate the activity of compound 1 in combination with bevacizumab based on the following endpoints: objective response rate (ORR); duration of response (DOR); and progression-free survival (PFS).

[0260] biomarkers This study aims to identify biomarkers that predict the response to compound 1 as a single agent or in combination with bevacizumab (i.e., predictive biomarkers), early surrogates of activity, and those associated with progression to more severe disease states (i.e., prognostic biomarkers), including KRAS. G12C Identify and / or evaluate biomarkers that may be associated with acquired tolerance to an inhibitor (e.g., compound 1), susceptibility to adverse events, or lead to improved adverse event monitoring or investigation (i.e., safety biomarkers), provide evidence of the activity of compound 1 in combination with bevacizumab (i.e., pharmacodynamic [PD] biomarkers), or enhance knowledge and understanding of disease biology and drug safety. Corresponding biomarker endpoints may include relationships between exploratory biomarkers in blood, plasma, and tumor tissue and safety, PK, activity, or other biomarker endpoints.

[0261] Patients are screened for safety outcomes over a period of up to 28 days, the subsequent treatment period, and a safety follow-up period during which they are tracked for safety outcomes after the final dose of the study drug or until they receive another anticancer therapy (whichever comes first).

[0262] If no unacceptable toxicity is detected by the investigators, and no clear disease progression is observed, the patient will continue treatment with compound 1 until the end of the study.

[0263] All patients will be closely monitored for adverse events throughout the study and for the treatment-specific period after the final dose of the study treatment or until the initiation of another anticancer therapy (whichever comes first). Adverse events will be graded according to NCI CTCAE v5.0.

[0264] The starting dose of compound 1 is 50 mg PO QD. A single-patient dose-escalation cohort will be treated with compound 1 at the escalating dose level.

[0265] Patients with locally advanced, relapsed, or metastatic incurable KRas have progressed or become intolerant to at least one prior systemic therapy, which may include monotherapy or combination therapy. G12C This includes patients with positive tumors (e.g., NSCLC, CRC, hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, ovarian cancer, or pancreatic cancer). Patients with NSCLC, CRC, or pancreatic cancer are included in KRas G12C Tests are conducted to identify positive cases.

[0266] KRas from tissue and circulating tumor DNA evaluation G12C Mutation state Approximately 12% of NSCLCs, 4% of CRCs, 2% of pancreatic cancers, and many other solid tumors (each with a prevalence of ≤4%) are KRas G12C It harbors a mutation. Compound 1 is KRas G12C It is a potent and highly selective inhibitor that targets KRAS, but does not target KRAS, the wild-type form of KRAS, or other mutations in other members of the RAS family. Therefore, KRas G12COnly patients with tumors bearing the mutation are eligible for the combination therapies described herein. KRAS mutation status may be determined by FoundationOne® CDx (F1CDx) assay, FDA-approved broad companion diagnostic (CDx) assay, FoundationOne® Liquid CDx (F1L CDx) assay, and other FDA-approved (FDA 2020) or well-validated laboratory development studies performed in a Clinical Laboratory Improvement Amendments (CLIA) validated or equivalently certified laboratory. Previous studies have been conducted in a Clinical Laboratory Improvement Amendment (CLIA)-validated laboratory. G12C The occurrence of the mutation indicates that it is an initial event (Jamal-Hanjani et al. N Engl J Med 2017;376:2109-21), and analysis of stored tissue indicates that compound 1 is for the treatment of KRas G12C - This suggests it is a good substitute for patient selection in patients with positive tumors.

[0267] Pharmacodynamic pathway regulation Compound 1 is KRas G12C KRas suppresses downstream MAPK signaling by alkylation, thereby locking it into its inactive GDP-bound state. G12C It is an inhibitor. In nonclinical models, compound 1 is used to reduce KRas G12C The level of alkylation and the degree of MAPK pathway inhibition correlate with the response to compound 1. Pre- and intra-treatment tumor tissue sampling will allow for evaluation of the correlation between MAPK pathway inhibition and antitumor activity and compound 1 treatment. The degree of MAPK pathway inhibition can be evaluated using RNA analysis of MAPK target genes (e.g., DUSP6, SPRY4) or immunohistochemical (IHC) analysis of downstream phosphorylation markers (e.g., pERK, pS6). Furthermore, intra-treatment tumor tissue biopsy will allow for evaluation of KRas by compound 1. G12C This may allow for direct assessment of the level of alkylation. Evaluation of these PD biomarkers may inform future dose selection.

[0268] Sequencing of genes related to resistance to compound 1 DNA sequencing technologies such as targeted next-generation sequencing (NGS) and whole-exome sequencing may offer unique opportunities to identify biomarkers of response and / or resistance to compound 1. Sequencing of cancer-related genes may lead to the identification of novel and acquired resistance mechanisms to compound 1.

[0269] Protein, RNA, and DNA analysis Evaluating signaling activity in tumor cells within the tumor microenvironment (e.g., MAPK, PI3K / AKT) can provide valuable insights into sensitivity or resistance to compound 1 therapy as monotherapy or in combination. VEGF expression, as assessed by IHC, can be used for the analysis of antitumor activity in subgroups based on VEGF expression.

[0270] In addition to protein mutational activation, changes in RNA expression levels or DNA can also modulate the activity of signaling pathways. Tumor RNA profiling allows for unique subtyping of patients enrolled in the study. Analysis of the potential association between subtypes and patient outcomes can identify the subgroup of patients most likely to respond to compound 1.

[0271] Plasma samples for somatic tumor mutation analysis and other biomarkers There is growing evidence that cell-free DNA obtained from blood samples of cancer patients contains ctDNA representing the DNA and mutational status of cells within tumors (Diehl et al. 2008; Maheswaran et al. 2008). Assays for detecting cancer-related mutations (e.g., KRAS) from plasma have been validated. The results of these assays may correlate with the mutational status determined from analysis of tumor specimens. The use of ctDNA to monitor response to treatment is a very interesting area and could enable early, non-invasive, and quantifiable methods for clinical use to identify specific treatment candidates and monitor the mutational status of cancer over time (Wan et al. Nat Rev Cancer 2017;17:223-38). Analysis of ctDNA collected at various time points during research treatment and after patients have progressed with compound 1 may help identify mechanisms of response to and acquired resistance to research treatment.

[0272] Blood samples for next-generation sequencing Next-generation sequencing (NGS) technology can generate large amounts of sequencing data. Tumor DNA may contain both reported and unreported chromosomal changes due to the tumorigenetic process. To help control sequencing calls in previously unreported genomic changes, blood samples are taken before drug administration to determine whether the changes are somatic.

[0273] Selection Criteria Patients must meet the following study registration criteria: · age ≧ 18 years old; • Diseases that can be evaluated or measured according to RECIST v1.1; • An East Coast Cancer Clinical Trials Group (ECOG) performance status of 0 or 1; · ≧ Average life expectancy of 12 weeks; • Sufficient hematological and organ function within 14 days prior to the start of the study treatment, as defined below: o Absolute number of good pitches ≧ 1200 / μL; o Hemoglobin ≧ 9 g / dL; o Platelet count ≧ 100,000 / μL; o Total bilirubin ≤ 1.5 × ULN; o Serum albumin ≧ 2.5 g / dL; o AST and ALT ≤ 2.5 × ULN, with the following exceptions: Patients with demonstrated liver metastases may have AST and / or ALT ≤ 5.0 × ULN. o Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≧ 50 mL / min (based on Cockcroft-Gault glomerular filtration rate estimation): (140 - age) × (weight in kg) × (0.85 for women) 72 × (Serum creatinine (mg / dL)) • For women of childbearing age: consent to maintain abstinence (refraining from heterosexual intercourse) or use contraception, and to refrain from donating eggs. • For men who have not undergone sterilization: Consent to maintain abstinence (refraining from heterosexual intercourse) or to use contraception, and to refrain from donating sperm. • Confirmation of biomarker eligibility: KRas G12C A valid result from either a central blood laboratory demonstrating the presence of the mutation, or from laboratory testing of blood or tumor tissue at any of the facilities (e.g., a validated polymerase chain reaction (PCR)-based or NGS assay performed in a CLIA or equivalent accredited laboratory).

[0274] Additional selection criteria: • Histologically demonstrated locally advanced, recurrent, or metastatic incurable solid tumors o Patients whose disease has progressed after at least one available standard treatment; or patients for whom standard treatment has been proven ineffective, unacceptable, or inappropriate; or patients for whom clinical trials of the investigational drug constitute an approved standard treatment. If a patient whose condition has progressed after at least one available standard treatment has additional available approved standard treatment options, the research physician must discuss the risks and benefits of these treatments before obtaining informed consent to participate in this study. This discussion must be documented in the patient's documentation. Patients with NSCLC and adenocarcinoma of the colon or rectum must not have known associated secondary oncogenic drivers (e.g., in the case of NSCLC: susceptible EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion, RET fusion; or in the case of adenocarcinoma of the colon or rectum: BRAF V600E mutation, ERBB2 amplification) as determined by FMI NGS assay or by a sponsor-approved valid PCR-based or NGS assay performed in a CLIA-accredited or equivalent laboratory at each institution.

[0275] General exclusion criteria Patients who meet any of the following criteria will be excluded. • Unable to swallow the pill, or unwilling to swallow it. • Inability to comply with research and follow-up procedures • Malabsorption or other symptoms that interfere with enteral absorption • Known, untreated, or active central nervous system (CNS) metastases; Patients with a history of treated CNS metastases must meet all of the following criteria: o Measurable or evaluable diseases outside the CNS; o No history of intracranial hemorrhage or spinal hemorrhage; There is no continued need for corticosteroids as a treatment for CNS metastases, and corticosteroids should be administered before the administration of the drugs described herein. ≧ Treatment was discontinued for two weeks, and there are no ongoing symptoms due to CNS metastasis; o No stereotactic radiotherapy within 7 days prior to day 1 of cycle 1, or no whole-brain radiotherapy within 14 days; There is no evidence of interim progress between the completion of treatment directed at the CNS and screening radiographs. • Leptomeningeal disease or carcinomatous meningitis; • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage every other week or more frequently; If the patient has recovered sufficiently from the procedure, is hemodynamically stable, and has improved symptomatically, a pleural or abdominal catheter may be permitted; • Any active infection that could affect patient safety, or a serious infection requiring intravenous administration of antibiotics within 7 days prior to day 1 of cycle 1; • A history of clinically significant liver disease, including viral or other hepatitis, current alcoholism, or cirrhosis; • Known HIV infection; • Uncontrolled hypercalcemia (ionized calcium >1.5 mmol / L or calcium >12 mg / dL or corrected serum calcium) ≧ Symptomatic hypercalcemia (ULN), or symptomatic hypercalcemia requiring continuous use of bisphosphonate therapy or denosumab; • Significant traumatic injury or major surgical procedure within 4 weeks prior to Cycle 1; Patients with a history of chronic diarrhea, short bowel syndrome, or significant upper gastrointestinal surgery including gastrectomy, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or any active bowel inflammation (including diverticulitis); • Treatment by chemotherapy, immunotherapy, or biological therapy as anticancer therapy within 3 weeks prior to administration of the drugs specified herein, or by endocrine therapy within 2 weeks prior to administration of the drugs specified herein, except as follows: o Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); o Kinase inhibitors approved by regulatory authorities may be used up to two weeks before the start of research treatment; Treatment with the investigational drug within 3 weeks or 5 half-lives (whichever is shorter) prior to administration of the drugs described herein. • Radiotherapy as cancer therapy within 4 weeks prior to administration of the drugs described herein (excluding palliative radiotherapy for bone metastases and radiotherapy for CNS metastases); • Palliative radiation therapy for bone metastases within two weeks prior to administration of compound 1; • Adverse events from previous anti-cancer therapies that have not resolved; • History of other malignancies within the five years prior to screening; • A history of clinically significant cardiovascular dysfunction or active clinically significant cardiovascular dysfunction: o A history of stroke or transient ischemic attack within 6 months prior to administration of the drugs described herein; o A history of myocardial infarction within 6 months prior to administration of the drugs described herein; o Class III or IV heart disease or congestive heart failure requiring drug therapy, as defined by the New York Cardiology Association. o Uncontrolled arrhythmia, history of ventricular arrhythmia requiring drug therapy, or active arrhythmia; o Coronary heart disease with symptomatic or unstable angina; o Congenital long QT syndrome or QT interval > 470 ms corrected using the Frederician formula (QTcF); Current treatments involve drug therapies known to prolong the QT interval; • Pregnant or breastfeeding, or intending to become pregnant within 6 months of the last dose of compound 1 during the study; • Uncontrolled hypertension (e.g., systolic > 150 mmHg or diastolic > 100 mmHg) • A history or evidence of a genetic bleeding diathesis or coagulation disorder that carries a risk of bleeding. • Current or recent use (<10 days prior to the start of the study treatment) of aspirin (>325 mg / day) or clopidogrel (>75 mg / day) • History of thrombotic disorders within the past six months prior to the start of the research treatment • Proteinuria of ≥2+ on a dipstick urine test during screening or evaluation on day 1 of the planned cycle 1 should be subjected to a 24-hour urine collection, demonstrating ≤1g of protein in the 24 hours prior to the start of the study treatment. • Severe non-healing wounds, active ulcers, or untreated fractures • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of the start of research treatment. • Pulmonary hemorrhage / hemoptysis (>1 / 2 red blood cell count) within one month prior to the start of research treatment • Clear tumor infiltration into the thoracic major blood vessels visible in the images. • Clear cavitation of lung lesions visible on imaging

[0276] Research and therapeutic formulations, packaging, and handling

[0277] compound 1 Compound 1 is supplied as active pharmaceutical ingredient (API) powder capsule (PIC) formulations in three strengths: 5 mg, 25 mg, and 100 mg (free base equivalent). Additionally, a film-coated tablet formulation in a 100 mg (free base equivalent) dose strength is also supplied for clinical use. Formulations of Compound 1 should be stored below 86°F (30°C) and protected from moisture.

[0278] To administer Compound 1 at home, a sufficient number of capsules or tablets should be distributed to the patient to last until the next clinic visit or over one cycle. The patient will self-administer Compound 1 as provided herein, except when visiting the clinic. Unless otherwise instructed, the patient should take Compound 1 at approximately the same time each day. The patient will be instructed regarding the number and strength of capsules or tablets to take, according to the assigned dose concentration and schedule.

[0279] Unless otherwise instructed, Compound 1 should be taken on an empty stomach; that is, food should be avoided at least 2 hours and 1 hour before administration. There are no restrictions on fluid intake. Importantly, the capsule or tablet of Compound 1 should be swallowed completely (without chewing) with at least 240 mL (8 fluid ounces) of water. If a patient misses any dose of Compound 1 or vomits up a capsule or tablet, that dose should be skipped and the patient should be instructed to resume administration with the next scheduled dose. Missed doses should not be supplemented.

[0280] Bevacizumab. Bevacizumab is supplied as an IV formulation in a 400 mg / 16 mL vial. Bevacizumab is administered by IV infusion at a fixed dose of 15 mg / kg IV on day 1 of each 21-day cycle, following administration of compound 1. Bevacizumab administration is performed in a monitored setting with trained personnel and immediate access to appropriate equipment and medications for managing potentially serious reactions. Bevacizumab is diluted with 0.9% sodium chloride injection (USP) to a total volume of 100 mL. The initial dose is delivered over 90 ± 15 minutes. If the first infusion is tolerable without infusion-related adverse events (i.e., fever and / or chills), the second infusion may be delivered over 60 ± 10 minutes. If a 60-minute infusion is well tolerable, all subsequent infusions may be delivered over 30 ± 10 minutes. In patients with infusion-related symptoms, bevacizumab infusion may be slowed or interrupted. If injection-related symptoms occur, the patient should be treated according to the best medical advice available.

[0281] If bevacizumab administration is temporarily suspended due to an adverse event in a given cycle, the next medication cycle should not be started until bevacizumab administration can be resumed. Therefore, the current cycle may be extended beyond 21 days, and the patient may continue receiving compound 1. Day 1 of the next cycle should correspond to the point in time when bevacizumab administration is resumed. Dose changes of bevacizumab are not permitted.

[0282] Combination therapy Combination therapy consists of any drug treatments used by the patient in addition to the drugs described herein (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic therapies, nutritional supplements) from seven days before the first dose of at least one drug described herein until the last dose of at least one drug described herein.

[0283] Approved treatments Patients may take the following: (a) anticonvulsants or warfarin; (b) oral contraceptives or other possible maintenance therapies as specified in the eligibility criteria; (c) antiemetics and antidiarrheals should not be administered prophylactically before initial treatment with the study drug; (d) analgesics; (e) bisphosphonates and denosumab therapy for bone metastases, osteopenia, or osteoporosis; or multivitamins, calcium, and vitamins C, D, and E supplements may be permitted.

[0284] Attention to treatment Drug therapies given with due consideration for effects related to CYP enzymes and compound 1 include, for example, (1) potent / moderate CYP3A4 inhibitors (but not limited to atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troleandmycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluvoxamylase (1) Xamine, diltiazem, nefazodone, mibeflazil, verapamil, and grapefruit juice or grapefruit supplements; (2) Strong / moderate CYP3A4 inducers, (but not limited to, rifampine, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's wort), and cyproterone). INR and / or aPTT are within the therapeutic limits (according to facility standards) within 14 days prior to administration of any of the drugs described herein, and the patient is in the pre-initiation of the study treatment. ≧Use of full doses of oral or parenteral anticoagulants for therapeutic purposes, provided that a stable dose of anticoagulant is taken for one week. The list of drug therapies is not intended to be exhaustive.

[0285] Prohibited treatments The use of the following combination therapies is prohibited during the first administration of the drugs described herein and for at least 7 days prior to administration. • Investigational therapy within 3 weeks or 5 half-lives (whichever is shorter) prior to the first dose of the drug described herein. • Combination therapies intended to treat cancer, whether approved by the FDA or experimental, including chemotherapy, radiation therapy, immunotherapy, biological therapy, herbal therapy, or hormone therapy, except for the following: o Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists for endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); o Hormone replacement therapy or oral contraceptives. • Radiotherapy for clearly progressive disease, excluding new brain metastases in the context of systemic response: patients who demonstrated control of systemic disease (clinical benefit [i.e., ≧ Patients who have received a PR, CR, or SD over a three-month period, but who have developed radiation-treated brain metastases, may continue treatment with compound 1 during the study until they experience either systemic progression of the disease and / or further progression in the brain (based on the investigator's assessment); • Quinidine or other antiarrhythmic agents; • Initiation or increase in dose of hematopoietic colony-stimulating factors (CSF; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; salglamostim, pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) starting 7 days prior to day 1 of the first cycle.

[0286] Risks associated with Compound 1 Administration of compound 1 is associated with diarrhea, nausea, vomiting, oral mucosal irritation, minimal to mild transaminase elevation, and phototoxicity.

[0287] Risks associated with bevacizumab Bevacizumab is associated with the following risks: gastrointestinal perforation, surgical and wound healing complications, bleeding (including severe or fatal bleeding such as hemoptysis, gastrointestinal bleeding, hematemesis, CNS bleeding, pulmonary hemorrhage, epistaxis, and vaginal bleeding), non-gastrointestinal fistula formation, arterial thromboembolic events (including stroke, transient ischemic attack, myocardial infarction, and angina), and hypertension.

[0288] The potential co-toxicity associated with the concomitant use of bevacizumab and compound 1 is gastrointestinal toxicity.

[0289] Interruption of treatment If compound 1 is retained for >21 days from the previous study treatment due to toxicity, the study treatment should not be resumed. Compound 1 may be suspended for up to 21 days due to unexpected concomitant medical events unrelated to the toxicity of the study treatment or disease progression.

[0290] Adverse events Adverse events as defined herein refer to any undesirable medical occurrence in a clinical trial subject receiving the drugs described herein in a combination therapy described herein, regardless of the cause attributable to the adverse event. The terms “severe” and “critical” are not synonymous. Severity refers to the intensity of the adverse event (e.g., whether it is assessed as mild, moderate, or severe, or according to the NCI CTCAE), and the event itself may be relatively insignificant (e.g., severe headache without further findings).

[0291] Adverse events to be monitored include nausea, vomiting, diarrhea, stomatitis, mucositis, hepatitis or elevated ALT or AST, elevated bilirubin or clinical jaundice, systemic lupus erythematosus, nephritis, events suggestive of hypersensitivity, infusion-mediated reactions, CRS, influenza-like illness and systemic inflammatory response syndrome, atrial fibrillation, myocarditis, pericarditis, vasculitis, myositis, uveitis, retinitis, optic neuritis, autoimmune hemolytic anemia, Stevens-Johnson syndrome, bullous dermatitis and toxic epidermal necrolysis.

[0292] Throughout this specification and the claims, the words “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense unless otherwise required by context. Embodiments described herein are understood to include embodiments that “consist of” and / or “essentially consist of.”

[0293] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, it should be understood that the upper and lower limits of the range and any other stated or intervening values ​​within that stated range, up to one-tenth of the lower limit unit, are included herein. The upper and lower limits of these smaller ranges, which can be independently included in smaller ranges, are also included herein, subject to the limits specifically excluded in the stated range. If a stated range includes one or both of the limits, the range excluding one or both of those included limits is also included herein.

[0294] Many modifications and other embodiments of the inventions described herein will be conceivable to those skilled in the art, benefiting from the teachings presented in the foregoing description and the accompanying drawings. Therefore, it should be understood that the invention is not to be limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. Certain terms are used herein, but these are used in a general and descriptive sense only and are not intended to be limiting.

Claims

1. (a) Compound 1 or a pharmaceutically acceptable salt thereof, (b) Anti-VEGF antibody and Combination therapy, including

2. The combination therapy according to claim 1, wherein the anti-VEGF antibody is bevacizumab.

3. The combination therapy according to either claim 1 or claim 2, wherein compound 1 is its adipine salt.

4. The combination according to any one of claims 1 to 3, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of a first 21-day cycle, and bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle.

5. The combination therapy according to any one of claims 1 to 4, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

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

7. The combination therapy according to any one of claims 1 to 6, wherein 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.

8. The combination therapy according to any one of claims 2 to 7, wherein bevacizumab is administered in a dose of approximately 5 to 20 mg / kg over Q3 weeks.

9. The combination therapy according to claim 5, wherein bevacizumab is administered in a dose of approximately 10-20 mg / kg over three weeks (Q3W).

10. The combination therapy according to any one of claims 2 to 9, wherein bevacizumab is administered intravenously to the patient at a dose of approximately 15 mg / kg in Q3W.

11. KRas Ｇ１２Ｃ A combination therapy according to any one of claims 1 to 10 for use in lung cancer including mutations.

12. The combination therapy according to claim 11, wherein the lung cancer is non-small cell lung cancer (NSCLC).

13. KRas Ｇ１２Ｃ The combination therapy according to any one of claims 1 to 10 for use in colorectal cancer (CRC) including mutations.

14. KRas Ｇ１２Ｃ The combination therapy according to any one of claims 1 to 10 for use in pancreatic cancer including mutations.

15. KRas Ｇ１２Ｃ The combination therapy according to any one of claims 1 to 10 for use in hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, including mutations.

16. (a) Compound 1 administered via QD on days 1-21 of the first 21-day cycle or a pharmaceutically acceptable salt thereof, (b) Bevacizumab administered Q3W on day 1 of the first 21-day cycle and Combination therapy, including

17. The combination therapy according to claim 16, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in a QD dose of approximately 50 mg to 500 mg on days 1 to 21 of a first 21-day cycle, and bevacizumab is administered in a Q3W dose of approximately 15 mg / kg on day 1 of the first 21-day cycle.

18. KRas Ｇ１２Ｃ A method for treating lung cancer in patients who have lung cancer mediated by mutations, (a) Compound 1 or a pharmaceutically acceptable salt thereof, (b) Anti-VEGF antibody and A method comprising administering an effective amount of combination therapy, including [a specific substance].

19. The combination therapy according to any one of claims 18, wherein the lung cancer is NSCLC.

20. The combination therapy according to any one of claims 18, wherein the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer.

21. KRas in patients with colorectal cancer (CRC) Ｇ１２Ｃ A method for treating mutation-mediated CRC, (a) Compound 1 or a pharmaceutically acceptable salt thereof, (b) Anti-VEGF antibody and A method comprising administering an effective amount of combination therapy, including [a specific substance].

22. In patients with such lung cancer, KRas Ｇ１２Ｃ A method for treating pancreatic cancer mediated by mutations, (a) Compound 1 or a pharmaceutically acceptable salt thereof, (b) Anti-VEGF antibody and A method comprising administering an effective amount of combination therapy, including [a specific substance].

23. KRas Ｇ１２Ｃ A method for treating hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer in patients who have such cancers mediated by mutations, (a) Compound 1 or a pharmaceutically acceptable salt thereof, (b) Anti-VEGF antibody and A method comprising administering an effective amount of combination therapy, including [a specific substance].

24. The method according to any one of claims 18 to 23, wherein the anti-VEGF antibody is bevacizumab.

25. The method according to any one of claims 18 to 24, wherein compound 1 is its adipine salt.

26. The method according to any one of claims 18 to 25, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD on days 1 to 21 of a first 21-day cycle, and bevacizumab is administered as a Q3W on day 1 of the first 21-day cycle.

27. The method according to any one of claims 18 to 26, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered orally as a tablet or capsule.

28. The method according to any one of claims 18 to 27, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg.

29. The method according to any one of claims 18 to 28, wherein 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.

30. The method according to any one of claims 18 to 29, wherein bevacizumab is administered in a dose of approximately 5 to 20 mg / kg over Q3 weeks.

31. The method according to any one of claims 18 to 30, wherein bevacizumab is administered in a dose of approximately 10 to 20 mg / kg over Q3 weeks.

32. The method according to any one of claims 18 to 31, wherein bevacizumab is administered intravenously to the patient at a dose of approximately 15 mg / kg in Q3W.

33. KRas Ｇ１２Ｃ A method of treating such cancer in a patient having NSCLC containing a mutation, (a) Compound 1 or a pharmaceutically acceptable salt thereof, compound 1 or a pharmaceutically acceptable salt thereof that is QD on days 1 to 21 of the first 21-day cycle, (b) Bevacizumab administered Q3W on day 1 of the first 21-day cycle and A method comprising administering an effective amount of combination therapy, including, to the patient.

34. (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD in an amount of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle. (b) The method according to claim 33, wherein bevacizumab is administered Q3W at a dose of 5 to 20 mg / kg on day 1 of the first 21-day cycle.

35. The method according to any one of claims 18 to 34, wherein bevacizumab is administered after administration of compound 1 or a pharmaceutically acceptable salt thereof.

36. A method for treating NSCLC, CRC, or pancreatic cancer in a patient, comprising administering to the patient a therapeutic regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof and an effective amount of an anti-VEGF antibody.

37. The method according to claim 32, wherein compound 1 is an adipine salt.

38. The method according to claim 32 or claim 33, wherein the anti-VEGF is bevacizumab.

39. (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered as a QD in an amount of approximately 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle. (b) The method according to any one of claims 36 to 38, wherein bevacizumab is administered Q3W at a dose of 5 to 20 mg / kg on day 1 of the first 21-day cycle.

40. The method according to any one of claims 18 to 39, wherein the patient is diagnosed as not having a mutation selected from the group consisting of susceptibility EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutations, NTRK fusions, and RET fusions, or combinations thereof.

41. Use of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab for the treatment of lung cancer, CRC, or pancreatic cancer as described herein.

42. The use according to claim 41, further comprising a drug regimen comprising (i) administering compound 1 or a pharmaceutically acceptable salt thereof as a QD dose on days 1 to 21 of a first 21-day cycle, and (ii) administering bevacizumab as a Q3W dose on day 1 of the first 21-day cycle.

43. The use according to claim 41 or claim 42, further comprising: (i) administering approximately 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof as a QD dose on days 1 to 21 of the first 21-day cycle; and (ii) administering approximately 5 to 20 mg / kg of bevacizumab as a Q3W dose on day 1 of the first 21-day cycle.

44. Use of combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof with bevacizumab for the manufacture of a medicament for the treatment of lung cancer, CRC, or pancreatic cancer.

45. The use according to claim 44, comprising (i) administering compound 1 or a pharmaceutically acceptable salt thereof as a QD dose on days 1 to 21 of a first 21-day cycle, and (ii) administering bevacizumab as a Q3W dose on day 1 of the first 21-day cycle.

46. The use according to claim 44 or claim 45, comprising (i) administering about 50 to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof as a QD dose on days 1 to 21 of a first 21-day cycle, and (ii) administering about 5 to 20 mg / kg of bevacizumab as a Q3W dose on day 1 of the first 21-day cycle. In one such embodiment, the administration regimen comprises two or more cycles as described herein.

47. KRas by compound 1 or a pharmaceutically acceptable salt thereof Ｇ１２Ｃ The method according to any one of claims 18 to 40 or the use according to any one of claims 41 to 46, wherein the alkylation of is measured in the patient.

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