Methods for treating solid tumors, including KRAS G12C Combination of inhibitors and VEGF inhibitors

Abstract

Provided herein are combination therapies comprising a KRas G12C inhibitor (e.g., Compound 1, or a pharmaceutically acceptable salt thereof) and a VEGF antagonist (e.g., bevacizumab), and methods of using such combination therapies.

Description

[0001] This application was filed on [date]. Year moon Date, Application Number The invention is entitled "Method for treating solid tumors and including KRAS". G12C This is a divisional application of the Chinese invention patent application for "A composition of inhibitors and VEGF inhibitors". Cross-reference to related applications

[0002] This application requires Year moon U.S. provisional patent application number filed on [date] Priority is claimed by the provisional patent application, which is incorporated herein by reference in its entirety and for all purposes. Technical Field

[0003] This article provides information including KRas G12C Combination therapy of inhibitors (e.g., compound 1) and VEGF antagonists (e.g., bevacizumab) and the method of using the combination therapy. Background Technology

[0004] The Kirsten rat sarcoma virus oncogene homolog (KRAS) is a core component of the RAS / MAPK signaling pathway, an intracellular protein network that transmits extracellular growth factor signals to regulate cell proliferation, differentiation, and survival. Mutations in KRAS can lead to several amino acid alterations, including glycine 12 (G12), glycine 13, and glutamine 61, which are commonly found in solid tumors and 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; Taparosky et al. Nature 1982;300:762-5; Capon et al. Nature 1983;304:507-13). Oncogenic KRAS mutations that cause G12 to become cysteine ​​(G12C) are prevalent in non-small cell lung cancer (NSCLC) (approximately 12%), colorectal cancer (CRC) (approximately 4%), and other types of tumors (≤ 4%) (Bailey et al. Nature 2016;531:47-52; Campbell et al. Nat Genet 2016;48:607-16; Giannikis et al. Cell Reports 2016;15:857-65; Hartmaier et al. Genome Med 2017;9(16); Jordan et al. Cancer Discov 2017;7:596-609).

[0005] Carrying KRas G12C Mutant advanced tumors (hereinafter referred to as KRas) G12C Positive tumors 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, which 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). ​​In addition, advanced KRas... G12C Patients with positive cancer may derive limited benefit from selective chemotherapy and targeted therapy, thus limiting the effective available treatment options (Roman et al. 2018).

[0006] Therefore, it is urgently needed to treat patients carrying KRas. G12CEffective treatments and combination therapies for mutated cancers such as lung cancer, colorectal cancer, hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, ovarian cancer, and pancreatic cancer. Summary of the Invention

[0007] This article provides solutions to these problems, as well as other problems in this field.

[0008] On the one hand, this article provides a combination therapy comprising compound 1 as described herein or a pharmaceutical salt thereof and an anti-VEGF antibody.

[0009] In one such embodiment, the anti-VEGF antibody is bevacizumab. In another such embodiment, compound 1 is its adipate. In yet another such embodiment, compound 1 or its pharmaceutically acceptable salt is administered QD on days 1 through 21 of the first 21-day cycle, and bevacizumab is administered Q3W on day 1 of the first 21-day cycle. In yet another embodiment, compound 1 or its pharmaceutically acceptable salt is administered QD at a dose of about 50 mg to 500 mg on days 1 through 21 of the first 21-day cycle, and bevacizumab is administered Q3W at a dose of about 5 mg / kg to 20 mg / kg on day 1 of the first 21-day cycle. In one such embodiment, bevacizumab is administered Q3W at a dose of 15 mg / kg on day 1 of the first 21-day cycle.

[0010] On the other hand, this article provides a treatment for patients suffering from KRas G12C A method for treating this type of lung cancer in patients with mutation-mediated lung cancer, comprising administering an effective amount of combination therapy comprising compound 1 as described herein or a pharmaceutical salt thereof and an anti-VEGF antibody.

[0011] On the other hand, this article provides a treatment for patients suffering from KRas G12C A method for treating this type of lung cancer in patients with mutation-mediated colorectal cancer, comprising administering an effective amount of combination therapy comprising compound 1 as described herein or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody.

[0012] On the other hand, this article provides a treatment for patients suffering from KRas G12C A method for treating this type of lung cancer in patients with mutation-mediated pancreatic cancer, comprising administering an effective amount of combination therapy comprising compound 1 as described herein or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody.

[0013] On the other hand, this article provides a treatment for patients suffering from KRas G12CA method for treating this type of lung cancer in patients with hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer mediated by mutations, comprising administering an effective amount of combination therapy comprising compound 1 as described herein or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody.

[0014] In such embodiments of the method, the anti-VEGF antibody is bevacizumab. In such embodiments of the method, compound 1 is its adipate. In such embodiments of the method, compound 1 or its pharmaceutically acceptable salt is administered QD on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered Q3W on day 1 of the first 21-day cycle. In yet another embodiment of the method, compound 1 or its pharmaceutically acceptable salt is administered QD at an amount of about 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered Q3W at an amount of about 5 mg / kg to 20 mg / kg on day 1 of the first 21-day cycle. In one such embodiment of the method, bevacizumab is administered Q3W at an amount of 15 mg / kg on day 1 of the first 21-day cycle.

[0015] On the other hand, this article provides a method for treating such cancers in patients with NSCLC, CRC, or pancreatic cancer, the method comprising administering a treatment regimen to the patient comprising an effective amount of compound 1 as described herein or a pharmaceutical salt thereof and an effective amount of an anti-VEGF antibody (e.g., bevacizumab).

[0016] On the other hand, this article provides the use of a combination therapy comprising compound 1 or a pharmaceutical salt thereof and bevacizumab for the treatment of the lung cancer, CRC or pancreatic cancer described herein.

[0017] On the other hand, this article provides the use of a combination therapy comprising compound 1 or a pharmaceutical salt thereof and bevacizumab for the preparation of a medicament for the treatment of lung cancer, CRC, or pancreatic cancer. Attached Figure Description

[0018] Figure 1 shows the effect of compound 1 (adipic acid salt) at a dose of 50 mg / kg alone and in combination with anti-VEGF antibody on NCI-H2122 NSCLC tumor xenografts in nude mice. The vector was 0.5% (w / v) methylcellulose. Individual tumor volume data are shown for the vector / anti-VEGF antibody control (top left), anti-VEGF antibody (bottom left), compound 1 (top right), and compound 1 + anti-VEGF antibody (bottom right). Each group (n=10) was administered the drug over 21 days. Dose levels are expressed as free base equivalents.

[0019] Figure 2 shows tumor volumes in nude mice with NCI-H2122 NSCLC tumors treated with compound 1 (adipate) alone or in combination with an anti-VEGF antibody. Carrier = 0.5% (w / v) methylcellulose; isotype anti-gD control antibody. Fitted tumor volumes are shown after 21 days of oral administration of compound 1 alone (QD) or in combination with anti-VEGF antibody (BIW). Dose levels are expressed in free base equivalents. Detailed Implementation

[0020] definition Unless otherwise defined, all technical or scientific terms used herein have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains. See, for example, Singleton et al., *DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY*, 2nd edition, J. Wiley & Sons (New York, NY 1994); Sambrook et al., *MOLECULAR CLONING*, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, apparatus, and materials similar to or equivalent to those described herein may be used to practice this invention.

[0021] The following definitions are provided to aid in understanding certain terms that are frequently used herein, but are not intended to limit the scope of this disclosure. All references cited herein are incorporated herein by reference in their entirety.

[0022] As used herein, unless otherwise specified, when the terms “about” and “approximately” refer to a dose, amount, or weight percentage of an ingredient in a composition or dosage form, they mean a dose, amount, or weight percentage that provides a pharmacological effect equivalent to that obtained from a specified dose, amount, or weight percentage, as is known to those skilled in the art. The equivalent dose, amount, or weight percentage may be within a range of 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percentage.

[0023] As used in this article, "KRas" G12C "Inhibitor" refers to a covalent inhibitor that specifically binds to the mutant KRas protein, including the Gly-to-Cys mutation corresponding to residue 12.

[0024] "Compound 1" refers to a compound having the following structure: It has the chemical name 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one. In one embodiment, compound 1 is an adipate.

[0025] The term "medicinal" refers to molecular entities and compositions that do not produce adverse, allergic or other adverse reactions when administered to animals such as humans (where appropriate).

[0026] The compounds of the present invention may be in the form of salts, such as pharmaceutical salts. "Pharmaceutical salts" include acid and base addition salts. "Pharmaceutical acid addition salts" refer to salts formed from inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc., which retain the bioavailability and properties of the free base and are not biologically or otherwise desired. The organic acid may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthraquinone, benzoic acid, cinnamic acid, mandelic acid, pyric acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In one embodiment, the salt is formed from adipic acid.

[0027] The term "medicinal base addition salts" includes base addition salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutical organic non-toxic bases include primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydatidamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Specific organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, thiamethoxam, dicyclohexylamine, choline, and caffeine.

[0028] In some embodiments, the salt is selected from hydrochloride, bromate, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, hydrogen sulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, glycoside, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furonate or 3-furonate), naphthyl disulfonate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethanedisulfonate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), hydroxyethyl Isothionate (2-hydroxyethyl sulfonate), 2-trisylbenzenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-amymidine, L-amymidine, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-trisylbenzenesulfonate), napsylate (2-naphthalenesulfonate), camsylate (camsylate-10-sulfonate, e.g., (1S)-(+)-10-camsylate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pyrate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylate).

[0029] The terms “inhibition” and “reduction” or any variations thereof include any measurable reduction or complete inhibition to achieve the desired result. For example, a reduction in activity relative to normal activity may be a reduction of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range inferred therefrom.

[0030] The term "vascular endothelial growth factor" or "VEGF" refers to vascular endothelial growth factor protein A, as exemplified by SwissProt accession number P15692, Gene ID (NCBI): 7422. The term "VEGF" encompasses proteins having the amino acid sequence of SwissProt accession number P15692, Gene ID (NCBI): 7422, as well as their homologues and isotypes. The term "VEGF" also encompasses known isotypes, such as splice isotypes of VEGF, such as VEGF... 111 VEGF 121 VEGF 145 VEGF 165 VEGF 189 and VEGF 206 Along with its naturally occurring alleles and processing forms, including those through VEGF 165 The 110-amino acid human vascular endothelial growth factor produced by the cleavage of cytoplasm is 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 (e.g., mice, rats, or primates). Sometimes, VEGF derived from a specific species is indicated by terms such as hVEGF (for human VEGF), mVEGF (for mouse VEGF), etc. The term "VEGF" refers to a truncated form of a polypeptide comprising 8 to 109 or 1 to 109 amino acids of human vascular endothelial growth factor, which is 165 amino acids. In this application, it can be referred to by, for example, "VEGF..." 109 ”, “VEGF(8-109)”, “VEGF (1-109)” or “VEGF 165The reference to any such form of VEGF is identified by the numbering. The amino acid position of the “truncated” natural VEGF is numbered according to the indication in the natural VEGF sequence. For example, amino acid position 17 (methionine) in the truncated natural VEGF is also position 17 (methionine) in the natural VEGF. The truncated natural VEGF has binding affinity for the KDR and Flt-1 receptors equivalent to that of the natural VEGF. As used herein, the term “VEGF variant” refers to a VEGF polypeptide that includes one or more amino acid mutations in the natural VEGF sequence. Where appropriate, the one or more amino acid mutations include amino acid substitutions. For the purpose of the abbreviated name of the VEGF variants used herein, it should be noted that the numbers refer to the amino acid residue positions along the presumed amino acid sequence of the natural VEGF (provided by Leung et al., ibid. and Houck et al., ibid.). Unless otherwise indicated, the term “VEGF” as used herein refers to VEGF-A.

[0031] "VEGF antagonists" or "VEGF-specific antagonists" refer to molecules that can bind to VEGF, reduce VEGF expression levels, or neutralize, block, inhibit, prevent, reduce, or interfere with VEGF biological activity. This VEGF biological activity includes, but is not limited to, VEGF binding to one or more VEGF receptors, VEGF signaling, VEGF-mediated angiogenesis, and endothelial cell survival or proliferation. For example, molecules capable of neutralizing, blocking, inhibiting, preventing, reducing, or interfering with VEGF biological activity can 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 used in the methods 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 thereby preventing it from binding to one or more receptors, fusion proteins (e.g., VEGF-Trap (Regeneron)), and VEGF. 121- Peregrine. VEGF-specific antagonists also include antagonist variants of VEGF peptides, antisense nucleoside oligomers complementary to at least one segment of a nucleic acid molecule encoding a VEGF peptide; small RNAs complementary to at least one segment of a nucleic acid molecule encoding a VEGF peptide; ribonucleases targeting VEGF; peptide bodies targeting VEGF; and VEGF aptamers. VEGF antagonists also include peptides that bind VEGFR, anti-VEGFR antibodies and their antigen-binding fragments, and derivatives that bind VEGFR to block, inhibit, prevent, reduce, or interfere with VEGF biological activity (e.g., VEGF signaling), or fusion proteins. VEGF-specific antagonists also include non-peptide small molecules that bind to VEGF or VEGFR and are capable of blocking, inhibiting, preventing, reducing, or interfering with VEGF biological activity. Therefore, the term "VEGF activity" specifically includes VEGF-mediated biological activity of VEGF. In some embodiments, the VEGF antagonist reduces or inhibits the expression level or biological activity of VEGF by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more. In some embodiments, the VEGF inhibited by the VEGF-specific antagonist is VEGF (8-10⁹), VEGF (1-10⁹), or VEGF-1. 165 .

[0032] "Anti-VEGF antibody" refers to an antibody capable of binding to VEGF with sufficient affinity and specificity. In some embodiments, the antibody will have a sufficiently high binding affinity to VEGF; for example, the antibody may have a K+ concentration between 100 nM and 1 pM. d The antibody binds to hVEGF. Antibody affinity can be determined, for example, by surface plasmon resonance-based assays (such as the BIAcore® assay described in PCT application publication number WO2005 / 012359); enzyme-linked immunosorbent assays (ELISA); and competitive assays (such as radioimmunoassays (RIA)).

[0033] In some embodiments, anti-VEGF antibodies can be used as therapeutic agents to target and interfere with diseases or symptoms involving VEGF activity. Furthermore, other bioactivity assays can be performed on the antibodies to assess, for example, their effectiveness as a therapeutic agent. Such assays are known in the art and depend on the target antigen and the intended use of the antibody. Examples include HUVEC inhibition assays; tumor cell growth inhibition assays (e.g., as described in WO 89 / 06692); antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) assays (US Patent No. 5,500,362); and stimulating activity or hematopoietic activity assays (see WO 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 P1GF, PDGF, or bFGF. In one embodiment, the anti-VEGF antibody is a monoclonal antibody that binds to the same antigenic determinant as the monoclonal anti-VEGF antibody A4.6.1 produced from the fusion tumor 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 antibodies known as bevacizumab (BV; AVASTIN®).

[0034] The anti-VEGF antibody “bevacizumab”, also known as “rhuMAb VEGF” or “BV”, is marketed under the trade names “AVASTIN®”, “Zirabev®”, and “Mvasi®”. It is a recombinant humanized anti-VEGF monoclonal antibody produced by Presta et al. (Cancer Res. 57:4593-4599, 1997).

[0035] “Bevacizumab” comprises a mutated human IgG1 backbone region and an 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 most 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 February 26, 2005, the entire disclosure of which is expressly incorporated herein by reference. Additional preferred antibodies include G6 or B20 series antibodies (e.g., G6-31, B20-4.1), as described in PCT Application Publication No. WO 2005 / 012359. For more preferred antibodies, see U.S. Patent Nos. 7,060,269, 6,582,959, 6,703,020, and 6,054,297; WO98 / 45332; WO 96 / 30046; WO94 / 10202; EP 0666868B1; U.S. Patent Application Publications 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 that bind to functional antigenic determinants on human VEGF, including residues F17, M18, D19, Y21, Y25, Q89, 191, K101, E103, and C104, or alternatively, residues F17, Y21, Q22, Y25, D63, 183, and Q89. Bevacizumab is approved for the treatment of a variety of solid tumors, 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.

[0036] The term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. In one embodiment, the cancer is lung cancer. In another embodiment, the cancer is NSCLC. In another embodiment, the cancer is colorectal cancer (e.g., metastatic CRC). In another embodiment, the cancer is pancreatic cancer. In yet another embodiment, the cancer is hepatocellular carcinoma (e.g., unresectable or metastatic). In another embodiment, the cancer is breast cancer (e.g., metastatic breast cancer "mBC"). In yet another embodiment, the cancer is renal cell carcinoma (e.g., advanced renal cell carcinoma). In another embodiment, the cancer is ovarian cancer. In yet another embodiment, the cancer is endometrial cancer. As used herein, "cancer" refers to cancer characterized by having KRas G12C Mutant cancer.

[0037] As used herein, “treatment” includes treatment with an effective amount of a therapeutic agent (e.g., bevacizumab or compound 1) or a combination of therapeutic agents (e.g., bevacizumab and compound 1). Treatment can be first-line treatment (e.g., the patient may not have previously received treatment or prior systemic therapy), or second-line or advanced treatment. For example, a patient is considered successfully “treated” if one or more symptoms associated with the cancer described herein are reduced or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), reducing symptoms caused by the disease, improving the quality of life of the patient with the disease, reducing the dosage of other medications required to treat the disease, and / or prolonging the patient's survival.

[0038] The term "delaying disease progression" refers to delaying, blocking, slowing, postponing, stabilizing, and / or postponing the development of the cancer described herein. Such delay can have varying durations depending on the cancer described herein and / or the patient's medical history. As will be apparent to those skilled in the art, adequate or significant delay can effectively encompass prevention, as the patient's cancer has not progressed.

[0039] In this document, "effective amount" means the amount of a therapeutic agent (e.g., bevacizumab and / or compound 1) described herein that achieves a therapeutic effect. In some instances, the effective amount of a therapeutic agent or combination of therapeutic agents is the amount of the agent or combination of agents that achieves the clinical endpoints provided herein. The effective amount described herein may vary depending on factors such as disease state, patient age, sex, weight, and the desired response of the agent in the patient. The effective amount is also the amount by which any toxic or adverse effect of the treatment is exceeded by the beneficial effect of the treatment. In some embodiments, the effective amount of a drug may have the following effects: reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing or terminating) the invasion of cancer cells into surrounding organs; inhibiting (i.e., slowing or terminating) tumor metastasis; inhibiting (i.e., slowing or terminating) tumor growth; and / or alleviating one or more symptoms associated with the disease. The effective amount may be administered in one or more doses. The effective amount of a drug, compound, pharmaceutical composition, or combination therapy described herein may be an amount sufficient to directly or indirectly achieve a therapeutic treatment.

[0040] The "objective response rate" or "ORR" refers to the percentage of patients who have two consecutive complete or partial responses with a confirmed interval of ≥4 weeks, as determined by investigators according to RECIST v1.1.

[0041] "Duration of Remission" or "DOR" refers to the time from the first occurrence of a documented objective remission to the time from disease exacerbation or death from any cause as determined by the investigator according to RECIST v1.1, whichever occurs first.

[0042] "Disease-free survival" or "PFS" refers to the time from registration to the date on which disease progression or death from any cause occurs, as determined by the investigator in RECIST v1.1, whichever comes first.

[0043] As used in this article, “complete remission” or “CR” refers to the disappearance of all target lesions and (if applicable) normalization of tumor marker levels.

[0044] As used in this article, "partial response" or "PR" refers to the persistence of one or more non-target lesions and / or (if applicable) tumor marker levels remaining above normal limits. PR may also refer to a reduction of ≥ 30% in the sum of the diameters of target lesions, without CR, new lesions, or clear deterioration of non-target lesions.

[0045] The term "application period" or "cycle" refers to a period of time that includes the application of one or more of the agents described herein (e.g., compound 1 and bevacizumab) and, if necessary, a period of time that does not include the application of one or more of the agents described herein. For example, a cycle may be 21 days in total and includes the application of one or more of the agents described herein (e.g., compound 1 and bevacizumab) on each day of the cycle. In another example, a cycle may be 28 days in total and includes 21 days of application of one or more of the agents described herein (e.g., compound 1 and bevacizumab) and a 7-day rest period. "Rest period" refers to a period of time during which at least one of the agents described herein (i.e., compound 1 and bevacizumab) is not applied. In one embodiment, a rest period refers to a period of time during which none of the agents described herein (i.e., compound 1 and bevacizumab) are applied. In some instances, a rest period as provided herein may include the application of another agent other than compound 1 or bevacizumab. In such cases, the application of another agent during the rest period should not interfere with or impair the application of the agents described herein. In one instance, as used in this article, the cycle refers to a 21-day cycle excluding rest periods.

[0046] "Dosing regimen" refers to an administration period comprising one or more cycles of administering the drug described herein, wherein each cycle may include administration of the drug described herein at different times and in different amounts.

[0047] "QD" means that the medication described in this article is administered once a day.

[0048] "BID" refers to applying the medication described in this article twice a day.

[0049] "Q3W" means applying the medication described in this article once every three weeks.

[0050] "PO" refers to oral administration of the medication described in this article.

[0051] “IV” means intravenous administration of any of the medications described herein.

[0052] Graded adverse events refer to severity grading tables established by NCI CTCAE. In one implementation, adverse events are graded according to the table below.

[0053] The term "patient" refers to a human patient. Patients can be adults.

[0054] The term "antibody" as used in this article specifically encompasses monoclonal antibodies (including full-length monoclonal antibodies), multiclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, as long as they exhibit the desired biological activity. In one instance, the antibody is a full-length monoclonal antibody.

[0055] As used herein, the term IgG “isotype” or “subtype” refers to any subtype of immunoglobulin as defined by the chemical and antigenic properties of its constant region.

[0056] Antibodies (immunoglobulins) can be classified into different classes based on the amino acid sequence of their heavy chain constant domain. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these classes can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, γ, α, γ, and μ, respectively. The subunit structures and three-dimensional conformations of different classes of immunoglobulins are well known and generally described as described by Abbas et al., Cellular and Mol. Immunology, 4th ed. (WBSaunders, Co., 2000). Antibodies can be part of a larger fusion molecule, formed by the covalent or non-covalent association of the antibody with one or more other proteins or peptides.

[0057] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used interchangeably herein to refer to antibodies that are in their substantially complete form and are not antibody fragments as defined below. The term refers to antibodies that include the Fc region.

[0058] The term "Fc domain" or "Fc region" used herein is used to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of a constant region. This terminology includes native sequence Fc regions and variant Fc regions. On one hand, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the C-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, specifically one or two, amino acids at the C-terminus of the heavy chain. Therefore, antibodies produced by host cells through the expression of a specific nucleic acid molecule encoding the full-length heavy chain may include the full-length heavy chain, or may include cleaved variants of the full-length heavy chain. 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. Unless otherwise stated, the amino acid sequence of the heavy chain including the Fc region herein indicates the absence of a C-terminal lysine (Lys447). On one hand, the heavy chain including the Fc region specified herein in the antibodies disclosed herein includes additional C-terminal glycine-lysine dipeptides (G446 and K447). On another hand, the heavy chain including the Fc region specified herein in the antibodies disclosed herein includes additional C-terminal glycine residue (G446). On yet another hand, the heavy chain including the Fc region specified herein in the antibodies disclosed herein includes additional C-terminal lysine residue (K447). In one embodiment, the Fc region includes a single amino acid substitution of N297A in the heavy chain. Unless otherwise stated herein, the amino acid residues in the Fc region or constant region are numbered according to the EU numbering system (also known as the EU index), as described by Kabat et al. (Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991) (see also above).

[0059] "Naked antibody" refers to an antibody that is not bound to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabeled substance. Naked antibodies may be present in pharmaceutical compositions.

[0060] An "antibody fragment" includes a portion of a complete antibody, preferably including its antigen-binding region. In some instances, the antibody fragments described herein are antigen-binding fragments. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; bivalent antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0061] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homologous population of antibodies, meaning that the individual antibodies in the population are identical and / or bind to the same antigenic determinant, but excludes, for example, antibodies containing naturally occurring mutations or possible variants generated during the production of monoclonal antibody formulations, which are typically present in small quantities. In contrast to multiclonal antibody formulations, which typically comprise different antibodies targeting different determinants (antigenic determinants), each monoclonal antibody in a monoclonal antibody formulation targets a single determinant on an antigen. Therefore, the modifier "monoclonal" indicates that the antibody is characterized and obtained from a substantially homogeneous population of antibodies, and should not be construed as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies intended for use according to the invention can be manufactured using a variety of techniques, including but not limited to fusion tumor methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals comprising all or part of the human immunoglobulin loci.

[0062] As used herein, the term “hypervariable region” or “HVR” refers to the regions in the antibody variable domain that are highly variable in sequence and determine antigen binding specificity, such as the “complementarity-determining region” (“CDR”).

[0063] Generally, antibodies comprise six CDRs; three in the VH region (CDR-H1, CDR-H2, CDR-H3) and three in the VL region (CDR-L1, CDR-L2, CDR-L3). In this document, exemplary CDRs include: (a) A highly variable ring located at amino acid residues 26–32 (L1), 50–52 (L2), 91–96 (L3), 26–32 (H1), 53–55 (H2), and 96–101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901–917 (1987)); (b) CDRs, located at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) Antigen contact, which is present at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2) and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)).

[0064] Unless otherwise stated, the CDR is determined according to the method described by Kabat et al. in the aforementioned literature. Those skilled in the art will understand that the CDR name can also be determined according to the method described by Chothia in the aforementioned literature, McCallum in the aforementioned literature, or any other scientifically accepted naming system.

[0065] "Frame" or "FR" refers to the variable domain residues outside the complementarity-determining region (CDR). The variable domain FR typically consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the CDR and FR sequences usually appear in VH (or VL) in the following order: FR1-CDR-H1 (CDR-L1)-FR2-CDR-H2 (CDR-L2)-FR3-CDR-H3 (CDR-L3)-FR4.

[0066] The terms “variable domain residue numbering as in Kabat” or “amino acid position numbering as in Kabat” and their variations refer to the numbering system used for the compilation of antibodies in Kabat et al. (see above) for heavy chain or light chain variable domains. Using this numbering system, the actual linear amino acid sequence may include fewer or additional amino acids corresponding to shortenings or insertions of the FR or HVR of the variable domain. For example, the heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat number of the antibody residues can be determined by comparing the sequence homology regions of a given antibody with a “standard” Kabat numbering sequence.

[0067] The Kabat numbering system is generally used when referring to residues in the variable domain (roughly 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 above by Kabat et al.). “EU index as in Kabat” refers to the residue numbering of human IgG1 EU antibodies.

[0068] The term "instructions for use" refers to instructions typically included in the commercial packaging of a therapeutic product, which include information on the indications, usage, dosage, route of administration, combination therapy, contraindications, and / or warnings for using such a therapeutic product.

[0069] As used herein, “in combination with” means administering another treatment in addition to one treatment, for example, a treatment regimen including the administration of a VEGF antagonist (e.g., bevacizumab) as described herein with compound 1 or a pharmaceutically acceptable salt thereof. Therefore, “in combination with” means administering another treatment before, during, or after administering one treatment to a patient.

[0070] A drug administered "concurrently" with one or more other drugs may be administered during the same treatment cycle, on the same day of treatment, or, as appropriate, concurrently with one or more other drugs. For example, in a cancer therapy administered every three weeks, each concurrently administered drug may be administered on day 1 of the three-week cycle.

[0071] Combination therapy This document provides a combination therapy (composition) comprising compound 1 described herein or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-VEGF antagonist. This document further provides a combination therapy (composition) comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-VEGF antibody (e.g., bevacizumab).

[0072] This document considers and describes various anti-VEGF antibodies. In some instances, the anti-VEGF antibody is a monoclonal antibody. In some instances, 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 instances, the anti-VEGF antibody is a humanized antibody. In some instances, the anti-VEGF antibody is a human antibody. In one embodiment, the anti-VEGF is bevacizumab (e.g., AVASTIN®, ZIRABEV® (bevacizumab-bvzr), or MVASI® (bevacizumab-awwb)).

[0073] On one hand, this article provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab. In one embodiment, the combination therapy described herein is used to treat certain individuals including those with KRas G12C Mutated solid tumors. In one implementation, the combination therapy described herein is used to treat certain KRas-containing tumors as described herein. G12C The type of lung cancer with mutations. In one such implementation, lung cancer includes KRas. G12C Mutant non-small cell lung cancer (NSCLC). In another embodiment, the combination therapy described herein is used to treat KRas-related cancers. G12C Mutant colorectal cancer. In another embodiment, the combination therapy described herein is used to treat KRas-related cancers. G12C Mutant pancreatic cancer.

[0074] In another embodiment, the combination therapy described herein is used to treat KRas G12C Mutated hepatocellular carcinoma. In another embodiment, the combination therapy described herein is used to treat KRas-related hepatocellular carcinoma. G12CMutated breast cancer. In another embodiment, the combination therapy described herein is used to treat KRas-related breast cancer. G12C Mutated renal cell carcinoma. In another embodiment, the combination therapy described herein is used to treat KRas-related diseases. G12C Mutated endometrial cancer. In another embodiment, the combination therapy described herein is used to treat KRas-related endometrial cancer. G12C Mutant ovarian cancer.

[0075] On one hand, this article provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof, administered via QD on days 1 through 21 of the first 21-day cycle, and an anti-VEGF antibody. In such embodiments, the combination therapy is used to treat conditions as described herein, including KRas G12C Mutated solid tumors (e.g., lung cancer, colorectal cancer, pancreatic cancer).

[0076] On the one hand, this article provides a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof administered on days 1 through 21 of the first 21-day cycle (QD) and bevacizumab administered on day 1 (Q3W) of the first 21-day cycle.

[0077] In one embodiment of the combination therapy described herein, compound 1 or its pharmaceutical salt is administered at a fixed dose, QD. In one embodiment, administration is by oral administration (PO), wherein compound 1 or its pharmaceutical salt is formulated as a tablet or capsule. In such an embodiment, compound 1 or its pharmaceutical salt is formulated as a film-coated tablet pharmaceutical salt (and administered in the aforementioned form).

[0078] In one embodiment of the combination therapy described herein, compound 1 or its pharmaceutically acceptable salt is administered in doses of approximately 5 mg to 600 mg, 5 mg to 500 mg, 5 mg to 400 mg, 5 mg to 300 mg, 5 mg to 250 mg, 5 mg to 200 mg, 5 mg to 150 mg, 5 mg to 100 mg, 5 mg to 50 mg, 5 mg to 25 mg, 25 mg to 600 mg, 25 mg to 500 mg, 25 mg to 400 mg, 25 mg to 300 mg, 25 mg to 250 mg, 25 mg to 200 mg, 25 mg to 150 mg, 25 mg to 100 mg, 25 mg to 50 mg, 50 mg to 600 mg, 50 mg to 500 mg, 50 mg to 400 mg, 50 mg to 300 mg, 50 mg to 250 mg, 50 mg The compound is administered in doses of up to 200 mg, 50 mg to 150 mg, or 50 mg to 100 mg QD. In another embodiment, compound 1 or its pharmaceutically acceptable salt is administered in doses of about 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg. In another embodiment, compound 1 or its pharmaceutically acceptable salt is administered in doses of about 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg. In yet another embodiment, compound 1 or its pharmaceutically acceptable salt is administered in doses 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 adipic acid salt. In such embodiments, the amount of compound 1 or its pharmaceutically acceptable salt is administered relative to the amount in free base form. In one embodiment, compound 1 or its pharmaceutical salt is administered by BID in amounts described herein (e.g., 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg).

[0079] In one embodiment of the combination therapy described herein, the anti-VEGF antibody is administered according to the product information leaflet. In a preferred embodiment, the anti-VEGF antibody is bevacizumab. In one such embodiment, bevacizumab is administered at a fixed dose of 15 mg / kg according to the product information leaflet. In one such embodiment, bevacizumab is administered over 90 minutes ± 15 minutes.

[0080] As a general recommendation, the effective dose of anti-VEGF antibodies (such as bevacizumab) administered to humans is in the range of about 1 mg / kg to about 50 mg / kg of patient body weight, whether administered as a single dose or multiple doses.

[0081] In some exemplary embodiments, for example, the anti-VEGF antibody is administered once daily, weekly, every two weeks, every three weeks, or every four weeks at doses ranging from about 1 mg / kg to about 45 mg / kg, from about 1 mg / kg to about 40 mg / kg, from about 1 mg / kg to about 35 mg / kg, from about 1 mg / kg to about 30 mg / kg, from about 1 mg / kg to about 25 mg / kg, from about 1 mg / kg to about 20 mg / kg, from about 1 mg / kg to about 15 mg / kg, from about 1 mg / kg to about 10 mg / kg, from about 1 mg / kg to about 5 mg / kg, or from about 5 mg / kg to about 15 mg / kg. In one such embodiment, the anti-VEGF antibody is administered once every two weeks or every three weeks at a dose ranging from about 5 mg / kg to about 15 mg / kg. In another such embodiment, the anti-VEGF antibody is administered once every two weeks or every three weeks at a dose ranging from about 10 mg / kg to about 20 mg / kg.

[0082] In one embodiment, the anti-VEGF antibody is administered every three weeks at a dose of approximately 15 mg / kg (Q3W). In another embodiment, the anti-VEGF antibody is administered every two weeks at a dose of approximately 10 mg / kg (Q2W). In such embodiments, the anti-VEGF antibody is bevacizumab.

[0083] In a preferred embodiment, the combination therapy described herein comprises a compound 1 as described herein or a pharmaceutically acceptable salt thereof, administered via QD, and bevacizumab, wherein bevacizumab is administered intravenously to the patient at a dose of approximately 15 mg / kg Q3W.

[0084] In one implementation, the combination therapy described herein is used to treat KRas G12C Mutant lung cancer. In one particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab, wherein the combination therapy is used to treat lung cancer as described herein, including KRas... G12C Mutated lung cancer. 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 stage II. In one embodiment, the lung cancer is stage III or stage IV.

[0085] On the one hand, this article provides a method for treating KRas G12CCombination therapy for mutated lung cancer, wherein the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab. In one such embodiment, the lung cancer is NSCLC.

[0086] On the other hand, this article provides a treatment for KRas G12C A combination therapy for mutated lung cancer, wherein the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1 through 21 of the first 21-day cycle (QD), and bevacizumab is administered on day 1 of the first 21-day cycle (Q3W). In a preferred embodiment, the lung cancer is NSCLC.

[0087] On the other hand, this article provides a treatment for KRas G12C A combination therapy for mutated lung cancer, wherein the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD at a dose of about 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered Q3W at a dose of about 15 mg / kg on day 1 of the first 21-day cycle. In a preferred embodiment, the lung cancer is NSCLC. In one embodiment, bevacizumab is administered according to the product information label.

[0088] In such implementations, the combination therapy is used to treat conditions including KRas as described herein. G12C For mutated lung cancer, this combination therapy may further include the administration of one or both of carboplatin and paclitaxel.

[0089] In one implementation, the combination therapy described herein is used to treat KRas G12C Mutated CRC. In one particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab, wherein the combination therapy is used to treat CRC as described herein, including KRas G12C Mutated CRC. In one such implementation, the CRC is metastatic CRC (mCRC). In one implementation, the combination therapy is used for treatment of KRas-related CRC. G12C The combination therapy is used as a first-line treatment for mutated CRC. In another embodiment, the combination therapy is used for treatment of KRas-related CRC. G12CSecond-line treatment for mutated CRC. In one such implementation, the patient has a prior history of progressive disease and has received bevacizumab as a first-line therapy.

[0090] On the other hand, this article provides a treatment for KRas G12C Combination therapy for mutated CRC, wherein the combination therapy comprises 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 at a dose of about 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 about 15 mg / kg on day 1 of the first 21-day cycle.

[0091] In such implementations, the combination therapy is used to treat KRas G12C For mutated CRC, this combination therapy may further include the administration of chemotherapy based on fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin.

[0092] In one implementation, the combination therapy described herein is used to treat KRas G12C Mutated pancreatic cancer. In one particular embodiment, the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab, wherein the combination therapy is used to treat KRas-related cancers as described herein. G12C Mutant pancreatic cancer.

[0093] On the other hand, this article provides a treatment for KRas G12C Combination therapy for mutated pancreatic cancer, wherein the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1 through 21 of the first 21-day cycle (QD), and bevacizumab is administered on day 1 of the first 21-day cycle (Q3W).

[0094] On the other hand, this article provides a treatment for KRas G12CCombination therapy for mutated pancreatic cancer, wherein the combination therapy comprises 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 at a dose of about 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 about 5 mg / kg to 20 mg / kg on day 1 of the first 21-day cycle. In one such embodiment, as described herein, bevacizumab is administered Q3W at a dose of about 15 mg / kg. In one embodiment, bevacizumab is administered according to the product information label.

[0095] On the other hand, this article provides a treatment for KRas G12C Combination therapy for mutated hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, wherein the combination therapy comprises compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt), wherein compound 1 or a pharmaceutically acceptable salt thereof is administered QD at a dose of about 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered Q3W at a dose of about 5 mg / kg to 20 mg / kg on day 1 of the first 21-day cycle. In one such embodiment, as described herein, bevacizumab is administered Q3W at a dose of about 15 mg / kg. In one embodiment, bevacizumab is administered according to the product information label.

[0096] Treatment This article also provides treatment options for patients with the solid tumors described herein, including KRas. G12C Methods for treating mutated solid tumors (e.g., lung cancer, CRC, pancreatic cancer, hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer). In one embodiment, a method is provided for treating patients with such solid tumors, including those with KRas. G12C A method for treating mutated lung cancer, CRC, pancreatic cancer, hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, comprising administering an effective amount of combination therapy to the patient, the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and an anti-VEGF antibody (e.g., bevacizumab) as described herein.

[0097] On the one hand, this article provides a treatment for patients with this type of lung cancer, including KRas. G12CA method for treating mutated lung cancer, comprising administering an effective amount of combination therapy to the patient, the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and the anti-VEGF antibody described herein. In one aspect, this article provides a treatment for patients with this type of lung cancer using KRas... G12C A method for treating mutation-mediated lung cancer, comprising administering an effective amount of combination therapy to the patient, the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and bevacizumab.

[0098] In one embodiment of the method provided herein, the lung cancer is non-small cell lung cancer (NSCLC). In one such 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 one such embodiment, the cancer is 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 still another embodiment, the lung cancer is adenoma, carcinoid tumor, or undifferentiated carcinoma. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer.

[0099] This article also provides a treatment for patients with KRas G12C A method for treating such cancer in patients with mutated NSCLC, wherein the method comprises administering an effective amount of a combination therapy as described herein to the patient, the combination therapy comprising the following dosing regimen: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle; and (ii) administering an effective amount of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one embodiment of the method provided herein, the method is used for treating adenocarcinoma. In one embodiment of the method provided herein, the method comprises two or more cycles. In one such embodiment, the method is used for treating first-line NSCLC.

[0100] This article also provides a treatment for patients with KRas G12C A method for treating this type of cancer in patients with mutated NSCLC, wherein the method comprises administering an effective amount of a combination therapy as described herein to the patient, the combination therapy comprising the following dosing regimens: (i) administering approximately 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administering approximately 5 mg / kg to 20 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W).

[0101] In treatments including KRas as described in this article G12C In one embodiment of the method for treating mutated lung cancer, the method further includes administering an effective amount of one or both of carboplatin and paclitaxel to the patient.

[0102] On the other hand, this article provides a treatment for patients with CRC, including KRas G12C A method for treating mutated colorectal cancer (CRC) includes administering an effective amount of a combination therapy to the patient, the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and the anti-VEGF antibody described herein. In another embodiment of such a method, this document provides a method for treating CRC comprising administering an effective amount of a combination therapy to the patient, the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and bevacizumab.

[0103] This article also provides a treatment for patients with KRas G12C A method for treating this type of cancer in patients with mutated CRC, wherein the method comprises administering an effective amount of a combination therapy as described herein to the patient, the combination therapy comprising the following dosing regimen: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administering an effective amount of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, bevacizumab is administered at an amount of about 5 mg / kg to 20 mg / kg, as described herein. In another such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered at an amount of about 50 mg to 500 mg, as described herein. In one embodiment, bevacizumab is administered at an amount of about 15 mg / kg.

[0104] In the treatment of including KRas G12C In one embodiment of such a method for mutated CRC, the method further includes administering an effective amount of chemotherapy based on fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin to the patient.

[0105] This article also provides a treatment for patients with KRas G12CA method for treating pancreatic cancer in a patient with mutated pancreatic cancer, the method comprising administering an effective amount of a combination therapy to the patient, the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and the anti-VEGF antibody described herein. In another embodiment of such a method, this document provides a method for treating pancreatic cancer comprising administering an effective amount of a combination therapy to the patient, the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and bevacizumab.

[0106] In another embodiment, a treatment for patients suffering from KRas is provided. G12C A method for treating such pancreatic cancer in a patient with mutated pancreatic cancer, wherein the method comprises administering an effective amount of a combination therapy as described herein to the patient, the combination therapy comprising the following dosing regimen: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle (QD); and (ii) administering an effective amount of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, as described herein, bevacizumab is administered at an amount of about 5 mg / kg to 20 mg / kg. In one embodiment, bevacizumab is administered at an amount of about 15 mg / kg. In another such embodiment, as described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered at an amount of about 50 mg to 500 mg.

[0107] This article also provides a treatment for patients with KRas G12C A method for treating such cancers in patients with mutated hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, the method comprising administering an effective amount of a combination therapy to the patient, the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and the anti-VEGF antibody described herein. In another embodiment of such a method, this document provides a method for treating such cancers in patients with hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, the method comprising administering an effective amount of a combination therapy to the patient, the combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipic acid salt) and bevacizumab.

[0108] In another embodiment, a treatment for patients suffering from such cancers includes KRas G12CA method for treating mutated hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, wherein the method comprises administering an effective amount of a combination therapy as described herein to the patient, the combination therapy comprising the following dosing regimen: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle (QD); and (ii) administering an effective amount of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, as described herein, bevacizumab is administered in an amount of about 10 mg to 20 mg. In one embodiment, bevacizumab is administered in an amount of about 15 mg / kg. In another such embodiment, as described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50 mg to 500 mg.

[0109] In one embodiment of the method described herein, compound 1 or a pharmaceutically acceptable salt thereof is administered at a fixed dose (QD). In one embodiment, administration is by oral administration (PO), wherein compound 1 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, compound 1 or its pharmaceutical salt is used 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, 25 mg to 300 mg, 25 mg to 250 mg, 25 mg to 200 mg, 25 mg to 150 mg, 25 mg to 100 mg, 25 mg to 50 mg, 50 mg to 600 mg, 50 mg to 500 mg, 50 mg to 400 mg, 50 mg to 300 mg, 50 mg to 250 mg, 50 mg The compound is administered in doses of up to 200 mg, 50 mg to 150 mg, or 50 mg to 100 mg QD. In another embodiment, compound 1 or its pharmaceutical salt is administered in doses of about 5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, or 500 mg. In another embodiment, compound 1 or its pharmaceutical salt is administered in doses of about 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg. In yet another embodiment, compound 1 or its pharmaceutical salt is administered in doses of about 50 mg, 100 mg, or 400 mg. In a preferred embodiment, compound 1 or its pharmaceutical salt of the combination therapy described herein is administered as an adipic acid salt. In such embodiments, the amount of compound 1 or its pharmaceutical salt is administered relative to the amount in free base form.

[0110] In one embodiment of the methods described herein, bevacizumab is administered once daily, weekly, every two weeks, every three weeks, or every four weeks at a dose of about 1 mg / kg to about 45 mg / kg, about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to about 35 mg / kg, about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 25 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 15 mg / kg, about 1 mg / kg to about 10 mg / kg, about 1 mg / kg to about 5 mg / kg, or about 5 mg / kg to about 15 mg / kg. In one such embodiment, bevacizumab is administered once every two weeks or every three weeks at a dose of about 5 mg / kg to about 15 mg / kg. In another such embodiment, bevacizumab is administered once every two weeks or every three weeks at a dose of about 10 mg / kg to about 20 mg / kg.

[0111] 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).

[0112] This article also provides a treatment for patients with KRas G12C A method for treating such cancer in patients with mutated NSCLC, wherein the method comprises administering an effective amount of a combination therapy as described herein to the patient, the combination therapy comprising the following dosing regimen: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof at QD on days 1 to 21 of the first 21-day cycle; and (ii) administering an effective amount of bevacizumab at 15 mg / kg at Q3W on day 1 of the first 21-day cycle. In one embodiment of the method provided herein, the method is used for treating adenocarcinoma.

[0113] This article also provides a treatment for patients with KRas G12C A method for treating this type of cancer in patients with mutated CRC, wherein the method comprises administering an effective amount of a combination therapy as described herein to the patient, the combination therapy comprising the following dosing regimen: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof at QD on days 1 to 21 of the first 21-day cycle; and (ii) administering an effective amount of bevacizumab at Q3W on day 1 of the first 21-day cycle.

[0114] This article also provides a treatment for patients with KRas G12C A method for treating such cancer in a patient with mutated pancreatic cancer, wherein the method comprises administering an effective amount of a combination therapy as described herein to the patient, the combination therapy comprising the following dosing regimen: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof at days 1 to 21 of the first 21-day cycle; and (ii) administering an effective amount of bevacizumab at day 1 of the first 21-day cycle at day 3W.

[0115] This article also provides a treatment for patients with KRas G12C A method for treating lung cancer in patients with mutated hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, wherein the method comprises administering an effective amount of a combination therapy as described herein to the patient, the combination therapy comprising the following dosing regimen: (i) administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof at QD on days 1 to 21 of the first 21-day cycle; and (ii) administering an effective amount of bevacizumab at Q3W on day 1 of the first 21-day cycle.

[0116] The methods provided herein may include administering the combination therapy described herein as part of a dosing regimen. In one such embodiment, the dosing regimen comprises one or more cycles. In another embodiment, the dosing regimen comprises at least two cycles. Alternatively, this document provides a dosing regimen comprising 2, 3, 4, 5, 6, 8, 10, 12, 16, 18, 20, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles. Yet another aspect, the dosing regimen comprises approximately 2 to 72, approximately 2 to 66, approximately 2 to 60, approximately 2 to 54, approximately 2 to 48, approximately 2 to 42, approximately 2 to 36, approximately 2 to 30, approximately 2 to 24, approximately 2 to 18, approximately 2 to 12, or approximately 2 to 6 cycles. In one embodiment, the dosing regimen includes administering the combination therapy described herein for any number of cycles until the desired remission (e.g., PFS, OS, ORR, and / or DOR) is achieved (e.g., an improvement in PFS, OS, ORR, and / or DOR compared to the control group described herein). In another embodiment, the dosing regimen includes administering the combination therapy described herein for any number of cycles until toxicity occurs or the patient experiences one or more adverse events (AEs) that prevent further administration. In yet another embodiment, the dosing regimen includes administering the combination therapy described herein for any number of cycles until disease progression.

[0117] In one embodiment of the method described herein, bevacizumab is administered to the patient in a total of 1 to 50 doses, for example, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 15 doses, 3 to 25 doses, 3 to 20 ...25 doses, 3 to 15 doses, 3 to 25 doses, 10 to 10 doses, 3 to 5 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses, 4 to 10 doses, 4 to 5 doses, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 50 doses, 15 15 to 45 doses, 15 to 40 doses, 15 to 35 doses, 15 to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 to 50 doses, 20 to 45 doses, 20 to 40 doses, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 50 doses, 25 to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 to 30 doses, 30 to 50 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 45 doses, 35 to 40 doses, 40 to 50 doses, 40 to 45 doses or 45 to 50 doses. In a preferred embodiment, the dose is administered intravenously.

[0118] In some embodiments, the therapeutic agents of the combination therapy described herein (e.g., compound 1 or its pharmaceutically acceptable salt and bevacizumab) can be administered in any suitable manner known in the art. For example, bevacizumab and compound 1 or its pharmaceutically acceptable salt can be administered sequentially (on different dates) or simultaneously (on the same day or within the same treatment cycle). In one embodiment, bevacizumab is administered after the administration of compound 1 or its pharmaceutically acceptable salt. In some instances, bevacizumab administered after the administration of compound 1 or its pharmaceutically acceptable salt can be administered on the same day. In one embodiment, bevacizumab can be administered on the same day after the administration of compound 1 or its pharmaceutically acceptable salt. For example, compound 1 or its pharmaceutically acceptable salt can be administered on day 1 of each cycle before the administration of bevacizumab on day 1 of each cycle, and then compound 1 or its pharmaceutically acceptable salt can be administered QD for the next 20 days of a 21-day cycle.

[0119] In a preferred embodiment, bevacizumab is administered intravenously after compound 1 or its pharmaceutically acceptable salt (e.g., about 60 minutes). In one instance, bevacizumab may be administered intravenously over 90 minutes ± 15 minutes. If the first infusion is tolerated, a second intravenous administration of bevacizumab is administered over 60 minutes ± 10 minutes. If the 60-minute administration is tolerated, all subsequent infusions may be delivered over 30 minutes ± 10 minutes. In some instances, bevacizumab is administered as an intravenous bolus or bolus.

[0120] This article also provides treatment for patients with KRas G12C A method for treating such cancer in a patient with mutated lung cancer, the method comprising administering to the patient an effective amount of a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipic acid salt) and an anti-VEGF antibody (e.g., bevacizumab) as described herein. In one embodiment of such a method, compound 1 is an adipic acid salt, 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 a QD manner as described herein and in an amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, bevacizumab is administered in a Q3W manner as described herein and in an amount as described herein (e.g., 5 mg / kg 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 may be including KRas G12C Mutant NSCLC.

[0121] This article also provides treatment for patients with KRas G12CA method for treating this type of cancer in a patient with mutated CRC, the method comprising administering to the patient an effective amount of a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipic acid salt) and an anti-VEGF antibody (e.g., bevacizumab) as described herein. In one embodiment of this method, compound 1 is an adipic acid salt, and the anti-VEGF antibody as described herein is bevacizumab. In another embodiment of this method, compound 1 or a pharmaceutically acceptable salt thereof is administered in a QD manner as described herein and in an amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of this method, bevacizumab is administered in a Q3W manner as described herein and in an amount as described herein (e.g., 5 mg / kg to 20 mg / kg). In this method, compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab may be administered as described herein.

[0122] This article also provides treatment for patients with KRas G12C A method for treating such cancer in a patient with mutated pancreatic cancer, the method comprising administering to the patient an effective amount of a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipic acid salt) and an anti-VEGF antibody (e.g., bevacizumab) as described herein. In one embodiment of such a method, compound 1 is an adipic acid salt, 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 a QD manner as described herein and in an amount as described herein (e.g., 50 mg to 500 mg). In yet another embodiment of such a method, bevacizumab is administered in a Q3W manner as described herein and in an amount as described herein (e.g., 5 mg / kg to 20 mg / kg). In such methods, compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab may be administered as described herein.

[0123] This article also provides treatment for patients with KRas G12CMethods for treating such cancers in patients with mutated hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer, comprising administering to the patient an effective amount of a treatment regimen comprising an effective amount of compound 1 or a pharmaceutically acceptable salt thereof (e.g., adipic acid salt) and an anti-VEGF antibody (e.g., bevacizumab) as described herein. In one embodiment of such a method, compound 1 is an adipic acid salt, 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 a QD manner as described herein and in an amount as described herein (e.g., 50 mg to 500 mg). In another embodiment of such a method, bevacizumab is administered in a Q3W manner as described herein and in an amount as described herein (e.g., 5 mg / kg to 20 mg / kg). In such methods, compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab may be administered as described herein.

[0124] In some instances, the treatment regimen includes the administration of one or more additional therapies, wherein the additional therapies are one or more side effect limiters (e.g., agents designed to reduce the occurrence and / or severity of treatment side effects, such as antiemetics, corticosteroids (e.g., prednisone or equivalent agents, e.g., at doses of 1 mg / kg to 2 mg / kg / day), hormone replacement drugs, etc.).

[0125] Patients described in this article must be evaluated and have a proven KRas as described in this article. G12C Mutation testing results. Patients with confirmed NSCLC described herein must not have known secondary oncogenic drivers (e.g., for NSCLC: sensitized EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion, RET fusion; for colorectal adenocarcinoma: BRAF V600E mutation, ERBB2 amplification). In one embodiment, such secondary oncogenic drivers are determined using NGS (e.g., by Foundation Medicine, Inc. (FMI) NGS).

[0126] In one implementation, the patients described herein have no known and untreated or active central nervous system (CNS) metastases (that have progressed or require anticonvulsants or corticosteroids to control symptoms). Patients who have a history of treated CNS metastases may be treated using the methods described herein, wherein such patients: (1) have a measurable or evaluable disease outside the CNS; (2) have no history of intracranial or spinal hemorrhage; (3) do not require ongoing corticosteroid treatment for CNS metastases, have discontinued corticosteroids for ≥ 2 weeks prior to administration of the combination therapy described herein, and have no persistent symptoms caused by CNS metastases; (4) have not received stereotactic radiotherapy within 7 days prior to day 1 of cycle 1 described herein or whole-brain radiotherapy within 14 days; and (5) have no evidence of transitional progression between completion of CNS-directed therapy and screening radiographic studies.

[0127] In one implementation scheme, the patients described herein have received KRas G12C Treatment with specific inhibitors.

[0128] In another implementation, the patients described herein have not received chemotherapy, immunotherapy, or biotherapy as anticancer therapy within 3 weeks prior to administration of the combination therapy described herein, or have not received endocrine therapy within 2 weeks prior to administration of the combination therapy described herein, except in the following circumstances: (a) Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists to treat endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (b) Regulatoryly approved kinase drugs may be used up to two weeks prior to administration of the combination therapy described herein, provided that any drug-related toxicities have completely subsided; 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.

[0129] In another embodiment, the patients described herein have not received radiation therapy (other than the palliative radiation for bone metastases and radiation for CNS metastases) as cancer therapy within 4 weeks prior to initiating the combination therapy described herein. In yet another embodiment, the patients described herein have not received palliative radiation for bone metastases within 2 weeks prior to initiating the combination therapy described herein.

[0130] In another embodiment, the patients described herein do not have poorly controlled hypertension (e.g., systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg). In another embodiment, the patients described herein have no history or evidence of a hereditary bleeding predisposition or coagulation disorder with a risk of bleeding. In another embodiment, the patients described herein have not used aspirin (>325 mg / day) or clopidogrel (>75 mg / day) currently or recently (e.g., <10 days prior to the start of study treatment). In yet another embodiment, the patients described herein have no history of thrombotic disease within the most recent 6 months prior to the start of study treatment. In another embodiment, the patients described herein do not have ≥2+ proteinuria in a test strip urine analysis during screening, or, on day 1 of the planned cycle 1, an assessment should be made to collect 24-hour urine, and the patient must express ≤1 g of protein within 24 hours prior to administration of an anti-VEGF antibody (e.g., bevacizumab) as described herein.

[0131] In one embodiment, the patient described herein has no severe, non-healing wounds, active ulcers, or untreated fractures. In another embodiment, the patient described herein has no history of abdominal fistulas, gastrointestinal perforation, or intra-abdominal abscesses within 6 months of administration of an anti-VEGF antibody (e.g., bevacizumab) as described herein. In yet another embodiment, the patient described herein has no pulmonary hemorrhage / hemoptysis (>1 / 2 teaspoon of red blood) within one month of administration of an anti-VEGF antibody (e.g., bevacizumab) as described herein. In yet another embodiment, the patient described herein does not show clear tumor infiltration into the thoracic vessels or clear cavitation of lung lesions on imaging.

[0132] This document further provides the use of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the treatment of lung cancer as described herein (UL1). In one embodiment, the use of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the treatment of NSCLC as described herein (UL2).

[0133] This document further provides the use (UL3) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the treatment of lung cancer as described herein, comprising the following dosing regimen: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle (QD); and (ii) administration of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 mg / kg to 20 mg / kg.

[0134] This document further provides the use (UL4) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the treatment of lung cancer as described herein, comprising the following dosing regimens: (i) administration of about 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 (QD); and (ii) administration of about 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0135] This document further provides the use (UL5) of the combination therapy described herein, comprising compound 1 or a pharmaceutical salt thereof and bevacizumab, for the preparation of a medicament for the treatment of lung cancer as described herein.

[0136] This document further provides the use (UL6) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the preparation of a medicament for the treatment of lung cancer as described herein, comprising the following dosing regimens: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle (QD); and (ii) administration of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 mg / kg to 20 mg / kg.

[0137] This document further provides the use (UL7) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the preparation of a medicament for the treatment of lung cancer as described herein, comprising the following dosing regimens: (i) administration of about 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 (QD); and (ii) administration of about 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0138] In such an embodiment of the use described herein, the lung cancer may be NSCLC. In another such embodiment of the use described herein, the patient described herein is diagnosed with KRas. G12C NSCLC mediated by mutation.

[0139] This article further provides the use of the combination therapy described herein, comprising compound 1 or its pharmaceutical salt and bevacizumab, for the treatment of CRC as described herein (UC1).

[0140] This document further provides the use (UC2) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the treatment of CRC as described herein, comprising the following dosing regimen: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle (QD); and (ii) administration of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 mg / kg to 20 mg / kg.

[0141] This document further provides the use (UC3) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the treatment of CRC as described herein, comprising the following dosing regimens: (i) administration of approximately 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 (QD); and (ii) administration of approximately 15 mg / kg bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0142] This article further provides the use of the combination therapy described herein, comprising compound 1 or a pharmaceutical salt thereof and bevacizumab, in the preparation of a medicament for the treatment of CRC as described herein (UC4).

[0143] This document further provides the use (UC5) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the preparation of a medicament for the treatment of CRC as described herein, comprising the following dosing regimens: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle (QD); and (ii) administration of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 mg / kg to 20 mg / kg.

[0144] This document further provides the use (UC6) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the preparation of a medicament for the treatment of CRC as described herein, comprising the following dosing regimens: (i) administration of about 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 (QD); and (ii) administration of about 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0145] This article further provides the use of the combination therapy described herein, including compound 1 or its pharmaceutical salt and bevacizumab, for the treatment of pancreatic cancer as described herein (UP1).

[0146] This document further provides the use of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the treatment of pancreatic cancer as described herein (UP2), comprising the following dosing regimen: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle (QD); and (ii) administration of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 mg / kg to 20 mg / kg.

[0147] This document further provides the use of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the treatment of pancreatic cancer as described herein (UP3), comprising the following dosing regimens: (i) administration of about 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 (QD); and (ii) administration of about 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0148] This article further provides the use of the combination therapy described herein, including compound 1 or its pharmaceutical salt and bevacizumab, in the preparation of a medicament for the treatment of pancreatic cancer as described herein (UP4).

[0149] This document further provides the use (UP5) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the preparation of a medicament for the treatment of pancreatic cancer as described herein, comprising the following dosing regimens: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle (QD); and (ii) administration of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 mg / kg to 20 mg / kg.

[0150] This document further provides the use (UP6) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the preparation of a medicament for the treatment of pancreatic cancer as described herein, comprising the following dosing regimens: (i) administration of about 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 (QD); and (ii) administration of about 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0151] This article further provides the use of the combination therapy described herein, comprising compound 1 or its pharmaceutical salt and bevacizumab, for the treatment of hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer or ovarian cancer as described herein (UA1).

[0152] This document further provides the use (UA2) of the combination therapy described herein, 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, comprising the following dosing regimens: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle (QD); and (ii) administration of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 mg / kg to 20 mg / kg.

[0153] This document further provides the use (UA3) of the combination therapy described herein, 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, comprising the following dosing regimens: (i) administration of about 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 (QD); and (ii) administration of about 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0154] This article further provides the use of the combination therapy described herein, comprising compound 1 or a pharmaceutical salt thereof and bevacizumab, for the preparation of a medicament for the treatment of hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer as described herein (UA4).

[0155] This document further provides the use (UA5) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the preparation of a medicament for the treatment of hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer as described herein, comprising the following dosing regimens: (i) administration of compound 1 or a pharmaceutically acceptable salt thereof on days 1 through 21 of the first 21-day cycle (QD); and (ii) administration of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 50-500 mg. In another such embodiment, bevacizumab is administered in an amount of about 5 mg / kg to 20 mg / kg.

[0156] This document further provides the use (UA6) of the combination therapy described herein, comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab, for the preparation of a medicament for the treatment of hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer as described herein, comprising the following dosing regimens: (i) administration of about 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 (QD); and (ii) administration of about 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

[0157] Developing combination therapies is challenging, including, for example, selecting agents for combination therapies that improve efficacy while maintaining acceptable toxicity. A specific challenge is the need to differentiate the incremental toxicity of the combination. In one embodiment of the methods described herein, the combination therapy described herein (e.g., compound 1 or its pharmaceutically acceptable salt and bevacizumab) is administered with a dosing regimen that includes staggered dosing schedules. In one such embodiment, patients experience a reduced number or lower grade of adverse events (AEs) compared to a control (e.g., SOC therapy, treated alone with one of the agents described herein (e.g., compound 1 or its pharmaceutically acceptable salt or bevacizumab)).

[0158] Generally, it is understood that in the event of an adverse event, there are four options: (1) continue treatment as is, with combination therapy as appropriate; (2) adjust the dosage of one or more agents in the dosing regimen; (3) suspend the administration of one or more agents in the dosing regimen; or (4) discontinue the administration of one or more agents in the dosing regimen. In one embodiment, the amount of compound 1 or its pharmaceutically acceptable salt is not modified. In another embodiment, the amount of bevacizumab administered is not modified. In one embodiment, in the event of interruption of bevacizumab administration, the next administration of compound 1 or its pharmaceutically acceptable salt occurs on the same day as the resumption of bevacizumab administration. In one embodiment, compound 1 or its pharmaceutically acceptable salt is not administered with food (i.e., the patient must not eat for at least 2 hours before and 1 hour after administration).

[0159] In one embodiment, the patient described herein experienced gastrointestinal toxicity as an adverse event (AE) of grade 2 or less. In one such embodiment, gastrointestinal toxicity is diarrhea, nausea, or vomiting. In another embodiment, the patient described herein experienced phototoxicity. In such an embodiment, the patient should apply sunscreen and wear protective clothing when outdoors.

[0160] Combination therapy may be administered to the patients described herein, which includes: (a) antiepileptic drugs or warfarin; (b) oral contraceptives or other permitted maintenance therapy; (c) antiemetics and antidiarrheals, provided that such drugs are not administered prophylactically prior to initial treatment with the investigational drug; (d) analgesics administered in accordance with standard clinical practice; (e) bisphosphonates and denosumab for the treatment of bone metastases or osteoporosis; or (f) multivitamins, calcium, and vitamin C, D, and E supplements.

[0161] Patients described in this article must not receive the following treatments concurrently, including: (1) potent / intermediate-potency CYP3A4 inhibitors (e.g., atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troleandomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluvoxamine, diltiazem, nefazodone, mibefradil, verapamil). (and grapefruit juice or grapefruit supplement) or (2) potent / medium potency CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's Wort), and cyproterone).

[0162] In another implementation, the patient described herein shall not be given any of the following treatments: (a) Any other investigational therapy (excluding compound 1 or its pharmaceutical salt or bevacizumab) administered within 3 weeks prior to or within five half-lives (whichever is shorter) of the combination therapy described herein or during such treatment. (b) Combination therapies intended for the treatment of cancer (whether FDA-approved or investigational), including chemotherapy, radiation therapy, immunotherapy, biotherapy, herbal remedies, or hormone therapy, except in the following cases: (i) Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists to treat endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); (ii) Hormone replacement therapy or oral contraceptives; (c) Radiotherapy for a well-defined progressive disease, except for new brain metastases in the following systemic response scenarios: Patients whose systemic disease has been demonstrated to be under control (defined as having clinical benefit [i.e., PR, CR or SD ≥3 months]) but who have developed radiotherapy-available brain metastases will be permitted to continue receiving Compound 1 or its pharmaceutical salt during the study period until their disease progresses systemically and / or further progression occurs in the brain (based on investigator assessment).

[0163] (d) Quinidine or other antiarrhythmic agents; or (e) Starting or increasing the dose of hematopoietic colony-stimulating factors (CSF; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; sargramostim, pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) 7 days before day 1 of cycle 1. In one embodiment of this method, the patient is diagnosed with the cancer described herein. In another embodiment of this method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is collected prior to the administration of any of the treatments described herein. In another such embodiment, the sample is collected prior to the administration of at least one of the pharmaceutical agents described herein. In some embodiments, tumor samples may be collected at specified intervals during treatment with the combination therapy described herein to assess treatment efficacy.

[0164] Determine if a tumor or cancer includes KRas G12C Mutation can be assessed by evaluating the nucleotide sequence encoding the K-Ras protein, evaluating the amino acid sequence of the K-Ras protein, or assessing the characteristics of a putative K-Ras mutant protein. The sequence of wild-type human K-Ras (e.g., accession number NP203524) is known in the art. In one such embodiment, KRas from samples from the patients described herein is evaluated using, for example, immunohistochemistry (IHC) or NGS sequencing. G12C mutation.

[0165] This article further provides information on the treatment of KRas by administering combination therapies as described herein. G12CA method for detecting mutated tumors that are not definitively cancerous. One embodiment of such a method includes: (a) Determining the presence of KRas in samples collected from suspected cancer patients. G12C Mutation; and (b) Administer the combination therapy described herein to the patient, which comprises an effective amount of compound 1 or a pharmaceutical salt thereof and bevacizumab.

[0166] In one such embodiment, compound 1 or its pharmaceutically acceptable salt is administered at a dose of about 50-500 mg QD. In another such embodiment, bevacizumab is administered at a dose of about 5 mg / kg to 20 mg / kg Q3W.

[0167] This article further provides treatment options including KRas. G12C A method for identifying cancerous mutated tumors, wherein the method includes: (a) Determining the presence of KRas in samples collected from suspected cancer patients. G12C Mutation; and (b) Administer to the patient the combination therapy as described herein, comprising the following dosing regimens: (i) administering 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administering 15 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W).

[0168] In one embodiment of the method provided herein, after treatment with combination therapy according to the method provided herein, the patient is diagnosed with complete remission (CR). In one embodiment of the method provided herein, after treatment with combination therapy according to the method provided herein, the patient is diagnosed with partial remission (PR). In one embodiment of the method provided herein, after treatment with combination therapy according to the method provided herein, the patient is diagnosed with severe septicemia (SD).

[0169] This document also provides methods for inhibiting tumor growth or producing tumor regression in patients described herein by administering the combination therapy described herein. In one embodiment, this document provides a method for inhibiting tumor growth in a patient with the cancer described herein by administering a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab over one or more 21-day cycles as described herein. In another embodiment, this document provides a method for inhibiting tumor growth in a patient with NSCLC, CRC, or pancreatic cancer described herein by administering a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab over one or more 21-day cycles as described herein.

[0170] In one embodiment, this document provides a method for inducing or improving tumor regression in a patient with the cancer described herein by administering a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab over one or more 21-day cycles as described herein. In another embodiment, this document provides a method for inducing or improving tumor regression in a patient with NSCLC, CRC, or pancreatic cancer described herein by administering a combination therapy comprising compound 1 or a pharmaceutically acceptable salt thereof and bevacizumab over one or more 21-day cycles as described herein.

[0171] Reagent test kit The combination therapies described herein can be provided as kits comprising one or more of the substances 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 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, wherein the kit comprises individually formulated doses of each agent.

[0172] This document also provides an article or kit comprising compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate) and an anti-VEGF antibody (e.g., bevacizumab). In some instances, the article further includes a package insert containing instructions for treating or delaying 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 article further includes a package insert containing instructions for treating or delaying the progression of NSCLC in a patient using bevacizumab in combination with compound 1 or a pharmaceutically acceptable salt thereof (e.g., compound 1 adipate).

[0173] In some instances, anti-VEGF antibodies (e.g., bevacizumab) are contained in the same or a different container as compound 1 or its pharmaceutically acceptable salt (e.g., compound 1 adipate). Suitable containers include, for example, bottles, vials, bags, and syringes. Containers can be formed from a variety of materials, such as glass, plastics (e.g., polyvinyl chloride or polyolefins), or metal alloys (e.g., stainless steel or Hastelloy). In some instances, the container holds the formulation, and a label on or associated with the container indicates the direction of use. The product or kit may further include other materials required commercially and by the user, including additional buffers, diluents, filters, needles, syringes, and a product information leaflet with instructions for use. In some instances, the product further includes one or more other pharmaceutical agents (e.g., additional chemotherapeutic agents or antitumor agents). Suitable containers for one or more pharmaceutical agents include, for example, bottles, vials, bags, and syringes.

[0174] Any product or kit described herein may include instructions for administering compound 1 or a pharmaceutical salt thereof (e.g., compound 1 adipate) and / or an anti-VEGF antibody (e.g., bevacizumab) to a patient according to any of the methods described herein.

[0175] biomarkers In one embodiment, the KRas effect induced by compound 1 or its pharmaceutical salt in a patient is measured. G12C Alkylation. In one such embodiment, the measurements are performed using a sample and KRas as provided herein is detected. G12C Alkylation. In another embodiment, ctDNA biomarkers (e.g., KRas) from peripheral blood are alkylated. G12C An evaluation will be conducted.

[0176] In one implementation, 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 pre-treatment and in-treatment fresh tumor biopsies.

[0177] Implementation Plan The following provides some exemplary embodiments of the present invention.

[0178] Implementation Plan 1: A combination therapy comprising: (a) Compound 1 , Or its medicinal salt; and (b) Anti-VEGF antibody.

[0179] Implementation Plan 2: A combination therapy as described in Implementation Plan 1 or 2, wherein the anti-VEGF antibody is bevacizumab.

[0180] Implementation scheme 3: The combination therapy as described in any one of implementation scheme 1 or implementation scheme 2, wherein compound 1 is its adipic acid salt.

[0181] Implementation Scheme 4: The combination of any one of Implementation Schemes 1 to 3, wherein compound 1 or its pharmaceutical salt is administered on days 1 to 21 of the first 21-day cycle (QD), and bevacizumab is administered on day 1 of the first 21-day cycle (Q3W).

[0182] Implementation Scheme 5: A combination therapy as described in any one of Implementation Schemes 1 to 4, wherein compound 1 or its pharmaceutical salt is administered orally as a tablet or capsule.

[0183] Implementation Scheme 6: The combination therapy as described in any one of Implementation Schemes 1 to 5, wherein compound 1 or its pharmaceutical salt is administered in an amount of about 50 mg to 500 mg.

[0184] Implementation Scheme 7: The combination therapy as described in any one of Implementation Schemes 1 to 6, wherein compound 1 or its pharmaceutical salt 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.

[0185] Implementation scheme 8: The combination therapy as described in any one of implementation schemes 2 to 7, wherein bevacizumab is administered at a dose of about 5 mg / kg to 20 mg / kg Q3W.

[0186] Implementation Plan 9: A combination therapy as described in Implementation Plan 5, wherein bevacizumab is administered at a dose of approximately 10 mg / kg to 20 mg / kg Q3W.

[0187] Implementation scheme 10: The combination therapy as described in any one of implementation schemes 2 to 9, wherein bevacizumab is administered intravenously to the patient at a dose of about 15 mg / kg Q3W.

[0188] Implementation Scheme 11: A combination therapy as described in any one of Implementation Schemes 1 to 10, used for KRas G12C Mutant lung cancer.

[0189] Implementation Plan 12: A combination therapy as described in Implementation Plan 11, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[0190] Implementation Scheme 13: A combination therapy as described in any one of Implementation Schemes 1 to 10, used for KRas G12C Mutant colorectal cancer (CRC).

[0191] Implementation Scheme 14: A combination therapy as described in any one of Implementation Schemes 1 to 10, used for KRas G12C Mutant pancreatic cancer.

[0192] Implementation Scheme 15: A combination therapy as described in any one of Implementation Schemes 1 to 10, used for KRas G12C Mutated hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer.

[0193] Implementation Scheme 16: A combination therapy comprising: (a) Compound 1 or a pharmaceutically acceptable salt thereof, administered via QD on days 1 through 21 of the first 21-day cycle; and (b) Bevacizumab, administered on day 1 (Q3W) of the first 21-day cycle.

[0194] Implementation Scheme 17: The combination therapy as in Implementation Scheme 16, wherein compound 1 or its pharmaceutical salt is administered QD at a dose of about 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle, and bevacizumab is administered Q3W at a dose of about 15 mg / kg on day 1 of the first 21-day cycle.

[0195] Implementation Plan 18: A treatment for patients suffering from KRas G12C A method for treating this type of lung cancer in patients with mutation-mediated lung cancer, the method comprising administering an effective dose of a combination therapy, the combination therapy comprising: (a) Compound 1 or its medicinal salt; and (b) Anti-VEGF antibody.

[0196] Implementation Scheme 19: The combination therapy as described in any one of Implementation Scheme 18, wherein the lung cancer is NSCLC.

[0197] Implementation Plan 20: The combination therapy as described in any one of Implementation Plan 18, wherein the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer.

[0198] Implementation Scheme 21: A treatment for patients with CRC using KRas G12CA method for treating mutation-mediated colorectal cancer (CRC) comprising administering an effective dose of combination therapy, the combination therapy comprising: (a) Compound 1 or its medicinal salt; and (b) Anti-VEGF antibody.

[0199] Implementation Scheme 22: A treatment for patients suffering from KRas G12C A method for treating this type of lung cancer in patients with mutation-mediated pancreatic cancer, comprising administering an effective dose of a combination therapy, the combination therapy comprising: (a) Compound 1 or its medicinal salt; and (b) Anti-VEGF antibody.

[0200] Implementation Plan 23: A treatment for patients suffering from KRas G12C A method for treating such cancers in patients with hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer mediated by mutations, the method comprising administering an effective dose of a combination therapy comprising: (a) Compound 1 or its medicinal salt; and (b) Anti-VEGF antibody.

[0201] Implementation Scheme 24: The method of any one of Implementation Schemes 18 to 23, wherein the anti-VEGF antibody is bevacizumab.

[0202] Implementation Scheme 25: The method of any one of Implementation Schemes 18 to 24, wherein compound 1 is its adipic acid salt.

[0203] Implementation Scheme 26: The method of any one of Implementation Schemes 18 to 25, wherein compound 1 or a pharmaceutical salt thereof is administered on days 1 to 21 of the first 21-day cycle (QD), and bevacizumab is administered on day 1 of the first 21-day cycle (Q3W).

[0204] Implementation Scheme 27: The method of any one of Implementation Schemes 18 to 26, wherein compound 1 or its pharmaceutical salt is administered orally as a tablet or capsule.

[0205] Implementation Scheme 28: The method of any one of Implementation Schemes 18 to 27, wherein compound 1 or its pharmaceutical salt is administered in an amount of about 50 mg to 500 mg.

[0206] Implementation Scheme 29: The method of any one of Implementation Schemes 18 to 28, wherein compound 1 or its pharmaceutical salt is applied 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.

[0207] Implementation scheme 30: The method of any one of implementation schemes 18 to 29, wherein bevacizumab is administered at an amount of about 5 mg / kg to 20 mg / kg Q3W.

[0208] Implementation Scheme 31: The method of any one of Implementation Schemes 18 to 30, wherein bevacizumab is administered at an amount of about 10 mg / kg to 20 mg / kg Q3W.

[0209] Implementation scheme 32: The method of any one of implementation schemes 18 to 31, wherein bevacizumab is administered intravenously to the patient at a dose of about 15 mg / kg Q3W.

[0210] Implementation Plan 33: A treatment for patients with KRas G12C A method for treating this type of cancer in patients with mutated NSCLC, the method comprising administering an effective amount of a combination therapy to the patient, the combination therapy comprising: (a) Compound 1 or a pharmaceutical salt thereof, wherein Compound 1 or a pharmaceutical salt thereof is administered via QD on days 1 to 21 of the first 21-day cycle; and (b) Bevacizumab, administered on day 1 (Q3W) of the first 21-day cycle.

[0211] Implementation Scheme 34: The method as described in Implementation Scheme 33, wherein: (a) Compound 1 or its pharmaceutically acceptable salt is administered QD at a dose of about 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle; and (b) Bevacizumab was administered on day 1 of the first 21-day cycle at a dose of 5 mg / kg to 20 mg / kg Q3W.

[0212] Implementation Scheme 35: The method of any one of Implementation Schemes 18 to 34, wherein bevacizumab is administered after the administration of compound 1 or its pharmaceutical salt.

[0213] Implementation Scheme 36: A method of treating such cancers in a patient with NSCLC, CRC, or pancreatic cancer, the method comprising administering a treatment regimen to the patient, the treatment regimen comprising an effective amount of compound 1 or a pharmaceutical salt thereof and an effective amount of anti-VEGF antibody.

[0214] Implementation Scheme 37: The method as described in Implementation Scheme 32, wherein compound 1 is an adipate.

[0215] Implementation Scheme 38: The method as described in Implementation Scheme 32 or Implementation Scheme 33, wherein the anti-VEGF is bevacizumab.

[0216] Implementation Scheme 39: The method as described in any one of Implementation Schemes 36 to 38, wherein: (a) Compound 1 or its pharmaceutically acceptable salt is administered QD at a dose of about 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle; and (b) Bevacizumab was administered on day 1 of the first 21-day cycle at a dose of 5 to 20 mg / kg Q3W.

[0217] Implementation Scheme 40: The method of any one of Implementation Schemes 18 to 39, wherein the patient is diagnosed as not having a mutation selected from the group consisting of: sensitized EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAFV600E mutation, NTRK fusion and RET fusion, or a combination thereof.

[0218] Implementation Scheme 41: Use of a combination therapy comprising compound 1 or a pharmaceutical salt thereof and bevacizumab for the treatment of lung cancer, CRC or pancreatic cancer as described herein.

[0219] Implementation Scheme 42: The use as described in Implementation Scheme 41 further includes a dosing regimen comprising: (i) administration of compound 1 or a pharmaceutical salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administration of bevacizumab on day 1 of the first 21-day cycle.

[0220] Implementation Scheme 43: The use as described in Implementation Scheme 41 or Implementation Scheme 42 further includes (i) administering about 50 mg to 500 mg of compound 1 or a pharmaceutical salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administering about 5 mg / kg to 20 mg / kg of bevacizumab on day 1 of the first 21-day cycle.

[0221] Implementation Scheme 44: Use of a combination therapy comprising compound 1 or a pharmaceutical salt thereof and bevacizumab for the preparation of a medicament for the treatment of lung cancer, CRC or pancreatic cancer.

[0222] Implementation Scheme 45: The use as described in Implementation Scheme 44 further includes: (i) administering compound 1 or a pharmaceutical salt thereof on days 1 to 21 of the first 21-day cycle (QD); and (ii) administering bevacizumab on day 1 of the first 21-day cycle (Q3W).

[0223] Implementation Scheme 46: The use as described in Implementation Scheme 44 or Implementation Scheme 45, further comprising: (i) administering about 50 mg to 500 mg of compound 1 or a pharmaceutically acceptable salt thereof on days 1 to 21 of the first 21-day cycle; and (ii) administering about 5 mg / kg to 20 mg / kg of bevacizumab on day 1 of the first 21-day cycle (Q3W). In one such implementation scheme, the dosing regimen comprises two or more cycles as described herein.

[0224] Implementation Scheme 47: The method as described in any one of Implementation Schemes 18 to 40 or the use as described in any one of Implementation Schemes 41 to 46, wherein compound 1 or its pharmaceutical salt is used in the patient to treat KRas. G12C The alkylation was measured.

[0225] The following examples are presented in an illustrative rather than restrictive manner.

[0226] Example Example 1: Preclinical Research The Kirsten rat sarcoma virus oncogene homolog (KRAS) gene encodes a GTPase that plays a central role in mediating cell growth and survival signaling. Mutations in KRAS that alter the amino acids in glycine 12 (G12), glycine 13 (G13), and glutamine 61 (Q61) are common in tumors and are associated with tumorigenesis and the maintenance of invasive tumor growth (Der et al. Proc Natl Acad Sci USA 1982;79(11):3637-40; Parada et al. Nature 1982;297(5866):474-8; Santos et al. Nature 1982;298(5872):343-7; Taparosky et al. Nature 1982;300(5894):762-5; Capon et al. Nature 1983;304(5926):507-13). KRAS G12C Mutations are prevalent in non-small cell lung cancer (NSCLC), colorectal cancer, and other types of tumors (Prior et al., Cancer Res 2012;72(10):2457-67; Vogelestein et al., Science 2013;339(6127):1546-58). Compound 1 is an oral anticancer agent that selectively targets KRAS. G12C This led to KRAS G12C It is covalently and irreversibly inhibited. For the examples described herein, unless otherwise stated, compound 1 refers to the adipate of compound 1. Compound 1 does not target other mutations in KRAS, wild-type KRAS, or other members of the RAS family. Treatment of KRAS with compound 1 G12C Positive cells or tumors lead to reduced KRAS pathway signaling, inhibited cell / tumor cell growth, and induced apoptosis. Constitutive RAS signaling in tumors alters the tumor microenvironment in multiple ways, including inducing various angiogenesis and the release of immunosuppressive cytokines such as VEGF, IL-6, IL-8, GCSF, and GM-CSF. Therefore, a combined strategy targeting intrinsic KRAS-mediated growth and survival signaling in tumors, combined with drugs that effectively target and support tumor stromal pathways, has significant therapeutic implications.

[0227] In NCI-H2122 (KRAS) G12CThe in vivo antitumor efficacy of compound 1 (50 mg / kg, PO, QD) alone or in combination with anti-VEGF was evaluated in an NSCLC xenograft tumor model. Compound 1 monotherapy resulted in tumor arrest (tumor growth inhibition rate (TGI) of 98%), while anti-VEGF monotherapy showed slower growth inhibition (TGI of 70%). These studies indicate that, compared to compound 1 monotherapy, the combination of compound 1 with anti-VEGF resulted in an initial improvement in early tumor response and enhanced antitumor activity (TGI of 102%). All doses and combinations tested were well tolerated based on minimal changes in body weight and overall animal condition.

[0228] Compound 1 (adipic acid salt) is 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) is prepared in a histidine buffer (20 nM histidine-acetate, 240 nM sucrose, 0.02% polysorbate 20). TM The solution was prepared in saline (pH 5.5). The carrier control for oral administration was 0.5% (w / v) methylcellulose. The anti-gD isotype control (Hu anti-gD 5B6; hereinafter referred to as the isotype control) was prepared in saline.

[0229] Female nude mice aged 9 to 10 weeks were obtained from Charles River Laboratory (Hollister, CA), with an average weight of 26.0 g. Mice were housed in standard rodent miniature isolation cages and acclimatized to the study conditions for at least 3 days prior to tumor cell transplantation. Only animals that appeared healthy and without obvious abnormalities were used in the study.

[0230] Human non-small cell lung cancer NCI-H2122 cells were obtained from the American Type Culture Collection (Rockville, MD) and carried the G12C oncogenic mutation in K-RAS. Cells were cultured in vitro, and cells in the logarithmic growth phase were harvested and resuspended 1:1 in Hank balanced salt solution (HBSS) containing Matrigel (BD Biosciences; San Jose, CA). The cells were then subcutaneously implanted into the right thorax of 60 nude mice. Each mouse was injected with 10 × 10⁻⁶ cells. 6 100 μL of cells were injected. Tumors were monitored until the mean tumor volume reached 115 to 228 mm. 3Mice were divided into four groups of n = 10 mice each, based on tumor volume. At the start of drug administration, the mean tumor volume across all four groups was 146 mm. 3 .

[0231] Mouse vector (100 μL 0.5% MC) or 50 mg / kg of compound 1 (expressed as free base equivalents) were administered. MC vector and compound 1 were administered orally (PO) daily (QD) at a volume of 100 μL for 21 days via tube feeding. Isotype control and anti-VEGF antibody were administered intravenously (IV) at an initial dose of 10 mg / kg, followed by intraperitoneal (IP) administration at a dose of 5 mg / kg on a twice-weekly (BIW) schedule.

[0232] Tumor size and mouse weight were recorded twice weekly during the study. Tumor volume exceeding 2000 mm was recorded. 3 If the mouse's weight decreases to ≥ 20% of its initial weight, it should be euthanized immediately.

[0233] Table 1

[0234] All concentrations were calculated based on the average 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, MA), and analyzed using Excel version 14.2.5 (Microsoft Corporation; Redmond WA). Tumor volume was calculated using the following formula: Tumor size (mm) 3 = (long side measurement value × short side measurement value) 2 ) × 0.5 An antitumor response was observed, with partial remission (PR) defined as a reduction in tumor volume of >50% from the initial level and complete remission (CR) defined as a reduction in tumor volume of 100%.

[0236] Weigh the animal using an Adventura Pro AV812 balance (Ohaus Corporation; Pine Brook, NJ). Calculate the percentage change in body weight using the following formula: Weight change (%) = [(current weight / initial weight) – 1) × 100] A generalized additive mixture model (GAMM) was used to analyze the changes in transformed tumor volume over time because this method addresses repeated measurements from the same subject 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 typically grow exponentially, a natural logarithmic transformation of the tumor volume was performed before analysis.

[0237] The efficacy estimate is obtained by calculating the percentage difference between the daily mean baseline-corrected AUCs fitted to the original (i.e., untransformed) proportions of the relevant groups within the same time period.

[0238] A generalized additive mixed model (GAMM) was also used to analyze changes in original body weight (i.e., grams) over time. After data fitting, the original body weight data at each time point from all individual animals and all groups were standardized and replotted in two different ways: 1) standardized to the initial body weight and reported as a percentage to obtain the percentage change in body weight; and 2) standardized to the maximum body weight to date and reported as a percentage to obtain the percentage loss in body weight.

[0239] The antitumor efficacy of compound 1 (50 mg / kg, PO, QD) monotherapy in nude mice with human NCI-H2122 NSCLC xenografts was evaluated compared to antiVEGF monotherapy (initial dose 10 mg / kg, IV; subsequent doses 5 mg / kg, IP, BIW). Monotherapy resulted in tumor growth inhibition (TGI). Compared to the vector control, compound 1 achieved a 98% TGI and 2 / 10 partial responses (PR), while antiVEGF achieved a 70% TGI and 0 / 10 PR. In contrast, the combination of compound 1 and antiVEGF produced more consistent antitumor efficacy in the first week of treatment, with only 2 / 10 mice showing increased tumor volume, compared to 5 / 10 in the compound 1 group and 9 / 10 in the antiVEGF group. The improvement in antitumor efficacy compared to compound 1 monotherapy was 102% TGI and 1 / 10 PR (see Figure 1 and ). Figure 2 ).

[0240] Table 2. Summary of the antitumor activity of Compound 1, alone or in combination with anti-VEGF, in NCI-H2122 NSCLC tumor xenografts in nude mice.

[0241] A combined antitumor efficacy study was conducted in the NCI-H2122 human NSCLC xenograft tumor model, demonstrating that compound 1 and anti-VEGF inhibited tumor growth as single agents (TGI of 98% and 70%, respectively). The combination of compound 1 and anti-VEGF resulted in an antitumor response, with 80% (8 / 10) of mice showing initial tumor reduction, compared to 50% (5 / 10) in the compound 1 group and 10% (1 / 10) in the anti-VEGF control group. The combination of compound 1 and anti-VEGF demonstrated improved antitumor efficacy compared to compound 1 alone (98% TGI) (102% TGI). These data indicate that the combination of compound 1 and anti-VEGF is well-tolerated in the NCI-H2122 human NSCLC xenograft tumor model, and improves both initial tumor response and overall antitumor activity.

[0242] Example 2: KRAS is the most common mutated oncogene in up to 25% of cancers and is associated with resistance to standard-of-care therapy and poor overall prognosis. Although selective inhibitors have been developed as anticancer therapies targeting other nodes in the RAS / MAPK pathway, the KRAS oncogene was considered untreatable until the recent discovery of the Switch II pocket (Ostrem et al., Nature 2013;503:548-51). Based on this discovery, drugs specifically targeting KRAS are being evaluated in early clinical development. G12C Mutant covalent small molecule inhibitors.

[0243] Other KRAS G12C Inhibitor. AMG 510 (sotorasib) is a small molecule that inhibits KRAS. G12CIt is locked in its inactive GDP-binding state for irreversible inhibition. AMG-510 is currently in clinical trials. Patients in these studies had received a median of three lines of anticancer therapy (range 0 to 11) for metastatic disease prior to enrollment. Overall, 56.6% of patients reported treatment-related adverse events; 11.6% experienced treatment-related grade 3 or 4 events, and 1.6% experienced treatment-related serious adverse events. Grade 3 events occurring in more than one patient included elevated ALT, diarrhea, anemia, elevated AST, and elevated alkaline phosphatase. One patient experienced a grade 4 treatment-related ALT elevation, and one patient discontinued AMG-510 due to grade 3 treatment-related ALT and AST elevations. Despite reported antitumor activity, adverse events associated with AMG-510 have been observed. In 32.2% of NSCLC patients, a confirmed objective response was achieved, and the median duration of response was 10.9 months (range 1.1+ to 13.6 months). The median progression-free survival (PFS) for NSCLC patients was reported to be 6.3 months (range 0.0+ to 14.9+ months) (Hong et al., New Eng J Med 2020;383:1207-17).

[0244] MRTX849 is a mutant selective small molecule KRAS. G12C Inhibitors are being developed targeting KRAS-positive individuals. G12CA clinical study was conducted on patients with advanced solid tumors harboring mutations. Data from a total of 17 patients (10 with NSCLC and 4 with CRC) were recently reported, of whom 12 had received at least one in-treatment tumor assessment (6 with NSCLC and 4 with CRC). Most patients had received three or more prior anticancer regimens prior to enrollment (12 of the 17 patients, 71%). >10% of patients reported the following treatment-related adverse events: diarrhea, nausea, elevated AST, vomiting, fatigue, elevated ALT, elevated creatinine, abdominal distension, abdominal pain, elevated ALP, anemia, decreased appetite, dehydration, dry mouth, dysgeusia, dyspnea, QT interval prolongation, hypomagnesemia, and rash. Grade 3 events included fatigue, decreased appetite, and dyspnea (1 patient each). At all evaluated dose levels, 3 out of 6 NSCLC patients and 1 out of 4 CRC patients achieved PR (Jänne et al. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics October 2019).

[0245] Compound 1. Compound 1 against KRAS G12C The specificity and mechanism of action of KRAS lead to the G12C It provides effective and irreversible inhibition and holds promise for achieving broad therapeutic indices, maximizing antitumor activity while minimizing treatment-related toxicities. Targeting KRAS... G12C Specific therapies for KRAS-positive cancers may be available for those carrying KRAS. G12C It provides more tolerable and more effective treatment options for patients with advanced cancer.

[0246] In vitro and in vivo pharmacological studies have shown that compound 1 is a KRAS G12C Highly selective covalent inhibitors for KRAS G12C The growth inhibition selectivity of positive cell lines exceeded that of KRAS. G12C The negative cancer cell line was 20,000 times larger. Studies on the mechanism of action of compound 1 showed that in KRAS... G12C In positive cancer cell lines, in addition to KRAS target genes such as DUSP6 and SPRY4, downstream MAPK pathway components such as phosphorylated (p)ERK and pS6 were also inhibited, and apoptosis induction was observed. Furthermore, compound 1 exhibits potent single-drug activity and is effective in many KRAS-related cancers. G12CIn a nonclinical xenograft model of positive lung tumors, compound 1 inhibited tumor growth. These in vitro and in vivo pharmacological studies support the use of compound 1 for the treatment of locally advanced or metastatic KRAS. G12C Patients with positive solid tumors.

[0247] The results of the non-clinical toxicology studies completed to date provide a robust characterization of the toxicity profile of compound 1 and support its administration in cancer patients. A comprehensive non-clinical toxicity study should be completed to evaluate the potential single-dose and repeated-dose oral toxicity, genotoxicity, phototoxicity, and safety pharmacology of compound 1. Due to KRAS G12C The mutation does not exist in healthy animals, therefore KRAS G12C Inhibit non-clinical species that are not pharmacologically relevant.

[0248] Bevacizumab is a recombinant humanized IgG1 monoclonal antibody specifically targeting vascular endothelial growth factor (VEGF) and recognizing all VEGF isoforms. It contains a human backbone and a mouse complementarity-determining region. It exerts a direct anti-angiogenic effect by binding to and clearing VEGF in the tumor environment. Additional antitumor activity may derive from its effects on the tumor vascular system, interstitial pressure, and vascular permeability, enhancing chemotherapy delivery to tumor cells (Jain, NatMed 2001;7:987-9).

[0249] Bevacizumab has been approved for the treatment of various types of solid tumors, including metastatic colorectal cancer, advanced NSCLC, unresectable or metastatic hepatocellular carcinoma, metastatic breast cancer, advanced renal cell carcinoma, and ovarian cancer, as well as recurrent glioblastoma.

[0250] Early Phase I clinical data from ongoing studies using AMG-510 and MRTX849 as monotherapy indicate that KRAS... G12C Inhibitors are tolerable and have promising antitumor activity in patients with metastatic NSCLC and CRC (Janne et al. 2019; Hong et al. New Eng J Med 2020;383:1207-17). However, there remains a great need to improve the reported antitumor activity and durability of these inhibitors as monotherapy in NSCLC and CRC, while importantly maintaining their tolerable safety profile.

[0251] Rationale for choosing combination therapy with bevacizumab. Increased VEGF expression has been reported in most solid tumors with poor prognostic outcomes (Zhan et al. J Thorac Oncol 2009;4:1094-103; Gentzler et al. CurrTreat Options Oncol 2013;14:595-609). Elevated VEGF mRNA levels have been detected in tumor cell lines expressing mutant KRAS, while genetic disruption of the mutant KRAS allele in human colon cancer cells leads to reduced VEGF secretion (Rak et al. N Eng J Med 2016;375:1823-33).

[0252] The VEGF pathway also plays a crucial role in the immunosuppressive tumor microenvironment through multiple mechanisms. For example, VEGF-A has been shown to induce FasL expression on endothelial cells, which can kill effector CD8+ T cells but not T-reg cells. Anti-VEGF-A administration attenuates FasL expression in tumor endothelial cells, significantly increasing the influx of tumor-rejecting CD8+ relative to FasL-dependent FoxP3+ T cells, leading to CD8-dependent tumor growth inhibition (Motz et al. 2014). In contrast, bevacizumab can restore and / or maintain the antigen-presenting capacity of dendritic cells, thereby enhancing 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 increasing 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 repressive cytokines, and reduce the expression of inhibitory checkpoints on CD8+ T cells in tumors (Roland et al., PLOS One 2009;4:e7669; Voron et al., J Exp Med 2015;212:139-48). Therefore, the immunomodulatory effects of bevacizumab hold promise for increasing CD8-positive T cell recruitment and alleviating intratumoral immunosuppression.

[0253] Given the mounting evidence suggesting KRAS G12C Both KRAS and VEGF inhibition have immunomodulatory effects, which can alleviate intratumoral immunosuppression and increase T cell infiltration. Therefore, KRAS... G12C There is a scientific basis for combining inhibition with VEGF blockade.

[0254] In in vivo mouse studies, the combination of compound 1 with anti-VEGF monoclonal antibody therapy increased the initial tumor response and improved the overall antitumor efficacy compared to compound 1 treatment alone.

[0255] Will be in patients with advanced or metastatic KRAS G12C The combination of compound 1 and bevacizumab was investigated in patients with positive solid tumors. On day 1 of each 21-day cycle, the dose of bevacizumab in combination with compound 1 was 15 mg / kg IV. Potential additive toxicities include gastrointestinal toxicities, which are expected to be monitored and managed through supportive care and potential dose adjustments.

[0256] 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).

[0257] Biomarkers. This study will identify and / or evaluate compound 1 as a biomarker of response as a monotherapy or in combination with bevacizumab (i.e., predictive biomarkers), an early active alternative, a biomarker associated with progression to a more severe disease state (i.e., prognostic biomarkers), and a biomarker related to KRAS response. G12C Biomarkers associated with acquired resistance to inhibitors (e.g., compound 1), biomarkers associated with susceptibility to adverse events or that could lead to improved monitoring or research of adverse events (i.e., safety biomarkers), biomarkers that could provide evidence of the activity of compound 1 when used in combination with bevacizumab (i.e., pharmacodynamic [PD] biomarkers), or biomarkers that could increase knowledge and understanding of disease biology and drug safety. Relevant biomarker endpoints include the relationship between exploratory biomarkers in blood, plasma, and tumor tissue and safety, PK, activity, or other biomarker endpoints.

[0258] Patients were screened for up to 28 days, followed by a treatment period and a safety follow-up period, during which patient safety outcomes were monitored either during a specific treatment period following the last dose of the study drug or until the patient received another anticancer therapy (whichever occurred first).

[0259] In the absence of investigator-determined unacceptable toxicity and clear disease progression, patients may continue treatment with compound 1.

[0260] Adverse events in all patients will be closely monitored throughout the study period and during specific treatment periods following the last dose of the study drug, or until the patient receives another anticancer therapy (whichever occurs first). Adverse events will be graded according to NCICTCAE v5.0.

[0261] The starting dose of compound 1 will be 50 mg PO QD. The single-patient dose escalation group will receive treatment with escalating dose levels of compound 1.

[0262] Patients include those with locally advanced, recurrent, or metastatic KRas that are incurable. G12C Patients with positive tumors (e.g., NSCLC, CRC, hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, ovarian cancer, or pancreatic cancer) who have experienced disease progression or are intolerant to at least one prior systemic therapy (which may include monotherapy or combination therapy). Patients with NSCLC, CRC, or pancreatic cancer will be screened for KRas. G12C Positive.

[0263] KRas obtained from tissue and circulating tumor DNA assessment G12C Mutation status. Approximately 12% of NSCLC, 4% of CRC, 2% of pancreatic cancer, and many other solid tumors (each with an incidence ≤ 4%) carry KRas. G12C Mutation. Compound 1 is a KRas-targeting compound. G12C It is a potent and highly selective inhibitor, but does not target other mutations in KRAS, the wild-type form of KRAS, or other members of the RAS family. Therefore, it only targets KRas... G12C Only patients with KRAS mutations are eligible to receive the combination therapy described in this article. KRAS mutation status can be determined using FoundationOne. ® CDx (F1CDx) assay (FDA-approved broadly defined companion diagnostic (CDx) assay), FoundationOne ® Liquid CDx (F1L CDx) assays, along with other FDA-approved assays (FDA 2020) or other well-validated, laboratory-developed assays performed in laboratories validated or equivalent to the Clinical Laboratory Improvement Amendments (CLIA), are used to determine this. Previous studies have shown that KRas G12C The occurrence of mutations as an early event (Jamal-Hanjani et al. N Engl J Med 2017;376:2109-21) suggests that archival tissue analysis is a viable alternative for selecting patients with KRas.G12C Patients with positive tumors were treated with compound 1.

[0264] Pharmacodynamic pathway regulation. Compound 1 is a KRas... G12C Inhibitors, which are mediated by KRas G12C Alkylation inhibits downstream MAPK signaling, thereby locking it into its inactive GDP-binding state. In non-clinical models, compound 1 induces KRas... G12C Alkylation levels and the degree of MAPK pathway inhibition were correlated with the response to compound 1. Pre-treatment and in-treatment tumor tissue collection will allow for the assessment of the correlation between MAPK pathway inhibition and antitumor activity and compound 1 treatment. The degree of MAPK pathway inhibition can be assessed using RNA analysis of MAPK target genes (e.g., DUSP6, SPRY4) or immunohistochemical (IHC) analysis of phosphorylated downstream markers (e.g., pERK, pS6). Furthermore, in-treatment tumor tissue biopsy can directly assess the KRas induced by compound 1. G12C Alkylation levels. The assessment of these PD biomarkers can provide data for future dosage selection.

[0265] Sequencing of genes associated with resistance to compound 1. DNA sequencing technologies, such as targeted next-generation sequencing (NGS) and whole-exome sequencing, offer unique opportunities to identify biomarkers of response to and / or resistance to compound 1. Sequencing of cancer-related genes can enable the identification of reactivation and acquired mechanisms of resistance to compound 1.

[0266] Protein, RNA, and DNA analyses. Assessing the signaling activity of tumor cells in the tumor microenvironment (e.g., MAPK, PI3K / AKT) can provide valuable insights into the sensitivity or resistance of compound 1 as a monotherapy or combination therapy. VEGF expression can be assessed via IHC to analyze antitumor activity in subgroups based on VEGF expression.

[0267] Besides protein mutations that activate proteins, alterations in RNA expression levels or DNA can also modulate the activity of signaling pathways. RNA analysis of tumors will allow for intrinsic subtype analysis of participating patients. Analysis of the potential association between subtypes and patient outcomes can identify the patient subgroups most likely to respond to compound 1.

[0268] Plasma samples are used for somatic tumor mutation analysis and other biomarkers. Increasing evidence suggests that cell-free DNA obtained from blood samples from cancer patients contains ctDNA, which represents the DNA and mutational status of tumor cells (Diehl et al. 2008; Maheswaran et al. 2008). Assays have been proven to detect cancer-related mutations (e.g., KRAS) in plasma. The results of these assays may correlate with the mutational status identified by tumor sample analysis. Monitoring response to treatment using ctDNA is an area of ​​interest and could provide an early, non-invasive, and quantifiable method in a clinical setting to identify candidates for specific therapies and monitor changes in cancer status over time (Wan et al., Nat Rev Cancer 2017;17:223-38). Analysis of ctDNA collected at different times during study treatment and after progression of compound 1 treatment can help identify response mechanisms to study treatments and acquired resistance.

[0269] Blood samples are used for next-generation sequencing. Next-generation sequencing (NGS) technology generates a large amount of sequencing data. Due to the tumorigenesis process, tumor DNA may contain both reported and unreported chromosomal alterations. To help control sequencing calls for previously unreported somatic alterations, blood samples are collected before drug administration to determine whether such alterations are present in somatic cells.

[0270] Inclusion criteria. Patients must meet the following study inclusion criteria: Age ≥ 18 years; • Suffering from an assessable or measurable disease according to RECIST v1.1; • Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1; Life expectancy ≥ 12 weeks; • Sufficient hematological and organ function within 14 days prior to the start of treatment, as defined below: • Absolute neutrophil count ≥1200 / µL; Heme ≥ 9 g / dL; Platelet count ≥100,000 / µL; Total bilirubin ≤ 1.5 × ULN; Serum albumin ≥ 2.5 g / dL; AST and ALT ≤2.5 × ULN, except in the following cases: Patients with a history of liver metastases may have AST and / or ALT ≤5.0 × ULN.

[0271] Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL / min, based on Cockcroft-Gault glomerular filtration rate estimates: (140 - age) × (weight in kilograms) × (0.85 for women) 72 × (serum creatinine, in mg / dL) For women of childbearing age: consent to abstinence (avoidance of heterosexual intercourse) or the use of contraception, and consent not to donate eggs; For men with non-surgical infertility: agree to abstinence (avoiding heterosexual intercourse) or use of contraception, and agree not to donate sperm; • Confirmation that the biomarker meets the requirements: Valid results from central blood tests or blood or local tumor tissue tests demonstrating the presence of KRas G12C Mutations (e.g., empirically validated polymerase chain reaction (PCR) or NGS assays performed in CLIA or equivalent certified laboratories).

[0272] Other selection criteria  Histologically documented locally advanced, recurrent, or metastatic incurable solid tumors • Disease progression after at least one available standard treatment; or standard treatment has proven ineffective, unacceptable, or deemed inappropriate; or clinical trials of the investigational drug represent the recognized standard of care. If a patient has progressed after at least one available standard treatment, other approved standard treatment options are available, the investigation physician must discuss the risks and benefits of these treatments before obtaining informed consent to participate in the study. Such discussions must be documented in the patient's medical record.

[0273] Patients with NSCLC and colorectal adenocarcinoma must not have known secondary oncogenic drivers (e.g., for NSCLC: sensitized EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion, RET fusion; for colorectal adenocarcinoma: BRAF V600E mutation, ERBB2 amplification), as determined by an FMI NGS assay performed in a local CLIA-certified or equivalent laboratory or by an empirically validated PCR- or NGS-based assay approved by the sponsor.

[0274] General exclusion criteria. Patients meeting any of the following criteria will be excluded: Unable or unwilling to swallow pills; Unable to adhere to research and follow-up procedures;  Malabsorption syndrome or other conditions that interfere with intestinal absorption; Known and untreated or active central nervous system (CNS) metastases; Patients with a history of CNS metastasis treatment who meet all of the following criteria: • Measurable or assessable diseases outside the CNS; • No history of intracranial hemorrhage or spinal cord hemorrhage; • There is no requirement for continuous use of corticosteroids to treat CNS metastases. Corticosteroids should be discontinued ≥2 weeks prior to administration of the agents described herein, and there should be no persistent symptoms attributable to CNS metastases. • No stereotactic radiation within 7 days prior to day 1 of cycle 1, or no whole-brain radiation within 14 days; There is no evidence of a transitional progression between completing CNS-targeted therapy and screening radiography studies;  Leptomeningeal disease or carcinomatous meningitis; Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once every two weeks or more); • Indwelling of thoracic or abdominal catheters is permissible, provided that the patient has fully recovered from surgery, is hemodynamically stable, and has improved symptoms; • Any active infection that may affect patient safety, or a serious infection requiring intravenous antibiotics within the first 7 days of cycle 1; A significant clinical history of liver disease, including viral hepatitis or other types of hepatitis, current alcoholism, or cirrhosis; Known HIV infection; Uncontrolled hypercalcemia (>1.5 mmol / L ionized calcium or calcium >12 mg / dL or corrected serum calcium ≥ ULN) or symptomatic hypercalcemia requires continued bisphosphonate therapy or denosumab. • A major injury or major surgery occurred within 4 weeks prior to day 1 of cycle 1; Patients with a history of chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery (including gastrectomy), inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), or any active enteritis (including diverticulitis); • Individuals who have received chemotherapy, immunotherapy, or biological therapy as anticancer treatment within 3 weeks prior to administration of the medication described herein, or who have received endocrine therapy within 2 weeks prior to administration of the medication described herein, except in the following circumstances: Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists to treat endocrine-sensitive cancers (e.g., prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); • Regulatoryly approved kinase inhibitors may be used within 2 weeks prior to the start of study treatment; Treatment with the investigational drug within 3 weeks or 5 half-lives (whichever is shorter) prior to administration of the drug described herein.

[0275] • Patients who have received radiation therapy (excluding palliative radiation for bone metastases and radiation for CNS metastases) as cancer treatment within 4 weeks prior to the administration of the drugs described herein; • The patient had received palliative radiotherapy for bone metastases within 2 weeks prior to administration of compound 1; Adverse events caused by previous anticancer treatments have not yet subsided; • History of other malignant tumors within the 5 years prior to screening; A history of clinically significant cardiovascular dysfunction or active cardiovascular dysfunction, including: • A history of stroke or transient ischemic attack within 6 months prior to administration of the medication described herein; • A history of myocardial infarction within 6 months prior to administration of the medication described herein; • New York Heart Association Class III or IV heart disease or congestive heart failure requiring medication • Uncontrolled arrhythmias, a history of ventricular arrhythmias requiring medication, or active ventricular arrhythmias; • Coronary artery disease with symptomatic or unstable angina; • Congenital long QT syndrome or a QT interval (QTcF) > 470 ms after correction using the Fridericia formula;  Currently receiving drug treatment known to prolong the QT interval; Pregnant or breastfeeding, or planning to become pregnant during the study period or within 6 months after the last administration of compound 1; Poorly controlled hypertension (e.g., systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) A history or evidence of a hereditary bleeding predisposition or coagulopathy that carries a risk of bleeding. • Currently or recently (<10 days before starting study treatment) using aspirin (>325 mg / day) or clopidogrel (>75 mg / day).  History of thrombotic disease within 6 months prior to initiating treatment If proteinuria ≥ 2+ is detected in a test strip urine analysis during screening or on day 1 of the planned cycle 1, a 24-hour urine sample should be collected, and it must be demonstrated that the protein content was ≤ 1 g within 24 hours prior to the start of the study treatment.

[0276]  Severe non-healing wounds, active ulcers, or untreated fractures • A history of abdominal fistula, gastrointestinal perforation, or abdominal abscess within 6 months prior to the start of treatment. • Patients with pulmonary hemorrhage / hemoptysis (>1 / 2 teaspoon of red blood) within one month prior to starting the study treatment.  Imaging revealed clear tumor infiltration into the thoracic vessels  Clear cavities in the lungs were detected on imaging. Research on therapeutic formulations, packaging, and processing.

[0277] Compound 1. Compound 1 will be provided as an active pharmaceutical ingredient (API) powder-capsule (PIC) formulation in three strengths: 5 mg, 25 mg, and 100 mg (free base equivalent). Additionally, a film-coated tablet formulation in a 100 mg (free base equivalent) strength will also be provided for clinical use. Compound 1 should be stored at 86℉ (30°C) or lower and protected from moisture.

[0278] For Compound 1 administered at home, the patient should be given an adequate number of capsules or tablets to continue until the next appointment or completion of a cycle. Unless the patient visits a clinic, they will self-medicate with Compound 1 as described herein. Unless otherwise instructed, the patient should take Compound 1 at approximately the same time each day. The number and strength of capsules or tablets to be taken will be instructed according to the patient's specified dosage level and schedule.

[0279] Unless otherwise stated, Compound 1 should be taken on an empty stomach; that is, food should be avoided for at least 2 hours before and 1 hour after administration. There is no restriction on fluid intake. It is important that the Compound 1 capsule or tablet be swallowed whole (without chewing) with at least 240 mL (8 fluid ounces) of water. If a patient misses any dose of Compound 1 or spits out a capsule or tablet, the patient should be instructed to skip that dose and continue with the next scheduled dose. Missed doses will not be administered.

[0280] Bevacizumab. Bevacizumab will be provided as an IV formulation in 400 mg / 16 mL vials. On day 1 of each 21-day cycle, bevacizumab will be administered intravenously at a fixed dose of 15 mg / kg following administration of compound 1. All bevacizumab administrations will be performed in a monitored environment with immediate access to trained personnel and adequate equipment and medication to manage any serious reactions that may occur. Bevacizumab will be diluted to a total volume of 100 mL in 0.9% sodium chloride injection (USP grade). The initial dose will be delivered over 90 ± 15 minutes. If the first infusion is tolerated without any infusion-related adverse events (i.e., fever and / or chills), the second infusion may be delivered over 60 ± 10 minutes. If the 60-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 ± 10 minutes. For patients experiencing infusion-related symptoms, the bevacizumab infusion may be slowed or interrupted. If infusion-related symptoms occur, the patient should be treated in accordance with best medical practice.

[0281] If bevacizumab administration is interrupted due to an adverse event during a specific cycle, the next dosing cycle must not be started until bevacizumab administration is resumed. Therefore, the current cycle may be extended by more than 21 days, and the patient may continue receiving compound 1. Day 1 of the next cycle should correspond to the point at which bevacizumab administration is resumed. Dosage adjustments to bevacizumab are not permitted.

[0282] Combination therapy. Combination therapy includes any medications other than those described herein used by the patient between the first administration of at least one of the medications described herein and the last administration of at least one of the medications described herein, for a period of 7 days prior to the first administration of at least one of the medications described herein. (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements)

[0283] Permitted therapies. Patients may take (a) antiepileptic drugs or warfarin; (b) oral contraceptives or other permitted maintenance therapies as specified in the eligibility criteria; (c) antiemetics and antidiarrheals, but should not be administered prophylactically prior to initial treatment with the investigational drug; (d) analgesics; (e) bisphosphonates and denosumab for the treatment of bone metastases or osteoporosis; or may take multivitamins, calcium, and vitamin C, D, and E supplements.

[0284] Preventive therapy. Medications that prevent the effects associated with CYP enzymes and compound 1 include, for example: (1) potent / intermediate CYP3A4. Inhibitors, including but not limited to: atazanavir, ritonavir, indinavir, nelfinavir, saquinavir, clarithromycin, telithromycin, erythromycin, troleandomycin, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, aprepitant, conivaptan, fluvoxamine, diltiazem, nefazodone, mibefradil, verapamil, and grapefruit juice or grapefruit supplements; (2) potent / intermediate CYP3A4 Inducers, including but not limited to, the following: rifampin, carbamazepine, phenytoin, oxcarbazepine, phenobarbital, efavirenz, nevirapine, etravirine, modafinil, hyperforin (St. John's Wort), and cyproterone. Full-dose oral or parenteral anticoagulants may be used for therapeutic purposes provided that the INR and / or aPTT are within the therapeutic range (according to institutional standards) for 14 days prior to initiating any of the medications described herein, and the patient has received a stable dose of anticoagulant therapy for ≥ 1 week prior to initiating study treatment. The above list of medications is not exhaustive.

[0285] Contraindicated therapies. The following combination therapies are contraindicated during and for at least 7 days prior to the first administration of the medication described herein: • Use the study therapy within 3 weeks or five half-lives (whichever is shorter) prior to the first administration of the drug described herein; Combination therapies intended to treat cancer (whether FDA-approved or investigational), including chemotherapy, radiation therapy, immunotherapy, biotherapy, herbal remedies, or hormone therapy, except in the following cases: Hormone therapy using gonadotropin-releasing hormone (GnRH) agonists or antagonists to treat endocrine-sensitive cancers (such as prostate cancer, endometrial cancer, hormone receptor-positive breast cancer); Hormone replacement therapy or oral contraceptives.

[0286]  For radiotherapy of well-defined progressive disease, except for new brain metastases in cases of systemic response: Patients whose systemic disease has been demonstrated to be under control (defined as having achieved clinical benefit [i.e., PR, CR, or SD ≥3 months]) but who have developed radiotherapy-available brain metastases will be allowed to continue treatment with Compound 1 during the study period until their disease progresses systemically and / or further progression occurs in the brain (based on investigator assessment). Quinidine or other antiarrhythmic drugs; Start or increase the dose of hematopoietic colony-stimulating factors (CSFs; e.g., granulocyte CSF; filgrastim, granulocyte / macrophage CSF; sargramostim, pegfilgrastim, erythropoietin, darbepoetin, and thrombopoietin) from day 7 before day 1 of cycle 1.

[0287] Risks associated with Compound 1. Administration of Compound 1 has been associated with diarrhea, nausea, vomiting, oral mucosal irritation, very mild to mild elevation of transaminases, and phototoxicity.

[0288] Risks associated with bevacizumab. Bevacizumab is associated with the following risks: gastrointestinal perforation, surgical and wound healing complications, bleeding (severe or fatal bleeding, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, pulmonary hemorrhage, epistaxis, and vaginal bleeding), non-gastrointestinal bleeding fistula formation, arterial thromboembolic events (including cerebral infarction, transient ischemic attack, myocardial infarction, and angina), and hypertension.

[0289] The potential additive toxicity associated with the combined use of bevacizumab and compound 1 is gastrointestinal toxicity.

[0290] Treatment interruption. If Compound 1 was suspended for more than 21 days after the last study treatment due to toxicity, the study treatment should not be restarted. Compound 1 may be suspended for up to 21 days for unexpected medical events unrelated to the toxicity of the study treatment or disease progression.

[0291] Adverse events. As defined herein, an adverse event refers to any adverse medical event that occurs in a clinical study subject receiving administration of the drug described herein as part of the combination therapy described herein, regardless of causality. The terms “severe” and “serious” are not synonyms. Severity refers to the intensity of an adverse event (e.g., based on mild, moderate, or severe, or according to the NCITCCAE classification); the event itself may have relatively minor medical significance (e.g., severe headache without any further findings).

[0292] 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 anaphylactic reaction, 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.

[0293] Throughout this specification and in the claims, the word "comprising" is used in a non-exclusive sense unless the context requires otherwise. It should be understood that the embodiments described herein include embodiments that are "consisting of" and / or "substantially constitute" of.

[0294] Essentially, when a range of values ​​is provided, it should be understood that, unless the context explicitly specifies otherwise, each intervention value within the upper and lower limits of the range, along with any other said or intervention range, is within the range covered herein, up to one-tenth of the lower limit unit. The upper and lower limits of these smaller ranges may also be independently included within even smaller ranges, which also cover any explicitly excluded restrictions within the range. Where the range includes one or two restrictions, the range excluding the one or two included restrictions is also included herein.

[0295] Benefiting from the teachings presented in the foregoing description and related drawings, those skilled in the art will conceive of many modifications and other embodiments of the invention described herein. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terminology is used herein, it is for general and descriptive purposes only and not for limiting purposes.

Claims

1. A combination in the preparation of a treatment for patients suffering from KRas G12C Use in drugs for this type of lung cancer in patients with mutation-mediated lung cancer, the combination comprising: (a) Compound 1 ， Or its medicinal salt; and (b) Anti-VEGF antibody.

2. The use according to claim 1, wherein the lung cancer is NSCLC.

3. The use according to claim 1, wherein the lung cancer is adenocarcinoma, squamous cell lung cancer, or large cell lung cancer.

4. A combination in the preparation of a treatment for patients suffering from KRas G12C Use of drugs in patients with mutation-mediated colorectal cancer (CRC), the combination comprising: (a) Compound 1 ， Or its medicinal salt; and (b) Anti-VEGF antibody.

5. A combination in the preparation of a treatment for patients suffering from KRas G12C Use of such cancer drugs in patients with mutation-mediated pancreatic cancer, the combination comprising: (a) Compound 1 ， Or its medicinal salt; and (b) Anti-VEGF antibody.

6. A combination in the preparation of a treatment for patients suffering from KRas G12C Use in drugs for patients with hepatocellular carcinoma, breast cancer, renal cell carcinoma, endometrial cancer, or ovarian cancer mediated by mutations, the combination comprising: (a) Compound 1 ， Or its medicinal salt; and (b) Anti-VEGF antibody.

7. The use according to any one of claims 1-6, wherein the anti-VEGF antibody is bevacizumab.

8. The use according to any one of claims 1-7, wherein compound 1 is its adipate.

9. The use according to any one of claims 1-8, wherein compound 1 or a pharmaceutical salt thereof is administered on days 1 to 21 of the first 21-day cycle (QD), and bevacizumab is administered on day 1 of the first 21-day cycle (Q3W).

10. Use according to any one of claims 1-9, wherein compound 1 or a pharmaceutical salt thereof is administered orally as a tablet or capsule.

11. The use according to any one of claims 1-10, wherein compound 1 or its pharmaceutical salt is administered in an amount of about 50 mg to 500 mg.

12. Use according to any one of claims 1-11, wherein compound 1 or its pharmaceutical salt is applied 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.

13. The use according to any one of claims 1-12, wherein bevacizumab is administered at an amount of about 5 mg / kg to 20 mg / kg Q3W.

14. The use according to any one of claims 1-13, wherein bevacizumab is administered at an amount of about 10 mg / kg to 20 mg / kg Q3W.

15. The use according to any one of claims 1-14, wherein bevacizumab is administered intravenously to the patient at a dose of about 15 mg / kg Q3W.

16. A combination in the preparation of a treatment for patients suffering from KRas G12C Use of drugs in patients with mutated NSCLC for this type of cancer, the combination comprising: (a) Compound 1 Or its pharmaceutical salt, wherein compound 1 or its pharmaceutical salt is administered QD on days 1 to 21 of the first 21-day cycle; and (b) Bevacizumab, administered on day 1 (Q3W) of the first 21-day cycle.

17. The use according to claim 16, wherein: (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered QD at a dose of about 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle; and (b) Bevacizumab was administered on day 1 of the first 21-day cycle at a dose of 5 mg / kg to 20 mg / kg Q3W.

18. Use according to any one of claims 1-17, wherein bevacizumab is administered after administration of compound 1 or a pharmaceutically acceptable salt thereof.

19. Use of a combination in the preparation of a medicament for treating patients with NSCLC, CRC, or pancreatic cancer, said combination comprising compound 1 or a pharmaceutical salt thereof and an anti-VEGF antibody.

20. The use according to claim 15, wherein compound 1 is an adipate.

21. The use according to claim 15 or claim 16, wherein the anti-VEGF is bevacizumab.

22. The use according to any one of claims 19-21, wherein: (a) Compound 1 or a pharmaceutically acceptable salt thereof is administered QD at a dose of about 50 mg to 500 mg on days 1 to 21 of the first 21-day cycle; and (b) Bevacizumab was administered on day 1 of the first 21-day cycle at a dose of 5 mg / kg to 20 mg / kg Q3W.

23. The use according to any one of claims 1-22, wherein the patient is diagnosed as not having a mutation selected from the group consisting of: sensitized EGFR mutation, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, NTRK fusion and RET fusion, or a combination thereof.

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