Combination therapies with bispecific Anti-EGFR / c-met antibodies and third generation EGFR tyrosine kinase inhibitors

Abstract

To provide improved therapeutic agents or a combination therapy of therapeutic agents and patient stratification biomarkers, for more effective treatment of a disease, such as EGFR or c-Met positive cancer.SOLUTION: Provided is a combination therapy for treating a subject having an EGFR or c-Met expressing cancer, the therapy comprising a bispecific anti-epidermal growth factor receptor / hepatocyte growth factor receptor antibody and a compound of formula (I), or solvate, hydrate, tautomer, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a continuation of U.S. Provisional Patent Application No. 62 / 847,605, filed May 14, 2019. No. 62 / 847,563, filed May 14, 2019. The disclosure of each of the aforementioned applications is incorporated herein by reference in its entirety. Incorporated into the specification.

[0002] (Reference to electronically submitted sequence listing) This application is filed under the name "JBI6093USNP1SEQLIST.TXT" and As an ASCII sequence listing with a size of 22kb, created on April 30, 2020 Contains sequence listings submitted electronically via EFS-Web. The sequence listing provided is a part of the present specification and is incorporated herein by reference in its entirety. do.

[0003] FIELD OF THE INVENTION The present invention relates to a bispecific anti-EGFR / c-Met antibody and a third-generation EGFR tyrosine kinase inhibitor. Combination therapy with enzyme inhibitors. [Background technology]

[0004] The individual roles of both the EGFR and c-Met receptors in cancer are well established These targets are attractive for combination therapy. Both receptors signal through the T survival pathway and the anti-apoptotic pathway. These pathways are often upregulated as a mechanism of resistance to drug treatment, and so this pair of pathways Inhibition limits the possibility of activation of compensatory pathways, thereby inhibiting tumor growth-promoting pathways. These compounds may act synergistically to inhibit signal transmission, improving the overall clinical effect. Summary of the Invention [Problem to be solved by the invention]

[0005] Relapse or resistance to existing treatments is common. Improved therapeutic agents or treatments to develop more effective treatments for diseases such as Met-positive cancer There is a need for a combination of drugs and patient stratification biomarkers. [Means for solving the problem]

[0006] An embodiment of the present disclosure is a method of treating a subject with an EGFR or c-Met expressing cancer. and administering a combination therapy to the subject, the combination therapy being therapeutically effective. Quantities of isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I):

[0007] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. According to a particular embodiment, the compound of formula (I) or a solvate, hydrate, tautomer thereof The compound or pharmaceutically acceptable salt is the mesylate salt of lazertinib.

[0008] An embodiment of the present disclosure includes: (1) HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and a first domain that binds to EGFR comprising an LCDR3 of SEQ ID NO: 6 and an HCDR1 of SEQ ID NO: 7; HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, a second c-Met-binding fragment comprising an LCDR2 of SEQ ID NO: 11 and an LCDR3 of SEQ ID NO: 12; (2) a bispecific anti-EGFR / c-Met antibody containing the EGFR domain and lazertinib or its derivatives and a pharmaceutically acceptable salt thereof (e.g., a mesylate salt of lazertinib). We provide services. [Brief explanation of the drawings]

[0009] [Figure 1] 1 shows the effect of JNJ-61186372 monotherapy or in combination with lazertinib or osimertinib on body weight in nude mice bearing H1975 xenografts. [Figure 2] 1 shows the mean tumor volume (mm3) in nude mice bearing H1975 xenografts treated with JNJ-61186372 monotherapy or in combination with lazertinib or osimertinib. [Figure 3] Kaplan-Meier plot of the percentage of surviving animals in mice bearing H1975 xenografts treated with JNJ-61186372 monotherapy or in combination with lazertinib or osimertinib. [Figure 4] 1 shows the effect of JNJ-61186372 monotherapy or in combination with lazertinib or osimertinib on body weight in nude mice bearing H1975-HGF xenografts. [Figure 5] 1 shows the mean tumor volume (mm3) days after tumor implantation in nude mice bearing H1975-HGF xenografts treated with JNJ-61186372 monotherapy or in combination with lazertinib or osimertinib. [Figure 6] Kaplan-Meier plot of the percentage of surviving animals in mice bearing H1975-HGF xenografts treated with JNJ-61186372 monotherapy or in combination with lazertinib or osimertinib. DETAILED DESCRIPTION OF THE INVENTION

[0010] definition All patents, patent applications, and related publications cited herein, including but not limited to: publications are incorporated herein by reference as if fully set forth.

[0011] The terminology used herein is used only to describe particular embodiments and is not intended to be limiting. It should be understood that this is not intended to be a All technical and scientific terms used herein are commonly understood by one of ordinary skill in the art to which this invention belongs. has the same meaning as understood in

[0012] Any methods and materials similar or equivalent to those described herein may be used in testing the present invention. Although exemplary materials and methods can be used to perform the method, the present invention is not limited to the materials and methods described herein. In describing and claiming the present invention, the following terminology will be used.

[0013] Where a list is presented, unless otherwise specified, each individual element of the list and its sublists It should be understood that all combinations of the above are separate embodiments. A list of embodiments presented as "A," "B," "C," or "D" is not intended to be limiting. shall be interpreted to include "A or B," "A or C," "B or C," or "A, B, or C." should be.

[0014] "About" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art. This means that the value is determined by the way it is measured or determined, i.e., by the limitations of the measurement system. To some extent, the examples or examples are provided in the context of a particular assay, result, or embodiment. Unless expressly stated otherwise elsewhere in the specification, "about" is used to refer to any number of elements within the meaning of the present invention. This means that the difference is within one standard deviation or 5% of the range, whichever is greater. do.

[0015] "About once a week" or "once a week" refers to administration about once a week. "During" refers to 7 days ± 2 days, i.e., 5 to 9 days. Therefore, "approximately once a week" The frequency of administration of "once" is once every 5 days, once every 6 days, once every 7 days, once every 8 days, or once every 9 days. It can be once per day.

[0016] "Approximately once every two weeks" refers to administration approximately once every two weeks. Approximately two weeks is 14 days. ±2 days, i.e., 12 to 16 days. Therefore, administration "approximately once every two weeks" The frequency can be once every 12 days, once every 13 days, once every 14 days, once every 15 days, or once every 16 days. It can be once per day.

[0017] As used in this specification and the appended claims, the singular forms "a," "an," "an" and "an" are used interchangeably. and "the" includes plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a reference to a group of two or more cells. This includes combinations and the like.

[0018] The term "and / or" connecting multiple listed elements refers to both the individual and combined For example, if two elements are combined in "and / or" Thus, when connected, the first option is applicable to the first element without the second element. The second option indicates that the second element is applicable without the first element. The third option indicates that the first and second elements are applicable together. Any one of the alternatives is encompassed within the meaning and therefore, as used herein, It is understood that the requirement of the term "and / or" is met. The simultaneous application of two or more of the alternatives is also met. It is understood that the use of "and / or" is also included in the meaning and therefore meets the requirements of the term "and / or." will be done.

[0019] An "antagonist" or "inhibitor" is a substance that, when bound to a cellular protein, inhibits the activity of the protein. A molecule that inhibits at least one reaction or activity induced by a natural ligand of a substance. At least one response or activity is expressed in the absence of an antagonist (e.g., a negative at least about 20%, 30%, or more than at least one reaction or activity that is inhibited in a control %, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85 %, 90%, 95%, or 100% greater inhibition, or in the absence of antagonist. If the inhibition is statistically significant compared to the inhibition in the absence of is.

[0020] "Antibody" is intended in a broad sense and includes murine, human, humanized, and chimeric monoclonal antibodies. monoclonal antibodies, antigen-binding fragments, bispecific, trispecific, tetraspecific, etc. Multispecific antibodies, dimeric, tetrameric or multimeric antibodies, single chain antibodies, antibody domains and any other modification of the immunoglobulin molecule to contain an antigen-binding site of the required specificity. "Full-length antibodies" include immunoglobulin molecules containing disulfide bond-bound structures. Two heavy chains (HC) and two light chains (LCH) are interconnected Each heavy chain consists of a heavy chain variable region (he LC), and a multimer thereof (e.g., IgM). heavy chain variable region (VH), and heavy chain constant region (domain CH1, hinge, Each light chain is composed of a light chain variable region (CH2, CH3). It consists of a light chain constant region (CL) and a variable region (VL). The VH and VL regions are interspersed with framework regions (FR) and complementarity determining regions ( Each VH and VL can be further divided into hypervariable regions called CDRs. From the carboxy terminus to the carboxy terminus, the order is: FR1, CDR1, FR2, CDR2, FR3 It consists of three CDR and four FR segments arranged as CDR1, CDR2, and FR3. Immunoglobulins are divided into five major classes depending on the amino acid sequence of the heavy chain constant domain. IgA can be assigned to one of the following classes: IgA, IgD, IgE, IgG, and IgM. and IgG isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and The antibody light chains of any vertebrate species are classified as IgG4, which is further subdivided as IgG5. Based on the amino acid sequence of the polypeptides, two distinct types are identified: kappa (κ) and It can be assigned to one of two lambdas (λ).

[0021] "Antigen-binding fragment" refers to a portion of an immunoglobulin molecule that binds to an antigen. The fragments may be synthetic polypeptides, enzymatically accessible polypeptides, or genetically engineered polypeptides. polypeptides, such as VH, VL, VH and VL, Fab, F(ab'), Fd and Fv fragments, domain antibodies (dA) consisting of one VH domain or one VL domain. b), shark variable IgNAR domain, camelized VH domain, FR3-CDR3-FR The smallest recognition unit, HCDR, consists of amino acid residues that replicate the CDR of an antibody, such as a 4-part 1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or L The VH and VL domains are linked to each other via a synthetic linker, and the VH and VL domains are linked to each other via a synthetic linker. Various types of single chain antibody designs can be created, where the VH and VL domains are When expressed as a single chain antibody construct, the VH / VL domains may be expressed intramolecularly or intermolecularly. and form a monovalent antigen-binding site, e.g., a single chain Fv (scFv) or can form bispecific antibodies, which are described, for example, in WO 1998 / 440 No. 01, No. 1988 / 01649, No. 1994 / 13804, and No. 1992 It is described in issue / 01047.

[0022] "Bispecific" refers to a molecule that is specific for two different antigens or two different epitopes on the same antigen. Bispecific antibodies refer to antibodies that bind to different antigens. Bispecific antibodies can bind to different antigens, e.g., human or monkey, For example, Macaca cynomolgus (cynomolgus monkey, cyno) or Pan cross-reactive with the same antigen in other species (homologues), such as troglodytes Alternatively, it may bind to an epitope shared between two or more different antigens.

[0023] “Bispecific anti-EGFR / c-Met antibody” or “bispecific EGFR / c-Met anti-antibody” The antibody comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met. This refers to a bispecific antibody with a second domain that specifically binds to EGFR and c-Met. The domains that bind are typically VH / VL pairs. Bispecific antibodies can be structured as follows: It may be monovalent, bivalent, or multivalent with respect to binding to EGFR and c-Met. That is, one or more domains that bind to EGFR and one or more that bind to c-Met. It can have a domain.

[0024] A "biological sample" refers to a fluid, cell, or tissue isolated from a subject, as well as any sample obtained from the body of a subject. An exemplary sample is a biological fluid, e.g., a collection of fluids, cells, or tissues present in a sample. For example, blood, serum and serous fluid, plasma, lymph, urine, saliva, cyst fluid, tears, feces, sputum, Mucous secretions of secretory tissues and organs, vaginal secretions, ascites, pleural cavity, pericardial cavity, peritoneal cavity, abdominal cavity, and others fluids from body cavities, fluids recovered by bronchial lavage, synovial fluids, fluids of any object or biological origin, e.g. For example, liquids that have come into contact with cell and organ culture media, including cell or organ conditioned media, washing solutions, etc. Solution, tissue biopsy, tumor tissue biopsy, tumor tissue sample, fine needle aspirate, surgically resected tissue, organ culture or cell culture.

[0025] A "complementarity determining region" (CDR) is the region of an antibody that binds to an antigen. at(Wu et al. (1970) J Exp Med 132:211-50) (Kabat et al.,Sequences of Proteins of Immunological Interest,5th Ed.Public Hea National Institutes of Health h, Bethesda, Md., 1991), Chothia (Chothia et al. al. (1987) J Mol Biol 196:901-17), IMGT ( Lefranc et al.(2003) Dev Comp Immunol 27 :55-77), and AbM (Martin and Thornton (1996 ) J Bmol Biol 263:800-15) The correspondence between the various descriptions and the numbering of the variable regions is given (e.g. , Lefranc et al. (2003) Dev Comp Immunol 2 7:55-77, Honegger and Pluckthun, (2001) J Mol Biol 309:657-70, International Immuno GeneTics (IMGT) database; web resource, http: / / www_ imgt_org). abYsi by UCL Business PLC CDRs can be delineated using available programs such as . When used, "CDR", "HCDR1", "HCDR2", "HCDR3", "LC The terms "LCDR1," "LCDR2," and "LCDR3" may be used interchangeably unless expressly stated otherwise herein. Unless otherwise stated, the methods of Kabat, Chothia, IMGT, or AbM, as described above, It contains CDRs defined by either

[0026] The transitional phrases "comprising" and "consisting essentially of" "ly of" and "consisting of" are generally accepted terms in patent language. is intended to imply the meanings set forth therein, namely, (i) "comprises" or "contains" "featuring" is synonymous with "including," "containing," or "featuring" and is inclusive or non-exclusive. It is intended to be limiting and not to exclude other unrecited elements or method steps. and (ii) "consisting of" is not specified in the claims. and (iii) "consisting essentially of" The patent defines the specified materials or steps, as well as the "basic and novel characteristics ( The phrase "comprises" limits the scope of the claim to "not substantially affecting the An embodiment described in terms of "comprising / comprising" (or its equivalents) also includes an embodiment. As a form, "consisting of" and "consisting essentially of" are independently described. Provide.

[0027] "Cancer" is a type of cancer that grows uncontrollably and, in some cases, metastasizes (spreads) to other areas of the patient's body. It refers to an abnormal growth of cells that tends to spread.

[0028] "co-administration," "administered in conjunction with," "administered in combination with," "in conjunction with," "combination therapy" etc. encompasses the administration of two or more therapeutic agents to a single patient, where the therapeutic agents may be the same or different. It is intended to include therapeutic regimens administered by different routes of administration or at the same or different times. Figure.

[0029] "Diagnose" or "diagnosis" refers to determining whether a subject is suffering from a given disease or condition. or whether a person may develop a given disease or condition in the future, or whether a person has a previously diagnosed disease or whether a patient is likely to respond to treatment for a condition, i.e., whether a patient is likely to respond to treatment for a condition. refers to a method of stratifying a patient population for the likelihood of responding to a diagnostic test. General guidance about the disease being treated, or that a subject is likely to respond to a particular treatment This is done by a physician based on other criteria that indicate

[0030] "Dosage" refers to the amount of a therapeutic agent or drug taken by a subject, and the amount of drug taken by a subject. This refers to information about the frequency of the number of times a therapeutic drug is administered.

[0031] "Dose" refers to the amount or quantity of a therapeutic agent or drug taken at each time.

[0032] "EGFR- or c-Met-expressing cancer" refers to cancers in which there is detectable expression of EGFR or c-Met. It refers to cancers with EGFR or c-Met mutations or amplifications. GFR or c-Met expression, amplification, and mutation status were assessed using tumor biopsies or blood samples. sequencing, fluorescent in situ hybridization, immunohistochemistry, flow -Detect using known methods such as cytometry or Western blotting Expression can also be assessed by sequencing circulating tumor DNA (ctDNA). It can also be detected.

[0033] "Epidermal growth factor receptor" or "EGFR" is GenBank accession number NP Human EGFR (HER1 or Erb) having the amino acid sequence shown in Also known as B1 (Ullrich et al., Nature 309:4 18-425, 1984), as well as its naturally occurring variants.

[0034] "Fucose content" refers to the fucose monosaccharide in the glycan at Asn297 in an antibody preparation. Refers to the quantity of a species.

[0035] "Hepatocyte growth factor receptor" or "c-Met" as used herein refers to GenB ank accession number NP_001120972 It refers to human c-Met, as well as its naturally occurring variants.

[0036] A "human antibody" is an antibody that is optimized to provoke a minimal immune response when administered to a human subject. Human antibodies refer to antibodies whose variable regions are derived from human immunoglobulin sequences. If the antibody contains a constant region or a portion of a constant region, the constant region may also contain human immunoglobulin sequences. Human antibodies are antibodies in which the variable regions of the human antibody are derived from human germline immunoglobulins or rearrangements. If obtained from a system that uses modified immunoglobulin genes, the sequence is "derived" from a human source. Such an exemplary system comprises a heavy chain variable region and a light chain variable region that are "displayed" on a phage. The human immunoglobulin gene library and the human immunoglobulin locus "Human antibodies" includes transgenic non-human animals, such as mice or rats, that possess the antibodies. The differences in the systems used to obtain human antibodies and human immunoglobulin loci typically the deliberate introduction of somatic mutations or substitutions into the framework or CDRs; or both, resulting in amino acid differences when compared to human-expressed immunoglobulins. Typically, a "human antibody" is a human antibody derived from human germline immunoglobulins or rearranged or modified human antibodies. The amino acid sequence is compared to the amino acid sequence encoded by the immunoglobulin gene. Columns are at least approximately 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical. In some cases, "human antibodies" are antibodies, e.g., as described by Knappik et al., (2000) J Mol Biol 296:57-86 Consensus framework sequences obtained from human framework sequence analysis, or e.g. Shi et al., (2010) J MolBiol 397:385-96 and The human immunoglobulins displayed on phage described in International Publication No. 2009 / 085462 are The library may contain a synthetic HCDR3 incorporated into the purine gene library. Antibodies in which the CDRs are derived from a non-human species are not included in the definition of "human antibody."

[0037] "Isolated" means substantially free from other components of the system in which a molecule is produced, such as a recombinant cell. A homogenous population of systematically isolated and / or purified molecules (e.g., synthetic polynucleotides, polynucleotides, peptide, vector, or virus) and subjected to at least one purification or isolation step. "Isolated" refers to a protein that is substantially free from other cellular material and / or chemicals. It refers to molecules that are essentially free of soluble soluble ions, and those with higher purity, e.g., 80%, 81%, 82%, 83%, 84% %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94 Molecules isolated to 95%, 96%, 97%, 98%, 99%, or 100% purity Includes.

[0038] "Low fucose" or "low fucose content" refers to a fucose content of approximately 1% to 15%. It means antibody.

[0039] A "monoclonal antibody" is a substantially homogeneous population of antibody molecules (i.e., The individual antibodies to be produced may be modified in a variety of ways, including known modifications such as removal of the C-terminal lysine from the antibody heavy chain. or amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamic acid oxidation. It refers to antibodies obtained from a human antibody that is identical to the human antibody except for post-translational modifications such as glutamate deamidation. Monoclonal antibodies typically bind to one antigenic epitope. Clonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies are There may be heterogeneous glycosylation within an antibody population. Monoclonal antibodies are monospecific. or may be multispecific, such as bispecific, and may be monovalent, bivalent, or multivalent. That's fine.

[0040] "Newly diagnosed" means a cancer that has been diagnosed, e.g., an EGFR- or c-Met-expressing cancer. refers to subjects who have received treatment for cancer but have not yet received treatment for cancer.

[0041] "Normal fucose" or "normal fucose content" refers to more than about 50%, typically It refers to an antibody having a fucose content of greater than about 80%, or greater than about 85%.

[0042] "Pharmaceutical composition" or "pharmaceutical combination" refers to a compound, such as a bispecific EGFR / c-Met antibody. and one or more pharmaceutically acceptable carriers, or a third-generation EGFR tyrosine kinase inhibitor a tautomer, or a solvate, hydrate, or tautomer thereof; refers to a composition comprising a pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers. It is intended that each active ingredient be given to the patient in combination, either sequentially or simultaneously.

[0043] A "pharmaceutically acceptable carrier" or "excipient" is any substance other than an active ingredient that is not toxic to a subject. The term "compound" refers to a component in a pharmaceutical composition of the present invention. The pharmaceutically acceptable carrier may be a buffer, stabilizer, or antiseptic. Pharmaceutically acceptable carriers include, but are not limited to, diluents, disintegrating agents, preservatives, etc. or a diluent, disintegrant, wetting agent, glidant, or lubricant. However, the present invention is not limited to these.

[0044] "Preventing," "preventing," "prevention," or "prophylaxis" of a disease or disorder This means preventing the occurrence of disorders in elephants.

[0045] "Recombinant" refers to the joining of segments from different sources to form recombinant DNA, antibodies, or When producing a protein, it is prepared, expressed, produced, or isolated by recombinant means. Refers to DNA, antibodies, and other proteins.

[0046] "Refractory" refers to a disease that does not respond to treatment. Refractory diseases are those that are A disease may be resistant to treatment or a refractory disease may become resistant during treatment.

[0047] "Recurrent" means that the disease or signs and symptoms of the disease return after a period of improvement following prior treatment with a therapeutic agent. It means to restart.

[0048] "Respond," "responsive," or "likely to respond" refers to detectable or undetectable Any kind of improvement or positive response, whether possible or not, e.g., one or more alleviation or amelioration of symptoms, reduction in the extent of disease, or a stabilized (i.e., not worsening) disease state , prevention of the spread of disease, delay or slowing of disease progression, amelioration or alleviation of the disease state, and remission (part (whether partial or holistic).

[0049] "Solvates" and "hydrates" are solvent addition forms that the compounds of the present invention are able to form, This allows the multi-component compound to be composed of a host molecule (e.g., a compound of formula (I) or a salt thereof) and and guest molecules (water ("hydrate") or another solvent ("solvate")) incorporated into the structure. Contains both.

[0050] "Specific binding" or "specifically binds" or "specific binding" or "binding" " refers to an antibody that binds to an antigen or an epitope within an antigen with higher affinity than to other antigens. Typically, antibodies bind to approximately 5 x 10 -8 M or less, e.g., about 1×10 - 9 M or less, approximately 1×10 -10 M or less, approximately 1×10 -11 M or less, or about 1 x 10 -12 M The following equilibrium dissociation constants (K D ) binds to the antigen or epitope within the antigen, and binds to non-specific antigens (e.g. For binding to antibodies (e.g., BSA, casein), the K D At least 1 00 times smaller K D The dissociation constant can be measured using known protocols. However, antibodies that bind to an antigen or an epitope within an antigen may bind to other related antigens, e.g. For example, a human or a monkey, such as Macaca fascicularis (cynomolgus monkey) cyno), or Pan troglodytes (chimpanzee, chimp), etc. may have cross-reactivity to the same antigen (homologue) from other species. A monospecific antibody binds to one antigen or epitope, whereas a bispecific antibody binds to two different antigens or epitopes. The antibody binds to different antigens or two different epitopes.

[0051] A "subject" includes any human or non-human animal. A "non-human animal" includes all vertebrates, For example, mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, and cows. This includes mammals, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" are used interchangeably herein. Used interchangeably.

[0052] "Tautomers" or "tautomeric forms" are different forms that are interconvertible via a low energy barrier. For example, proton tautomers (proton tautomers) isomers) are prototypical isomers such as keto-enol and imine-enamine isomerizations. Valence tautomers involve interconversions via the reorganization of some of the bonding electrons. Includes mutual conversions.

[0053] A "therapeutically effective amount" is an amount effective to achieve a desired therapeutic result, at dosages and for periods of time necessary. The therapeutically effective amount depends on factors such as the individual's condition, age, sex, and weight, as well as the individual's The ability of a single therapeutic agent or combination of therapeutic agents to elicit the desired response varies. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example: , and improved health of the patient.

[0054] "Treating," "treating," or "treatment" of a disease or disorder, such as cancer, includes the following: This refers to achieving one or more of the following: reducing the severity and / or duration of the disorder; inhibits the worsening of symptoms characteristic of the disorder being treated; limiting or preventing the recurrence of the disorder in a subject who is previously symptomatic for the disorder; Limit or prevent the recurrence of symptoms in

[0055] In the context of EGFR tyrosine kinase inhibitors (TKIs), "treatment-naive" refers to FR refers to subjects who have not received TKI treatment.

[0056] A "humanized antibody" is an antibody in which at least one CDR is derived from a non-human species and at least one FDR is derived from a non-human species. Humanized antibodies refer to antibodies whose framework is derived from human immunoglobulin sequences. The framework can contain substitutions, so that the framework is or may not be an exact copy of the human immunoglobulin germline gene sequence.

[0057] "First-generation EGFR tyrosine kinase inhibitors" (first-generation TKIs) are those that target genes within exon 19. NS with EGFR activating mutations such as deletions and exon 21 L858R mutation Reversible EGFR inhibitors such as gefitinib and erlotinib are effective in the first-line treatment of CLC. Refers to...

[0058] "Second-generation EGFR tyrosine kinase inhibitors" (second-generation TKIs) are those that target genes within exon 19. NS with EGFR activating mutations such as deletions and exon 21 L858R mutation Covalent bonds such as afatinib and dacomitib are effective in the first-line treatment of CLC. It refers to a compound, irreversible EGFR inhibitor.

[0059] "Third generation EGFR tyrosine kinase inhibitors" (third generation TKIs) are those that target genes within exon 19. EGFR activating mutations such as exon 21 L858R and exon 21 deletions alone or 0M mutation, which has lower inhibitory activity against wild-type EGFR. Refers to covalent, irreversible EGFR inhibitors such as rutinib and lazertinib.

[0060] Methods of the present disclosure NSCLC is characterized by an in-frame deletion in exon 19 or an L858R mutation in exon 21. Activating mutations in the kinase domain of EGFR are the most commonly occurring mutations. Most patients with these activating EGFR mutations Patients initially respond to first-generation EGFR TKIs such as gefitinib and erlotinib. However, drug resistance limits responses to an average duration of less than one year (Kobayash i et al.,New Engl J Med 2005;352(8):786- 792;Perez-Soler R et al.,J Clin Oncol 20 04;22(16):3238-3247). The T790M secondary mutation in EGFR is EGFR-mutant NSCLC patients with resistant disease have been identified in approximately 50% of cases (Chen et al., Pathol Oncol Res 2009;15(4):651- 658;Jeffers et al., J Mol Med (Berl).1996 ;74(9):505-513;Pao et al.,PLoS Med 2005; 2(3):e73;Sequist et al., Sci Transl Med 2 011;3(75):75ra26). This mutation reduces the affinity for adenosine triphosphate. reduces the efficacy of reversible TKIs by resulting in increased EGFR kinase activity (Yun et al.,Proc Natl Acad Sci US A.200 8;105(6):2070-2075). In addition, resistant tumors have MET gene amplification, Increased c-Met protein expression and / or increased c-Met ligand expression, HGF Thus, it can activate the c-Met pathway (Engelman et al., Science ce 2007;316(5827):1039-1043;Yano et al., Cancer Res 2008;68(22):9479-9487). c-Met Sutra Stimulation of this pathway activates the phosphatidylinositol 3-kinase / Akt signaling pathway. provide an alternative mechanism for activating EGFR, thereby bypassing TKI blockade of EGFR, These two mechanisms promote cancer cell survival. occur simultaneously in 5% to 33% of patients (Bean et al., Proc Natl Acad Sci USA 2007;104(52):20932-20937) .

[0061] JNJ-61186372 (JNJ-372) inhibits ligand-induced activation and inhibits receptor inhibits both EGFR and c-Met signaling by inducing the breakdown of and a bispecific anti-EGFR / c-Met antibody, which is incorporated herein by reference. In addition, it is known that the IL-12 receptor is expressed at high levels on the surface of tumor cells. The presence of EGFR and c-Met promotes antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent Immune effectors via Fc-mediated effector mechanisms such as cellular phagocytosis (ADCP) JNJ-372 targets these cells for destruction by inflammatory cytokines. The EGFR binding domain is defined by the amino acid sequence of SEQ ID NO: 1. Heavy chain complementarity determining region 1 (HCDR1), HCDR2 of SEQ ID NO: 2, HCDR of SEQ ID NO: 3 3, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, an LCDR2 of SEQ ID NO: 5, and the c-Met binding domain comprises an LCDR3 of SEQ ID NO: 6, an HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, and an LCDR2 of SEQ ID NO: 11, and an LCDR3 of SEQ ID NO: 12, and the EGFR binding domain is A heavy chain variable domain (VH) of SEQ ID NO: 13 and a light chain variable domain (VL) of SEQ ID NO: 14 and the c-Met binding domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16. The antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17, a first light chain (LC1) of SEQ ID NO: 18 , a second heavy chain (HC2) of SEQ ID NO: 19, and a second light chain (LC2) of SEQ ID NO: 20. nothing.

[0062] >SEQ ID NO: 1 (HCDR1, EGFR binding arm) TYGMH >SEQ ID NO: 2 (HCDR2, EGFR binding arm) VIWDDGSYKYYGDSVKG >SEQ ID NO: 3 (HCDR3, EGFR binding arm) DGITMVRGVMKDYFDY >SEQ ID NO: 4 (LCDR1, EGFR binding arm) RASQDISSALV >SEQ ID NO: 5 (LCDR2, EGFR binding arm) DASSLES >SEQ ID NO: 6 (LCDR3, EGFR binding arm) QQFNSYPLT >SEQ ID NO: 7 (HCDR1, c-Met binding arm) SYGIS >SEQ ID NO: 8 (HCDR2, c-Met binding arm) WISAYNGYTNYAQKLQG >SEQ ID NO: 9 (HCDR3, c-Met binding arm) DLRGTNYFDY >SEQ ID NO: 10 (LCDR1, c-Met binding arm) RASQGISNWLA >SEQ ID NO: 11 (LCDR2, c-Met binding arm) AASSLLS >SEQ ID NO: 12 (LCDR3, c-Met binding arm) QQANSFPIT >SEQ ID NO: 13 (VH, EGFR binding arm) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQ APGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGT LVTVSS >SEQ ID NO: 14 (VL, EGFR binding arm) AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQK PGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQ PEDFATYYCQQFNSYPLTFGGGTKVEIK >SEQ ID NO: 15 (VH, c-Met binding arm) QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQ APGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTA YMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS >SEQ ID NO: 16 (VL, c-Met binding arm) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHK PGKAPKLLIYAASSLLSGVPSRFSGSGSGTFTLTISSLQ PEDFATYYCQQANSFPITFGQGTRLEIK >SEQ ID NO: 17 HC1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQ APGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTL YLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPA PELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK >SEQ ID NO: 18 LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQK PGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQ PEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC >SEQ ID NO: 19 HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQ APGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTA YMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK >SEQ ID NO: 20 LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHK PGKAPKLLIYAASSLLSGVPSRFSGSGSGTFTLTISSLQ PEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC

[0063] Lazertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) The structure and synthesis of tinib are described in U.S. Patent No. 9,593,000, which is incorporated herein by reference. The chemical name of the lazertinib free base represented by formula (I) herein is described in US Pat. No. 6,629,498. is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-2-yl)methyl (1-zol-1yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophen The compound is a hydroxybenzoate (herein referred to as lazertinib). The phosphate salt has the formula II:

[0064] [ka] It can be expressed by:

[0065] Embodiments of lazertinib (e.g., salts and crystalline forms) are described in International Application PCT / KR201 No. 8 / 004473, which is also incorporated herein by reference. .

[0066] According to certain embodiments, lazertinib in its free base form inhibits wild-type EGFR. Little or no effect, but strong inhibitory activity against T790M single and double mutations and highly selective and irreversible EGFR TKIs, e.g., activated EGFR It targets the mutations del19 and L858R, as well as the T790M mutation. the mutation may be delE746-A750, L858R, or T790M; Dual-mode selectable from delE746-A750 / T790M or L858R / T790M It may be a mutation.

[0067] An embodiment of the present disclosure is a method of treating a subject with cancer, comprising administering a combination therapy to the subject. and administering to said patient a therapeutically effective amount of an isolated bispecific antibody. Anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibodies and treatment A therapeutically effective amount of a compound of formula (I):

[0068] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. include.

[0069] An embodiment of the present disclosure is a method of treating a subject with an EGFR or c-Met expressing cancer. and administering a combination therapy to the subject, the combination therapy being therapeutically effective. an isolated bispecific anti-EGFR / c-Met antibody and a therapeutically effective amount of a compound of formula (I) ):

[0070] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. include.

[0071] Embodiments of the present disclosure are directed to methods for use as a pharmaceutical, particularly for use as a pharmaceutical in a subject. a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGF) R) / hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I):

[0072] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The present invention provides a pharmaceutical combination comprising:

[0073] Embodiments of the present disclosure are directed to methods for use in the treatment of cancer, particularly for use in the treatment of cancer in a subject. a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / a hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I):

[0074] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The present invention provides a pharmaceutical combination comprising:

[0075] Embodiments of the present disclosure are directed to compounds, particularly those for use in treating EGFR- or c-Met-expressing cancers. A therapeutically effective amount of EGFR or c-Met expressing cancer in an elephant. Isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c- Met) antibody and a therapeutically effective amount of a compound of Formula (I):

[0076] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The present invention provides a pharmaceutical combination comprising:

[0077] Embodiments of the present disclosure provide a method for the manufacture of a medicament for the treatment of cancer, particularly for the treatment of cancer in a subject. a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte a c-Met antibody and a therapeutically effective amount of a compound of Formula (I):

[0078] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The present invention provides for the use of a combination comprising:

[0079] Embodiments of the present disclosure are directed to methods for treating EGFR- or c-Met-expressing cancers, particularly methods for treating EGFR- or c-Met-expressing cancers in a subject. A therapeutically effective amount of isolated FR- or c-Met-expressing cancer for the manufacture of a medicament for the treatment of cancer. A bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) ) antibody and a therapeutically effective amount of a compound of formula (I):

[0080] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The present invention provides for the use of a combination comprising:

[0081] An embodiment of the present disclosure is directed to a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) compound. (EGFR) / hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I ):

[0082] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. The present invention provides a pharmaceutical combination comprising:

[0083] Embodiments of the present disclosure provide for the treatment of cancer, particularly cancer in a subject, by simultaneously or separately administering or as a combined preparation for sequential use, a therapeutically effective amount of isolated Bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I):

[0084] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. Provide a product containing

[0085] Embodiments of the present disclosure provide for the treatment of EGFR or c-Met expressing cancers, particularly EGF- For simultaneous, separate or sequential use in the treatment of R or c-Met expressing cancers Therapeutically effective amounts of isolated bispecific anti-epidermal growth factor receptor agonists as combined preparations an EGFR / c-Met antibody and a therapeutically effective amount of the formula ( I):

[0086] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. Provide a product containing

[0087] Embodiments of the present disclosure include the use of a compound of formula (I) in the treatment of cancer, particularly in the treatment of cancer in a subject. a compound, particularly a compound of formula (I), in a therapeutically effective amount:

[0088] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof Isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatic agents for combined use A therapeutically effective amount of an isolated bispecific c-Met antibody, particularly a c-Met antibody, is administered. We offer a specific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody. do.

[0089] Embodiments of the present disclosure provide for the treatment of EGFR or c-Met expressing cancers, particularly EGF- In the treatment of R- or c-Met-expressing cancers, a compound of formula (I), particularly a therapeutically effective amount of formula (I):

[0090] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof Isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatic agents for combined use A therapeutically effective amount of an isolated bispecific c-Met antibody, particularly a c-Met antibody, is administered. We offer a specific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody. do.

[0091] In embodiments, the bispecific anti-EGFR / c-Met antibody and the lazertinib compound are or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is also included herein. As described above, the compounds may be administered simultaneously (e.g., as part of the same pharmaceutical composition or in separate pharmaceutical compositions). The doses may be administered at the same time (in the same dose), or at different times.

[0092] Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic salts. Pharmaceutically acceptable acidic / anionic salts include acetic acid salts. Salt, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, edetate potassium Calcium, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edis Salt, estrus, esylate, fumarate, gluceptate, gluconate, gluconate Salt, Glycolyl Arsanilate, Hexylresorcinol, Hydrobromide, Hydrochloride Salt, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, Malate, maleate, malonate, mandelate, mesylate, methylsulfate, Coate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, Ligalacturonate, salicylate, stearate, acetate, succinate, sulfate Salt, hydrogen sulfate, tannate, tartrate, octyl salt, tosylate and triethoxysilane Pharmaceutically acceptable basic / cationic salts include sodium, cation salts. Sodium, Calcium, Magnesium, Diethanolamine, N-Methyl-glucamine, L -Lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine Examples include phenolamine salts.

[0093] Pharmaceutically acceptable acid salts include the free base form of the compound of formula (I) and the salts of hydrobromic, hydrochloric, or , sulfuric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, formic acid, acetic acid, propionic acid, fumaric acid, Citric acid, tartrate, lactic acid, benzoate, salicylic acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, Naphthalenesulfonic acids, such as 2-naphthalenesulfonic acid, or hexanoic acid is formed by reaction with a suitable inorganic or organic acid, including but not limited to: ) is a pharmaceutically acceptable acid addition salt of the compound of formula (I), for example, hydrobromide, hydrochloride, sulfate, Nitrate, phosphate, succinate, maleate, formate, acetate, propionate, humectant Salt, citrate, tartrate, lactate, benzoate, salicylate, glutamate, Aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate acid salts, ethanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates) The salt may comprise or be a hexanoate salt, or a hexanoate salt.

[0094] The free acid or free base forms of the compounds of formula (I) may be converted into the corresponding base addition salts or acid salts, respectively. For example, the compounds of the present invention in the form of an acid addition salt may be prepared from the salt form. by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.) Compounds of the invention in their base addition salt form can be converted to the corresponding free base form by is converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.) It is possible.

[0095] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises the double stranded sequence of SEQ ID NO: 1. Strand complementarity determining region 1 (HCDR1), HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3 , light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, a first domain that binds to EGFR, comprising an LCDR3 of SEQ ID NO: 6, and an HCDR of SEQ ID NO: 7; 1, HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, Contains LCDR2 of sequence number 11 and LCDR3 of sequence number 12, which binds to c-Met and a second domain.

[0096] In some embodiments, the first domain that binds to EGFR comprises the heavy chain of SEQ ID NO: 13. A human ovarian tumor suppressor comprising a variable region (VH) of the human ovarian tumor suppressor and a light chain variable region (VL) of SEQ ID NO: 14, which binds to c-Met. The second domain comprises a VH of SEQ ID NO:15 and a VL of SEQ ID NO:16.

[0097] In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgG1 isoform. There is some diversity within the IgG1 constant domain (e.g., the well-known allotypes). ) exists and is ranked 214th, 356th, 358th, 422nd, 431st, 435th, or 436th (EU Residue numbering according to the numbering system) (e.g., IMGT web resource; IM GT Repertoire (IG and TR);Proteins and a (See allotypes). Bispecific anti-EGFR / c-Me The t antibody may be G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28. It may be any IgG1 allotype. Representative IgG1 constant domain amino acids The sequence is shown in SEQ ID NO:21.

[0098] IgG1 constant domain (SEQ ID NO: 21) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG KEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPSRD ELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGK

[0099] In some embodiments, the bispecific anti-EGFR / c-Met antibody has the sequence of SEQ ID NO: 17 HC1 of SEQ ID NO: 18, LC1 of SEQ ID NO: 19, and LC2 of SEQ ID NO: 20. nothing.

[0100] In some embodiments, the bispecific anti-EGFR / c-Met antibody is from about 1% to about 15% It has a biantennary glycan structure with a fucose content of .

[0101] In some embodiments, the bispecific anti-EGFR / c-Met antibody is from about 1% to about 15% % of, for example, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, Biantennary glycans with a fucose content of 6%, 5%, 4%, 3%, 2%, 1%, or 1% It has a structure.

[0102] The relative amount of fucose is the ratio of fucose-containing structures to the total sugar structures. The construction can be carried out in several ways, for example, 1) as described in WO 2008 / 0775462; Such N-glycosidase F treated samples (e.g., complexes, hybrids, and oligo- 1) the use of MALDI-TOF for the Asn297 glycan (and high mannose structures); release, followed by derivatization, and HPLC (UPLC) and / or HPLC with fluorescence detection detection / quantification by LC-MS (UPLC-MS); 3) the first GlcNAc monosaccharide and the second GlcNAc monosaccharide. The fucose is then cleaved between the first GlcNAc monosaccharide and the second GlcNAc monosaccharide. or involving processing of the Asn297 glycan by Endo S or other enzymes, 4) intact protein analysis of native or reduced mAb without this treatment, 5) enzymatic digestion (e.g. For example, trypsin or endopeptidase Lys-C can be used to break down the constituent peptides of mAbs. digestion, followed by separation, detection, and quantification by HPLC-MS (UPLC-MS); 5) As Specific enzymatic deglycosylation with PNGase F at n297 resulted in the deglycosylation of the mAb protein. By separating the mAb oligosaccharides from the protein, they can be characterized and quantified. The oligosaccharides thus released are labeled with fluorophores, allowing for detailed characterization of the glycan structure. These can be isolated and identified by a variety of complementary techniques that allow for their assessment. is determined by comparing the experimental mass with the theoretical mass using matrix-assisted laser desorption / ionization (MAD) LDI) mass spectrometry, and the degree of sialylation by ion-exchange HPLC (GlycoSep C). Determination of oligosaccharides according to hydrophilicity criteria by normal-phase HPLC (GlycoSep N) Separation and quantification of α- and β-glucan species, and high performance capillary electrophoresis-laser induced fluorescence (HPCE-L Separation and quantification of oligosaccharides by IF.

[0103] The ability of an antibody to induce ADCC can be enhanced by manipulating its oligosaccharide components. Human IgG1 or IgG3 is N-glycosylated at Asn297. The majority of glycans are of the known biantennary G0, G0F, G1, G1F, G2, or G2F Antibodies produced by non-genetically engineered CHO cells are typically in the form of , and has a glycan fucose content of at least about 85%. Removal of core fucose alters antigen binding or antibody-dependent cellular cytotoxicity (CDC) activity Improved FcγRIIIa binding enhances antibody-dependent cell-mediated cytotoxicity without Antibodies with reduced fucose content enhance ADCC (antibody-specific cell death). Konno et al.,Cytotechnology 64:249-65,20 12), and application of the mutant CHO line Lec13 as a host cell line (Shields et al. al., J Biol Chem 277:26733-26740, 2002), mutation Application of the CHO line EB66 as a host cell line (Olivier et al., MAb s;2(4),2010;Epub ahead of print;PMID:205 62582), and application of rat hybridoma cell line YB2 / 0 as a host cell line (Sh inkawa et al., J Biol Chem 278:3466-3473, 2003), specific for the αα1,6-fucosyltransferase (FUT8) gene Targeted delivery of small interfering RNA (Mori et al., Biotechnol Bio eng 88:901-908,2004), or β-1,4-N-acetylglucosamine α-mannosidase III and Golgi α-mannosidase II or potent α-mannosidase Co-expression of kifunensin, a phosphodiesterase I inhibitor (Ferrara et al., Biotechnol Bioeng 93:851-861,2006; et al.,Biotechnol Bioeng 99:652-65,2008) This resulted in relatively high expression of defucosylated antibodies bearing biantennary complex-type Fc oligosaccharides. It can be made using a variety of methods that have been reported to be effective.

[0104] In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer thereof, or a pharmaceutically acceptable salt thereof, has the formula (II):

[0105] [ka] In some embodiments, the compound is represented by a compound, solvate, hydrate, or tautomer of the formula: In the present invention, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is The salt to be prepared has the formula (II):

[0106] [ka] is represented by the compound

[0107] In some embodiments, the cancer is an EGFR or c-Met expressing cancer.

[0108] In some embodiments, the cancer is an EGFR and c-Met expressing cancer.

[0109] In some embodiments, the cancer is an EGFR-expressing cancer.

[0110] In some embodiments, the cancer is a c-Met-expressing cancer.

[0111] In some embodiments, the EGFR or c-Met expressing cancer is a cancer that expresses wild-type EGFR, EGF R mutation, EGFR gene amplification, elevated levels of circulating HGF, wild-type c-Met, c-Me t mutation, c-Met gene amplification, or mutant KRAS. EGFR mutations are It may also be an activating mutation such as a son19 deletion or an L858R mutation.

[0112] Exemplary EGFR mutations that may be associated with cancer, e.g., activating EGFR mutations, include tyrosine Increased kinase activity, receptor homodimer and heterodimer formation, enhanced ligand binding, etc. Point mutations, deletion mutations, insertion mutations, and reverse mutations that increase at least one biological activity of EGFR Mutations include mutations in the EGFR gene or genes associated with the EGFR gene. It can be located in any part of the regulatory region, and can be located in exons 18, 19, 20, or 21. Other examples of EGFR activating mutations are known in the art (e.g., (See U.S. Patent Application Publication No. 2005 / 0272083). Helodimers, receptor ligands, autophosphorylation sites, and ErbB-mediated signaling Information on EGFR and other ErbB receptors, including the signaling molecules involved in transduction, is available at , are known in the art (e.g., Hynes and Lane, Nature (See Re Reviews Cancer 5:341-354, 2005) .

[0113] In some embodiments, the EGFR mutation is E709K, L718Q, L718V, G 719A, G719X, G724X, G724S, I744T, E746K, L747S , E749Q, A750P, A755V, V765M, C775Y, T790M, L79 2H, L792V, G796S, G796R, G796C, C797S, T854I, L 858P, L858R, L861X, delE746-A750, delE746_T7 51InsKV, delE746_A750InsHS, delE746_T751In sFPT, delE746_T751InsL, delE746_S752InsIP, delE746_P753InsMS, delE746_T751InsA, delE7 46_T751InsAPT, delE746_T751InsVA, delE746_ S752InsV, delE746_P753InsVS, delE746_K754I nsGG, delE746_E749, delE746_E749InsP, delL7 47_E749, delL747_A750InsP, delL747_T751Ins P, delL747_T751InsN, delL747_S752InsPT, del L747_P753InsNS, delL747_S752InsPI, delL747 _S752, delL747_P753InsS, delL747_K754, delL 747_T751InsS, delL747_T751, delL747_P753In sS, delA750_I759InsPT, delT751_I759InsT, de lS752_I759, delT751_I759InsN, delT751_D761 InsNLY, delS752_I759, delR748-P753, delL747 -P753insS, delL747-T751, M766_A767InsA, S76 8_V769InsSVA, P772_H773InsNS, D761_E762Ins X, A763_Y764InsX, Y764_Y765 InsX, M766_A767 InsX, A767_V768 InsX, S768_V769 InsX, V769_ D770 InsX, D770_N771 InsX, N771_P772 InsX, P772_H773 InsX, H773_V774 InsX, V774_C775 InsX, one or more deletions within exon 20 of EGFR or exon 20 of EGFR one or more insertions in exon 19 of EGFR, one or more deletions in exon 19 of EGFR, or or any combination thereof, wherein X is a naturally occurring It refers to any of the amino acids present in the gene and may be 1 to 7 amino acids in length. The nomenclature is well known.

[0114] In some embodiments, the EGFR mutation is one or more deletions or deletions in exon 19. L858R, L858R, or any combination thereof. lE746-A750, delE746_T751InsKV, delE746_A75 0InsHS, delE746_T751InsFPT, delE746_T751In sL, delE746_S752InsIP, delE746_P753InsMS, d elE746_T751InsA, delE746_T751InsAPT, delE7 46_T751InsVA, delE746_S752InsV, delE746_P7 53InsVS, delE746_K754InsGG, delE746_E749, d elE746_E749InsP, delL747_E749, delL747_A75 0InsP, delL747_T751InsP, delL747_T751InsN, delL747_S752InsPT, delL747_P753InsNS, delL 747_S752InsPI, delL747_S752, delL747_P753I nsS, delL747_K754, delL747_T751InsS, delL74 7_T751, delL747_P753InsS, delA750_I759InsP T, delT751_I759InsT, delS752_I759, delT751_ I759InsN, delT751_D761InsNLY, delS752_I759 , delR748-P753 and delL747-P753insS, delL747- It's T751.

[0115] Exemplary c-Met mutations include those that result in increased tyrosine kinase activity, receptor homodimerization, and and at least one of the c-Met proteins, such as the formation of heterodimers and enhanced ligand binding. These include point mutations, deletion mutations, insertion mutations, inversions, or gene amplifications that increase one biological activity. Mutations can occur in any part of the c-Met gene or in the kinase domain of c-Met. Exemplary c-Met mutations may be located in regulatory regions associated with the gene, such as mutations at residues Position N375, V13, V923, R175, V136, L229, S323, R988 , mutations at S1058 / T1010, and E168, or exon 14 skipping It is a mutation.

[0116] In some embodiments, the c-Met mutation is exon 14 skipping of c-Met. It is a mutation.

[0117] Methods for detecting EGFR and c-Met mutations or gene amplifications are well known.

[0118] In some embodiments, the cancer is KRAS mutant. Exemplary KRAS mutations include , G12V, G12C or G12A substitutions.

[0119] In some embodiments, the subject has been diagnosed with an EGFR mutation prior to administering the combination therapy. .

[0120] In some embodiments, the subject has a newly diagnosed cancer.

[0121] In some embodiments, the subject has a newly diagnosed EGFR or c-Met expressing cancer. Has.

[0122] In some embodiments, the subject has a newly diagnosed EGFR- and c-Met-expressing cancer. Has.

[0123] In some embodiments, the subject has a newly diagnosed EGFR-expressing cancer.

[0124] In some embodiments, the subject has a newly diagnosed c-Met-expressing cancer.

[0125] In some embodiments, the subject with newly diagnosed cancer has one or more EGFR enzymes. In some embodiments, newly diagnosed EGFR or c- Subjects with Met-expressing cancer have one or more EGFR exon 20 mutations. 20 Mutations (insertion of one or more amino acids) are used in combination with EGFR tyrosine kinase inhibitors (T KI) (see, for example, WO 2018 / 094225 Exemplary exon 20 mutations include M766_A767InsA, S 768_V769InsSVA, P772_H773InsNS, D761_E762I nsX, A763_Y764InsX, Y764_Y765 InsX, M766_A7 67InsX, A767_V768 InsX, S768_V769 InsX, V76 9_D770 InsX, D770_N771 InsX, N771_P772 Ins X, P772_H773 InsX, H773_V774 InsX, and V774_C 775 InsX, where X is 1 to 7 amino acids.

[0126] In some embodiments, the subject is refractory to treatment with poziotinib.

[0127] In some embodiments, the subject is tyrosine kinase inhibitor (TKI) treatment naive. do.

[0128] In some embodiments, the subject is EGFR tyrosine kinase inhibitor (TKI) treatment naive. It's an experience.

[0129] In some embodiments, the subject is resistant to treatment with a first generation EGFR TKI. It is persistent or recurrent.

[0130] In some embodiments, the first generation EGFR TKI is erlotinib or gefinib is.

[0131] In some embodiments, the subject is resistant to treatment with a second-generation EGFR TKI. It is persistent or recurrent.

[0132] In some embodiments, the second-generation EGFR TKI is afatinib.

[0133] In some embodiments, the subject is resistant to treatment with a third generation EGFR TKI. It is persistent or recurrent.

[0134] In some embodiments, the third generation EGFR TKI is osimertinib.

[0135] In some embodiments, the subject is refractory to treatment with a previous anti-cancer therapy. or has acquired resistance.

[0136] In some embodiments, the previous anti-cancer therapy is chemotherapy, targeted anti-cancer therapy, or kinase inhibitor. It is an inhibitor.

[0137] In some embodiments, the TKI is selected from the group consisting of EGFR, c-Met, HER2, HER3, H It is an inhibitor of ER4, VEGFR, or AXL.

[0138] In some embodiments, the TKI is erlotinib, gefitinib, lapatinib, Detanib, afatinib, osimertinib, poziotinib, criotinib, cabozantinib capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib panib, sorafenib, or sunitinib.

[0139] In some embodiments, the subject is resistant or refractory to an EGFR inhibitor. Exemplary EGFR inhibitors to which cancers can develop resistance are anti-EGFR antibodies. Some of the drugs include cetuximab (ERBITUX®), pancinumumab (VECTIBIX®), (R), matuzumab, nimotuzumab, and the small molecule EGFR inhibitor erlotinib (TARCEVA®), gefitinib (IRESSA®), EKB -569 (pelitinib, irreversible EGFR TKI), pan-ErbB and other receptor tyrosine kinase inhibitors The kinase inhibitors lapatinib (EGFR and HER2 inhibitor), pelitinib (EG FR and HER2 inhibitor), vandetanib (ZD6474, ZACTIMA™, E GFR, VEGFR2, and RET TKI), PF00299804 (dacomitinib, CI-1033 (irreversible pan-ErbB TKI), Af atinib (BIBW2992, irreversible pan-ErbB TKI), AV-412 (double EG FR and ErbB2 inhibitor), EXEL-7647 (EGFR, ErbB2, GEVGR , and EphB4 inhibitor), CO-1686 (irreversible mutant-selective EGFR TKI) , AZD9291 (irreversible mutant-selective EGFR TKI), and HKI-272 ( and neratinib, an irreversible EGFR / ErbB2 inhibitor).

[0140] A variety of qualitative and / or quantitative methods can be used to determine whether a subject is resistant to treatment with an anti-cancer therapy. whether the plant is resistant, has developed resistance, or is susceptible to developing resistance Symptoms that may be associated with resistance to anti-cancer therapy include: Decline or steady state of health, increase in tumor size, cessation or slowing of tumor growth and / or the transfer of cancerous cells from one location to other organs, tissues, or cells within the body. Symptoms include loss of appetite, cognitive impairment, depression, difficulty breathing, fatigue, hormone disruption, and neutrophil deficiency. Re-establishment or re-establishment of various symptoms associated with cancer, such as cytopenia, pain, peripheral neuropathy, and sexual dysfunction or worsening of the condition is an indication that the subject is developing or is susceptible to developing resistance to anti-cancer therapy. Symptoms associated with cancer may vary depending on the type of cancer. For example, symptoms associated with cervical cancer may include: Associated symptoms include abnormal bleeding, abnormal heavy vaginal discharge, and bleeding that is not related to the normal menstrual cycle. Pelvic pain, bladder pain, or pain during urination, and during regular menstrual periods, sexual intercourse, douching, or pelvic examination Symptoms associated with lung cancer include persistent cough, coughing up blood, and shortness of breath. Symptoms may include wheezing, chest pain, loss of appetite, unintentional weight loss, and fatigue. Symptoms of liver cancer include loss of appetite and weight, especially in the upper right part of the abdomen which may extend to the back and shoulders. abdominal pain, nausea and vomiting, general weakness and fatigue, enlarged liver, abdominal swelling (ascites), and Symptoms of jaundice include yellowing of the skin and whites of the eyes (jaundice). Symptoms associated with different types of cancer can be easily identified.

[0141] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), epithelial cell carcinoma, breast cancer, ovarian cancer, Focal cancer, lung cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer Cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer Cancer, cervical cancer, spleen cancer, testicular cancer, stomach cancer, thymus cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular Hepatocellular Carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC). In some embodiments, the cancer is a metastatic cancer.

[0142] In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is epithelial In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is lung cancer. The cancer is lung adenocarcinoma. In some embodiments, the cancer is lung squamous cell carcinoma. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is anal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is In some embodiments, the cancer is nasal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is oral cancer. In some embodiments, the cancer is tongue cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is vaginal cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is cancer of the spleen. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is thymic cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is HCC. In some embodiments, the cancer is P It is RCC.

[0143] In some embodiments, NSCLC includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. In some embodiments, the cells of the NSCLC have an epithelial phenotype. In this study, NSCLC acquired resistance to treatment with one or more EGFR inhibitors. It's a good deal.

[0144] In NSCLC, specific mutations in the EGFR gene result in EGFR tyrosine kinase inhibitors. It is associated with a high response rate (70-80%) to EGFR TKIs. The five amino acid deletion within 9 or the point mutation L858R in EGFR is a promising candidate for EGFR TKIs. (Nakata and Gotoh, Expert Opinion Ther Targets 16:771-781, 2012). These mutations are Activating EGFR mutations result in ligand-independent activation of R kinase activity. It occurs in 10-30% of patients with C, and is more common in East Asians, women, never-smokers, and those with adenocarcinoma. It is significantly more common in patients with histological findings (Janne and Joh nson Clin Cancer Res 12(14 Suppl):4416s- 4420s, 2006). EGFR gene amplification also strongly influences response to EGFR TKI therapy. (Cappuzzo et al., J Natl Cancer Inst 97:643-55, 2005). EGFR exon 20 insertions are associated with EGFR TKI resistance. It is associated with resistance.

[0145] The majority of patients with EGFR-mutated NSCLC initially respond to EGFR TKI therapy. However, virtually all develop resistance that prevents a sustained response (50-60% of patients) Resistance is due to a second site point mutation (T790M) in the kinase domain of EGFR. Almost all tumors that have become resistant to EGFR tyrosine kinase inhibitors In 60% of cases, c-Met expression is increased, c-Met is amplified, or its only known link The growth factor HGF increases (Turke et al., Cancer Cell, 17:77-88,2010).

[0146] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 200 mg to It is administered in a dose of approximately 2000 mg.

[0147] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 350 mg to It is administered in a dose of approximately 1400 mg.

[0148] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 200 mg, Approx. 210mg, approx. 220mg, approx. 230mg, approx. 240mg, approx. 250mg, approx. 260m g, approx. 270mg, approx. 280mg, approx. 290mg, approx. 300mg, approx. 310mg, approx. 32 0mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, approximately 390mg, approximately 400mg, approximately 410mg, approximately 420mg, approximately 430mg , about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490 mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 5 50mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, About 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg g, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 72 0mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, approximately 790mg, approximately 800mg, approximately 810mg, approximately 820mg, approximately 830mg , about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 9 50mg, approximately 960mg, approximately 970mg, approximately 980mg, approximately 990mg, approximately 1000mg , about 1010mg, about 1020mg, about 1030mg, about 1040mg, about 1050mg , about 1060mg, about 1070mg, about 1080mg, about 1090mg, about 1100mg , about 1110mg, about 1120mg, about 1130mg, about 1140mg, about 1150mg , about 1160mg, about 1170mg, about 1180mg, about 1190mg, about 1200mg , about 1210mg, about 1220mg, about 1230mg, about 1240mg, about 1250mg , about 1260mg, about 1270mg, about 1280mg, about 1290mg, about 1300mg , about 1310mg, about 1320mg, about 1330mg, about 1340mg, about 1350mg , about 1360mg, about 1370mg, about 1380mg, about 1390mg, about 1400mg , about 1410mg, about 1420mg, about 1430mg, about 1440mg, about 1450mg , about 1460mg, about 1470mg, about 1480mg, about 1490mg, about 1500mg , approximately 1510mg, approximately 1520mg, approximately 1530mg, approximately 1540mg, approximately 1550mg , about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg , about 1610mg, 1620mg, about 1630mg, about 1640mg, about 1650mg, Approx. 1660mg, approx. 1670mg, approx. 1680mg, approx. 1690mg, approx. 1700mg, Approximately 1710mg, approximately 1720mg, approximately 1730mg, approximately 1740mg, approximately 1750mg, Approx. 1760mg, approx. 1770mg, approx. 1780mg, approx. 1790mg, approx. 1800mg, Approximately 1810mg, approximately 1820mg, approximately 1830mg, approximately 1840mg, approximately 1850mg, Approx. 1860mg, Approx. 1870mg, Approx. 1880mg, 1890mg, Approx. 1900mg, Approx. 1910mg, about 1920mg, about 1930mg, about 1940mg, about 1950mg, about 1960 mg, approximately 1970 mg, approximately 9810 mg, approximately 1990 mg, or approximately 2000 mg is administered at a dose of

[0149] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 350 mg, It is administered in doses of about 700 mg, about 1050 mg, or about 1400 mg. In one embodiment, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a dose of is administered at a dose of about 1050 mg. The R / c-Met antibody is administered at a dose of approximately 1400 mg.

[0150] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once a week. It is given.

[0151] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered once every two weeks. It is given.

[0152] In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer thereof, or a pharmaceutically acceptable salt (e.g., the compound of formula (II), lazertinib mesylate The compound of formula (I) described herein is administered in a dose of about 20 mg to about 320 mg. or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof refers to the amount of free base of the compound of formula (I) in that dose. According to embodiments comprising the mesylate salt of tinib (a compound of formula (II)), the dose is refers to the amount of nib free base (compound of formula (I)), e.g., mg / dose, as shown in Table 1 is.

[0153] [Table 1]

[0154] In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer thereof, Or a pharmaceutically acceptable salt thereof is administered at a dose of about 40 mg to about 320 mg. In some embodiments, a compound of Formula (I) or a solvate, hydrate, tautomer, or The pharmaceutically acceptable salt is administered in a dose of about 80 mg to about 320 mg. In embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutical thereof The physiologically acceptable salt is administered in a dose of about 160 mg to about 320 mg. In the form of a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The acceptable salt is administered in a dose of about 240 mg to about 320 mg. In the present invention, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is The salt is administered in a dose of about 20 mg to about 240 mg. A compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The salt is administered in a dose of about 40 mg to about 240 mg. In some embodiments, the salt of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, In some embodiments, the compound of formula (I) is administered in a dose of about 80 mg to about 240 mg. The compound, or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is In some embodiments, the compound of formula (I) is administered at a dose of from about 0 mg to about 300 mg. or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, is about 160 m In some embodiments, the compound of formula (I) or The solvates, hydrates, tautomers, or pharmaceutically acceptable salts thereof are in an amount of about 100 mg to It is administered in a dose of approximately 300 mg.

[0155] In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer thereof, or a pharmaceutically acceptable salt (e.g., the compound of formula (II), lazertinib mesylate salt) is at least about 20 mg, at least about 40 mg, at least about 60 mg, At least about 80 mg, at least about 100 mg, at least about 120 mg, at least about 14 0 mg, at least about 160 mg, at least about 180 mg, at least about 200 mg, At least about 220 mg, at least about 240 mg, at least about 260 mg, at least at least about 280 mg, at least about 300 mg, or at least about 320 mg. can be.

[0156] In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer thereof, or a pharmaceutically acceptable salt (e.g., the compound of formula (II), lazertinib mesylate Salt) is approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, Approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, Approx. 140mg, approx. 150mg, approx. 160mg, approx. 170mg, approx. 180mg, approx. 190m g, approx. 200mg, approx. 210mg, approx. 220mg, approx. 230mg, approx. 240mg, approx. 25 0mg, approx. 260mg, approx. 270mg, approx. 280mg, approx. 290mg, approx. 300mg, approx. It is administered in a dose of 310 mg, or approximately 320 mg.

[0157] In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer thereof, or a pharmaceutically acceptable salt (e.g., the compound of formula (II), lazertinib mesylate Salt) is administered once daily.

[0158] In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer thereof, or a pharmaceutically acceptable salt (e.g., the compound of formula (II), lazertinib mesylate salt) is administered at a dose of about 20 mg to about 320 mg per day (e.g., about 240 mg per day). do.

[0159] In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer thereof, or a pharmaceutically acceptable salt (e.g., the compound of formula (II), lazertinib mesylate salt) is administered at a dose of about 160 mg to about 240 mg per day.

[0160] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 200 mg to It is administered at a dose of approximately 2000 mg once a week for 4 weeks, then once every 2 weeks, and is given in the form of I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof , any dose described herein, for example, about 20 mg to about 320 mg per day (e.g., It is administered at a dose of approximately 240 mg.

[0161] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 200 mg to It is administered at a dose of approximately 2000 mg once a week for 4 weeks, then once every 2 weeks, and is given in the form of The compound of formula II) or a solvate, hydrate, or tautomer thereof may be any of the compounds described herein. Any dose, for example, a dose of about 20 mg to about 320 mg per day (for example, about 240 mg per day) It is administered at .

[0162] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 350 mg to It is administered at a dose of approximately 1400 mg once a week for 4 weeks, then once every 2 weeks, and is given in the form of I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof , any dose described herein, for example, about 160 mg to about 240 mg per day (e.g., 1 It is administered at a dose of approximately 240 mg per day.

[0163] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 350 mg to It is administered at a dose of approximately 1400 mg once a week for 4 weeks, then once every 2 weeks, and is given in the form of The compound of formula II) or a solvate, hydrate, or tautomer thereof may be any of the compounds described herein. Any dose, for example, about 160 mg to about 240 mg per day (for example, about 240 mg per day) It is administered in doses.

[0164] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 700 mg. once a week for four weeks and then once every two weeks, Its solvates, hydrates, tautomers, or pharmaceutically acceptable salts are administered at a dose of about 160 mg / day. It is administered at a dose of 1 g.

[0165] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 700 mg. once a week for four weeks, then once every two weeks, or its solvates, hydrates, or tautomers are administered at a dose of about 160 mg per day. .

[0166] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 1050 mg. once a week for four weeks and then once every two weeks, or its solvates, hydrates, tautomers, or pharmaceutically acceptable salts are administered at a dose of about 160 mg / day. It is administered in mg doses.

[0167] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 1050 mg. once a week for four weeks and then once every two weeks, or a solvate, hydrate, or tautomer thereof is administered at a dose of about 160 mg per day. do.

[0168] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a concentration of about 1400 mg. once a week for four weeks and then once every two weeks, or its solvates, hydrates, tautomers, or pharmaceutically acceptable salts are administered at a dose of about 160 mg / day. It is administered in mg doses.

[0169] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a concentration of about 1400 mg. once a week for four weeks and then once every two weeks, or a solvate, hydrate, or tautomer thereof is administered at a dose of about 160 mg per day. do.

[0170] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 700 mg. once a week for four weeks and then once every two weeks, Its solvates, hydrates, tautomers, or pharmaceutically acceptable salts are administered at a dose of about 240 mg / day. It is administered at a dose of 1 g.

[0171] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 700 mg. once a week for four weeks, then once every two weeks, or its solvates, hydrates, or tautomers are administered at a dose of about 240 mg per day. .

[0172] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 1050 mg. once a week for four weeks and then once every two weeks, or its solvates, hydrates, tautomers, or pharmaceutically acceptable salts are administered at a dose of about 240 mg / day. It is administered in mg doses.

[0173] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 1050 mg. once a week for four weeks and then once every two weeks, or a solvate, hydrate, or tautomer thereof is administered at a dose of about 240 mg per day. do.

[0174] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a concentration of about 1400 mg. once a week for four weeks and then once every two weeks, or its solvates, hydrates, tautomers, or pharmaceutically acceptable salts are administered at a dose of about 240 mg / day. It is administered in mg doses.

[0175] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at a concentration of about 1400 mg. once a week for four weeks and then once every two weeks, or a solvate, hydrate, or tautomer thereof is administered at a dose of about 240 mg per day. do.

[0176] According to certain embodiments, the methods described herein (e.g., those described above and in Example 3) JNJ-61 for use as described herein according to a dosing regimen (as described herein) Lazertinib in combination with JNJ-61186372 or lazertinib in combination with JNJ-61186372 Treating patients with rituximab is effective in reducing tumor volume in patients ( For example, see Example 4. For example, such effects are seen in patients with first-generation TKIs. Patients diagnosed with NSCLC with EGFR T790M-negative disease after progression and those with a third It can be observed in patients with progression after prior treatment with a first-generation TKI.

[0177] In some embodiments, the subject is immunized with a phenylalanine at position 158 of CD16. or heterozygous for valine and phenylalanine at position 158 of CD16. It is a b-junction type.

[0178] Subjects homozygous for phenylalanine at position 158 of CD16 are He has the γRIIIa-158F / F genotype. He has a valine at position 158 of CD16 and Subjects heterozygous for phenylalanine have FcγRIIIa-158F / V CD16 has the genotype Fc gamma receptor IIIa (FcγRIIIa) or low Affinity immunoglobulin gamma Fc region receptor also known as III-A isoform The valine / phenylalanine ( The V / F polymorphism has been shown to affect FcγRIIIa affinity for human IgG. FcγRIIIa-158F / F or FcγRIIIa-158F / V polymorphisms Receptors with reduced Fc binding compared to FcγRIIIa-158V / V and therefore exhibits reduced ADCC. The R / c-Met antibody is FcγRIIIa-158F / F or FcγRIIIa-158 It may be more effective in treating patients with the F / V genotype. Patients can be analyzed for FcγRIIIa polymorphisms.

[0179] In some embodiments, the subject is further administered a third anti-cancer therapy.

[0180] In some embodiments, the third anticancer therapy is a chemotherapy, a targeted anticancer therapy, or a kinase inhibitor. It is an inhibitor.

[0181] In some embodiments, the kinase inhibitor is selected from the group consisting of EGFR, c-Met, HER2, HE In some embodiments, the inhibitor is an inhibitor of R3, HER4, VEGFR, or AXL. The kinase inhibitor is an inhibitor of EGFR. In some embodiments, the kinase inhibitor is In some embodiments, the kinase inhibitor is an inhibitor of HER2. In some embodiments, the kinase inhibitor is an inhibitor of HER3. In some embodiments, the kinase inhibitor is an inhibitor of HER4. In some embodiments, the kinase inhibitor is an inhibitor of VEGFR. The enzyme inhibitor is also an inhibitor of AXL.

[0182] In some embodiments, the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, poziotinib, cliotinib, cabozantinib Zantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib ib, pazopanib, sorafenib, or sunitinib.

[0183] In some embodiments, the kinase inhibitor is erlotinib. In some embodiments, the kinase inhibitor is gefitinib. In some embodiments, the kinase inhibitor is vandetanib. In some embodiments, the kinase inhibitor is afatinib. In embodiments, the kinase inhibitor is osimertinib. In some embodiments, the kinase inhibitor is poziotinib. In some embodiments, the kinase inhibitor is cabozantinib. In some embodiments, the kinase inhibitor is capmatinib. In some embodiments, the kinase inhibitor is axitinib. In some embodiments, the kinase inhibitor is lenvatinib. In some embodiments, the kinase inhibitor is regorafenib. In some embodiments, the kinase inhibitor is pazopanib. In some embodiments, the kinase inhibitor is sorafenib. It is nitinib.

[0184] In combination with a bispecific anti-EGFR / c-Met antibody and lazertinib in the methods of the disclosure Anti-cancer therapies that may be administered include chemotherapeutic agents or other anti-cancer therapeutic agents known to those skilled in the art. Chemotherapeutic agents include any one or more of the following: antiproliferative or other cytotoxic agents, including alkylating agents, antimetabolites, antimicrotubule inhibitors, topoisomers, Examples include somerase inhibitors, receptor tyrosine kinase inhibitors, and angiogenesis inhibitors. Examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclophosphamide (CY TOXAN®, etc.; alkyl sulfonates, such as busulfan, impro sulfane and piposulfan; aziridines, such as benzodopa, carboquone, meth Redopam, uredopa, etc.; altretamine, triethylenemelamine, triethylenephosphatase Ethylene including methylformamide, triethylenethiophosphoramide and trimethylolmelamine imine and methylamelamine; nitrogen mustards, e.g. Chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosf amide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine , fenesterine, prednimustine, trofosfamide, uracil mustard, etc.; trosourea, e.g. carmustine, chlorozotocin, fotemustine, lomustine, nitric oxide mustine, ranimustine, etc.; antibiotics, such as aclacinomycin , actinomycin, autramycin, azaserine, bleomycin , cactinomycin, calicheamicin, carabicin, carminomycin , carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esophageal Rubicin, idarubicin, marcellomycin, mitomycin, myco Phenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin (potfiromycin), puromycin, quelamycin, rodorubicin ( rodorubicin), streptonigrin, streptozocin, tubercidin, ubenimex , zinostatin, zorubicin, etc.; antimetabolites, such as methotrexate and 5-FU Folic acid analogues, such as denopterin, methotrexate, pteropterin, trimethoprim purine analogues, such as fludarabine, 6-mercaptopurine, thiampic acid phosphorus, thioguanine, etc.; pyrimidine analogues, e.g. ancitabine, azacitidine, 6- Azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, ethoxyl Nocitabine, floxuridine, etc.; androgens, e.g. calsterone, propionic acid Dromostanolone, epithiostanol, mepitiostane, testolactone, etc.; adrenal cortex hormone synthesis inhibitors, such as aminoglutethimide, mitotane, and trilostane; folic acid Folic acid replenishers, such as folinic acid; Laton; Aldophosphamide glycoside; Aminolevulinic acid; Amsacrine; Bestlab Sil; Bisantrene; Edatraxate; Defofamine ;Demecolcine;Diaziquone;Elfornithine;Elliptinium a elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine ;Pentostatin;Fenamet;Pirarubicin;Podophyllic acid;2-Ethylhydrazine Procarbazine; PSK (registered trademark); Razoxane; Sizofiran; Spirogermani 2,2',2"-Trichloroethane;Tenuazonic acid;Triaziquone;2,2',2"-Trichloroethane Triethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitrite ol; mitolactol; pipobroman; gacytosine; arabinoside ("A ra-C); cyclophosphamide; thiotepa; a member of the taxoid or taxane family agents such as paclitaxel (TAXOL®) and docetaxel (TAXOTER®) E®) and its analogs; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxanthin Mycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novant ron; teniposide; daunomycin; aminopterin; xeloda; ibandronate; C PT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (D MFO; retinoic acid; esperamicin; capecitabine; sorafenib (NEXAVA R®), sunitinib (SUTENT®), pazopanib (VOTRI ENT™), toceranib (PALLADIA™), vandetanib (ZACT IMA™), cediranib (RECENTIN®), regorafenib (B AY73-4506), axitinib (AG013736), lestaurtinib (CEP -701), erlotinib (TARCEVA®), gefitinib (IRESS A (trademark), afatinib (BIBW 2992), lapatinib (TYKERB (registered trademark) receptor tyrosine kinases, including neratinib (HKI-272), and / or Inhibitors of angiogenesis, as well as pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing, are also included. Antihormonal agents that act to control or inhibit hormone action on tumors, For example, tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole, 4 -Hydroxytamoxifen, trioxifene, ketoxifene, LY 117018, onapristone, and toremifene (FARESTON®) antiestrogens, including benzodiazepines, ... , bicalutamide, leuprolide and goserelin; and any pharmaceutically acceptable salts of the foregoing. Also included in this definition are salts, acids, or derivatives thereof. Wiemann et al., 1 985, Medical Oncology (Calabresi et al., eds. .), Chapter 10, McMillan Publishing Other common cytotoxic compounds such as are also applicable to the methods of the present invention.

[0185] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a compound of formula (I): Prior to administration of the compound or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof It is administered as follows.

[0186] In some embodiments, the bispecific anti-EGFR / c-Met antibody has the formula (II): The compound or a solvate, hydrate, or tautomer thereof is administered prior to administration of the compound or a solvate, hydrate, or tautomer thereof.

[0187] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a compound of formula (I): or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof It is given.

[0188] In some embodiments, the bispecific anti-EGFR / c-Met antibody has the formula (II): The compound or a solvate, hydrate, or tautomer thereof is administered after administration of the compound or a solvate, hydrate, or tautomer thereof.

[0189] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a compound of formula (I): or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, It is given more than once.

[0190] In some embodiments, the bispecific anti-EGFR / c-Met antibody has the formula (II): The compound or a solvate, hydrate, or tautomer thereof may be administered one or more times after administration of the compound or a solvate, hydrate, or tautomer thereof.

[0191] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a compound of formula (I): or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, Two, three, four, five, six, seven, eight, nine, or ten or more doses may be administered.

[0192] In some embodiments, the bispecific anti-EGFR / c-Met antibody has the formula (II): or a solvate, hydrate, or tautomer thereof, Seven, eight, nine, or ten or more doses may be administered.

[0193] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises a compound of formula (I): or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, It is administered intermittently.

[0194] In some embodiments, the bispecific anti-EGFR / c-Met antibody has the formula (II): The compound or a solvate, hydrate, or tautomer thereof is administered intermittently after administration of the compound or a solvate, hydrate, or tautomer thereof.

[0195] A bispecific anti-EGFR / c-Met antibody and a compound of formula (I) or a solvate or hydrate thereof a compound, tautomer, or pharmaceutically acceptable salt thereof, or a compound of formula (II) or a solvate thereof, The length of time between administration of the hydrate, or tautomer, or the third anti-cancer therapy is several minutes. , for example, about 1, 2, 5, 10, 30, or 60 minutes, or for several hours, for example, about 2, 4, 6, 10, 12, 24, or 36 hours, or for example, about 2, 4, 7, 14, 21 , 28, 35, 42, 49, 56 days or more.

[0196] A bispecific anti-EGFR / c-Met antibody, a compound of formula (I) or a solvate thereof, water a solvate, tautomer, or pharmaceutically acceptable salt thereof, or a third anticancer agent, It can be administered as follows.

[0197] a bispecific anti-EGFR / c-Met antibody, and a compound of formula (II) or a solvate thereof; The hydrate, or tautomer, or the third anti-cancer agent may be administered as a pharmaceutical composition.

[0198] Bispecific anti-EGFR / c-Met antibody is a bispecific anti-EGFR / c-Met antibody and a pharmaceutically acceptable carrier. A carrier may be one or more diluents, adjuvants, excipients, vehicles, etc. The vehicle may be water and oil, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil. The liquid may be oil, soybean oil, mineral oil, sesame oil, etc. For example, 0.4% saline and 0. Bispecific anti-EGFR / c-Met antibodies may be formulated using 0.3% glycine These solutions are sterile and generally free of particulate matter. Sterilization may be achieved by aseptic techniques (eg, filtration).

[0199] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered by intravenous injection. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered It is administered by subcutaneous injection.

[0200] In some embodiments, a compound of Formula (I) or a solvate, hydrate, tautomer, or or a pharmaceutically acceptable salt thereof, or a compound of formula (II), or a solvate or hydrate thereof or tautomers may be used in oral formulations, e.g., solid oral formulations such as powders, capsules, and tablets. It is administered as a drug.

[0201] For example, powders, capsules, and tablets of the compound of formula (I) or the compound of formula (II) In the case of oral solid formulations such as cereals containing glutamic acid, suitable carriers and additives include starches, sugars, diluents, These include granulating agents, lubricants, binders, and disintegrants. Oral solid preparations are made by coating the formulation with substances such as sugars. It may be coated with an enteric coating to regulate the main absorption site. For parenteral administration, the carrier may comprise sterile water, or other suitable solvents for solubility or preservation. Excipients may be added. Injectable suspensions or solutions may also be prepared by mixing an aqueous carrier with suitable excipients. The preparation may be carried out using a suitable vehicle and other human proteins, such as human serum albumin. Formulations containing albumin are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition,Troy, DBed., Lipincott Williams and Wilkins, P. hiladelphia,PA 2006,Part 5,Pharmaceutica Manufacturing pp. 691-1092, especially pp. 958 Please refer to -989.

[0202] The composition contains pharmaceutically acceptable adjuvants required to approximate physiological conditions. and other substances, such as pH adjusters and buffers, stabilizers, thickeners, lubricants, and colorants. The concentration of the bispecific anti-EGFR / c-Met antibody in the pharmaceutical formulation is about 0.5 wt. %, typically at least about 1% by weight, up to 15%, 20%, 30% by weight %, 40%, or 50% by weight, depending on the particular mode of administration selected. Thus, the selection may be based primarily on the required dose, fluid volume, viscosity, etc. The pharmaceutical composition may be administered in a range of about 0.1 mg to about 2000 mg, for example, about 1 mg, about 5 mg, or about 10 mg. , about 25mg, about 50mg, about 100mg, about 150mg, about 200mg, about 300mg , about 500 mg, about 600 mg, or about 1000 mg of the active ingredient.

[0203] The mode of administration is via the administration of the drug to the host using tablet, capsule, liquid, powder, gel, or particulate formulations. Any suitable route of delivery of the antibody, for example, parenteral administration, e.g., intradermal, intramuscular, intraperitoneal It may be intravenous, subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal), may be included in a device, implantable device, osmotic pump, cartridge, or micropump. or other means well known in the art and recognized by those skilled in the art. Parenteral administration, for example, intradermal, intramuscular, intraperitoneal, intravenous, or subcutaneous, pulmonary, transmucosal, By any suitable route of delivery of the antibody to the host, such as intravenous administration (oral, intranasal, intravaginal, rectal). Site-specific administration can be, for example, intratumoral, intraarticular, intrabronchial, intraperitoneal, intracapsular, or intramuscular. Intraosseous, intrasinus, intracavity, intracerebellar, intraventricular, intracolonic, intracervical, intragastric, intrahepatic, intramyocardial, intraosseous, pelvic Intrapericardium, peritoneal cavity, pleura, prostate, lung, rectum, kidney, retina, spinal cord, synovial fluid Intravesical, intrathoracic, intrauterine, intravascular, intravesical, intralesional, intravaginal, intrarectal, intraoral, sublingual, intranasal or transdermal delivery.

[0204] The invention will now be described with reference to the following specific, non-limiting examples.

[0205] Example 1. JNJ-372 in combination with lazertinib improves the survival of H1975 human lung cancer xenograft models demonstrated tumor cell death in the DEL. The purpose of this study is to evaluate the efficacy and safety of activating EGFR mutations (L858R) and second-site resistance EGFR mutations. H1975 human lung xenografts with (T790M) and human c-Met pathway H1975-HG, activated by overexpression of HGF (c-Met ligand) In combination with the third-generation TKIs lazertinib and osimertinib in F xenografts The objective of this study was to evaluate the antitumor activity of JNJ-372.

[0206] method Female athymic nude mice (Crl:NU(Ncr)-Foxn1nu, Charles River) were 9 weeks old and weighed 19.0 to 27.2 grams (g) at the start of treatment. The animals had free access to water (reverse osmosis, 1 ppm Cl) and 18.0 % crude protein, 5.0% crude fat, and 5.0% crude fiber, NIH 31 Feed them on a Modified and Irradiated Lab Diet® 20-22°C (68-72°F) and 40-60% humidity, 12-hour light cycle Enrich-o'cobs™ gamma sterilized in static microisolators Mice were housed in laboratory bedding. All studies were conducted under the supervision of the competent authority. Guide for Care and Us on Water Regulation and Veterinary Care The recommendations of the Institute of Laboratory Animals were followed.

[0207] Tumor cell culture NCI-H1975 cells were cultured in 10% fetal bovine serum, 2 mM glutamine, 100 units 100 μg / mL penicillin G, 25 μg / mL gentamicin, and 100 μg / mL streptomycin. Grow to mid-logarithmic phase in RPMI 1640 medium containing leptomycin sulfate The tumor cells were cultured in a humidified incubator at 37°C under an atmosphere of 5% CO2 and 95% air. The cells were cultured in tissue culture flasks under atmospheric conditions.

[0208] In vivo implantation and tumor growth On the day of transplantation, NCI-H1975 cells were harvested during logarithmic growth and 5 × 10 7 cells / mL The xenografts were resuspended in phosphate-buffered saline (PBS) at a concentration of 5 × 10 6 N pieces CI-H1975 cells / animal (0.1 mL suspension) were subcutaneously implanted into the right flank of each test animal. The tumor volume is 150-200 mm 3 approaching the target range of After 15 days, tumor width and length were measured in mm using a vernier caliper. Animals were then binned according to tumor volume calculated for each group. Heuristic selection was performed to average the distribution of small to large tumor volumes between group assignments. The remaining animals were added until the number of animals assigned to each cohort met the protocol design. The tumor volumes were subjectively arranged to minimize standard error in tumor volumes between groups. 08~288mm 3 The group mean tumor volumes ranged from 206 to 209 for all groups. mm 3 Tumor size (mm3) was calculated using the following formula: Tumor volume = (w 2 ×l) / 2 where ww = tumor width (mm) and l = tumor length (mm). Tumor weight is 1mg is 1mm 3 The tumor volume was estimated assuming it was equivalent to that of a normal tumor.

[0209] Test Article JNJ-372 (also called CNTO4424 or HH80) and an isotype control , administered in 1 mg / mL PBS to give a dosage of 10 mg / kg. Osimertinib powder in 20% (w / v) hydroxypropyl β-cyclodextrin (20% HPBCD) at 1 mg / mL and stirred magnetically for 15 minutes to obtain a uniformly dispersed suspension. A suspension was prepared using lazertinib (JNJ-70080595, JNJ-595, or YH- The carbon nanotubes (CNT) powder was dissolved in 0.5% (w / v) methylcellulose (0.5 % MC, vehicle) at 1.17 mg / mL, and an active agent dose of 10 mg / kg All dosing solutions were administered at the stated mg / kg dose in a 10 mL / kg volume. It was formulated as follows.

[0210] treatment Female athymic nude mice were used in the study (n=10 / group). SC tumors were approximately 100-300 μg / mL. 00mm 3 Treatment was initiated when the animals reached a size of 100 mm and administered according to the treatment schedule summarized in Table 2. JNJ-372, an isotype control antibody, osimertinib, and lazerti Nib (also called JNJ-595) was administered at 10 mg / kg (effective concentration). -372 was administered IP twice weekly for 3 weeks, and osimertinib and lazertinib were administered intravenously daily. The control group received the vehicle orally daily for 21 days, and the isotype control group received the vehicle orally daily for 21 days. Control antibodies were administered IP twice weekly for 3 weeks. Mice were monitored for body weight and tumor volume up to day 95. and individual tumor volumes were monitored at 2,000 mm 3 or at the end of the test He was euthanized.

[0211] [Table 2]

[0212] Calculations and Data Analysis The relative body weight of each individual mouse was calculated using the formula: (W / W) × 100 (where "W " represents the weight on a particular day, and "W0" represents the weight at the start of treatment). The results are graphed as mean %±SEM.

[0213] Tumor volume data were graphed as mean tumor volume ± SEM. Tumor volume was calculated using the formula: tumor volume. Tumor volume (mm 3 ) = (D × d2) / 2 (when measured with a vernier caliper, where "D" represents the larger diameter and "d" represents the smaller tumor diameter).

[0214] %TGI was calculated as the difference in tumor burden between the treated and control groups, %ΔTGI = ([(TV Calculated as c-TVc0)-(TVt-TVt0)] / (TVc-TVc0)) × 100 (where "TVc" is the mean tumor burden for a given control group, and "TVc0" is the mean tumor burden for a given control group) "TVt" is the mean initial tumor volume of the treatment group, and "TVt0" is the mean tumor volume of the treatment group. (The mean initial tumor volume in the placebo group is ≥ 2,000 mm.) 3 When the maximum tumor volume of Animals were removed from the study when adverse clinical signs were observed. CR was calculated on the final day of analysis. A complete response (complete tumor regression) was defined as when the tumor was no longer measurable after 24 h of treatment.

[0215] Tumor volume and body weight data were analyzed using Prism software (GraphPad, version Statistical significance was determined when at least eight mice remained in each group. All pairwise comparisons were evaluated on the final day of the study when p < 0.05 indicated a significant difference between groups. Differences between treatments and time were considered significant. Statistical significance for tumor volume and body weight was determined at fixed treatment and time. Effect, animal as a random effect, R software version 3.4.2 (Jansse n Linear mixing in an in-house developed Shiny application (using version 3.3) The results were calculated using joint effect analysis. When individual longitudinal response trajectories were not linear, logarithmic transformation (baseline The information derived from this model was used to compare the effects of the control group or Pairwise comparisons of treatment were performed between all treatment groups.

[0216] Survival data were graphed and analyzed using GraphPa for Windows on day 1 as the treatment start date. d Analyzed using Prism 7.04. Log-rank (Mantel-Cox) analysis The data for all animals in the group except those assessed as non-treatment related (NTR) deaths are included. Two-sided statistical analysis was performed with a significance level of P = 0.05. Statistical tests were performed using multiple comparisons. No correction was made for differences between groups. Differences between groups were considered significant when p ≤ 0.05.

[0217] result body weight JNJ-372 does not bind to mouse EGFR or c-Met. Tolerability as monotherapy or in combination with any TKI could not be assessed in these studies. Consistent with this, JNJ-372 monotherapy did not significantly improve H1975 xenograft survival. In nude mice, there was no significant weight loss compared to the control group on day 29 ( Figure 1). Osimertinib or Raselase, either as monotherapy or in combination with JNJ-372, was Treatment with tinib resulted in some transient weight loss in the H1975 model and in control induced a lack of weight gain compared to osimertinib or lazertinib (p<0.05). The combination of osimertinib or lazertinib plus JNJ-372 compared with either monotherapy Weight loss was not significantly different between lazertinib, JNJ-372, One animal each in the groups treated with JNJ-372 and the combination of JNJ-372 and lazertinib The patients were admitted to the hospital on days 21, 43, and 71 due to unfavorable clinical signs. Sacrifices were made, but it was not known whether they were due to tumor burden or treatment.

[0218] Effectiveness In the H1975 study, single-agent JNJ-372, lazertinib, or osimertinib Therapy induced significant TGI in H1975 xenografts at day 28 compared to controls (86%, 112%, and 111%, respectively) (p≦0.0003). 72 in combination with either lazertinib or osimertinib compared with control at 28 days When administered, JNJ-37 resulted in a 112% TGI (p<0.0001). The combination of 2+osimertinib demonstrated statistically significant TGI when compared with either monotherapy (p≦0.03), with one animal achieving a CR. The combination of nib showed significant TGI compared to single JNJ-372 treatment (p<0.00 01), which delayed tumor regrowth for a longer period than lazertinib monotherapy, but not significantly The combination of JNJ-372 and lazertinib showed a tendency to improve survival compared with lazertinib alone. CR was observed in 1 of 10 mice treated with CR, whereas CR was observed in 7 of 10 mice treated with CR. The combination of JNJ-372 with either lazertinib or osimertinib resulted in The use of cefotaxime resulted in a statistically significant survival benefit compared with the control (p≦0.0003). The combination of JNJ-372 and lazertinib was significantly superior to single JNJ-372 and single lazertinib treatments. showed a statistically significant survival benefit compared with JNJ-372 (p≦0.0344). The combination with osimertinib demonstrated a statistically significant survival benefit compared with single JNJ-372 treatment showed a non-significant survival benefit compared with single osimertinib treatment (p<0.0001). The results showed a trend.

[0219] Table 3 shows the p-values for tumor growth inhibition in the H1975 xenograft model. treated with JNJ-372 monotherapy or in combination with lazertinib or osimertinib, Mean tumor volume (m) after tumor implantation in nude mice bearing H1975 xenografts m 3 Figure 3 shows the results of JNJ-372 monotherapy or lazertinib or osimertinib. Survival in H1975 xenograft-bearing mice treated with ribozyme in combination with ribozyme Table 4 shows the Kaplan-Meier plot for the percentage of animals that were successfully transplanted. The p-values for survival statistics in the model are shown.

[0220] [Table 3]

[0221] [Table 4]

[0222] Example 2. J in combination with lazertinib or osimertinib in H1975-HGF NJ-372 demonstrated tumor cell killing in a human lung cancer xenograft model. The experimental design involved the use of cells stably transfected to express hepatocyte growth factor (HGF). H1975 cells (H1975-HGF cells) (hereinafter referred to as H1975-HGF-CNT) The cells were treated as described in Example 1, except that 2 Contains 10 mM L-glutamine (Invitrogen, Cat. No. 11875-127) The cells were cultured in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum and Puromycin was added at 2 μg / mL and 2 μg / mL of puromycin. The cells were incubated in a humidified incubator at 37°C, 5% CO2 and 9% CO2. They were cultured in tissue culture flasks in an atmosphere of 5% air.

[0223] result body weight In the H1975-HGF study, JNJ-372 monotherapy demonstrated a significant improvement in the survival of H1975-HGF tumor-bearing There was no significant weight loss in the mice receiving the treatment compared to the control group on day 28 (Figure 4). Osimertinib or lazertinib, either as monotherapy or in combination with JNJ-372 Treatment with induced some transient weight loss and lack of weight gain compared to the control group. (p<0.05) compared with osimertinib or lazertinib monotherapy, respectively. When osimertinib or lazertinib + JNJ-372 were administered, weight loss was The results were not significantly different for the osimertinib and JNJ-372 monotherapy groups. One mouse in the group treated with JNJ-372 and lazertinib, and two mice in the group treated with JNJ-372 and lazertinib The mice were then examined on days 51, 53, and 7 due to unfavorable clinical signs. Animals found dead or euthanized on days 0 and 36 were not attributable to tumor burden or treatment. I didn't know if I would.

[0224] Treatment groups are shown in Table 2.

[0225] Effectiveness In the H1975-HGF study, monotherapy with JNJ-372 or lazertinib 70% and 75% of H1975-HGF xenografts, respectively, compared with controls on day 28 (p=0.0059 and p=0.0030, respectively). Treatment with tinib resulted in a statistically non-significant 57% reduction in TGI compared to control at day 28 JNJ-372 and lazertinib or osimertinib significantly improved survival (p=0.0651). The combination of either In addition, JNJ-372 and Lazerci The combination of either nib or osimertinib was compared with JNJ-372 or each TKI monotherapy. When compared, JNJ-37 resulted in a significant TGI (p<0.0001). 2 + lazertinib resulted in CR in 3 of 10 mice, whereas lazertinib monotherapy The JNJ-372 + osimertinib combination resulted in a CR in 2 of 10 patients. JNJ-372 and lazertinib or osimertinib resulted in CR in the mice. Combination with either nib resulted in a statistically significant survival benefit compared with control (p< 0.0001). The combination of JNJ-372 and lazertinib was significantly superior to the single-agent JNJ-372 and single-agent lazertinib. showed a statistically significant survival benefit compared with single lazertinib treatment (p ≤ 0.0131 The combination of JNJ-372 and osimertinib was compared with the single JNJ-372 and single osimertinib combination. There was a statistically significant survival benefit compared to lutinib treatment (p<0.0001).

[0226] Table 5 shows the p-values for tumor growth inhibition in the H1975-HGF xenograft model. Figure 5 shows JNJ-372 monotherapy or in combination with lazertinib or osimertinib. The results are shown in Table 1. The results are shown in Table 1. The results are shown in Table 1. Mean tumor volume (mm 3 Figure 6 shows the results of JNJ-372 monotherapy or lazertinib. Mice bearing H1975-HGF xenografts treated with or in combination with osimertinib Table 6 shows the Kaplan-Meier plot of the percentage of surviving animals in H. The p-values for survival statistics in the 1975-HGF xenograft model are shown.

[0227] [Table 5]

[0228] [Table 6]

[0229] conclusion The purpose of these studies was to investigate the efficacy and safety of H1975 and H1975-HGF in human NSCLC tumors. JNJ- The objective of this study was to evaluate the antitumor activity of 372.

[0230] JNJ-372 in combination with osimertinib or lazertinib was In both 75-HGF xenograft models, JNJ-372 and each TKI alone demonstrated enhanced antitumor efficacy (by increasing TGI and / or CR) compared with chemotherapy alone Transient weight loss was observed in some patients with osimertinib or lazertinib treatment. JNJ-372 does not bind to mouse EGFR or c-MET, so JNJ-372+T Tolerability of concomitant KI could not be assessed.

[0231] Overall, the data from both the H1975 and H1975-HGF models support the TKI+J Combination treatment with NJ-61186372 demonstrated superior antitumor activity compared with TKI monotherapy This suggests that further testing in a clinical setting may be considered.

[0232] Example 3: Study 61186372EDI1001: in subjects with advanced non-small cell lung cancer Phase 1 study of JNJ-61186372, a human bispecific EGFR and c-Met antibody First-in-human, open-label, dose-escalation study This study will evaluate safety and PK in subjects aged 18 years and older with advanced NSCLC. , Recommended Phase 2 Dose (RP2D) and Recommended Phase 2 Combination Dose (RP2CD) Regimens Established a clinical trial of JNJ-61186372 as monotherapy and in combination with lazertinib A first-in-human, open-label, multicenter, two-part, Phase 1 dose-escalation study to evaluate preliminary efficacy The objectives and endpoints of this study are described in Table 7.

[0233] [Table 7]

[0234] Study design overview This study will evaluate safety and PK in subjects aged 18 years and older with advanced NSCLC. , Recommended Phase 2 Dose (RP2D) and Recommended Phase 2 Combination Dose (RP2CD) Regimens Established a clinical trial of JNJ-61186372 as monotherapy and in combination with lazertinib A first-in-human, open-label, multicenter, two-part, Phase 1 dose-escalation study to evaluate preliminary efficacy is.

[0235] Part 1 JNJ-61186372 monotherapy and combination dose escalation: traditional 3+3 design Utilizing the MTD (or if the MTD is not defined) in subjects with advanced NSCLC Maximum Administered Dose (MAD) if necessary) and RP2D regimen of JNJ-61186372, and The RP2CD of each dose escalation will be determined for the combination of JNJ-61186372 and lazertinib. The total number of subjects enrolled in the study will be determined based on the dose at which the MTD or MAD is reached and the expansion of dose cohorts. Depends on whether a dose already declared safe by SET has been shown to be safe. Within a cohort, up to 20 additional subjects per dose cohort will be enrolled to Additional safety and PK data may be collected if required by the respective health authorities. Additional subjects may be enrolled in national Part 1 dose cohorts to define safety and PK. stomach.

[0236] In the combination of JNJ-61186372 and lazertinib at dose escalation, Utilizing a strategy adapted from a previous antibody and TKI combination study in LC subjects, JN Determine the RP2CD of J-61186372 and lazertinib, and compare the RP2CD of each drug. The target doses of the agents are the same as the RP2D of each agent as monotherapy. The total number of subjects studied was determined by the dose levels tested and the number of dose cohorts that achieved RP2CD. and whether dose cohort expansion is required to determine RP2CD. Similar to monotherapy dose escalation, additional country-specific Combination cohorts may be enrolled to define safety and PK.

[0237] Part 2 JNJ-61186372 monotherapy and combination dose expansion: Part 2 Cohort A Part 1 of the RP2D registration study will include JNJ-61186372 monotherapy. The treatment begins after the diagnosis of activating EGFR mutations, measurable disease, and disease progression has been determined. Advanced NSCLC subjects diagnosed with progression after previous systemic anti-cancer treatment for the disease Approximately 120 patients will be enrolled in the RP2D regimen initially determined in Part 1. Part 2 The purpose of Cohorts A to D was to further confirm the safety and PK characteristics of JNJ-61186372. The objective of this study is to investigate clinical activity within molecularly defined tumor subgroups. Cohort C In and D, SET will consider additional subjects based on safety and efficacy data. It may be recommended to enroll up to 70 patients in each cohort. If demonstrated in a specifically defined population, SET may restrict enrollment to subpopulations.

[0238] RP2CD of JNJ-61186372 in combination with lazertinib is a combination dose-escalation study in Part 1 Once identified, consult with relevant health authorities regarding available safety, PK, and preliminary efficacy data. After consultation with the Agency, begin expansion of Part 2 Combination Cohort E. Progressive EGFR-mutated NS Approximately 25 subjects with CLC will be enrolled to characterize the safety, tolerability, and preliminary efficacy of the combination. Subjects must be treatment-naïve for advanced disease or have not received erlotinib. After first-line treatment with nib, gefitinib, or afitinib, or third-generation EGFR have progressed after first- or second-line TKI therapy.

[0239] Overall exam For both Part 1 and Part 2, the study is divided into three periods: Screening During the screening period, subject eligibility will be determined up to 28 days before the first dose of study drug. The follow-up period is from the first administration of the investigational drug to 30 days after the last administration of the investigational drug. The study will begin at the end of the trial and continue until the end of the trial, during which time subjects will be followed for survival and subsequent anticancer therapy. All patients will continue to receive the study if they discontinue the study for any reason other than radiological disease progression or withdrawal of consent. For subjects who permanently discontinued study treatment, radiological progression or new Patients will be treated according to the protocol schedule until new anticancer therapy is initiated, whichever comes first. Continue disease evaluation.

[0240] This study will be conducted as an outpatient program. Subjects will be monitored for study drug administration and study assessments (e.g., adverse events). monitoring, physical examination, concomitant medication use, laboratory evaluation, and PK sample collection) Based on new safety observations, More frequent visits may be scheduled if necessary. Safety monitoring will be conducted throughout the study. The same applies to both Part 1 and Part 2, and the NCI CTCAE (Version 4. 03) and evaluation of adverse events and laboratory abnormalities graded according to the safety and efficacy criteria. This includes monitoring vital signs, electrocardiogram (ECG), and physical examination values. Additional safety assessments, such as endoscopy and LVEF assessment (echocardiogram or MUGA), were performed at the end of the study. In Part 1 and Part 2, JNJ-61186372 was administered in combination with lazertinib. JNJ-6 as monotherapy and in combination with lazertinib The overall safety of 1186372 will be evaluated by the Safety Assessment Team (SET).

[0241] Antitumor activity was evaluated according to the Response Evaluation Criteria in Solid Tumors(RECIST v1.1)(Eisenhauer et al. al.,Eur J Cancer 2009;45(2):228-247) The investigator will conduct radiological and physical studies as needed to assess the clinical response. Evaluate the location of the disease by laboratory tests and other methods and document all results in the Case Report Form (CRF). In Part 2, the new or modified RP2D or RP2CD by the SET If selected, intrasubject dose escalation may be acceptable in subjects with non-progressing disease. (See Section 3.5).

[0242] Subject population This study demonstrates the potential for advanced NSCLC to respond to treatment with JNJ-61186372. Because of the potential risk of refractory tumors, subjects with these tumors will be enrolled. , have progressed on prior treatment, or are ineligible for all other currently available treatment options or has refused treatment and requires additional effective treatment.

[0243] Part 1 (dose escalation) of the study will enroll subjects with advanced NSCLC. In the combined dose escalation of EGFR 1 alone, subjects were randomly assigned to Diagnosed with a 58R activating mutation and are TKI-naive for progressive disease, or , have progressed after first-line treatment with a first- or second-generation TKI, or or have been treated with a third-generation TKI in either first-line or second-line therapy. and are not eligible for enrollment in Cohort C. The total number of subjects is shown to be 100, with doses reaching the MTD or MAD, and dose cohort expansion. It depends on whether

[0244] In Part 2 (dose expansion) of the study, Up to approximately 145 subjects diagnosed with previously treated advanced NSCLC will be initially enrolled in one of five cohorts, as defined below. Cohort A: Subjects with previously treated EGFR-driven tumor progression Cohort B: Subjects with previously treated EGFR-independent tumors who progressed. Cohort C: Prior treatment with third-generation TKI (e.g., osimertinib) or primary In the case of exon 20 insertion mutation diseases, activity against exon 20 insertion mutation diseases is known. EGFR receptor agonists mediate resistance to prior treatment with TKIs (e.g., poziotinib). or subjects with a documented c-Met mutation, which is appropriate for central testing. Until fully validated NGS of ctDNA or tumor tissue is available, screening is recommended. Pre-characterization using in-house testing of the same tumor tissue prior to treatment Once available, all subjects must be screened. Tumor samples obtained during the period, or recent systemic anticancer therapy before the screening period Eligible patients were randomly selected based on EGFR and c-Met characterization of the same tumor tissue obtained after treatment with the method. Sexuality is assessed centrally. Cohort D: Subjects diagnosed with EGFR exon 20 insertion mutations. Cohort E (JNJ-61186372 in combination with lazertinib): Exon 19 deletion Patients with advanced EGFR-mutant NSCLC characterized by loss of EGFR or L858R sensitive activating mutation Subjects.

[0245] In Cohorts C and D, SET will decide whether to transfer subjects to the study based on the results of interim monitoring. It may be recommended to enroll up to 70 additional patients. Subjects who are confirmed not to have the R mutation can be substituted. Due to overlapping target populations, Cohorts A and B were not recruited further when Cohorts C and D began recruiting. Approximately 25 subjects will be enrolled in combination cohort E, and JNJ will Further characterization of the safety, tolerability, and preliminary efficacy of -61186372 in combination with lazertinib Check with.

[0246] JNJ-61186372 in combination with lazertinib RP2D for monotherapy (JNJ-61186372 at 1050 / 1400 mg, Lazerti nib 240 mg), and PK profiles of both JNJ-61186372 and lazertinib The profile has been established through the respective FIH dose escalation study, in which: Doses exceeding the respective RP2D (JNJ-61186372 at 1400 mg, Lazerti No DLTs were observed for any of the compounds. The safety profiles and preliminary efficacy of both agents in the GFR-mutant NSCLC population were Approximately 100 subjects in each study (enrolled in expansion cohorts at each RP2D) In addition, both drugs are based on clinical experience with their respective RP2 Lower doses than D (700 mg for JNJ-61186372 and 240 mg for lazertinib) ) has demonstrated clinical activity in the target population and the safety profile of the combination This allows efficacy to be maintained when lower doses than the monotherapy RP2D of each agent are required. There is a possibility.

[0247] Rationale for dose and regimen selection The doses investigated in the combination study (Table 8) were determined based on the doses observed in the FIH studies of both agents, as described above. Based on currently available clinical safety, tolerability, efficacy, and clinical PK data, The study was selected based on the potential for DDI and the expected lack of DDI. The starting dose of the drug is set at one level lower than the monotherapy RP2D (700 / 1050 mg). However, lazertinib was set at RP2D (240 mg). Table 8 shows the results of the combination study. Describe the dose levels expected to be studied.

[0248] [Table 8] * Additional and / or intermediate dose levels may be added during the conduct of the study. to add cohorts at any dose level below the MTD to better understand PD. Good too. ** Dose level -1 is the dose for patients who require a dose reduction from the starting dose level. Represents tapering cohorts or treatment doses.

[0249] The target doses of both JNJ-61186372 and lazertinib in the combination were Although this is consistent with the RP2D at the time of administration (1050 / 1400 mg and 240 mg, respectively), However, emerging exposure data indicates that higher doses are required to achieve comparable target PK exposures. If further exposure data suggest that a Level 2 Higher doses than those in Table 8 achieved the exposure observed at the monotherapy RP2D of either agent. Combination safety, PK, and efficacy data will be available for the next combination cohort if needed to Consult with relevant health authorities regarding the rationale for the next proposed dose cohort level prior to initiation of the study. .

[0250] Combination dosing schedule In the current monotherapy dosing regimen, lazertinib is administered orally daily. 1186372 will be administered intravenously once weekly during cycle 1, then every other week starting on day 1 of cycle 2. It is administered internally.

[0251] The first dose of JNJ-61186372 may be associated with This is one of the toxicities that can occur, and the risk of infusion-related reactions occurs mainly with the first (C1D1) dose. As a mitigation measure, it is administered as a split dose over 2 days (i.e., day 1 of cycle 1). Day 1 [350 mg] and Day 2 of Cycle 1 [remaining dose]). In addition, steroid premedication , which is currently only required for this first dose.

[0252] Lazertinib was administered on Day 1 of Cycle 1 before the start of JNJ-61186372. Start within 2 hours before the first dose of JNJ-61186372 and then administer every dose in the same order. Continue for days.

[0253] The combination regimen will begin with an initial dose of JNJ-61186372 and lazertinib. The first 28-day cycle of the combination regimen (cycle 1) is , four weekly doses of JNJ-61186372, and 28 doses of lazertinib. However, cycle 2 and all subsequent cycles were This includes two every-other-week doses and 28 daily doses of lazertinib.

[0254] Subject selection Screening of eligible subjects will occur within 28 days prior to the first dose of study drug.

[0255] The inclusion and exclusion criteria for enrolling subjects in this study were divided into two subgroups: Subjects must meet all of these criteria to be eligible to participate in the study. must be met and exceptions to these criteria are not permitted by the sponsor. However, if there are any questions about the inclusion or exclusion criteria below, the investigator should: Appropriate sponsor representatives should be consulted before enrolling subjects in this study.

[0256] Inclusion criteria Each potential subject must meet all of the following criteria to be enrolled in this study: There is a need.

[0257] 1. Subjects must be 18 years of age or older and of legal age of consent in the jurisdiction in which the study is conducted. It needs to be fulfilled.

[0258] 2. Subject has metastatic or unresectable histologically or cytologically confirmed NSCLC Subjects must have progressed after prior treatment for metastatic disease. , are ineligible for or refuse all other currently available treatment options If a subject declines currently available treatment options, this should be documented in the study records. It is necessary to

[0259] 3. Part 1 Combination Dose Escalation Only: Subjects must have EGFR exon 19 deletion or L85 Diagnosed with an 8R activating mutation, and TKI-naive for progressive disease, or First-generation (erlotinib or gefitinib) or second-generation (afatinib) T Progressed after first-line treatment with KI, or Third-generation TKIs (e.g., osimertinib) in either first- or second-line therapy Patients must have been previously treated with EGFR-1 or EGFR-1 (previously untreated with EGFR-1 or EGFR-1) and be ineligible for enrollment in Cohort C. Part 2 only: Subjects also have activating EGFR mutations (exon 19 deletion and L Inhibitor-sensitive primary mutations such as 858R [cohorts C and E] and exon 20 insertions [ Cohorts C and D] (including both commercially available TKI-resistant mutations) EGFR should be tested in a CLIA-certified laboratory (or equivalent). Documentation of mutation eligibility is required.

[0260] 4. Part 1: Subjects must have evaluable disease. Part 2: Subjects must have measurable disease per RECIST v1.1 be.

[0261] 5. Part 2: Cohorts A and B: Subjects' disease had recently progressed after treatment with a commercially available EGFR inhibitor Exception: Mutations associated with de novo EGFR inhibitor resistance (e.g., In subjects diagnosed with EGFR (e.g., exon 20 insertion), prior treatment with concomitant platinum-based chemotherapy was Only treatment is needed. Cohort C: Subjects were randomly assigned to receive either a third-generation TKI (e.g., osimertinib) or For primary exon 20 insertion disease, known activity against exon 20 insertion disease EGFR mediates resistance to prior treatment with TKIs (e.g., poziotinib) or c-Met mutation and have been appropriately validated for central testing. Until NGS of the extracted ctDNA or tumor tissue is available, This must be substantiated by preliminary characterization using laboratory testing of tumor tissue. Once available, all subjects must undergo a follow-up of the tumors acquired during the screening period. Tumor samples or samples obtained before the screening period but after the most recent systemic anticancer therapy Eligibility was assessed centrally based on EGFR and c-Met characterization of the same tumor tissue. It is valued. Cohort D: Subjects must have been diagnosed with EGFR exon 20 insertions. do. Cohort E (JNJ-61186372 in combination with lazertinib): Subjects were randomly assigned to receive EGFR have been diagnosed with an exon 19 deletion or an L858R activating mutation, and TKI-naive for progressive disease, or First-generation (erlotinib or gefitinib) or second-generation (afatinib) T Progressed after first-line treatment with KI, or Third-generation TKIs (e.g., osimertinib) in either first- or second-line therapy Patients must have progressed after treatment with rituximab and be ineligible for enrollment in Cohort C .

[0262] 6. Subjects must have an ECOG performance status of 0 or 1 .

[0263] 7. Subjects must have the following organ and bone marrow function: Hemoglobin ≥ 10 g / dL ANC ≧1.5x10 9 / L Platelets ≥ 75 × 10 9 / L AST and ALT ≦3×ULN (upper limit of normal) Total bilirubin ≤ 1.5 × ULN; subjects with Gilbert syndrome had normal conjugated bilirubin If it is within the range, it can be registered. Serum creatinine <1.5 × ULN, or calculated or measured creatinine, if available Atinine clearance >50 mL / min / 1.73 m 2 Subjects must not have received red blood cell transfusions, platelet transfusions, or G-CSF supportive therapy within 7 days prior to the test date. Patients must meet the above testing criteria without a history of treatment for the disease.

[0264] 8. Before enrollment, women must be either: a. Not of childbearing potential: Premenarche, postmenopausal (>45 years of amenorrhea for at least 12 months) age), permanent infertility (e.g., bilateral tubal occlusion [including tubal ligation, when in accordance with national regulations] (including hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or other reasons for being unable to conceive , b. For subjects participating in a clinical trial who are of childbearing potential and who: Implement effective methods of birth control that comply with national regulations regarding the use of birth control methods: 1) Abstinence (if consistent with the subject's preferred and usual lifestyle), treatment Patients were required to abstain from heterosexual intercourse for the entire duration of the study, including up to 6 months after the final dose of study drug. Periodic abstinence (a contraceptive method that takes into account the menstrual cycle, basal body temperature, and post-ovulation) is acceptable contraception. It is not considered law. or 2) having a vasectomized only partner or 3) Use of two contraceptive methods, one of which is highly effective (i.e., oral, injectable, or steroid). or established use of implanted hormonal contraception, intrauterine device [IUD] or Placement of an intrauterine system [IUS] and a second method (e.g., spermicidal foam / gel) / film / cream / condoms with suppositories or spermicidal foam / gel / film / Occlusive cap (pessary or cervical / vaginal vault cap) with cream / suppository Subjects agree to continue contraception throughout the study and for 6 months after the last dose of study drug. It is necessary. Note: If pregnancy risk changes after study initiation (e.g., not having sexual relations with the opposite sex), women become sexually active and pre-menarcheal women experience menarche), and as mentioned above, women An effective method of contraception should always be initiated.

[0265] 9. Women of childbearing potential must be seronegative (β-human chorionic villus) at screening. gonadotropin [β-hCG]).

[0266] 10. Women are not permitted to use oocytes (eggs) for assisted reproduction purposes during the study and for 6 months after the last dose of investigational drug. You must agree not to donate eggs or oocytes.

[0267] 11. Men who are sexually active with women of childbearing potential should use spermicidal foam / dimethicone. You must agree to use condoms with gels / films / creams / suppositories and Your partner must also be using a highly effective method of contraception (i.e., oral, injection, or implant). Established use of hormonal contraception, intrauterine device [IUD] or intrauterine system It is necessary to carry out the placement of [IUS]. If the subject has had a vasectomy, continue with condoms (with or without spermicide) must use contraception, but their partner does not have to use contraception. All men were also required to refrain from donating semen during the study and for six months after their final dose of the investigational drug. do not have.

[0268] 12. Subjects are willing to abide by the prohibitions and restrictions specified in this protocol. And it must be possible.

[0269] 13. Each subject will be informed of their own individual circumstances, including information required during the follow-up period. demonstrate that they understand the purpose of the study and the procedures involved and are willing to participate in the study. An Informed Consent Form (ICF) must be signed.

[0270] 14. Part 2 eligible subjects must submit a pre-treatment tumor biopsy (or equivalent archived specimen) ) and consent to tumor biopsy at disease progression and corresponding blood collection for ctDNA analysis For subjects in Cohort C, comparable pretreatment tumor tissue should be obtained from the most recent prior systemic The samples must be taken after treatment with a specific anti-cancer therapy.

[0271] Exclusion criteria Any potential subject who meets any of the following criteria will be excluded from participation in this study: Be removed.

[0272] 1. Subject has uncontrolled hypertension or diabetes, progressive or active including but not limited to infectious diseases, or mental illnesses / social conditions that may limit compliance with study requirements. have uncontrolled intercurrent illnesses that are not controlled

[0273] 2. Subjects must be within 2 weeks or 4 half-lives prior to the first dose of JNJ-61186372. have received prior chemotherapy, targeted cancer therapy, immunotherapy, or investigational anti-cancer drugs For drugs with long half-lives, the maximum time from the last dose required is 4 weeks. Toxicity from previous anti-cancer therapy must have resolved to baseline levels or grade 1 or less. No (alopecia [all grades], peripheral neuropathy grade ≤2, and hormone replacement therapy (excluding stable grade <2 hypothyroidism). Part 1 Combination Dose Escalation: Includes anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents Prior treatment with systemic anti-cancer immunotherapy, including but not limited to: Part 2 only: Cohorts A and B: Tumor mutations associated with de novo resistance to EGFR TKIs (e.g. Prior chemotherapy for metastatic disease is recommended unless the patient harbors a mutated exon 20 insertion. Not allowed. Cohort C: >2 prior cytotoxic chemotherapy treatments for metastatic disease (maintenance therapy is not included). Cohort D: EGFR TKIs (Polymerase II) with activity against EGFR exon 20 insertions Prior treatment with vasodilator drugs such as diotinib. Cohort E (JNJ-61186372 in combination with lazertinib): anti-PD-1, anti-PD systemic anti-cancer immunotherapies, including but not limited to, anti-L1, and anti-CTLA-4 agents Pretreatment by law. NOTE: Palliative local radiation therapy is recommended for at least one year of treatment with JNJ-61186372. Must be completed 7 days in advance.

[0274] 3. Subjects with untreated brain metastases who are clinically stable and have been free of vasopressin for at least 2 weeks Patients with symptomatic treated metastases who have had at least 2 weeks of treatment with the study Corticosteroid therapy (≤10 mg prednisone or equivalent) has been completed, Those receiving low-dose therapy are eligible. Exception: Asymptomatic ulcers less than 1 cm in diameter each Subjects with treated brain metastases will be enrolled in Part 1 combination dose escalation or Part 2 combination expansion cohort E may be eligible for combination therapy with JNJ-61186372 and lazertinib in patients with refractory leukemia.

[0275] 4. Subject has a history of malignant tumor other than the disease being investigated within 3 years prior to screening. (Exceptions are squamous cell carcinoma and basal cell carcinoma of the skin, and intraepithelial carcinoma of the cervix, is considered cured in the opinion of the investigator in concert with the sponsor's medical monitor. or are considered to be at minimal risk of recurrence within one year of screening malignant tumors).

[0276] 5. Subject has a history of clinically significant cardiovascular disease, including but not limited to: Diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to the first dose of the investigational drug, or Diagnosis of any of the following within 6 months of the first dose: myocardial infarction, unstable angina, stroke, transient ischemic stroke acute ischemic stroke, coronary artery / peripheral artery bypass graft, or any acute coronary syndrome. Clinically insignificant thrombosis, such as catheter-related clots, is not excluded. QTcF interval prolongation >480 msec or clinically significant cardiac arrhythmia or electrical Physiological disorders (e.g., implantation of an implantable cardioverter-defibrillator or uncontrolled atrial fibrillation at rate). Uncontrolled (persistent) hypertension: systolic blood pressure >180 mmHg; diastolic Blood pressure >100 mmHg New York Heart Associates within six months of Day 1 of the trial tion (NYHA) class III-IV (Attachment 2) or CHF Congestive heart failure defined as any NYHA class Pericarditis / clinically significant pericardial effusion Myocarditis By screening echocardiogram or multi-gated acquisition (MUGA) scan LVEF ejection fraction at baseline below the lower limit of normal (LLN) to be assessed.

[0277] 6. The subject has leptomeningeal disease.

[0278] 7. Subject has a known allergy to JNJ-61186372 or its excipients. , hypersensitivity, or intolerance.

[0279] 8. Subject has received an investigational drug (investigational vaccine) within 6 weeks prior to the first planned dose of the investigational drug. received any of the following therapies (including but not limited to anti-cancer therapy [see Exclusion Criteria #2]) or invasive Investigational medical devices were used.

[0280] 9. Subject has not received any of the study medications during their enrollment in this study or within 6 months of their last dose. are women who are pregnant, breastfeeding, or planning to become pregnant.

[0281] 10. Subjects will not receive any of the study medications during their enrollment in this study or for 6 months after their last dose of study medication. He is a man who plans to become a father within the next few years.

[0282] 11. The subject has or will have any of the following: a. Intracavitary administration within 4 weeks prior to Day 1 of Cycle 1 or without complete recovery Invasive surgical procedures involving thoracentesis (if necessary) and baseline tumor tissue sampling Percutaneous biopsy for cutaneous steroids may be performed if, in the investigator's clinical judgment, the subject is not scheduled to undergo percutaneous steroid biopsy before the first dose of the study drug. If adequately recovered from surgery, performed less than 4 weeks prior to Day 1 of Cycle 1 Good, b. Major traumatic injury within 3 weeks prior to the start of Day 1 of Cycle 1 (all wounds must be (must be completely healed prior to the first day) c. Requires intact wound healing capacity and the wound healing capacity is significantly impaired during administration of the investigational drug any medical condition that, if present, could be expected to compromise the safety of the subject; d. Major surgery scheduled during treatment with the study drug or within 6 months after the final treatment with the study drug .

[0283] 12. The subject has agreed to participate in the study if, in the opinion of the investigator, participation is in the subject's best interest. (e.g., compromising health status) or preventing or limiting protocol-specified evaluation , or any situation that may cause confusion.

[0284] 13. Any investigator site personnel is directly associated with this study.

[0285] 14. Subject has hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) ) positive or have a history of other clinically active infectious liver disease, or have H BsAg or anti-HCV is positive. Note: At the time of screening, patients had completed antiviral treatment and subsequently had serum HCV RNA levels Subjects with a documented absence of hepatitis C are eligible to participate.

[0286] 15. Subject is human immunodeficiency virus (HIV) seropositive or has not undergone screening. HIV test result is positive at the time of screening.

[0287] 16. Subject has any serious underlying medical or psychiatric condition (e.g., alcohol or substance abuse), dementia or altered mental status, or to understand that the study may impair the subject's ability to receive or tolerate the planned treatment at the investigational site. or, in the opinion of the investigator, may contraindicate the subject's participation in the study or has any problem that may confound the test results.

[0288] 17. Requiring long-term treatment with steroids or other immunosuppressants for the past 2 years History of interstitial lung disease (ILD), e.g., drug-induced ILD or radiation pneumonitis.

[0289] Toxicity monitoring and dose modifications Toxicity in subjects receiving JNJ-61186372 in combination with lazertinib Monitoring will be identical to that for subjects receiving JNJ-61186372 monotherapy, except 1) Chest x-ray at baseline and end of cycle 1, and 2) at baseline and again at 6 Add LVEF assessment after 1 week.

[0290] If weight loss is felt to be indicated, it should be done as outlined in Table 9.

[0291] [Table 9]

[0292] Safety evaluation The safety of JNJ-61186372 as monotherapy or in combination with lazertinib was evaluated. Eastern Cooperativity for Physical Inspection, Performance Status Eastern Cooperative Oncology Group (ECOG) criteria, clinical tests, vital signs, Evaluate by electrocardiogram, monitoring for adverse events, and concomitant medication use. Additional chest x-ray and LVEF assessment were performed after treatment with JNJ-61186372 and lazertinib combination therapy. This is carried out for subjects who will receive the study drug from the time they sign the informed consent to the time they receive the study drug. Adverse events occurring up to 30 days after administration will be recorded. The severity of adverse events will be assessed by the National l Cancer Institute Common Terminology Cr iteria for Adverse Events (NCI CTCAE) Barge All subjects will be followed for survival until the end of the study. Patients who discontinue the study for any reason other than disease progression or withdrawal of consent for follow-up will be investigated. Subjects who discontinue study treatment must have documented radiological disease progression or the subject must have a new Disease assessments will continue until new cancer therapy is initiated. Therapy data will also be collected.

[0293] Pharmacokinetic evaluation Measurement of serum JNJ-61186372 concentrations and plasma lazertinib concentrations for PK analysis Blood samples will be collected from all subjects for the PK profile of JNJ-61186372. The profile is based on serum concentration data from the first and fifth doses. Blood samples for sparse PK will also be obtained after all other doses. Data are estimated for individuals and descriptive statistics are calculated for each dose level.

[0294] Immunogenicity assessment Blood samples were collected and analyzed using a validated immunoassay for JNJ-61. Serum samples were analyzed for antibodies against JNJ-61186372. 2. Serum titers are determined from positive samples screened for antibodies binding to 2. All samples collected for immune response analysis were analyzed for serum JNJ-6118637. Two concentrations were evaluated to ensure proper interpretation of immune response data. may be performed to further characterize any immune response that occurs. The incidence of antibodies to HIV was summarized for all subjects receiving at least one dose of the investigational drug. Meru.

[0295] Pharmacodynamic and biomarker evaluation Blood samples collected at screening and during the study were analyzed for circulating tumor DNA (ctDNA). A) Analysis of molecular alterations at baseline for cohort assignment , tracking response to treatment, and understanding mechanisms of resistance to JNJ-61186372 Additionally, blood samples will be taken for PD assessment. Tumor tissue obtained after treatment and after progression (within approximately 30 days of documented disease progression) was used to identify cancer-related Analysis of these tumor tissue samples can be used to assess biomarkers associated with cancer. , Molecular Biology of Tumors, Efficacy Observed with JNJ-61186372, and JNJ-61 These samples will help us understand the mechanism of acquired resistance to 186372. It can also be used to confirm ctDNA test results.

[0296] Efficacy analysis The primary efficacy analysis of confirmed best overall response (ORR) was performed in the last patient to receive their first infusion The data cutoff will be approximately 16 weeks after the initial dose or at the end of the study, whichever comes first. The all-treated analysis population will be used for the primary efficacy analysis. When all subjects are discontinued from study drug, any additional data in the CSR supplement will be retained for appropriate review. The case will be reported to health authorities.

[0297] For Cohorts A and B, due to the limited number of subjects and the nature of the study, , all efficacy analyses are considered descriptive.

[0298] Interim monitoring will be conducted for Cohort C and Cohort D.

[0299] Overall response rate (ORR), as defined by RECIST v1.1, was assessed in each expansion cohort. In the all-treated analysis population (or in the case of interim monitoring) in the first 2 h (part 2), In the analysis set where response rate could be evaluated, either a complete response (CR) or a partial response (PR) was achieved. The proportion of subjects achieving either of the above is defined as the proportion of subjects achieving either of the above. For dose levels, observed ORRs are presented with two-sided 95% confidence intervals.

[0300] The following Bayesian approach will be used as a sensitivity analysis: The first criterion is whether ORR is clinically significant. The second criterion is to ensure that the efficacy of the first type of The goal is to ensure that an error of 0.2 is controlled. 1. P(true ORR ≥ 50% | observed ORR, n = 100) ≥ 0.5; true OR The posterior probability of R ≥ 50% is at least 0.5 2. P(true ORR>30%|observed ORR, n=100)≥0.8; true OR The posterior probability of R>30% is at least 0.8

[0301] Using Bayesian power, we confirmed that a second criterion was met at the end of each cohort. The number of observed responses was at least 100 out of 100 subjects in each of Cohorts C and D. In 34 cases, preliminary evidence of antitumor activity can be demonstrated.

[0302] Clinical benefit rate (CBR) was calculated based on the complete response rate as defined by RECIST v1.1. Subjects achieving a response or partial response, or sustained stable disease (for at least 6 months) For each cohort and dose level, as appropriate, The observed ORR and CBR are presented with two-sided 95% confidence intervals.

[0303] Progression-free survival (PFS), duration of response (DOR), time to treatment failure (TTF), and overall survival Time-to-event endpoints, including overall survival (OS), were determined by Kaplan-Meier method. DOR is estimated using the C method only for subjects who achieved CR or PR. R or PR initial response followed by progressive disease (PD) or death from underlying disease, whichever occurs first PFS is calculated as the time from the first infusion of study drug to the end of progression or death from any cause. TTF is defined as the time from the first infusion of the investigational drug to disease progression, cure, or death. This is defined as the time until treatment is discontinued for any reason, such as toxicity or death, and is based on the RECIS Clinical benefit for patients who continue treatment beyond disease progression as defined by T v1.1 OS is the time from the first infusion of the investigational drug to death from any cause. The time-to-endpoint endpoint is defined as the duration of Meyer estimates are presented graphically, and median time to event is shown with the corresponding 95% CI. , which is obtained from Kaplan-Meier estimation.

[0304] Example 4. Clinical Results The combination of lazertinib and JNJ-61186372 was evaluated in the combination dose-escalation cohort (Part 1 (See Example 3) was investigated in a phase 1 trial. orally, once daily) and 1050 mg (subjects <80 kg) / 1400 mg (subjects >80 kg) Subjects) received JNJ61186372 (IV, once weekly in cycle 1, every other week from cycle 2 onwards) ) after no dose-limiting toxicities (DLTs) were observed in the dose cohorts evaluated. It was identified as safe and tolerable. The expansion cohort in Part 2 (Cohort E, see Example 3) Forty patients with EGFR-mutant NSCLC who started treatment with osimertinib and progressed on osimertinib were included. The safety, tolerability, and preliminary efficacy of the combination were further confirmed in treatment-naïve subjects. Evaluate an additional Part 1 cohort of subjects with EGFR-mutant NSCLC to confirm the dose in this population and subsequently expand to 20 subjects to The safety and tolerability of the combination in subjects without prior exposure to the drug were further confirmed. Thirty-six subjects were enrolled in a Phase 1 study to receive lazertinib in combination with JNJ-61186372. Most commonly, patients were treated with thrombus therapy (34 patients in Part 1 and 2 patients in the expansion cohort (Cohort E)). Adverse events (AEs) reported included rash, dermatitis acneiform, paronychia, stomatitis, pruritus, and diarrhea. This is consistent with EGFR inhibition-related toxicities in patients treated with the combination, including other AEs were similar to those observed with approved EGFR TKIs. Evidence of clinical activity, defined as tumor response or shrinkage evaluated, is needed to demonstrate unmet need. and any EGFR T790M-negative disease after progression on first-generation TKIs The first 26 patients included those who had progressed after prior treatment with a third-generation TKI. These results were observed in the majority of patients with the currently approved combination drug. demonstrated activity of the combination in subjects with no prior targeted therapy.

[0305] Embodiment The following sections describe specific embodiments of the present invention.

[0306] 1) a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / a hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I):

[0307] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof and a salt thereof for use in the treatment of EGFR- or c-Met-expressing cancer. Pharmaceutical combinations for:

[0308] 2) The bispecific anti-EGFR / c-Met antibody comprises a heavy chain complementarity-determining region 1 of SEQ ID NO: 1. (HCDR1), HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, light chain of SEQ ID NO: 4 Complementarity determining region 1 (LCDR1), LCDR2 of SEQ ID NO: 5, LCDR3 of SEQ ID NO: 6 a first domain that binds to EGFR, and an HCDR1 of SEQ ID NO: 7, an H of SEQ ID NO: 8 CDR2, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCD of SEQ ID NO: 11 R2, and a second domain that binds to c-Met, comprising LCDR3 of SEQ ID NO: 12. 2. The pharmaceutical combination for use according to embodiment 1, comprising

[0309] 3) The first domain that binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and and a light chain variable region (VL) of SEQ ID NO: 14, and a second domain that binds to c-Met 15 and VL of SEQ ID NO: 16, for use according to embodiment 2. Pharmaceutical combinations.

[0310] 4) The bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. A pharmaceutical combination for use according to any one of aspects 1 to 3.

[0311] 5) The bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17. ), a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and The use according to any one of embodiments 1 to 4, comprising a second light chain (LC2) of SEQ ID NO: 20. Pharmaceutical combinations for use.

[0312] 6) The bispecific anti-EGFR / c-Met antibody has a fucose content of approximately 1% to approximately 15%. For use according to any one of embodiments 1 to 5, wherein the glycan comprises a biantennary glycan structure having Pharmaceutical combinations.

[0313] 7) Compounds of formula (I) or their solvates, hydrates, tautomers, or pharmaceutically acceptable salts thereof Acceptable salts include those of formula (II):

[0314] [ka] The medicament for use according to any one of embodiments 1 to 6, represented by the compound combination.

[0315] 8) Compounds of formula (I) or their solvates, hydrates, tautomers, or pharmaceutically acceptable salts thereof The acceptable salt is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl- 1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-mol The use according to any one of embodiments 1 to 6, wherein the compound is a (phenyl)acrylamide. Pharmaceutical combinations for:

[0316] 9) EGFR or c-Met expressing cancer is classified as wild-type EGFR, EGFR mutated, or EGFR gene Gene amplification, elevated levels of circulating HGF, wild-type c-Met, c-Met mutation, c-Met The use according to any one of embodiments 1 to 8, which is related to gene amplification or mutant KRAS. Pharmaceutical combinations for use.

[0317] 10) EGFR mutations: E709K, L718Q, L718V, G719A, G71 9X, G724X, G724S, I744T, E746K, L747S, E749Q, A 750P, A755V, V765M, C775Y, T790M, L792H, L792V <h2 style=";text-align:left;direction:ltr">G796S, G796R, G796C, C797S, T854I, L858P, L85<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 8R、L861X、delE746-A750、delE746_T751InsKV、<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> delE746_A750InsHS、delE746_T751InsFPT、del<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> E746_T751InsL、delE746_S752InsIP、delE746_<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> P753InsMS、delE746_T751InsA、delE746_T751I<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> nsAPT、delE746_T751InsVA、delE746_S752InsV<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 、delE746_P753InsVS、delE746_K754InsGG、del<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> E746_E749, delE746_E749InsP, delL747_E749,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> delL747_A750InsP、delL747_T751InsP、delL74<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 7_T751InsN、delL747_S752InsPT、delL747_P75<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 3InsNS、delL747_S752InsPI、delL747_S752、de<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> lL747_P753InsS, delL747_K754, dekL747_T751<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> InsS、dekL747_T751、delL747_P753InsS、delA7<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 50_I759InsPT, delT751_I759InsT, delS752_I7<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 59、delT751_I759InsN、delT751_D761InsNLY、d<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> elS752_I759, delR748-P753, delL747-P753ins<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> S、delL747-T751、M766_A767InsA、S768_V769In<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> sSVA, P772_H773InsNS, D761_E762InsX<h2 style=";text-align:left;direction:ltr"> 1-7 <h2 style=";text-align:left;direction:ltr"> A76<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 3_Y764InsX<h2 style=";text-align:left;direction:ltr"> 1-7, Y764_Y765 InsX 1-7 , M766_A76 7InsX 1-7 , A767_V768 InsX 1-7 , S768_V769 Ins X 1-7 , V769_D770 InsX 1-7 , D770_N771 InsX 1-7 , N771_P772 InsX 1-7 , P772_H773 InsX 1-7 , H77 3_V774 InsX 1-7 , V774_C775 InsX 1-7 , EGFR expression One or more deletions in exon 20 or one or more insertions in exon 20 of EGFR, EG One or more deletions in exon 19 of RF or one or more deletions in exon 19 of EGFR or any combination thereof, wherein X is any amino acid. 1. A pharmaceutical combination for use as described in claim 1.

[0318] 11) EGFR mutations include one or more deletions or L858R in exon 19, or The pharmaceutical combination for use according to embodiment 10, which is any combination thereof.

[0319] 12) The c-Met mutation is a c-Met exon 14 skipping mutation. 10. The pharmaceutical combination for use according to form 9.

[0320] 13) The mutant KRAS has a G12V, G12C, or G12A substitution. 10. The pharmaceutical combination for use according to form 9.

[0321] 14) The subject has been diagnosed with an EGFR mutation prior to receiving the combination therapy. 14. A pharmaceutical combination for use according to any one of aspects 1 to 13.

[0322] 15) The embodiment in which the subject has a newly diagnosed EGFR- or c-Met-expressing cancer 15. A pharmaceutical combination for use according to any one of 1 to 14.

[0323] 16) Subjects are EGFR tyrosine kinase inhibitor (TKI) treatment-naive, 16. The pharmaceutical combination for use according to any one of Forms 1 to 15.

[0324] 17) The subject has resistant or recurrent disease to first-generation EGFR TKI treatment. 16. A pharmaceutical combination for use according to any one of embodiments 1 to 15.

[0325] 18) In an embodiment, the first-generation EGFR TKI is erlotinib or gefinib. 18. A pharmaceutical combination for use as described in 17.

[0326] 19) The subject has resistant or recurrent disease to second-generation EGFR TKI treatment. 15. The pharmaceutical combination for use according to any one of embodiments 1 to 14.

[0327] 20) The method according to embodiment 19, wherein the second-generation EGFR TKI is afatinib. Pharmaceutical combinations for use.

[0328] 21) The subject has resistant or recurrent disease to third-generation EGFR TKI treatment. 15. The pharmaceutical combination for use according to any one of embodiments 1 to 14.

[0329] 22) The method of embodiment 21, wherein the third-generation EGFR TKI is osimertinib. Pharmaceutical combinations for use.

[0330] 23) EGFR or c-Met expressing cancer is non-small cell lung cancer (NSCLC), epithelial cell carcinoma , breast cancer, ovarian cancer, lung cancer, lung squamous cell carcinoma, lung adenocarcinoma, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer Adenocarcinoma, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, Esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, stomach cancer, thymus cancer, colon cancer, thyroid cancer, liver cancer cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC). 23. The pharmaceutical combination for use according to any one of embodiments 1 to 22.

[0331] 24) The pharmaceutical combination for use according to embodiment 23, wherein the cancer is NSCLC.

[0332] 25) A bispecific anti-EGFR / c-Met antibody is administered in an amount of approximately 200 mg to approximately 2000 mg. The pharmaceutical combination for use according to any one of embodiments 1 to 23, wherein the pharmaceutical combination is administered in a dose of height.

[0333] 26) A bispecific anti-EGFR / c-Met antibody is administered in an amount of approximately 350 mg to approximately 1400 mg. 26. The pharmaceutical combination for use according to embodiment 25, wherein the pharmaceutical combination is administered in a dose of

[0334] 27) Bispecific anti-EGFR / c-Met antibody is approximately 350 mg, approximately 700 mg, approximately For the use according to embodiment 26, the compound is administered in a dose of about 1050 mg, or about 1400 mg. A pharmaceutical combination for this purpose.

[0335] 28) Bispecific anti-EGFR / c-Met antibody administered once a week A pharmaceutical combination for use according to any one of aspects 1 to 27.

[0336] 29) A bispecific anti-EGFR / c-Met antibody administered once every two weeks. A pharmaceutical combination for use according to any one of aspects 1 to 27.

[0337] 30) Compounds of formula (I) or their solvates, hydrates, tautomers, or pharmaceutically acceptable salts thereof Any of embodiments 1 to 29, wherein the acceptable salt is administered in a dose of about 20 mg to about 320 mg. A pharmaceutical combination for use as described in any one of the above.

[0338] 31) Compounds of formula (I) or their solvates, hydrates, tautomers, or pharmaceutically acceptable salts thereof The method of claim 30, wherein the acceptable salt is administered in a dose of about 160 mg or about 240 mg. The pharmaceutical combination for use as described above.

[0339] 32) Compounds of formula (I) or their solvates, hydrates, tautomers, or pharmaceutically acceptable salts thereof The use of any one of embodiments 1 to 31, wherein the acceptable salt is administered once daily. Pharmaceutical combinations for:

[0340] 33) A bispecific anti-EGFR / c-Met antibody is administered in an amount of approximately 350 mg to approximately 1400 mg. once a week for four weeks and then once every two weeks, A solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 160 mg / day. 25. The use according to any one of embodiments 1 to 24, wherein the dose is from 100 mg to about 240 mg. Pharmaceutical combinations for:

[0341] 34) A bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 700 mg once weekly for 4 weeks. for two weeks, and then once every two weeks, A solvate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 160 mg per day. 34. The pharmaceutical combination for use according to embodiment 33, wherein

[0342] 35) Bispecific anti-EGFR / c-Met antibody administered at a dose of approximately 1050 mg once weekly for four weeks, and then once every two weeks, containing a compound of formula (I) or a solvate thereof, Hydrate, tautomer, or pharmaceutically acceptable salt administered at a dose of approximately 160 mg daily 34. The pharmaceutical combination for use according to embodiment 33, wherein

[0343] 36) Bispecific anti-EGFR / c-Met antibody at a dose of approximately 1400 mg once weekly for four weeks, and then once every two weeks, containing a compound of formula (I) or a solvate thereof, Hydrate, tautomer, or pharmaceutically acceptable salt administered at a dose of approximately 160 mg daily 34. The pharmaceutical combination for use according to embodiment 33, wherein

[0344] 37) A bispecific anti-EGFR / c-Met antibody is administered at a dose of approximately 700 mg once weekly for 4 weeks. for two weeks, and then once every two weeks, A solvate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg per day. 34. The pharmaceutical combination for use according to embodiment 33, wherein

[0345] 38) Bispecific anti-EGFR / c-Met antibody administered at a dose of approximately 1050 mg once weekly for four weeks, and then once every two weeks, containing a compound of formula (I) or a solvate thereof, Hydrate, tautomer, or pharmaceutically acceptable salt administered at a dose of approximately 240 mg daily 34. The pharmaceutical combination for use according to embodiment 33, wherein

[0346] 39) Bispecific anti-EGFR / c-Met antibody administered at a dose of approximately 1400 mg once weekly for four weeks, and then once every two weeks, containing a compound of formula (I) or a solvate thereof, Hydrate, tautomer, or pharmaceutically acceptable salt administered at a dose of approximately 240 mg daily 34. The pharmaceutical combination for use according to embodiment 33, wherein

[0347] 40) The bispecific anti-EGFR / c-Met antibody is a compound of formula (I) or a solvate thereof administration of a compound, hydrate, tautomer, or pharmaceutically acceptable salt thereof; A pharmaceutical combination for use according to any one of aspects 1 to 39.

[0348] 41) The bispecific anti-EGFR / c-Met antibody is a compound of formula (I) or a solvate thereof administered one or more times after administration of the compound, hydrate, tautomer, or pharmaceutically acceptable salt thereof , a pharmaceutical combination for use according to embodiment 40.

[0349] 42) The bispecific anti-EGFR / c-Met antibody is a compound of formula (I) or a solvate thereof 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 For the use according to embodiment 41, the compound is administered 6, 7, 8, 9 or 10 or more times. A pharmaceutical combination for this purpose.

[0350] 43) Whether the subject is homozygous for phenylalanine at position 158 of CD16 or heterozygous for valine and phenylalanine at position 158 of CD16, A pharmaceutical combination for use according to any one of embodiments 1 to 42.

[0351] 44) The method of any one of embodiments 1 to 43, further comprising administering a third anticancer therapy. The pharmaceutical combination for use as described above.

[0352] 45) The third anticancer therapy is a chemotherapy, a targeted anticancer therapy, or a kinase inhibitor. A pharmaceutical combination for use according to embodiment 44.

[0353] 46) A therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / a hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I):

[0354] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof , combination medicines.

[0355] 47) Isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor The receptor (c-Met) antibody has HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and SEQ ID NO: 6 a first domain that binds to EGFR and comprises an LCDR3 of SEQ ID NO: 7; an HCDR1 of SEQ ID NO: 8; HCDR2 of sequence number 8, HCDR3 of sequence number 9, LCDR1 of sequence number 10, A second domain that binds to c-Met, comprising an LCDR2 of SEQ ID NO: 11 and an LCDR3 of SEQ ID NO: 12. 47. The method of claim 46, wherein the antibody is a bispecific anti-EGFR / c-Met antibody comprising: Pharmaceutical combinations.

[0356] 48) Formula (I):

[0357] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, The pharmaceutical combination according to embodiment 46 or 47, wherein the compound is lazertinib.

[0358] 49) Formula (I):

[0359] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, The pharmaceutical combination according to embodiment 46 or 47, which is lazertinib mesylate.

[0360] 50) Approximately 350 mg to approximately 1400 mg of a bispecific EGFR / c-Met antibody and approximately 160 mg to about 240 mg of a compound of formula (I) or a solvate, hydrate, or tautomer thereof, or a pharmaceutically acceptable salt thereof. Drug combination.

[0361] 51) Compounds of formula (I) or their solvates, hydrates, tautomers, or pharmaceutically acceptable salts thereof An acceptable salt is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl -1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-mo 48. The pharmaceutical combination according to embodiment 47, wherein the compound is a hydroxybenzoate (hydroxybenzoate) of formula (I) or (II) of formula (II).

[0362] 52) Any of embodiments 46 to 51, in which the pharmaceutical combination is a non-fixed combination. 1. The pharmaceutical combination described in Item 1.

[0363] 53) The first domain that binds to EGFR of the bispecific EGFR / c-Met antibody is , comprising a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and a second domain that binds to c-Met. 53. The method of any of embodiments 46 to 52, wherein the antibody comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16. The pharmaceutical combination according to any one of the preceding claims.

[0364] 54) The bispecific anti-EGFR / c-Met antibody is HCl of SEQ ID NO: 17, HCl of SEQ ID NO: 46. The method of claim 46, further comprising administering to said patient an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20. 54. The pharmaceutical combination according to any one of claims 1 to 53.

[0365] 55) Treatment of EGFR- or c-Met-expressing cancers, particularly EGFR or c-Met-expressing cancers in a subject In the treatment of et-expressing cancer,

[0366] [ka] or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof Isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (HGF) inhibitors for use in combination with hepatocyte growth factor receptor (EGFR) inhibitors Cellular growth factor receptor (c-Met) antibody.

[0367] 56) Isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor The receptor (c-Met) antibody has HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and SEQ ID NO: 6 a first domain that binds to EGFR and comprises an LCDR3 of SEQ ID NO: 7; an HCDR1 of SEQ ID NO: 8; HCDR2 of sequence number 8, HCDR3 of sequence number 9, LCDR1 of sequence number 10, A second domain that binds to c-Met, comprising an LCDR2 of SEQ ID NO: 11 and an LCDR3 of SEQ ID NO: 12. 56. The method of claim 55, wherein the antibody is a bispecific anti-EGFR / c-Met antibody comprising: Isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor for use - Patent Application 20070122997 Receptor (c-Met) antibody.

[0368] 57) Formula (I):

[0369] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, The isolated bispecific for use according to embodiment 55 or 56, which is lazertinib Anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

[0370] 58) Formula (I):

[0371] [ka] or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, The isolated dimer for use according to embodiment 55 or 56, which is lazertinib mesylate. Bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody .

[0372] 59) Approximately 350 mg to approximately 1400 mg of a bispecific EGFR / c-Met antibody and approximately 160 mg to about 240 mg of a compound of formula (I) or a solvate, hydrate, or tautomer thereof, or a pharmaceutically acceptable salt thereof. Isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (HGFR) antibody for use in c-Met antibodies.

[0373] 60) The first domain that binds to EGFR of the bispecific EGFR / c-Met antibody is , comprising a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and a second domain that binds to c-Met. 60. The method of any of embodiments 55 to 59, wherein the antibody comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16. An isolated bispecific anti-epidermal growth factor receptor (EGFR) for any one of the uses described herein. / Hepatocyte growth factor receptor (c-Met) antibody.

[0374] 61) The bispecific anti-EGFR / c-Met antibody is HC1 of SEQ ID NO: 17, HC2 of SEQ ID NO: 54. The method of claim 53, further comprising administering to said patient an LC1 of SEQ ID NO: 18, an HC2 of SEQ ID NO: 19, and an LC2 of SEQ ID NO: 20. 60. An isolated bispecific anti-epidermal growth factor receptor for use according to any one of claims 1 to 60. (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

Claims

1. 1. A method of treating a subject having an EGFR or c-Met expressing cancer, comprising administering to said subject a combination and administering a combination therapy comprising administering a therapeutically effective amount of an isolated bispecific antibody to a subject. Epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibodies and therapeutic An effective amount of formula (I): 【Chemical 1】 or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. The method comprising:

2. The bispecific anti-EGFR / c-Met antibody comprises a heavy chain complementarity-determining region 1 ( HCDR1 of SEQ ID NO: 2, HCDR2 of SEQ ID NO: 3, HCDR3 of SEQ ID NO: 4, Complementarity determining region 1 (LCDR1), LCDR2 of SEQ ID NO: 5, LCDR3 of SEQ ID NO: 6 The first domain binds to EGFR, and the HCDR1 of SEQ ID NO: 7 and the HC of SEQ ID NO:

8. DR2, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, LCDR of SEQ ID NO: 11 2, and a second domain that binds to c-Met, comprising LCDR3 of SEQ ID NO:

12. The method of claim 1 .

3. The first domain that binds to EGFR comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and the second domain comprising the light chain variable region (VL) of SEQ ID NO: 14 and binding to c-Met; The method of claim 2, wherein the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16 are included.

4. The bispecific anti-EGFR / c-Met antibody is of the IgG1 isotype.

5. The method according to any one of 1 to 4.

5. the bispecific anti-EGFR / c-Met antibody comprises a first heavy chain (HC1) of SEQ ID NO: 17 , a first light chain (LC1) of SEQ ID NO: 18, a second heavy chain (HC2) of SEQ ID NO: 19, and The method of any one of claims 1 to 5, comprising a second light chain (LC2) of sequence number 20.

6. The bispecific anti-EGFR / c-Met antibody has a fucose content of about 1% to about 15%. The method according to any one of claims 1 to 5, wherein the glycan has a biantennary structure.

7. The compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The salt to be prepared is of the formula (II): 【Chemistry 2】 The method of any one of claims 1 to 6, wherein the compound is represented by

8. The compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The salt to be prepared is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1 H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpho The method according to any one of claims 1 to 6, wherein the acrylamide is a methylaminophenyl acrylamide.

9. The EGFR or c-Met expressing cancer may be a wild-type EGFR, an EGFR mutation, an EGFR genetic Gene amplification, elevated levels of circulating HGF, wild-type c-Met, c-Met mutation, c-Met gene The method of any one of claims 1 to 8, which is associated with gene amplification or mutant KRAS.

10. The EGFR mutation is E709K, L718Q, L718V, G719A, G719X , G724X, G724S, I744T, E746K, L747S, E749Q, A75 0P, A755V, V765M, C775Y, T790M, L792H, L792V, G 796S, G796R, G796C, C797S, T854I, L858P, L858R , L861X, delE746-A750, delE746_T751InsKV, de lE746_A750InsHS, delE746_T751InsFPT, delE7 46_T751InsL, delE746_S752InsIP, delE746_P7 53InsMS, delE746_T751InsA, delE746_T751Ins APT, delE746_T751InsVA, delE746_S752InsV, d elE746_P753InsVS, delE746_K754InsGG, delE7 46_E749, delE746_E749InsP, delL747_E749, de lL747_A750InsP, delL747_T751InsP, delL747_ T751InsN, delL747_S752InsPT, delL747_P753I nsNS, delL747_S752InsPI, delL747_S752, delL 747_P753InsS, delL747_K754, dekL747_T751In sS, dekL747_T751, delL747_P753InsS, delA750 _I759InsPT, delT751_I759InsT, delS752_I759 , delT751_I759InsN, delT751_D761InsNLY, del S752_I759, delR748-P753, delL747-P753insS, delL747-T751, M766_A767InsA, S768_V769InsS <h2 style=";text-align:left;direction:ltr">VA、P772_H773InsNS、D761_E762InsX<h2 style=";text-align:left;direction:ltr"> １－７ <h2 style=";text-align:left;direction:ltr"> 、A763_ <h2 style=";text-align:left;direction:ltr">5Y764InsX<h2 style=";text-align:left;direction:ltr"> １－７ <h2 style=";text-align:left;direction:ltr"> 、Y764_Y765 InsX<h2 style=";text-align:left;direction:ltr"> １－７ <h2 style=";text-align:left;direction:ltr"> 、M766_A767I nsX １－７ 、A767_V768 InsX １－７ 、S768_V769 InsX １ －７ 、V769_D770 InsX １－７ 、D770_N771 InsX １－７ 、N <h2 style=";text-align:left;direction:ltr">771_P772 InsX<h2 style=";text-align:left;direction:ltr"> １－７ <h2 style=";text-align:left;direction:ltr"> 、P772_H773 InsX<h2 style=";text-align:left;direction:ltr"> １－７ <h2 style=";text-align:left;direction:ltr"> 、H773_ V774 InsX １－７ , V774_C775 InsX １－７ , EGFR exons one or more deletions in exon 20 or one or more insertions in exon 20 of EGFR, EGFR one or more deletions in exon 19 of EGFR or one or more insertions in exon 19 of EGFR or any combination thereof, and X is any amino acid. How to do it.

11. The EGFR mutation is one or more deletions in exon 19 or L858R, or The method of claim 10, wherein the method is any combination of the above.

12. 9. The method of claim 8, wherein the c-Met mutation is a c-Met exon 14 skipping mutation. The method described below.

13. 9. The mutant KRAS having a G12V, G12C, or G12A substitution. The method described below.

14. The subject has been diagnosed with an EGFR mutation prior to administering the combination therapy.

14. The method of any one of claims 13.

15. Claims 1 to 1, wherein the subject has a newly diagnosed EGFR or c-Met expressing cancer.

5. The method according to any one of claims 4 to 4.

16. 12. The method of claim 1, wherein the subject is EGFR tyrosine kinase inhibitor (TKI) treatment naive.

16. The method according to any one of claims 1 to 15.

17. the subject is resistant to or relapsed from treatment with a first-generation EGFR TKI; The method according to any one of claims 1 to 15.

18. 18. The method of claim 17, wherein the first generation EGFR TKI is erlotinib or gefinib. The method described.

19. the subject is resistant to or relapsed from treatment with a second-generation EGFR TKI; The method according to any one of claims 1 to 14.

20. 20. The method of claim 19, wherein the second-generation EGFR TKI is afatinib.

21. the subject is resistant to or relapsed from treatment with a third-generation EGFR TKI; The method according to any one of claims 1 to 14.

22. 22. The method of claim 21, wherein the third generation EGFR TKI is osimertinib.

23. The EGFR or c-Met expressing cancer is non-small cell lung cancer (NSCLC), epithelial cell carcinoma, breast cancer, Cancer, ovarian cancer, lung cancer, lung squamous cell carcinoma, lung adenocarcinoma, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer , kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer Cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, stomach cancer, thymus cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC) or sporadic or hereditary papillary renal cell carcinoma (PRCC); 23. The method according to any one of claims 1 to 22.

24. 24. The method of claim 23, wherein the cancer is NSCLC.

25. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 200 mg to about 2000 mg. The method of any one of claims 1 to 23, wherein the administration is

26. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 1400 mg.

26. The method of claim 25, wherein the

27. The bispecific anti-EGFR / c-Met antibody is about 350 mg, about 700 mg, about 10 27. The method of claim 26, wherein the dose is administered at a dose of 50 mg, or about 1400 mg.

28. The bispecific anti-EGFR / c-Met antibody of claim 1 is administered once a week.

28. The method of any one of 27.

29. The bispecific anti-EGFR / c-Met antibody of claim 1 is administered once every two weeks.

28. The method of any one of 27.

30. The compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof 30. The method of claim 1, wherein the salt is administered in a dose of about 20 mg to about 320 mg.

10. The method according to claim 1.

31. The compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof 31. The method of claim 30, wherein the salt is administered in a dose of about 160 mg or about 240 mg. Law.

32. The compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof 32. The method of any one of claims 1 to 31, wherein the salt is administered once a day.

33. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 350 mg to about 1400 mg. once a week for four weeks and then once every two weeks, A solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 160 mg / day.

25. The method of any one of claims 1 to 24, wherein the dose is administered at a dose of from about 240 mg to about 240 mg.

34. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg once a week for four weeks. and thereafter once every two weeks, A solvate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 160 mg per day.

34. The method of claim 33,

35. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1050 mg once weekly for 4 weeks. and thereafter once every two weeks, wherein the compound of formula (I) or a solvate thereof A hydrate, tautomer, or pharmaceutically acceptable salt is administered at a dose of about 160 mg daily. The method of claim 33, wherein

36. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg once weekly for 4 weeks. and thereafter once every two weeks, wherein the compound of formula (I) or a solvate thereof A hydrate, tautomer, or pharmaceutically acceptable salt is administered at a dose of about 160 mg daily. The method of claim 33, wherein

37. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 700 mg once a week for four weeks. and thereafter once every two weeks, A solvate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 240 mg per day.

34. The method of claim 33,

38. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1050 mg once weekly for 4 weeks. and thereafter once every two weeks, wherein the compound of formula (I) or a solvate thereof A hydrate, tautomer, or pharmaceutically acceptable salt is administered at a dose of about 240 mg daily. The method of claim 33, wherein

39. The bispecific anti-EGFR / c-Met antibody is administered at a dose of about 1400 mg once weekly for 4 weeks. and thereafter once every two weeks, wherein the compound of formula (I) or a solvate thereof A hydrate, tautomer, or pharmaceutically acceptable salt is administered at a dose of about 240 mg daily. The method of claim 33, wherein

40. The bispecific anti-EGFR / c-Met antibody is a compound of formula (I) or a solvate thereof 2. The method of claim 1, wherein the compound, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered after administration of the compound, hydrate, tautomer, or pharmaceutically acceptable salt thereof.

40. The method of any one of 1 to 39.

41. The bispecific anti-EGFR / c-Met antibody is a compound of formula (I) or a solvate thereof administered one or more times after administration of a compound, hydrate, tautomer, or pharmaceutically acceptable salt thereof 41. The method of claim 40.

42. The bispecific anti-EGFR / c-Met antibody is a compound of formula (I) or a solvate thereof after administration of the compound, hydrate, tautomer, or pharmaceutically acceptable salt thereof, 42. The method of claim 41, wherein the administration is 6, 7, 8, 9, or 10 or more times.

43. the subject is homozygous for phenylalanine at position 158 of CD16; or is heterozygous for valine and phenylalanine at position 158 of CD16, Item 43. The method according to any one of Items 1 to 42.

44. 44. The method of claim 1, further comprising administering to the subject a third anti-cancer therapy. How to post.

45. 2. The method of claim 1 , wherein the third anti-cancer therapy is a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.

44. The method according to claim 44.

46. Therapeutically effective amount of isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocytes a growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I): 【Chemistry 3】 or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof , combination medicines.

47. The isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3 HCDR3 of SEQ ID NO: 4, LCDR1 of SEQ ID NO: 5, and LCDR2 of SEQ ID NO: 6 a first domain that binds to EGFR comprising CDR3 and HCDR1 of SEQ ID NO: 7; HCDR2 of SEQ ID NO: 8, HCDR3 of SEQ ID NO: 9, LCDR1 of SEQ ID NO: 10, and LCDR2 of SEQ ID NO: 11 and a second domain that binds to c-Met comprising an LCDR2 of SEQ ID NO: 12, and an LCDR3 of SEQ ID NO:

13. and a bispecific anti-EGFR / c-Met antibody comprising: Combination.

48. Formula (I): 【Chemistry 4】 or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, 48. The pharmaceutical combination of claim 46 or 47, which is lazertinib.

49. Formula (I): 【Chemistry 5】 or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, 48. The pharmaceutical combination of claim 46 or 47, which is lazertinib mesylate.

50. about 350 mg to about 1400 mg of the bispecific EGFR / c-Met antibody; and about 16 0 mg to about 240 mg of the compound of formula (I) or a solvate, hydrate, or tautomer thereof, or a pharmaceutically acceptable salt thereof. combination.

51. The compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof The salt to be prepared is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1 H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpho The pharmaceutical composition according to any one of claims 46 to 50, wherein the compound is a hydroxypropyltrimethylsilyl (hydroxypropyltrimethylsilyl)acrylamide. Combination.

52. 52. The pharmaceutical combination according to any one of claims 46 to 51, wherein the pharmaceutical combination is a non-fixed combination. The pharmaceutical combination described above.

53. the first domain that binds to EGFR of the bispecific EGFR / c-Met antibody the second antibody comprising a VH of SEQ ID NO: 13 and a VL of SEQ ID NO: 14, and which binds to c-Met; 53. Any of claims 46 to 52, wherein the domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO:

16. The pharmaceutical combination according to any one of claims 1 to 4.

54. The bispecific anti-EGFR / c-Met antibody is selected from the group consisting of HC1 of SEQ ID NO: 17, HC2 of SEQ ID NO: 18 LC1 of SEQ ID NO: 19, HC2 of SEQ ID NO: 20, and LC2 of SEQ ID NO:

21. The pharmaceutical combination according to any one of the preceding claims.

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