Methods for reducing infusion-related reactions in patients treated with EGFR / MET bispecific antibodies

Abstract

The present invention relates to a method of reducing the incidence or severity of infusion-related reactions (IRR) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, comprising administering to the subject: (a) dexamethasone; (b) montelukast; or (c) methotrexate.

Description

[Technical field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 307,375, filed February 7, 2022, and U.S. Provisional Patent Application No. 63 / 389,042, filed July 14, 2022, the disclosures of which are incorporated by reference in their entireties herein.

[0002] (Reference to electronically submitted sequence listing) The sequence listing of the present application is submitted electronically through The United States Patent and Trademark Center Patent Center as an XML format sequence listing with the file name "JBI6706WOPCT1SEQLIST.xml", created on January 23, 2023, and 20 kilobytes (KB) in size. This submitted sequence listing is a part of the present specification and is incorporated by reference in its entirety.

[0003] FIELD OF THEINVENTION The present invention relates to a method of reducing the incidence or severity of infusion-related reactions (IRR) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, comprising administering to the subject: (a) dexamethasone; (b) montelukast; or (c) methotrexate. [Background technology]

[0004] Amivantamab is a bispecific EGF receptor-directed and MET receptor-directed antibody approved by the FDA for the treatment of adult patients with locally advanced or metastatic NSCLC who have been confirmed to have an EGFR exon 20 insertion mutation by an FDA-approved test and have progressed during or after platinum-based chemotherapy. Amivantamab administration can cause infusion-related reactions (IRR) in some patients. Signs and symptoms of IRR include, but are not limited to, dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. Systemic IRR, including severe reactions, are frequently observed upon introduction of new protein therapeutic infusions, but the mechanisms inducing the reactions are diverse. Summary of the Invention

[0005] There is a need for improved combinations of therapeutic agents that will reduce infusion-related reactions (IRR) in patients treated with EGFR / c-Met bispecific antibodies such as amivantamab.

[0006] The present disclosure relates generally to methods useful for treating IRR in patients treated with EGFR / c-Met bispecific antibodies.

[0007] In one aspect, the disclosure provides a method of reducing the incidence or severity of infusion-related reactions (IRR) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, the method comprising administering: (a) dexamethasone; (b) montelukast; or (c) methotrexate.

[0008] In some embodiments, the antibody comprises: - a first domain that specifically binds to EGFR, comprising the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; - a second domain that specifically binds to c-Met, comprising the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 7, 8, 9, 10, 11 and 12, respectively.

[0009] In some embodiments, the first domain comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16.

[0010] In some embodiments, the antibody is of the IgG1 isotype.

[0011] In some embodiments, 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.

[0012] In some embodiments, the antibody is an isolated bispecific antibody.

[0013] In some embodiments, the bispecific antibody is amivantamab.

[0014] In some embodiments, the antibody is administered at a dose of about 700 mg to about 1,400 mg.

[0015] In some embodiments, the antibody is administered at a dose of about 700 mg, about 1,050 mg, or about 1,400 mg.

[0016] In some embodiments, the antibody is administered at a dose of about 1,400 mg.

[0017] In some embodiments, the antibody is administered at a dose of about 1,050 mg.

[0018] In some embodiments, the antibody is administered at a dose of about 700 mg.

[0019] In some embodiments, the antibody is administered once a week or once every two weeks.

[0020] In some embodiments, the antibody is administered once a week for the first four weeks, then once every two weeks.

[0021] In some embodiments, the antibody is administered as a monotherapy.

[0022] In some embodiments, the subject treated with an anti-EGFR / c-Met antibody is further administered one or more chemotherapeutic agents.

[0023] In some embodiments, the one or more chemotherapeutic agents comprises a tyrosine kinase inhibitor (TKI).

[0024] In some embodiments, the one or more chemotherapeutic agents comprises lazertinib.

[0025] In some embodiments, the one or more chemotherapeutic agents comprises osimertinib.

[0026] In some embodiments, methotrexate is administered 3 to 7 days prior to administration of the anti-EGFR / c-Met antibody.

[0027] In some embodiments, methotrexate is administered at a dose of 25 mg.

[0028] In some embodiments, montelukast is administered daily beginning four days prior to administration of the anti-EGFR / c-Met antibody.

[0029] In some embodiments, montelukast is administered five times.

[0030] In some embodiments, montelukast is administered at a dose of 10 mg.

[0031] In some embodiments, the method further comprises administering IV dexamethasone on days 1 and 2 of administration of the anti-EGFR / c-Met antibody, wherein administration of the dexamethasone is 45 to 60 minutes prior to administration of the anti-EGFR / c-Met antibody.

[0032] In some embodiments, IV dexamethasone is administered at a dose of 10 mg.

[0033] In some embodiments, oral dexamethasone is administered one day prior to administration of the anti-EGFR / c-Met antibody.

[0034] In some embodiments, oral dexamethasone is administered at a total daily dose of 8 mg.

[0035] In some embodiments, the method further comprises administering IV dexamethasone on days 1 and 2 of administration of the anti-EGFR / c-Met antibody, wherein the IV dexamethasone is administered at a dose of 10-20 mg.

[0036] In some embodiments, the method further comprises administering premedication with one or more of an antihistamine, an antipyretic, or a glucocorticoid.

[0037] In some embodiments, the premedication further comprises diphenhydramine.

[0038] In some embodiments, diphenhydramine is administered in a dose of 25-50 mg.

[0039] In some embodiments, the premedication further comprises acetaminophen.

[0040] In some embodiments, acetaminophen is administered in a dose of 650 to 1,000 mg. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] definition All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if fully set forth.

[0042] It should be understood that the terms used herein are used only to describe particular embodiments and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0043] Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology is used.

[0044] When lists are presented, unless otherwise stated, it is to be understood that each individual element of that list and every combination of that list is a separate embodiment. For example, a list of embodiments presented as "A, B, or C" should be interpreted to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0045] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0046] The conjunction phrase "and / or" between multiple listed elements is understood to encompass both individual and combined options. For example, when two elements are connected by "and / or," the first option refers to the first element being applicable without the second element. The second option refers to the second element being applicable without the first element. The third option refers to the first and second elements being applicable together. Any one of these options is understood to be within the meaning and thus meets the requirements of the term "and / or" as used herein. The simultaneous applicability of two or more of the options is also understood to be within the meaning and thus meets the requirements of the term "and / or."

[0047] The transitional phrases "comprising," "consisting essentially of," and "consisting of" are intended to connote their generally accepted meanings in patent language, i.e., (i) "comprising" is synonymous with "comprising," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps; (ii) "consisting of" excludes any element, step, or ingredient not specified in the claim; and (iii) "consisting essentially of" limits the scope of the claim to the materials or steps specified and those that do not materially affect the "basic and novel characteristics" of the claimed invention. An embodiment described with the phrase "comprising" (or its synonyms) also provides as an embodiment an embodiment described independently with "consisting of" and "consisting essentially of."

[0048] "About" means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of the method by which the value is measured or determined, i.e., the measurement system. In the context of a particular assay, result, or embodiment, unless expressly stated otherwise in the Examples or elsewhere herein, "about" means within 1 standard deviation, or up to 5%, whichever is greater, as per practice in the art.

[0049] The term "antibody" (singular or plural) is intended in a broad sense and includes immunoglobulin molecules including monoclonal antibodies (including murine, human, humanized, and chimeric monoclonal antibodies), full-length antibodies, antigen-binding fragments, multispecific antibodies such as bispecific, trispecific, tetraspecific, etc., dimeric, tetrameric, or multimeric antibodies, single chain antibodies, domain antibodies, and any other modified form of immunoglobulin molecule that contains an antigen-binding site of the required specificity.

[0050] "Specific binding" or "specifically binds" or "specific binding" or "binds" refers to an antibody binding to an antigen or an epitope within an antigen with higher affinity than to other antigens. Typically, antibodies bind with an equilibrium dissociation constant (K D ) is the K for binding to non-specific antigens (e.g., BSA, casein) D At least 100 times smaller than about 5 × 10 -8 M or less, for example, 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 K below M D The dissociation constant can be measured using known protocols. However, an antibody that binds to an antigen or an epitope within an antigen may have cross-reactivity to other related antigens, e.g., the same antigen (homolog) from other species, such as humans or monkeys, e.g., Macaca fascicularis (cynomolgus monkey, cyno) or Pan troglodytes (chimp). A monospecific antibody binds to one antigen or one epitope, whereas a bispecific antibody binds to two different antigens or two different epitopes.

[0051] A "complementarity determining region (CDR)" is a region of an antibody that binds to an antigen. CDRs can be defined using a variety of descriptions, such as Kabat (Wu et al. (1970) J Exp Med 132:211-50) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et 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). Correspondence between the various descriptions and numbering of the variable regions has been described (see, for example, Lefranc et al. (2003) Dev Comp Immunol 27:55-77; Honegger and Pluckthun, (2001) J Mol Biol 309:657-70; and the International ImMunoGeneTics (IMGT) database; web resource, http: / / www_imgt_org). Available programs such as abYsis by UCL Business PLC can be used to describe the CDRs. As used herein, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" include CDRs defined by any of the methods of Kabat, Chothia, IMGT or AbM as described above, unless otherwise expressly stated herein.

[0052] A "full-length antibody" is composed of two heavy chains (HC) and two light chains (LC), and multimers thereof (e.g., IgM), interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (consisting of domains CH1, hinge, CH2, and CH3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions are interspersed with framework regions (FR) and may be further subdivided into regions of hypervariability called complementarity determining regions (CDRs). Each VH and VL is composed of three CDR and four FR segments, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0053] "Antigen-binding fragment" refers to a portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments may be synthetic, enzymatically obtainable, or recombinant polypeptides, and include VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments, domain antibodies (dAbs) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, and the minimum recognition unit consisting of amino acid residues reproducing the CDRs of an antibody, such as the FR3-CDR3-FR4 portion, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked to each other via synthetic linkers to form various types of single chain antibody designs; when the VH and VL domains are expressed as separate single chain antibody constructs, the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen binding sites, such as single chain Fvs (scFvs) or diabodies, as described, for example, in WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804, and WO 1992 / 01047.

[0054] By "monoclonal antibody" is meant an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., individual antibodies that make up the population, that are identical except for possible well-known alterations, such as removal of the C-terminal lysine from the antibody heavy chain, or post-translational modifications such as isomerization or deamidation of amino acids, oxidation of methionine, or deamidation of asparagine or glutamine. A monoclonal antibody typically binds to one antigenic epitope. A bispecific monoclonal antibody binds to two different antigenic epitopes. A monoclonal antibody may have heterogeneous glycosylation within the antibody population. A monoclonal antibody may be monospecific or multispecific, such as bispecific, and may be monovalent, bivalent, or multivalent.

[0055] "Humanized antibody" refers to an antibody in which the antigen binding site is derived from a species other than human and the variable region framework is derived from a human immunoglobulin sequence. Because humanized antibodies may contain mutations intentionally introduced within the framework regions, such frameworks may not be exact copies of expressed human immunoglobulin or germline gene sequences.

[0056] "Human antibody" refers to an antibody having heavy and light chain variable regions in which both the framework and antigen binding sites are derived from sequences of human origin. If the antibody contains a constant region or a portion of a constant region, the constant region also is derived from sequences of human origin. Antibodies in which the antigen binding site is derived from a non-human species are not included in the definition of "human antibody."

[0057] A human antibody comprises a heavy or light chain variable region derived from a sequence of human origin when the variable region of the antibody is obtained from a system using human germline immunoglobulin or rearranged immunoglobulin genes. Non-limiting exemplary systems include human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals carrying human immunoglobulin loci, such as mice or rats. Human antibodies typically contain amino acid differences compared to human germline or rearranged immunoglobulin sequences due to, for example, naturally occurring somatic mutations, deliberate substitutions in frameworks or antigen-binding sites, and substitutions introduced during cloning or VDJ recombination in the non-human animal. Typically, human antibodies are at least 80% identical in amino acid sequence to the amino acid sequences encoded by human germline or rearranged immunoglobulin genes. For example, about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical. In some cases, the human antibody may contain consensus framework sequences obtained from human framework sequence analysis (see, e.g., Knappik et al., J Mol Biol 296:57-86 (2000)), or synthetic HCDR3s incorporated into a human immunoglobulin gene library displayed on phage (see, e.g., Shi et al., J Mol Biol 397:385-96 (2010), and WO 2009 / 085462).

[0058] "Bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes on the same antigen. Bispecific antibodies may have cross-reactivity to other related antigens, e.g., the same antigen (homolog) from other species such as humans or monkeys, e.g., Macaca cynomolgus (cyno) or chimpanzees, or may bind to an epitope shared between two or more different antigens.

[0059] A "bispecific anti-EGFR / c-Met antibody" or "bispecific EGFR / c-Met antibody" refers to a bispecific antibody having a first domain that specifically binds EGFR and a second domain that specifically binds c-Met. The domains that specifically bind EGFR and c-Met are typically VH / VL paired, and the bispecific anti-EGFR / c-Met antibody is monovalent with respect to binding to EGFR and c-Met.

[0060] "Isolated" refers to a homogenous population of molecules (e.g., synthetic polynucleotides, polypeptides, vectors, or viruses) that have been substantially separated and / or purified away from other components of the system in which they are produced, such as recombinant cells, as well as to proteins that have been subjected to at least one purification or isolation step. "Isolated" refers to molecules that are substantially free of other cellular material and / or chemicals, and includes molecules that are isolated to greater degrees of purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0061] Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG, and IgM, depending on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be assigned to one of two clearly distinct types, kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0062] As used herein, "low fucose" or "low fucose content" refers to an antibody having a fucose content of about 1% to 15%.

[0063] As used herein, "normal fucose" or "normal fucose content" refers to an antibody having a fucose content of greater than about 50%, usually greater than 80%, or greater than 85%.

[0064] "Recombinant" refers to DNA, antibodies, and other proteins that are prepared, expressed, produced, or isolated by recombinant means when segments from different sources are joined to produce the recombinant DNA, antibody, or protein.

[0065] "Carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the present invention is administered. Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine may be used to formulate the bispecific anti-EGFR / c-Met antibody. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration). For parenteral administration, the carrier may comprise sterile water, and other excipients may be added to enhance or preserve solubility. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers with appropriate additives. Suitable vehicles and formulations (including other human proteins, e.g., human serum albumin) are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st Edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, see in particular pp. 958-989.

[0066] "Dosage" refers to information regarding the amount of a therapeutic agent or drug taken by a subject and the frequency of times the therapeutic agent is taken by a subject. "Dose" refers to the amount or quantity of a therapeutic agent or drug taken each time.

[0067] "Therapeutically effective amount" refers to an amount effective to obtain the desired therapeutic result at the dosage and duration required. The therapeutically effective amount may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved health of the patient.

[0068] "Co-administration," "administered with," "administered in combination with," "in combination with," and the like are intended to encompass administration of selected therapeutic agents or drugs to a single patient, and include treatment regimens in which the therapeutic agents or drugs are administered by the same or different routes of administration or at the same or different times.

[0069] A "fixed combination" refers to a single pharmaceutical composition which comprises two or more compounds.

[0070] A "non-fixed combination" refers to separate pharmaceutical compositions each containing one or more compounds. One or more compounds or unit dosage forms can be administered as separate entities simultaneously, concurrently, or sequentially without specific limitations on the time between administrations, such administration providing effective levels of the two compounds in the subject's body.

[0071] "Antagonist" or "inhibitor" refers to a molecule that, when bound to a cellular protein, inhibits at least one response or activity induced by the protein's natural ligand. A molecule is an antagonist when at least one response or activity is inhibited by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one response or activity inhibited in the absence of the antagonist (e.g., a negative control), or when the inhibition is statistically significant compared to inhibition in the absence of the antagonist.

[0072] "Treating," "treating," or "treatment" of a disease or disorder, such as cancer, refers to achieving one or more of the following: reducing the severity and / or duration of the disorder, inhibiting the worsening of symptoms characteristic of the disorder being treated, limiting or preventing the recurrence of the disorder in a subject who previously had the disorder, or limiting or preventing the recurrence of symptoms in a subject who was previously symptomatic for the disorder.

[0073] "Prevent", "preventing", "prevention", or "prophylaxis" of a disease or disorder means preventing the disorder from occurring in a subject.

[0074] "Responsive," "responsive," or "likely to respond" refers to any kind of improvement or positive response, whether detectable or undetectable, such as reduction or amelioration of one or more symptoms, a decrease in the extent of the disease, a stabilized (i.e., not worsening) disease state, prevention of the spread of the disease, a delay or slowing of the progression of the disease, recovery or palliation of the disease state, and remission (whether partial or total).

[0075] A "subject" includes any human or non-human animal. "Non-human animals" include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms "subject" and "patient" are used interchangeably herein.

[0076] "Cancer" refers to an abnormal growth of cells that tend to proliferate uncontrolled and, in some cases, metastasize (spread) to other areas of the patient's body.

[0077] "EGFR or c-Met expressing cancer" refers to a cancer that has detectable expression of EGFR or c-Met, or has mutations or amplifications of EGFR or c-Met. EGFR or c-Met expression, amplification, and mutation status can be detected using known methods such as sequencing, next generation sequencing, fluorescent in situ hybridization, immunohistochemistry, flow cytometry, or western blotting.

[0078] "Epidermal growth factor receptor" or "EGFR" refers to human EGFR (also known as HER1 or ErbB1 (Ullrich et al., Nature 309:418-425, 1984) having the amino acid sequence set forth in GenBank Accession No. NP_005219), as well as naturally occurring variants thereof.

[0079] As used herein, "hepatocyte growth factor receptor" or "c-Met" refers to human c-Met having the amino acid sequence set forth in GenBank Accession No. NP_001120972 and naturally occurring variants thereof.

[0080] "Newly diagnosed" refers to a subject who has been diagnosed with an EGFR or c-Met expressing cancer but has not yet received treatment for CRC (eg, mCRC).

[0081] "Refractory" refers to a disease that does not respond to treatment. A refractory disease may be resistant to treatment before or at the start of treatment, or a refractory disease may become resistant during treatment.

[0082] "Relapse" refers to the return of a disease or signs and symptoms of a disease after a period of improvement following prior treatment with a therapeutic agent.

[0083] "Diagnosing" or "diagnosis" refers to a method of determining whether a subject is afflicted with a given disease or condition, or may develop a given disease or condition in the future, or is likely to respond to treatment for a previously diagnosed disease or condition, i.e., stratifying a patient population for the likelihood of responding to treatment. Diagnosis is typically made by a physician based on a general guide to the disease being diagnosed, or other criteria that indicate that a subject is likely to respond to a particular treatment.

[0084] A "biological sample" refers to a collection of fluids, cells, or tissues present within a subject, as well as similar fluids, cells, or tissues isolated from a subject. Exemplary samples are biological fluids, such as blood, serum and serous fluid, plasma, lymphatic fluid, urine, saliva, cyst fluid, tears, feces, sputum, mucosal secretions of secretory tissues and organs, vaginal secretions, ascites, fluids of the pleural, pericardial, peritoneal, abdominal cavities, and other body cavities, fluids collected by bronchial lavage, synovial fluid, liquid solutions in contact with a subject or biological source, such as cell and organ culture media, including conditioned media of cells or organs, lavage fluids, and the like, tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine needle aspirations, surgically resected tissues, organ cultures, or cell cultures.

[0085] Methods of the Disclosure In one aspect, the disclosure provides a method of reducing the incidence or severity of infusion-related reactions (IRR) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, the method comprising administering one or more of methotrexate, montelukast, or dexamethasone.

[0086] In one aspect, the disclosure provides a method of reducing the incidence or severity of infusion-related reactions (IRR) in a subject treated with a combination treatment comprising an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, the method comprising administering one or more of methotrexate, montelukast, or dexamethasone.

[0087] Methods for reducing IRR The present disclosure provides a method of reducing the occurrence or severity of infusion-related reactions (IRR) in a subject treated with an antibody that specifically binds to epidermal growth factor receptor (EGFR) and / or hepatocyte growth factor receptor (c-Met). In one embodiment, the subject is treated with a combination treatment comprising an antibody that specifically binds to EGFR and / or c-Met. In one embodiment, the subject is treated with a combination treatment comprising amivantamab.

[0088] Parenterally administered EGFR / c-Met bispecific antibodies can cause adverse reactions or events (AEs) in patients or subjects, specifically infusion-related reactions (IRRs). As reported in the United States Prescribing Information for RYBREVANT (amivantamab) (www.janssenlabels.com / package-insert / product-monograph / prescribing-information / RYBREVANT-pi.pdf), among 302 patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who received IV amivantamab at the recommended Phase 2 dose (RP2D) as a single agent in the CHRYSALIS study, IRRs were one of the most commonly occurring adverse reactions with an incidence of 66%.

[0089] An adverse reaction or adverse event (AE) is any untoward medical occurrence in a patient or subject to whom an EGFR / c-Met bispecific antibody is being administered or has been administered. In some embodiments, the AE is an IRR. In some embodiments, the IRR is a mild IRR, manifesting as, but not limited to, chills, nausea, dyspnea, flushing, chest discomfort, hypotension, vomiting, tachycardia, fever, or any other symptoms during or after infusion. In some embodiments, the IRR is a systemic IRR, including a severe reaction upon introduction of a new protein therapeutic infusion, such as an EGFR / c-Met bispecific antibody. In some embodiments, the EGFR / c-Met bispecific antibody is amivantamab. In some embodiments, the severity of the IRR is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). The severity scale ranges from grade 1 (mild) to grade 5 (death). Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5: death associated with an adverse event. In some embodiments, the presence of an IRR in a patient or subject is assessed at any time starting on day 1 of cycle 1 of treatment with an EGFR / c-Met bispecific antibody and ending 30 days later. In some embodiments, the presence of an IRR in a patient or subject is assessed on day 1 of cycle 1 of treatment with an EGFR / c-Met bispecific antibody. In some embodiments, the presence of an IRR in a patient or subject is assessed at any time up to 3 months after the initiation of treatment with an EGFR / c-Met bispecific antibody. In some embodiments, the presence of an IRR in a patient or subject is assessed at any time between 1 day and 30 days after the end of treatment with an EGFR / c-Met bispecific antibody. In some embodiments, the presence of an IRR in a patient or subject is assessed at any time between 1 day and 5 days after the end of treatment with an EGFR / c-Met bispecific antibody. In some embodiments, the presence of an IRR in a patient or subject is assessed anywhere from 1 to 10 days after the end of treatment with the EGFR / c-Met bispecific antibody.In some embodiments, the presence of an IRR in a patient or subject is assessed any time between 1 and 15 days after the end of treatment with the EGFR / c-Met bispecific antibody. In some embodiments, the presence of an IRR in a patient or subject is assessed any time between 1 and 20 days after the end of treatment with the EGFR / c-Met bispecific antibody.

[0090] In some embodiments, the method of reducing the occurrence or severity of an IRR comprises administering one or more of methotrexate, montelukast, or dexamethasone. In some embodiments, the method of reducing the occurrence or severity of an IRR comprises administering methotrexate. In some embodiments, the method of reducing the occurrence or severity of an IRR comprises administering montelukast. In some embodiments, the method of reducing the occurrence or severity of an IRR comprises administering dexamethasone.

[0091] Methotrexate Methotrexate (MTX) [N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid] is an FDA approved folate antagonist indicated for the treatment of rheumatoid arthritis. MTX is an antimetabolite commonly used in chemotherapy and immunosuppressant in autoimmune diseases. Methotrexate inhibits dihydrofolate reductase, disrupting DNA synthesis, repair, and cell replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the bladder are generally more sensitive to this effect of methotrexate.

[0092] In some embodiments, methotrexate is administered subcutaneously (SC). In some embodiments, methotrexate is administered orally. In some embodiments, methotrexate is administered intramuscularly. In some embodiments, methotrexate is administered intravenously.

[0093] In some embodiments, methotrexate is administered several days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 1-7 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 1-5 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 1-6 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 1-4 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 1-3 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 1-2 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 3-7 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 3-6 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 3-5 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 2-7 days prior to treatment with the EGFR / c-Met bispecific antibody.

[0094] In some embodiments, methotrexate is administered 1 day prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 2 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 3 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 4 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 5 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 6 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 7 days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, methotrexate is administered 8 days prior to treatment with the EGFR / c-Met bispecific antibody.

[0095] In some embodiments, methotrexate is administered in a dose of 12-30 mg. In some embodiments, methotrexate is administered in a total dose of 20-30 mg. In some embodiments, methotrexate is administered in a total dose of 25 mg. In some embodiments, methotrexate is administered in a single dose of 20-30 mg. In some embodiments, methotrexate is administered in a single dose of 25 mg. In some embodiments, methotrexate is administered in a single dose of 20 mg. In some embodiments, methotrexate is administered in a single dose of 21 mg. In some embodiments, methotrexate is administered in a single dose of 22 mg. In some embodiments, methotrexate is administered in a single dose of 23 mg. In some embodiments, methotrexate is administered in a single dose of 24 mg. In some embodiments, methotrexate is administered in a single dose of 26 mg. In some embodiments, methotrexate is administered in a single dose of 27 mg. In some embodiments, methotrexate is administered in a single dose of 28 mg. In some embodiments, methotrexate is administered in a single dose of 29 mg. In some embodiments, methotrexate is administered in a single dose of 30 mg.

[0096] In some embodiments, methotrexate is administered in a single dose. In some embodiments, methotrexate is administered as two doses. In some embodiments, methotrexate is administered as two or more doses.

[0097] Montelukast Montelukast is an oral drug approved by the FDA for the treatment of chronic asthma and the prevention and prevention of exercise-induced bronchoconstriction. Montelukast is also approved for the relief of symptoms of both seasonal and perennial allergic rhinitis. Montelukast can be used to inhibit mast cell-mediated release of leukotrienes and reduce inflammation and bronchoconstriction. Montelukast is a highly selective leukotriene receptor antagonist that binds with high affinity to leukotrienes, which are secreted by various cell types, including mast cells, and are involved in the inflammatory process that can cause the signs and symptoms of asthma and allergic rhinitis. Leukotriene receptors are found in airway cells, such as macrophages and smooth muscle cells. Upon binding to leukotriene receptors, montelukast inhibits the physiological effects of leukotrienes, such as airway edema, smooth muscle contraction, and impairment of normal cell activity. This provides a rationale for montelukast to potentially reduce symptomatology (eg, dyspnea) associated with EGFR / c-Met bispecific antibody IRR.

[0098] In some embodiments, montelukast is administered orally, in some embodiments, montelukast is administered as an injection, in some embodiments, montelukast is administered subcutaneously, in some embodiments, montelukast is administered intravenously, in some embodiments, montelukast is administered intramuscularly.

[0099] In some embodiments, montelukast is administered prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 1-7 times prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered once prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 2 times prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 3 times prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 4 times prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 5 times prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 6 times prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 7 times prior to treatment with the EGFR / c-Met bispecific antibody.

[0100] In some embodiments, montelukast is administered 5 days prior to the initiation of treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 4 days prior to the initiation of treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 3 days prior to the initiation of treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 2 days prior to the initiation of treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 2 days prior to the initiation of treatment with the EGFR / c-Met bispecific antibody. In some embodiments, montelukast is administered 4 days prior to the initiation of treatment with the EGFR / c-Met bispecific antibody, with the last dose of montelukast being given on the first day of treatment with the EGFR / c-Met bispecific antibody.

[0101] In some embodiments, montelukast is administered in a dose of 4-20 mg. In some embodiments, montelukast is administered in a dose of 5-10 mg. In some embodiments, montelukast is administered in a dose of 4 mg. In some embodiments, montelukast is administered in a dose of 5 mg. In some embodiments, montelukast is administered in a dose of 8 mg. In some embodiments, montelukast is administered in a dose of 10 mg. In some embodiments, montelukast is administered in a dose of 15 mg. In some embodiments, montelukast is administered in a dose of 16 mg. In some embodiments, montelukast is administered in a dose of 20 mg.

[0102] Dexamethasone Dexamethasone is a synthetic corticosteroid available in oral and IV formulations approved by the FDA for allergic conditions. IV dexamethasone (10 mg) is the standard premedication administered to all patients prior to receiving IV amivantamab. The present disclosure provides a novel method of enhancing steroid preloading to reduce the incidence of EGFR / c-Met bispecific antibody IRR.

[0103] In some embodiments, dexamethasone is administered orally. In some embodiments, dexamethasone is administered subcutaneously. In some embodiments, dexamethasone is administered intravenously. In some embodiments, dexamethasone is administered intramuscularly.

[0104] In some embodiments, dexamethasone is administered prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, dexamethasone is administered two days prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, dexamethasone is administered one day prior to treatment with the EGFR / c-Met bispecific antibody. In some embodiments, dexamethasone is administered three or more days prior to treatment with the EGFR / c-Met bispecific antibody.

[0105] In some embodiments, dexamethasone is administered once daily. In some embodiments, dexamethasone is administered twice daily.

[0106] In some embodiments, dexamethasone is administered in a dose of 2-10 mg. In some embodiments, dexamethasone is administered in a dose of 4-8 mg. In some embodiments, dexamethasone is administered in a dose of 4 mg. In some embodiments, dexamethasone is administered in a dose of 8 mg.

[0107] In some embodiments, IV dexamethasone is administered in addition to methotrexate, montelukast, or oral dexamethasone.

[0108] In some embodiments, IV dexamethasone is administered in a dose of 10-20 mg. In some embodiments, IV dexamethasone is administered in a dose of 10 mg. In some embodiments, IV dexamethasone is administered in a dose of 15 mg. In some embodiments, IV dexamethasone is administered in a dose of 20 mg.

[0109] In some embodiments, IV dexamethasone is administered 45-60 minutes prior to the IV EGFR / c-Met bispecific antibody. In some embodiments, IV dexamethasone is administered prior to the IV EGFR / c-Met bispecific antibody on the same day as the IV EGFR / c-Met bispecific antibody. In some embodiments, IV dexamethasone is administered on days 1 and 2 of IV EGFR / c-Met bispecific antibody administration.

[0110] Patient population In some embodiments, the subject being treated with an antibody that specifically binds EGFR and / or c-Met has been diagnosed with cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is lung cancer, non-small cell lung cancer, or small cell lung cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the solid tumor is colorectal cancer (CRC). In some embodiments, the solid tumor is liver cancer. In some embodiments, the solid tumor is hepatocellular carcinoma. In some embodiments, the solid tumor is gastric cancer. In some embodiments, the solid tumor is esophageal cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is squamous cell carcinoma of the head and neck.

[0111] In some embodiments, the cancer is an epithelial cell cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is lung cancer. In some embodiments, 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 pharyngeal cancer. 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 splenic cancer. 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 PRCC.

[0112] In some embodiments, the cancer is an EGFR or c-Met expressing cancer.

[0113] In some embodiments, the cancer is an EGFR and c-Met expressing cancer.

[0114] In some embodiments, the cancer is an EGFR-expressing cancer.

[0115] In some embodiments, the cancer is a c-Met-expressing cancer.

[0116] In some embodiments, the EGFR or c-Met expressing cancer is associated with wild type EGFR, EGFR mutation, EGFR gene amplification, elevated levels of circulating HGF, wild type c-Met, c-Met mutation, c-Met gene amplification, or mutant KRAS. The EGFR mutation may be an activating mutation, such as an exon 19 deletion or an L858R mutation. In some embodiments, the EGFR mutation is an exon 19 mutation of EGFR. In some embodiments, the EGFR mutation is an L858R mutation.

[0117] Exemplary EGFR mutations, such as EGFR activating mutations that may be associated with cancer, include point mutations, deletion mutations, insertion mutations, inversions, or gene amplifications that increase at least one biological activity of EGFR, such as increased tyrosine kinase activity, formation of receptor homodimers and heterodimers, and enhanced ligand binding. The mutations may be located in any part of the EGFR gene or the regulatory region associated with the EGFR gene, including mutations in exons 18, 19, 20, or 21. Other examples of EGFR activating mutations are known in the art (see, for example, U.S. Patent Application Publication No. 2005 / 0272083). Information regarding EGFR and other ErbB receptors, including receptor homo- and heterodimers, receptor ligands, autophosphorylation sites, and signaling molecules involved in ErbB-mediated signal transduction, is known in the art (see, for example, Hynes and Lane, Nature Reviews Cancer 5:341-354, 2005).

[0118] In some embodiments, the EGFR mutations are E709K, L718Q, L718V, G719A, G719X, G724X, G724S, I744T, E746K, L747S, E749Q, A750P, A755V, V765M, C775Y, T790M, L792H, L792V, G796S, G796R, G796C, C797S, T854I, L858P, L858R, L861X, delE746-A750, delE746_T751InsKV, delE746_A 750InsHS, delE746_T751InsFPT, delE746_T751InsL, delE746_S752InsIP, delE746_P753InsMS, delE746_T751InsA, delE746_T7 51InsAPT, delE746_T751InsVA, delE746_S752InsV, delE746_P753InsVS, delE746_K754InsGG, delE746_E749, delE746_E749Ins P, delL747_E749, delL747_A750InsP, delL747_T751InsP, delL747_T751InsN, delL747_S752InsPT, delL747_P753InsNS, delL74 7_S752InsPI, delL747_S752, delL747_P753InsS, delL747_K754, delL747_T751InsS, delL747_T751, delL747_P753InsS, delA75 0_I759InsPT, delT751_I759InsT, delS752_I759, delT751_I759InsN, delT751_D761InsNLY, delS752_I759, delR748-P753, delL 747-P753insS, delL747-T751, M766_A767InsA, S768_V769InsSVA, P772_H773InsNS, D761_E762InsX, A763_Y764InsX, Y764_Y765 InsX, M766_A767InsX, A767_V768 InsX, S768_V769 InsX, V769_D770 InsX, D770_N771 InsX, N771_P772 InsX, P772_H773 InsX, H773_V774 InsX, V774_C775InsX, one or more deletions in exon 20 of EGFR or one or more insertions in exon 20 of EGFR, one or more deletions in exon 19 of EGFR or one or more insertions in exon 19 of EGFR, or any combination thereof, where X refers to any naturally occurring amino acid and may be 1-7 amino acids in length. In some embodiments, the EGFR mutation is L858R. The nomenclature of mutations is well known.

[0119] In some embodiments, the EGFR mutation is one or more deletions in exon 19, or L858R, or any combination thereof. Exemplary exon 19 deletions are delE746-A750, delE746_T751InsKV, delE746_A750InsHS, delE746_T751InsFPT, delE746_T751InsL, delE746_S752InsIP, delE746_P753InsMS, delE746_T751InsA, delE 746_T751InsAPT, delE746_T751InsVA, delE746_S752InsV, delE746_P753InsVS, delE746_K7 54InsGG, delE746_E749, delE746_E749InsP, delL747_E749, delL747_A750InsP, delL747_T7 51InsP, delL747_T751InsN, delL747_S752InsPT, delL747_P753InsNS, delL747_S752InsPI, delL747_S752, delL747_P753InsS, delL747_K754, delL747_T751InsS, delL747_T751, delL7 47_P753InsS, delA750_I759InsPT, delT751_I759InsT, delS752_I759, delT751_I759InsN, delT751_D761InsNLY, delS752_I759, delR748-P753 and delL747-P753insS, delL747-T751.

[0120] Exemplary c-Met mutations include point mutations, deletion mutations, insertion mutations, inversions, or gene amplifications that increase at least one biological activity of the c-Met protein, such as increased tyrosine kinase activity, formation of receptor homodimers and heterodimers, enhanced ligand binding, etc. The mutations can be located in any part of the c-Met gene or in regulatory regions associated with the gene, such as mutations in the kinase domain of c-Met. Exemplary c-Met mutations are mutations at residue positions N375, V13, V923, R175, V136, L229, S323, R988, S1058 / T1010, and E168, or exon 14 skipping mutations. In some embodiments, the c-Met mutation is an exon 14 skipping mutation of c-Met.

[0121] Methods for detecting EGFR and c-Met mutations or gene amplification are well known.

[0122] In some embodiments, the subject has been diagnosed with an EGFR mutation prior to administration of a therapy comprising an EGFR / c-Met bispecific antibody.

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

[0124] In some embodiments, the subject with newly diagnosed cancer has one or more EGFR exon 20 mutations. In some embodiments, the subject with newly diagnosed EGFR or c-Met expressing cancer has one or more EGFR exon 20 mutations. Exon 20 mutations (insertion of one or more amino acids) are generally resistant to EGFR tyrosine kinase inhibitors (TKIs) (see, e.g., WO 2018 / 094225). Exemplary exon 20 mutations include M766_A767InsA, S768_V769InsSVA, P772_H773InsNS, D761_E762InsX, A763_Y764InsX, Y764_Y765 InsX, M766_A767InsX, A767_V768 InsX, S768_V769 InsX, V769_D770 InsX, D770_N771 InsX, N771_P772 InsX, P772_H773 InsX, H773_V774 InsX, and the like. InsX, and V774_C775 InsX, where X is 1 to 7 amino acids.

[0125] In some embodiments, the subject is EGFR tyrosine kinase inhibitor (TKI) treatment naive.

[0126] In some embodiments, the subject is refractory or relapsed to treatment with a first generation EGFR TKI.

[0127] In some embodiments, the first generation EGFR TKI is erlotinib or gefinib.

[0128] In some embodiments, the subject is refractory or relapsed to treatment with a second generation EGFR TKI.

[0129] In some embodiments, the second generation EGFR TKI is afatinib.

[0130] In some embodiments, the subject is refractory or relapsed to treatment with a third generation EGFR TKI.

[0131] In some embodiments, the third generation EGFR TKI is osimertinib.

[0132] In some embodiments, the subject is resistant or has acquired resistance to treatment with a previous anti-cancer therapy.

[0133] In some embodiments, the previous anti-cancer therapy is a chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor, hi some embodiments, the previous anti-cancer therapy is a dual platinum chemotherapy.

[0134] In some embodiments, the TKI is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL.

[0135] In some embodiments, the TKI is mobocertinib, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, poziotinib, cliotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[0136] In some embodiments, the subject is resistant or has acquired resistance to an EGFR inhibitor. Exemplary EGFR inhibitors to which cancers may develop resistance include the anti-EGFR antibodies cetuximab (ERBITUX®), panchinumumab (VECTIBIX®), matuzumab, and nimotuzumab; the small molecule EGFR inhibitors erlotinib (TARCEVA®), gefitinib (IRESSA®), EKB-569 (pelitinib, an irreversible EGFR TKI); the pan-ErbB and other receptor tyrosine kinase inhibitors lapatinib (EGFR and HER2 inhibitor), pelitinib (EGFR and HER2 inhibitor), vandetanib (ZD6474, ZACTIMA™, an EGFR, VEGFR2, and RET TKI); PF00299804 (dacomitinib, an irreversible pan-ErbB TKI); CI-1033 (an irreversible pan-erbB TKI); TKI), afatinib (BIBW2992, irreversible pan-ErbB TKI), AV-412 (dual EGFR 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 (neratinib, irreversible EGFR / ErbB2 inhibitor).

[0137] Anti-EGFR / c-Met antibody In some embodiments, the anti-EGFR / c-Met antibody is a bispecific antibody. In certain embodiments, the antibody is an isolated antibody. In certain embodiments, the antibody is an isolated bispecific antibody.

[0138] In some embodiments, the antibody (eg, a bispecific antibody) comprises a first domain that specifically binds to EGFR and a second domain that specifically binds to c-Met.

[0139] EGFR binding arm In some embodiments, the first domain that specifically binds to EGFR is a) the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively; and / or b) comprising the amino acid sequences of light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 of SEQ ID NOs: 4, 5 and 6, respectively.

[0140] In certain embodiments, the first domain that specifically binds to EGFR is a) the amino acid sequences of HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively; and b) comprising the amino acid sequences of LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively.

[0141] HCDR1: TYGMH (SEQ ID NO: 1)

[0142] HCDR2: VIWDDGSYKYYGDSVKG (SEQ ID NO: 2)

[0143] HCDR3: DGITMVRGVMKDYFDY (SEQ ID NO: 3)

[0144] LCDR1: RASQDISSALV (SEQ ID NO: 4)

[0145] LCDR2: DASSLES (SEQ ID NO: 5)

[0146] LCDR3: QQFNSYPLT (SEQ ID NO: 6)

[0147] In some embodiments, the first domain comprises a heavy chain variable region (VH) amino acid sequence that is at least 90% identical to SEQ ID NO:13, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:13. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the first domain comprises a VH of SEQ ID NO:13.

[0148] In certain embodiments, the first domain comprises a light chain variable region (VL) amino acid sequence that is at least 90% identical to SEQ ID NO:14, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:14. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the first domain comprises a VL of SEQ ID NO:14.

[0149] As used herein, the term "identical" or "having sequence identity" refers to the degree to which two amino acid sequences have the same residues at the same positions when the sequences are aligned to achieve the maximum level of identity, expressed as a percentage. For sequence alignment and comparison, typically one sequence is designated as a reference sequence against which a test sequence is compared. The sequence identity between a reference sequence and a test sequence is expressed as the percentage of positions over the entire length of the reference sequence where the reference sequence and the test sequence share the same amino acid when the reference sequence and the test sequence are aligned to achieve the maximum level of identity. As an example, two sequences are considered to have 70% sequence identity if the test sequence has the same amino acid residues at 70% of the same positions over the entire length of the reference sequence when aligned to achieve the maximum level of identity.

[0150] In some embodiments the first domain comprises: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13, and / or b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO:14.

[0151] In some embodiments the first domain comprises: a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13, and b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO:14.

[0152] In some embodiments the first domain comprises: a) the VH of SEQ ID NO: 13, and / or b) comprises a VL of SEQ ID NO: 14.

[0153] In certain embodiments, the first domain comprises: a) the VH of SEQ ID NO: 13, and b) comprises a VL of SEQ ID NO: 14.

[0154] VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS (SEQ ID NO: 13)

[0155] VL: AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK (SEQ ID NO: 14)

[0156] In some embodiments, the first domain comprises a first heavy chain (HC1) amino acid sequence that is at least 80% identical to SEQ ID NO:17, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:17. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the first domain comprises the HC1 amino acid sequence of SEQ ID NO:17.

[0157] In some embodiments, the first domain comprises a first light chain (LC1) amino acid sequence that is at least 80% identical to SEQ ID NO:18, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:18. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the first domain comprises the LC1 amino acid sequence of SEQ ID NO:18.

[0158] In some embodiments the first domain comprises: a) an HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17, and / or b) an LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18.

[0159] In some embodiments the first domain comprises: a) an HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17, and b) an LC1 amino acid sequence that is at least 80% identical to SEQ ID NO:18.

[0160] In some embodiments the first domain comprises: a) HC1 of SEQ ID NO: 17, and / or b) Contains LC1 of sequence number 18.

[0161] In some embodiments the first domain comprises: a) HC1 of SEQ ID NO: 17, and b) Contains LC1 of sequence number 18.

[0162] HC1:QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYF DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 17)

[0163] LC1: AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 18)

[0164] c-Met binding arm In certain embodiments, the second domain that specifically binds to c-Met is a) the amino acid sequences of HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 7, 8, and 9, respectively; and / or b) comprising the amino acid sequences of LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, and 12, respectively.

[0165] In certain embodiments, the second domain that specifically binds to c-Met is a) the amino acid sequences of HCDR1, HCDR2, and HCDR3 of SEQ ID NOs: 7, 8, and 9, respectively; and b) comprising the amino acid sequences of LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 10, 11, and 12, respectively.

[0166] HCDR1: SYGIS (SEQ ID NO: 7)

[0167] HCDR2: WISAYNGYTNYAQKLQG (SEQ ID NO: 8)

[0168] HCDR3: DLRGTNYFDY (SEQ ID NO: 9)

[0169] LCDR1: RASQGISNWLA (SEQ ID NO: 10)

[0170] LCDR2: AASSLLS (SEQ ID NO: 11)

[0171] LCDR3: QQANSFPIT (SEQ ID NO: 12)

[0172] In some embodiments, the second domain comprises a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 15. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In a specific embodiment, the second domain comprises a VH of SEQ ID NO:15.

[0173] In certain embodiments, the second domain comprises a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 16, e.g., about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO: 16. In some embodiments, the sequence identity is about 90-99.9%, 90-99.8%, 92-99.8%, 92-99.6%, 94-99.6%, 94-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In a specific embodiment, the second domain comprises a VL of SEQ ID NO:16.

[0174] In some embodiments the second domain is a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15, and / or b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO:16.

[0175] In some embodiments the second domain is a) a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15, and b) a VL amino acid sequence that is at least 90% identical to SEQ ID NO:16.

[0176] In some embodiments the second domain is a) the VH of SEQ ID NO: 15, and / or b) comprises a VL of SEQ ID NO: 16.

[0177] In certain embodiments, the second domain comprises: a) the VH of SEQ ID NO: 15, and b) comprises a VL of SEQ ID NO: 16.

[0178] VH: QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS (SEQ ID NO: 15)

[0179] VL:DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK (SEQ ID NO: 16)

[0180] In some embodiments, the second domain comprises a second heavy chain (HC2) amino acid sequence that is at least 80% identical to SEQ ID NO:19, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:19. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the second domain comprises the HC2 amino acid sequence of SEQ ID NO:19.

[0181] In some embodiments, the second domain comprises a second light chain (LC2) amino acid sequence that is at least 80% identical to SEQ ID NO:20, e.g., about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% identical to SEQ ID NO:20. In certain embodiments, the sequence identity is about 80-99.9%, 80-99.8%, 85-99.8%, 85-99.6%, 90-99.6%, 90-99.5%, 95-99.5%, 95-99.4%, 96-99.4%, 96-99.2%, 97-99.2%, or 97-99%. In certain embodiments, the second domain comprises the LC2 amino acid sequence of SEQ ID NO:20.

[0182] In some embodiments the second domain is a) an HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19, and / or b) an LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0183] In some embodiments the second domain is a) an HC2 amino acid sequence that is at least 80% identical to SEQ ID NO:19, and b) an LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0184] In some embodiments the second domain is a) HC2 of SEQ ID NO: 19, and / or b) Contains LC2 of sequence number 20.

[0185] In some embodiments the second domain is a) HC2 of SEQ ID NO: 19, and b) Contains LC2 of sequence number 20.

[0186] HC2:QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 19)

[0187] LC2: DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20)

[0188] In some embodiments, the antibody (e.g., a bispecific antibody) a) a first domain that specifically binds to EGFR, comprising the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; and / or b) a second domain that specifically binds c-Met, comprising the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; Includes.

[0189] In certain embodiments, an antibody (e.g., a bispecific antibody) a) a first domain that specifically binds to EGFR, comprising the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; b) a second domain that specifically binds c-Met, comprising the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; Includes.

[0190] In some embodiments, the antibody (e.g., a bispecific antibody) a) a first domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13; b) a first domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 14; c) a second domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15, and / or d) a second domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO:16.

[0191] In certain embodiments, an antibody (e.g., a bispecific antibody) a) a first domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 13; b) a first domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO: 14; c) a second domain comprising a VH amino acid sequence that is at least 90% identical to SEQ ID NO: 15; and d) a second domain comprising a VL amino acid sequence that is at least 90% identical to SEQ ID NO:16.

[0192] In some embodiments, the antibody (e.g., a bispecific antibody) a) a first domain comprising a VH of SEQ ID NO: 13; b) a first domain comprising a VL of SEQ ID NO: 14; c) a second domain comprising a VH of SEQ ID NO: 15, and / or d) a second domain comprising the VL of SEQ ID NO:16.

[0193] In some embodiments, the antibody (e.g., a bispecific antibody) a) a first domain comprising a VH of SEQ ID NO: 13; b) a first domain comprising a VL of SEQ ID NO: 14; c) a second domain comprising a VH of SEQ ID NO: 15, and d) a second domain comprising the VL of SEQ ID NO:16.

[0194] In certain embodiments, an antibody (e.g., a bispecific antibody) a) an HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17; b) an LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18; c) an HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19, and / or d) an LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0195] In certain embodiments, an antibody (e.g., a bispecific antibody) a) an HC1 amino acid sequence that is at least 80% identical to SEQ ID NO:17; b) an LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18; c) an HC2 amino acid sequence that is at least 80% identical to SEQ ID NO:19; and d) an LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0196] In certain embodiments, an antibody (e.g., a bispecific antibody) a) HC1 of SEQ ID NO: 17, b) LC1 of SEQ ID NO: 18, c) HC2 of SEQ ID NO: 19, and / or d) LC2 of sequence number 20.

[0197] In certain embodiments, the antibody (e.g., a bispecific antibody) comprises: a) HC1 of SEQ ID NO: 17, b) LC1 of SEQ ID NO: 18, c) HC2 of SEQ ID NO: 19, and d) LC2 of sequence number 20.

[0198] In some embodiments, the antibody (e.g., bispecific antibody) is of the IgG isotype. In certain embodiments, the antibody (e.g., bispecific antibody) is of the IgG1 isotype. There is some variation (e.g., known allotypes) within the IgG1 constant domain, for example at positions 214, 356, 358, 422, 431, 435, and / or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web resources; IMGT Repertoire (IG and TR); Proteins and alleles; allotypes). The bispecific anti-EGFR / c-Met antibody may be of any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28.

[0199] In some embodiments, the antibody is a human antibody.

[0200] In a particular embodiment, the antibody is amivantamab. Amivantamab or JNJ-61186372 (JNJ-372) is an IgG1 anti-EGFR / c-Met bispecific antibody described in U.S. Patent No. 9,593,164.

[0201] Other anti-EGFR / c-Met antibodies (e.g., bispecific antibodies) can also be used in the methods of the disclosure, for example, by combining publicly available EGFR-binding VH / VL domains and c-Met-binding VH / VL domains.

[0202] In some embodiments, the antibody (eg, a bispecific antibody) comprises a biantennary glycan structure having a fucose content of about 1% to about 15%.

[0203] Antibodies with low fucose content can be produced using various methods that have been reported to successfully express relatively highly defucosylated antibodies with biantennary complex type Fc oligosaccharides, such as: control of the osmolarity of the culture (Konno et al., Cytotechnology 64(:249-65, 2012), application of the variant CHO line Lec13 as a host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), application of the variant CHO line EB66 as a host cell line (Olivier et al., MAbs;2(4), 2010; Epub ahead of print; PMID:20562582), application of the rat hybridoma cell line YB2 / 0 as a host cell line (Shinkawa et al., J Biol Chem 278:3466-3473,2003), introduction of small interfering RNA specific for the α1,6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908,2004), or co-expression of β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II or kifunensine, a potent alpha-mannosidase I inhibitor (Ferrara et al., J Biol Chem 281:5032-5036,2006; Ferrara et al., Biotechnol Bioeng 93:851-861,2006; Zhou et al., Biotechnol Bioeng 99:652-65,2008). In general, antibody-mediated cytotoxicity can be reduced by reducing the fucose content in the glycans of antibodies. Antibody-specific cellular cytotoxicity (ADCC) is enhanced.

[0204] Generation of anti-EGFR / c-Met antibodies The anti-EGFR / c-Met antibodies used in the disclosed methods can be generated using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies, for example, by introducing substitutions in the heavy chain CH3 interface in each half molecule to favor the formation of heterodimers of two antibody half molecules with different specificities, in a cell-free environment in vitro or using co-expression. The Fab arm exchange reaction is the result of a disulfide bond isomerization reaction and dissociation-association of the CH3 domains. The heavy chain disulfide bonds in the hinge region of the parent monospecific antibodies are reduced. The resulting free cysteine ​​of one of the parent monospecific antibodies forms an intra-heavy chain disulfide bond with a cysteine ​​residue of the second parent monospecific antibody molecule, and at the same time, the CH3 domain of the parent antibody is released and reformed by dissociation-association. The CH3 domain of the Fab arm can be engineered to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody with two Fab arms or half molecules that each bind a different epitope, i.e., an epitope in EGFR and an epitope in c-Met. For example, bispecific antibodies of the invention can be generated using the techniques described in WO 2011 / 131746. For IgG1 antibodies, the mutation F405L in one heavy chain and K409R in the other heavy chain can be used. For IgG2 antibodies, wild type IgG2 and IgG2 antibodies with F405L and R409K substitutions may be used. For IgG4 antibodies, wild type IgG4 and IgG4 antibodies with F405L and R409K substitutions may be used. To generate a bispecific antibody, a first monospecific bivalent antibody and a second monospecific bivalent antibody are engineered to have the aforementioned mutations in the Fc region, and the antibodies are incubated together under sufficient reducing conditions to allow the cysteines in the hinge region to undergo disulfide bond isomerization, thereby generating the bispecific antibody by Fab arm exchange. Incubation conditions may optimally be returned to non-reducing conditions.Exemplary reducing agents that may be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol. For example, incubation at a temperature of at least 20° C., in the presence of at least 25 mM 2-MEA or in the presence of at least 0.5 mM dithiothreitol, at a pH of 5-8, e.g., pH 7.0 or pH 7.4, for at least 90 minutes may be used.

[0205] Bispecific anti-EGFR / c-Met antibodies for use in the methods of the disclosure can also be generated using designs such as knobs-in-holes (Genentech), CrossMAb (Roche) and electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), LUZ-Y (Genentech), Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), and Biclonic (Merus).

[0206] In the "knobs-in-holes" approach (see, for example, WO 2006 / 028936), selected amino acids that form the interface of the CH3 domain of human IgG can be mutated at positions that affect CH3 domain interactions to promote heterodimer formation. Amino acids with small side chains (holes) are introduced into the heavy chain of an antibody that specifically binds to a first antigen, and amino acids with large side chains (knobs) are introduced into the heavy chain of an antibody that specifically binds to a second antigen. After co-expression of the two antibodies, heterodimers are formed as a result of the preferential interaction of heavy chains with "holes" and heavy chains with "knobs". Exemplary CH3 substitution pairs that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V (expressed as modification position in the first CH3 domain of the first heavy chain / modification position in the second CH3 domain of the second heavy chain).

[0207] In addition to utilizing the "knobs-in-holes" approach to facilitate Fab arm exchange, CrossMAb technology utilizes CH1 / CL domain swapping in one half-arm to ensure correct light chain pairing of the resulting bispecific antibody (see, e.g., U.S. Pat. No. 8,242,247).

[0208] Other crossover techniques may be used to generate full length bispecific antibodies of the invention by swapping variable or constant, or both, domains in one or both arms between the heavy and light chains of the bispecific antibody or within the heavy chain, including, for example, VH-CH1 and VL-CL, VH and VL, CH3 and CL, and CH3 and CH1 as described in WO 2009 / 080254, WO 2009 / 080251, WO 2009 / 018386, and WO 2009 / 080252.

[0209] Other approaches, such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues on one CH3 surface and negatively charged residues on the second CH3 surface, may be used as described in U.S. Patent Application Publication No. 2010 / 0015133, U.S. Patent Application Publication No. 2009 / 0182127, U.S. Patent Application Publication No. 2010 / 028637, or U.S. Patent Application Publication No. 2011 / 0123532. In another approach, heterodimerization can be achieved by the following substitutions: L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A, as described in U.S. Patent Application Publication No. 2012 / 0149876 or U.S. Patent Application Publication No. 2013 / 0195849. / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W (represented as modification position in the first CH3 domain of the first heavy chain / modification position in the second CH3 domain of the second heavy chain).

[0210] SEEDbody technology may be utilized to generate bispecific antibodies of the invention. SEEDbodies have selected IgG residues in their constant domains substituted with IgA residues to promote heterodimerization, as described in US Patent Application Publication No. 20070287170.

[0211] Mutations are typically made at the DNA level, using standard methods, on molecules such as the constant domain of an antibody.

[0212] Administration The anti-EGFR / c-Met antibody (e.g., a bispecific antibody) may be administered in a pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises a pharma- ceutical acceptable carrier.

[0213] In some embodiments, a pharmaceutical composition comprising an anti-EGFR / c-Met antibody (eg, a bispecific antibody) is administered via intravenous infusion.

[0214] In some embodiments, a pharmaceutical composition comprising an anti-EGFR / c-Met antibody is administered subcutaneously (SC).

[0215] In some embodiments, the antibody is administered at a dose of about 700 mg to about 2,240 mg. In some embodiments, the antibody is administered at a dose of about 700 mg, about 1,050 mg, about 1,400 mg, about 1,600 mg, or about 2,240 mg. In some embodiments, the antibody is administered at a dose of about 1,050 mg. In certain embodiments, the antibody is administered at a dose of about 1,400 mg. In certain embodiments, the antibody is administered at a dose of about 700 mg. In some embodiments, the antibody is administered at a dose of about 1,600 mg. In some embodiments, the antibody is administered at a dose of about 2,240 mg.

[0216] In some embodiments, the antibody is administered at a dose of about 350 mg.

[0217] In some embodiments, the antibody is administered at a dose of about 750 mg.

[0218] In some embodiments, the antibody is administered at a dose of about 800 mg.

[0219] In some embodiments, the antibody is administered at a dose of about 850 mg.

[0220] In some embodiments, the antibody is administered at a dose of about 900 mg.

[0221] In some embodiments, the antibody is administered at a dose of about 950 mg.

[0222] In some embodiments, the antibody is administered at a dose of about 1,000 mg.

[0223] In some embodiments, the antibody is administered at a dose of about 1,100 mg.

[0224] In some embodiments, the antibody is administered at a dose of about 1,150 mg.

[0225] In some embodiments, the antibody is administered at a dose of about 1,200 mg.

[0226] In some embodiments, the antibody is administered at a dose of about 1,250 mg.

[0227] In some embodiments, the antibody is administered at a dose of about 1,300 mg.

[0228] In some embodiments, the antibody is administered at a dose of about 1,350 mg.

[0229] In some embodiments, the antibody is administered at a dose of about 1,500 mg.

[0230] In some embodiments, the antibody is administered at a dose of about 1,600 mg.

[0231] In some embodiments, the antibody is administered at a dose of about 1,700 mg.

[0232] In some embodiments, the antibody is administered at a dose of about 1,800 mg.

[0233] In some embodiments, the antibody is administered at a dose of about 1,900 mg.

[0234] In some embodiments, the antibody is administered at a dose of about 2,000 mg.

[0235] In some embodiments, the antibody is administered at a dose of about 2,100 mg.

[0236] In some embodiments, the antibody is administered at a dose of about 2,200 mg.

[0237] In some embodiments, the antibody is administered at a dose of about 2,240 mg.

[0238] In some embodiments, the antibody is administered at a dose of about 2,300 mg.

[0239] In certain embodiments, the antibody is administered at a dose of 1,050 mg for those weighing less than 80 kg and 1,400 mg for those weighing 80 kg or more.

[0240] In a specific embodiment, the antibody is administered at a dose of 700 mg for those weighing less than 80 kg and 1,050 mg for those weighing 80 kg or more.

[0241] In certain embodiments, the antibody is administered at a dose of 1,600 mg for those weighing less than 80 kg and 2,240 mg for those weighing 80 kg or more.

[0242] In some embodiments, the antibody is administered twice weekly.

[0243] In certain embodiments, the antibody is administered once a week.

[0244] In some embodiments, the antibody is administered once every two weeks.

[0245] In certain embodiments, the antibody is administered once every three weeks.

[0246] In some embodiments, the antibody is administered once every four weeks.

[0247] In certain embodiments, the antibody is administered once a week or once every two weeks. In certain embodiments, the antibody is administered once a week for the first four weeks, then once every two weeks.

[0248] In some embodiments, the antibody is administered in a 28 day cycle.

[0249] In some embodiments, the subject weighs less than 80 kg and the antibody (e.g., a bispecific antibody such as amivantamab) is administered at a dose of 700 mg once a week for the first four weeks, then once every two weeks for a 28-day cycle. In other embodiments, the subject weighs less than 80 kg and the antibody (e.g., a bispecific antibody such as amivantamab) is administered at a dose of 1,050 mg once a week for the first four weeks, then once every two weeks for a 28-day cycle. In other embodiments, the subject weighs less than 80 kg and the antibody (e.g., a bispecific antibody such as amivantamab) is administered at a dose of 1,600 mg once a week for the first four weeks, then once every two weeks for a 28-day cycle.

[0250] In certain embodiments, the subject weighs 80 kg or more and the antibody (e.g., a bispecific antibody such as amivantamab) is administered at a dose of 1,050 mg once a week for the first 4 weeks, then once every 2 weeks for a 28-day cycle. In other embodiments, the subject weighs 80 kg or more and the antibody (e.g., a bispecific antibody such as amivantamab) is administered at a dose of 1,400 mg once a week for the first 4 weeks, then once every 2 weeks for a 28-day cycle. In other embodiments, the subject weighs 80 kg or more and the antibody (e.g., a bispecific antibody such as amivantamab) is administered at a dose of 2,240 mg once a week for the first 4 weeks, then once every 2 weeks for a 28-day cycle.

[0251] Pharmaceutical compositions containing 1,400 mg, 1,050 mg, and 700 mg doses of an anti-EGFR / c-Met antibody can be administered in total volumes of approximately 28 mL, 21 mL, and 14 mL, respectively, using a 350 mg / 7 mL (50 mg / mL) solution in a single-dose vial.

[0252] Additional information regarding amivantamab can be found, for example, in the prescribing information of the RYBREVANT® product insert (amivantamab-vmjw) (www.janssenlabels.com / package-insert / product-monograph / prescribing-information / RYBREVANT-pi.pdf), which is incorporated herein by reference.

[0253] In some embodiments, the antibody is administered as a monotherapy.

[0254] Additional Therapeutic Agents In one aspect, the disclosure provides a method of reducing the incidence or severity of infusion-related reactions (IRR) in a subject treated with a combination treatment comprising an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, the method comprising administering one or more of methotrexate, montelukast, or dexamethasone.

[0255] In some embodiments, the combination treatment comprising an EGFR / c-Met bispecific antibody also includes one or more anti-cancer therapies including one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer therapies or kinase inhibitors, or any combination thereof.

[0256] In some embodiments, the kinase inhibitor is an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR, or an inhibitor of AXL.

[0257] In some embodiments, the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, mobocertinib, poziotinib, cliotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib. In some embodiments, the kinase inhibitor is lazertinib. In some embodiments, the kinase inhibitor is osimertinib. In some embodiments, the kinase inhibitor is mobocertinib.

[0258] In some embodiments, the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, inhibitors of EGFR, inhibitors of c-Met, inhibitors of HER2, inhibitors of HER3, inhibitors of HER4, inhibitors of VEGFR, inhibitors of AXL, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, mobocertinib, poziotinib, cliotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof.

[0259] Lazertinib is a third generation EGFR tyrosine kinase inhibitor (TKI), and its structure and synthesis are described in U.S. Patent No. 9,593,098, which is incorporated herein by reference. The chemical name of lazertinib free base, represented by formula (I) herein, is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (referred to herein as lazertinib). The mesylate salt of lazertinib can be represented by formula II:

[0260] [ka]

[0261] Embodiments of lazertinib (e.g., salts and crystalline forms) are described in International Application No. PCT / KR2018 / 004473, which is also incorporated herein by reference.

[0262] According to certain embodiments, lazertinib in its free base form is a highly selective and irreversible EGFR TKI with little or no effect on wild type EGFR and strong inhibitory activity against T790M single and double mutations, for example targeting activating EGFR mutations del19 and L858R, as well as T790M mutation. In one aspect of the invention, the mutation may be delE746-A750, L858R, or T790M, or a double mutation selected from delE746-A750 / T790M or L858R / T790M.

[0263] An embodiment of the disclosure is a method of treating a subject having cancer, comprising administering to the subject a combination therapy comprising a therapeutically effective amount of an 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):

[0264] [ka] or a solvate, hydrate, tautomer, or pharma- ceutically acceptable salt thereof.

[0265] Embodiments of the present disclosure provide a pharmaceutical combination comprising a therapeutically effective amount of an isolated bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for use as a medicament, in particular for use as a medicament in a subject, and a therapeutically effective amount of a compound of Formula (I), or a solvate, hydrate, tautomer, or pharma- ceutically acceptable salt thereof.

[0266] In each embodiment, the bispecific anti-EGFR / c-Met antibody and the lazertinib compound, or a solvate, hydrate, tautomer, or pharma- ceutically acceptable salt thereof, may be administered simultaneously (e.g., as part of the same pharmaceutical composition or in separate pharmaceutical compositions) or at different times, as described herein.

[0267] Pharmaceutically acceptable salt forms include pharma- ceutically acceptable acidic / anionic or basic / cationic salts. Pharmaceutically acceptable acidic / anionic salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estrus, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, Salts include iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucoate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, acetate, succinate, sulfate, hydrogen sulfate, tannate, tartrate, theoclate, tosylate and triethiodide salts. Pharmaceutically acceptable basic / cationic salts include sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.

[0268] Pharmaceutically acceptable acid salts are formed by reaction of the free base form of the compound of formula (I) with a suitable inorganic or organic acid, including, but not limited to, hydrobromic acid, hydrochloric acid, 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. Pharmaceutically acceptable acid addition salts of the compounds of formula (I) may include or be, for example, hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), or hexanoate salts.

[0269] The free acid or free base form of the compound of formula (I) can be prepared from the corresponding base addition salt or acid addition salt form, respectively.For example, the compound of the present invention in the form of an acid addition salt can be converted to the corresponding free base form by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.).The compound of the present invention in the form of a base addition salt can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0270] In certain embodiments, the method further comprises administering to the subject one or more additional therapeutic agents. Non-limiting examples of the one or more additional therapeutic agents include chimeric antigen receptor (CAR)-expressing T cells (CAR-T cells), CAR-expressing natural killer cells (CAR-NK cells), CAR-expressing macrophages (CAR-M cells), chemotherapeutic agents, immune checkpoint inhibitors, T cell redirectors, radiation therapy, surgery, and standard of care. In certain embodiments, the one or more additional therapeutic agents comprise chemotherapy, radiation therapy, surgery, targeted anti-cancer therapy, kinase inhibitors, or any combination thereof.

[0271] In some embodiments, the one or more additional therapeutic agents are one or more anti-cancer therapies, hi some embodiments, the one or more additional therapeutic agents include one or more chemotherapeutic agents.

[0272] A non-exhaustive list of chemotherapeutic agents contemplated for use in combination therapy includes anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxan®), busulfan (Myleran®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purintor®), methotrexate (Folex®), mitoxantrone (Novantron®), Milotarg, paclitaxel (Taxol®), and rifampicin (Ricin®). ), Phoenix (Yttrium 90 / MX-DTPA), Pentostatin, Polypheprosan 20 with Carmustine Implant (Gliadel®), Dactinomycin (Actinomycin D, Cosmegen), Daunorubicin Hydrochloride (Cerbidine®), Daunorubicin Citrate Liposome Injection (Daunoxom®), Dexamethasone, Docetaxel (Taxotere®), Doxorubicin Hydrochloride (Adriamycin®, Rubex®), Etoposide (Bepesid®) , busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®) , cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adolcil®, Efudex®), flutamide (Eurexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea®), idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®),L-asparaginase (ELSPAR®), tamoxifen citrate (Nolvadex®), teniposide (Bumone®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamtin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0273] Examples of alkylating agents include, but are not limited to, nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas and triazenes), uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Hemanthamin®, Nordpan®, Uracil Nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustalgen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune®), isoflurane (Isofen®), and cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune®). These include phosphamide (Mitoxana®), melphalan (Alkeran®), chlorambucil (Leukeran®), pipobroman (Amedel®, Vercite®), triethylenemelamine (Hemel®, Hexylene®, Hexastat®), desmethyldopan®, desmethyldopan®, triethylenethiophosphoramine, temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilbex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and dacarbazine (DTIC-Dome®).Further examples of alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®); melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); altretamine (hexamethylmelamine (HMM), also known as Hexylen®); carmustine (BiCNU®); bendamustine (Treanda®); busulfan (Busulfex® and Myleran®); carboplatin (Paraplatin®); temozolomide (Temodar® and Temodal®); dactinomycin (Actinomycin-D, also known as Cosmegen®); lomustine (CCNU, also known as CeeNU®); cisplatin (CDDP, also known as Platinol® and Platinol®-AQ); chlorambucil (Leukeran®). ; cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, DTIC-Dome®); altretamine (hexamethylmelamine (HMM), also known as Hexylen®); ifosfamide (Ifex®); prednisolone; procarbazine (Matulane®); mechlorethamine (nitrogen mustard, mustine , and mechlorethamine hydrochloride, also known as Mustargen®); streptozocin (Zanosar®); thiotepa (thiophosphoamide, TESPA, and TSPA, also known as Thioplex®), cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and bendamustine HCl (Treanda®).

[0274] In some embodiments, the one or more additional therapeutic agents comprise a kinase inhibitor. In some embodiments, the kinase inhibitor comprises an inhibitor of EGFR, an inhibitor of c-Met, an inhibitor of HER2, an inhibitor of HER3, an inhibitor of HER4, an inhibitor of VEGFR, an inhibitor of AXL, or a combination thereof. In certain embodiments, the kinase inhibitor is an inhibitor of EGFR. In certain embodiments, the kinase inhibitor is an inhibitor of c-Met. In some embodiments, the kinase inhibitor is an inhibitor of HER2. In certain embodiments, the kinase inhibitor is an inhibitor of HER3. In certain embodiments, the kinase inhibitor is an inhibitor of HER4. In some embodiments, the kinase inhibitor is an inhibitor of VEGFR. In certain embodiments, the kinase inhibitor is an inhibitor of AXL.

[0275] In some embodiments, the kinase inhibitor comprises erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, mobocertinib, poziotinib, cliotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, sunitinib, or combinations thereof. In certain embodiments, the kinase inhibitor is erlotinib. In certain embodiments, the kinase inhibitor is gefitinib. In some embodiments, the kinase inhibitor is lapatinib. In certain embodiments, the kinase inhibitor is vandetanib. In some embodiments, the kinase inhibitor is afatinib. In some embodiments, the kinase inhibitor is osimertinib. In certain embodiments, the kinase inhibitor is lazertinib. In certain embodiments, the kinase inhibitor is poziotinib. In some embodiments, the kinase inhibitor is cliotinib. In certain embodiments, the kinase inhibitor is cabozantinib. In some embodiments, the kinase inhibitor is capmatinib. In some embodiments, the kinase inhibitor is axitinib. In certain embodiments, the kinase inhibitor is lenvatinib. In some embodiments, the kinase inhibitor is nintedanib. In certain embodiments, the kinase inhibitor is regorafenib. In certain embodiments, the kinase inhibitor is pazopanib. In some embodiments, the kinase inhibitor is sorafenib. In certain embodiments, the kinase inhibitor is sunitinib. In some embodiments, the kinase inhibitor is mobocertinib.

[0276] In certain embodiments, the one or more prior anticancer therapies comprise carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD-(L)1 axis inhibitors, inhibitors of EGFR, inhibitors of c-Met, inhibitors of HER2, inhibitors of HER3, inhibitors of HER4, inhibitors of VEGFR, inhibitors of AXL, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, mobocertinib, poziotinib, cliotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib, or any combination thereof.

[0277] Anti-cancer therapies that may be administered in combination with anti-EGFR / c-Met antibodies (e.g., bispecific antibodies) in the methods of the present disclosure include any one or more of chemotherapeutic agents or other anti-cancer therapeutics known to those of skill in the art. Chemotherapeutic agents are chemical compounds useful in the treatment of cancer, including growth inhibitory agents or other cytotoxic agents, including alkylating agents, antimetabolites, anti-microtubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors, and the like. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;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, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, icin), streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-FU; folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, etc; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements (folic acid replenishers, such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenameth; pirarubicin; podophyllic acid;2-Ethylhydrazide; Procarbazine; PSK®; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2',2"-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Members of the taxoid or taxane family, such as paclitaxel (TAXOL®), docetaxel (TAXOTERE®), (registered trademark) and its analogues;Chlorambucil;Gemcitabine;6-Thioguanine;Mercaptopurine;Methotrexate;Platinum analogues such as cisplatin and carboplatin;Vinblastine;Platinum;Etoposide (VP-16);Ifosfamide;Mitomycin C;Mitoxantrone;Vincristine;Vinorelbine;Navelbine;Novantrone;Teniposide;Daunomycin;Aminopterin;Xeloda;Ibandronate;CPT-11, topoisomerase inhibitors RFS2000;Difluoromethylornithine (DMFO);Retinoic acid;Esperamicin;Capecitabine;Inhibitors of receptor tyrosine kinases and / or inhibitors of angiogenesis, including sorafenib (NEXAVAR®), sunitinib (SUTENT®), pazopanib (VOTRIENT™), toceranib (PALLADIA™), vandetanib (ZACTIMA™), cediranib (RECENTIN®), regorafenib (BAY73-4506), axitinib (AG013736), lestaurtinib (CEP-701), erlotinib (TARCEVA®), gefitinib (IRESSA™), afatinib (BIBW 2992), lapatinib (TYKERB®), neratinib (HKI-272), and the like, as well as pharmaceutical acceptable salts, acids, or derivatives of any of the foregoing. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens, including tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY 117018, onapristone, and toremifene (FARESTON®); and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as pharma- ceutical acceptable salts, acids, or derivatives of any of the above. Other conventional cytotoxic compounds disclosed in Wiemann et al., 1985, Medical Oncology (Calabresi et al, eds.), Chapter 10, McMillan Publishing, are also applicable to the methods of the present invention.

[0278] In some embodiments, the anti-EGFR / c-Met antibody (e.g., a bispecific antibody) and one or more additional therapeutic agents (e.g., chemotherapeutic agents) are administered simultaneously. In other embodiments, the antibody and one or more additional therapeutic agents are administered separately (e.g., sequentially).

[0279] In the case of combination therapy, one or more anti-cancer agents may be administered using the recommended doses and administration amounts of the anti-cancer agents.

[0280] subject The terms "subject" and "patient" can be used interchangeably herein. A "patient in need thereof" or "subject in need thereof" refers to a mammalian subject, preferably a human, diagnosed with or suspected of having a disease to which a bispecific anti-EGFR, anti-MET antibody is or has been administered in accordance with the methods of the invention. A "patient in need thereof" or "subject in need thereof" includes subjects already having an undesirable physiological change or disease as well as subjects predisposed to having a physiological change or disease.

[0281] In some embodiments, the subject is 18 years of age or older, e.g., 18-40 years of age or younger, 18-45 years of age or younger, 18-50 years of age or younger, 18-55 years of age or younger, 18-60 years of age or younger, 18-65 years of age or younger, 18-70 years of age or younger, 18-75 years of age or younger, 40-75 years of age or younger, 45-75 years of age or younger, 50-75 years of age or younger, 55-75 years of age or younger, 60-75 years of age or younger, 65-75 years of age or younger, 60-75 years of age or younger, 40 years of age or older, 45 years of age or older, 50 years of age or older, 55 years of age or older, 60 years of age or older, 60 years of age or older, 65 years of age or older, 70 years of age or older, or 75 years of age or older.

[0282] In some embodiments, the subject is a child. In some embodiments, the subject is 18 years of age or younger, e.g., 0-18 years of age, 0-12 years of age, 0-16 years of age, 0-17 years of age, 2-12 years of age, 2-16 years of age, 2-17 years of age, 2-18 years of age, 3-12 years of age, 3-16 years of age, 3-17 years of age, 3-18 years of age, 4-12 years of age, 4-16 years of age, 4-17 years of age, 4-18 years of age, 6-12 years of age, 6-16 years of age, 6-17 years of age, 6-18 years of age, 9-12 years of age, 9-16 years of age, 9-17 years of age, 9-18 years of age, 12-16 years of age, 12-17 years of age, or 12-18 years of age.

[0283] In some embodiments, the subject has been diagnosed with CRC (e.g., mCRC) for at least about 1 month, e.g., at least about 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 18 months, 2 years, 30 months, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. In certain embodiments, the subject is newly diagnosed with CRC (e.g., mCRC). In some embodiments, the CRC is an adenocarcinoma.

[0284] In certain embodiments, the subject is treatment naive.

[0285] In some embodiments, the subject has previously undergone one or more anti-cancer therapies. In certain embodiments, the previous one or more anti-cancer therapies include one or more chemotherapeutic agents, checkpoint inhibitors, targeted anti-cancer therapies, or kinase inhibitors, or any combination thereof. In certain embodiments, the subject is relapsed or refractory to treatment with the previous one or more anti-cancer therapies.

[0286] In some embodiments, the subject is resistant or has acquired resistance to an EGFR inhibitor. Exemplary EGFR inhibitors to which cancers may develop resistance include the anti-EGFR antibodies cetuximab (ERBITUX®), panchinumumab (VECTIBIX®), matuzumab, and nimotuzumab; the small molecule EGFR inhibitors erlotinib (TARCEVA®), gefitinib (IRESSA®), EKB-569 (pelitinib, an irreversible EGFR TKI); the pan-ErbB and other receptor tyrosine kinase inhibitors lapatinib (EGFR and HER2 inhibitor), pelitinib (EGFR and HER2 inhibitor), vandetanib (ZD6474, ZACTIMA™, an EGFR, VEGFR2, and RET TKI); PF00299804 (dacomitinib, an irreversible pan-ErbB TKI); CI-1033 (an irreversible pan-erbB TKI); TKI), afatinib (BIBW2992, irreversible pan-ErbB TKI), AV-412 (dual EGFR 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 (neratinib, irreversible EGFR / ErbB2 inhibitor).

[0287] Various qualitative and / or quantitative methods can be used to determine whether a subject is resistant, develops resistance, or is prone to develop resistance to treatment with anti-cancer therapy. Symptoms that may be associated with resistance to anti-cancer therapy include a decline or plateau in the patient's health, an increase in tumor size, a halt or slowdown in tumor growth reduction, and / or the spread of cancerous cells from one location to other organs, tissues, or cells in the body. Re-establishment or worsening of various symptoms associated with cancer, such as loss of appetite, cognitive impairment, depression, dyspnea, fatigue, hormone disruption, neutropenia, pain, peripheral neuropathy, and sexual dysfunction, can also be indicators that a subject is developing or is prone to develop resistance to anti-cancer therapy. Symptoms associated with cancer can vary depending on the type of cancer. For example, symptoms associated with cervical cancer can include abnormal bleeding, abnormal heavy vaginal discharge, pelvic pain not associated with the normal menstrual cycle, bladder pain or pain during urination, and bleeding during regular menstrual periods, sexual intercourse, vaginal douching, or pelvic exam. Symptoms associated with lung cancer can include persistent cough, hemoptysis, shortness of breath, wheezing chest pain, loss of appetite, unintentional weight loss, and fatigue.Symptoms associated with liver cancer can include loss of appetite and weight, abdominal pain, especially in the upper right part of the abdomen, which may extend to the back and shoulders, nausea and vomiting, general weakness and fatigue, liver enlargement, abdominal swelling (ascites), and yellowing of the skin and whites of the eyes (jaundice).Those skilled in the art of oncology can easily identify the symptoms associated with certain types of cancer.

[0288] Exemplary PD-(L)1 axis inhibitors are antibodies that bind to PD-1, such as nivolumab (OPDIVO®), pembrolimab (KEYTRUDA®), sintilimab, cemiplimab (LIBTAYO®), tripolibamab, tislelizumab, spartalizumab, camrelizumab, dostralimab, genolimuzumab, or cetrelimab, or antibodies that bind to PD-L1, e.g., PD-L1 antibodies are embafolimab, atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®), and avelumab (BAVENCIO®).

[0289] Commercially available antibodies can be purchased through an authorized distributor or pharmacy. The amino acid sequence structures of the small molecules can be found in the USAN and / or INN deposits by the companies in the CAS registry.

[0290] Premedication In some embodiments, the combination treatment comprising an EGFR / c-Met antibody also comprises one or more premedications. In some embodiments, the premedication comprises an antihistamine, an antipyretic, or a glucocorticoid. In some embodiments, the premedication comprises an antihistamine. In some embodiments, the premedication comprises an antipyretic. In some embodiments, the premedication comprises a glucocorticoid. In some embodiments, the one or more premedications are administered as described in Table 1.

[0291] [Table 1] * All doses were required. ‡ Required for initial doses (week 1, days 1 and 2); optional for subsequent doses.

[0292] Embodiment 1. A method for reducing the incidence or severity of infusion-related reactions (IRR) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, comprising: a) Dexamethasone b) montelukast, or c) methotrexate, The method comprises administering to a subject. 2.Antibody, a) a first domain that specifically binds to EGFR, comprising the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; b) a second domain that specifically binds c-Met, comprising the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; 2. The method of embodiment 1, comprising: 3. The method of embodiment 2, wherein the first domain comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO: 16. 4. The method of any one of embodiments 1 to 3, wherein the antibody is of the IgG1 isotype. 5. The method of any one of embodiments 1 to 4, wherein 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. 6. The method of any one of embodiments 1 to 5, wherein the antibody is an isolated bispecific antibody. 7. The method of embodiment 6, wherein the bispecific antibody is amivantamab. 8. The method of any one of embodiments 1 to 7, wherein the antibody comprises a biantennary glycan structure having a fucose content of about 1% to about 15%. 9. The method of any one of embodiments 1-8, wherein the antibody is administered at a dose of about 700 mg to about 2,240 mg. 10. The method of embodiment 9, wherein the antibody is administered at a dose of about 700 mg, about 1,050 mg, about 1,400 mg, about 1,600 mg, or about 2,240 mg. 11. The method of embodiment 10, wherein the antibody is administered at a dose of about 1,400 mg. 12. The method of embodiment 10, wherein the antibody is administered at a dose of about 1,050 mg. 13. The method of embodiment 10, wherein the antibody is administered at a dose of about 700 mg. 13a. The method of embodiment 10, wherein the antibody is administered at a dose of about 1,600 mg. 13b. The method of embodiment 10, wherein the antibody is administered at a dose of about 2,240 mg. 14. The method of any one of embodiments 1-13, wherein the antibody is administered once a week or once every two weeks. 15. The method of embodiment 14, wherein the antibody is administered once a week for the first 4 weeks, then once every 2 weeks. 16. The method of any one of embodiments 1-15, wherein the antibody is administered in a 28 day cycle. 17. The method of any one of embodiments 1-16, wherein the antibody is administered as a monotherapy. 18. The method of any one of embodiments 1-16, wherein the subject treated with the anti-EGFR / c-Met antibody further receives one or more chemotherapeutic agents. 19. The method of embodiment 18, wherein the one or more chemotherapeutic agents comprises a tyrosine kinase inhibitor (TKI). 20. The method of embodiment 18, wherein the one or more chemotherapeutic agents comprise lazertinib, osimertinib, capmatinib, or mobocertinib. 20a. The method of embodiment 20, wherein the one or more chemotherapeutic agents comprises lazertinib. 20b. The method of embodiment 20, wherein lazertinib is administered at a dose of 240 mg. 20c. The method of embodiment 20, wherein the one or more chemotherapeutic agents comprises osimertinib. 20d. The method of embodiment 20, wherein the one or more chemotherapeutic agents comprises mobocertinib. 20e. The method of embodiment 20, wherein the one or more chemotherapeutic agents comprises capmatinib. 21. The method according to any one of embodiments 1 to 20, wherein the cancer is non-small cell lung cancer (NSCLC), epithelial cell carcinoma, breast cancer, ovarian cancer, lung cancer, squamous cell carcinoma of the lung, adenocarcinoma of the lung, 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, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, stomach cancer, thymic cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC), head and neck squamous cell carcinoma (HNSCC). 22. The method of embodiment 21, wherein the cancer is NSCLC. 22a. The method of any one of embodiments 1, 21, or 22, wherein the cancer is associated with an EGFR exon 19 deletion. 22b. The method of any one of embodiments 1, 21, or 22, wherein the cancer is associated with an L858R mutation. 23. The method of any one of embodiments 1-22, wherein the subject has been diagnosed with left-sided mCRC. 24. The method of any one of embodiments 1-22, wherein the subject has been diagnosed with right-sided mCRC. 25. The method of any one of embodiments 1-24, wherein the subject is anti-EGFR therapy naive. 26. The method of any one of embodiments 1-24, wherein the subject has previously received anti-EGFR therapy. 27. The method of any one of embodiments 1-25, wherein the subject is treatment naive. 28. The method of any one of embodiments 1-26, wherein the subject is relapsed or refractory to prior treatment with one or more anti-cancer therapies. 28a. The method of embodiment 28, wherein the previous anticancer therapy is osimertinib. 28b. The method of embodiment 28, wherein the previous anti-cancer therapy is platinum chemotherapy. 29. The method of any one of embodiments 1-28, wherein the subject is 18 years of age or older. 30. The method of any one of embodiments 1-29, further comprising administering premedication with one or more of an antihistamine, an antipyretic, or a glucocorticoid. 30a. The method of embodiment 30, wherein the premedication comprises an antihistamine. 30b. The method of embodiment 30, wherein the premedication comprises an antipyretic. 30c. The method of embodiment 30, wherein the premedication comprises a glucocorticoid. 31. The method of any one of embodiments 1-30, wherein methotrexate is administered 5 days to 1 day prior to administration of the anti-EGFR / c-Met antibody. 32. The method of embodiment 31, wherein methotrexate is administered in a dose of 25 mg. 33. The method of any one of embodiments 1-30, wherein montelukast is administered daily starting 4 days prior to administration of the anti-EGFR / c-Met antibody. 34. The method of embodiment 33, wherein montelukast is administered five times. 35. The method of embodiment 33, wherein montelukast is administered in a dose of 10 mg. 36. The method of any one of embodiments 30-35, further comprising administering IV dexamethasone on days 1 and 2 of administration of the anti-EGFR / c-Met antibody, wherein administration of the dexamethasone is 45-60 minutes prior to administration of the anti-EGFR / c-Met antibody. 37. The method of embodiment 36, wherein IV dexamethasone is administered at a dose of 10 mg. 38. The method of any one of embodiments 1-30, wherein oral dexamethasone is administered one day prior to administration of the anti-EGFR / c-Met antibody. 39. The method of embodiment 38, wherein oral dexamethasone is administered in a total daily dose of 8 mg. 40. The method of embodiment 38 or 39, further comprising administering IV dexamethasone on days 1 and 2 of administration of the anti-EGFR / c-Met antibody, wherein the IV dexamethasone is administered at a dose of 10-20 mg. 41. The method of embodiment 40, wherein IV dexamethasone is administered at a dose of 20 mg on day 1 and 10 mg on day 2. 42. The method of any one of the preceding embodiments, further comprising administering premedication with one or more of an antihistamine, an antipyretic, or a glucocorticoid. 43. The method of embodiment 42, wherein the premedication comprises diphenhydramine. 44. The method of embodiment 43, wherein diphenhydramine is administered in a dose of 25 to 50 mg. 45. The method of embodiment 42, wherein the premedication comprises acetaminophen. 46. ​​The method of embodiment 45, wherein acetaminophen is administered in a dose of 650 to 1,000 mg.

[0293] Example 1. Methotrexate, montelukast, or dexamethasone to reduce amivantamab infusion-related reactions. Objectives and Endpoints The primary objective is to evaluate the efficacy of prophylactic methotrexate, montelukast, or dexamethasone prior to lazertinib and IV amivantamab infusion to reduce the incidence and / or severity of IRR.

[0294] Overall Plan This is a proof-of-concept, open-label, multicenter study in participants with EGFR exon 19 deletion or L858R mutant NSCLC who have progressed on or after prior osimertinib and platinum chemotherapy and who may benefit from IV amivantamab + lazertinib combination therapy. In the study, participants will receive standard prophylaxis with antihistamines, antipyretics, and glucocorticoids.

[0295] The study has three cohorts. Cohort A: Participants will receive oral dexamethasone (4 mg) twice daily (8 mg total daily dose) on day -1 prior to lazertinib and IV amivantamab combination therapy (Cycle 1), in addition to all other standard premedications. Cohort B: Participants will receive oral montelukast (10 mg) in the morning on days -4, -3, -2, -1, and C1D1 prior to lazertinib and IV amivantamab combination therapy (for a total of 5 doses). Cohort C: Participants will receive a single dose of 25 mg subcutaneous (SC) methotrexate on any day between days -7 and -3 prior to lazertinib and IV amivantamab combination therapy (Cycle 1).

[0296] Study treatments will be administered in addition to all other standard premedications.

[0297] Study population Screening for eligible participants will occur within 28 days prior to dosing with lazertinib and IV amivantamab. The inclusion and exclusion criteria for enrolling participants in this study are described below.

[0298] Inclusion Criteria: 18 years of age (or the legal age of consent in the jurisdiction in which the study is conducted) or older at the time of informed consent.

[0299] Participants must have advanced or metastatic NSCLC.

[0300] Progressed during or after prior treatment with osimertinib and platinum-based chemotherapy. Prior use of a first- or second-generation EGFR TKI is permitted if administered prior to osimertinib.

[0301] Previously identified EGFR-mutated NSCLC (EGFR exon 19 deletion or L858R) (identified locally in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory [or equivalent])

[0302] ECOG performance status grade of 0 or 1 (Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair (Oken, 1982)).

[0303] Subjects must have the following organ and bone marrow function: a) Hemoglobin ≥ 9g / dL b) ANC ≥ 1.5 × 109 / L c) Platelets ≥75×10 9 / L d) ALT and AST ≤ 3 × ULN e) total bilirubin ≦1.5×ULN; subjects with Gilbert's syndrome Can be enrolled if conjugated bilirubin is within normal range f) Have an estimated glomerular filtration rate (eGFR) of >30 mL / min based on the Modified Diet in Renal Disease (MDRD) 4-parameter formula (see Appendix 5).

[0304] Treatment Group and Duration EGFR exon 19 or L858R mutated advanced NSCLC with disease progression on or after osimertinib and doublet platinum chemotherapy will continue study treatment with IV amivantamab plus lazertinib, as determined by the investigator.

[0305] Description of study procedures. Methotrexate Methotrexate (MTX) [N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid] is an FDA-approved folate antagonist indicated for the treatment of rheumatoid arthritis. MTX is an antimetabolite commonly used in chemotherapy and as an immunosuppressant in autoimmune diseases.

[0306] Methotrexate inhibits dihydrofolate reductase, disrupting DNA synthesis, repair, and cell replication. Actively proliferating tissues, such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the bladder, are generally more sensitive to this effect of methotrexate.

[0307] The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function by inhibiting the enzyme aminoimidazolecarboxamide riboside transformylase, resulting in interference with adenosine and guanine metabolism, adenosine accumulation, and due to the anti-inflammatory effects of adenosine, suppression of T cell activation, downregulation of B cells, increased sensitivity of activated CD-95 T cells, and inhibition of methyltransferase activity, inhibiting the binding of beta-1 interleukin to its cell surface receptor.

[0308] Montelukast Montelukast is an oral medication approved by the FDA for the treatment of chronic asthma and for the prevention and prophylaxis of exercise-induced bronchoconstriction. Montelukast is also approved for the relief of symptoms of both seasonal and perennial allergic rhinitis.

[0309] Montelukast inhibits mast cell-mediated release of leukotrienes and can be used to reduce inflammation and bronchoconstriction.

[0310] Montelukast is a highly selective leukotriene receptor antagonist that binds with high affinity to leukotrienes, which are secreted by various cell types, including mast cells, and are involved in inflammatory processes that may lead to the signs and symptoms of asthma and allergic rhinitis. Leukotriene receptors are found in airway cells, such as macrophages and smooth muscle cells. Upon binding to leukotriene receptors, montelukast inhibits the physiological effects of leukotrienes, such as airway edema, smooth muscle contraction, and impairment of normal cell activity. This serves as the rationale for montelukast to potentially reduce symptomology (e.g., dyspnea) associated with amivantamab IRR.

[0311] Dexamethasone Dexamethasone is a synthetic corticosteroid available in oral and IV formulations approved by the FDA for allergic conditions. IV dexamethasone (10 mg) is the standard premedication administered to all patients before receiving IV amivantamab. This study investigates the role of augmented steroid preloading to reduce the incidence of IV amivantamab IRR.

[0312] The study treatments, dexamethasone, montelukast, and methotrexate, will be administered prior to administration of the background anticancer combination regimen of lazertinib plus IV amivantamab to assess the incidence of IRR.

[0313] Study treatment will be administered in addition to all other standard premedication. Standard premedication with antihistamines, antipyretics, and / or glucocorticoids is recommended, including premedication with dexamethasone 10 mg IV required with the first dose of IV amivantamab (Week 1, Days 1 and 2).

[0314] The schedule of activities is outlined in Table 2. The recommended order of administration is shown in Tables 3-5.

[0315] [Table 2]

[0316] [Table 3] * Premedication required for amivantamab

[0317] [Table 4] * Premedication required for amivantamab

[0318] [Table 5] * Premedication required for amivantamab

[0319] Dose adjustment. The dose of IV amivantamab or lazertinib may be adjusted as determined by qualified study site personnel. If experienced toxicity is thought to be attributable to either IV amivantamab or lazertinib, the dose of the causative agent should be adjusted preferentially.

[0320] In some embodiments, if dose adjustment is required, the adjustment may occur as listed below (Table 6).

[0321] [Table 6]

[0322] In some embodiments, if withholding lazertinib or IV amivantamab is deemed clinically indicated, the decision to withhold administration of lazertinib or IV amivantamab may be guided by the toxicity experienced and the potential of either treatment contributing to toxicity, based on the safety profiles of both treatments.

[0323] In some embodiments, if both treatments are withheld and then restarted, lazertinib may be restarted first and administered about 7 days prior to the next IV amivantamab infusion.

[0324] Treatment of infusion-related reactions Participants who experience early symptoms of IRR, manifested as, but not limited to, chills, nausea, dyspnea, flushing, chest discomfort, vomiting, or any other symptoms upon infusion, may discontinue their infusion, if indicated, and symptoms may be managed according to the recommendations provided in Table 7. For the first dose of IV amivantamab (Cycle 1, Days 1 and 2), interruption of the infusion may be considered even for mild symptoms to prevent the more severe manifestations of IRR.

[0325] [Table 7] * According to the NCI Common Terminology Criteria for Adverse Events (CTCAE): Version 4.03

[0326] Infusion-related reactions Infusion-related reactions have been observed during treatment with various monoclonal anti-EGFR antibodies. Infusion-related reactions have also been observed during treatment with bispecific anti-EGFR / anti-MET antibodies. The severity of the infusion reactions has varied.

[0327] Signs and symptoms of IRR may include chills, dyspnea, flushing, nausea, chest discomfort, vomiting, tachycardia, hypotension, and fever.

[0328] Combination therapy considerations. Methotrexate cohort. Contraindicated therapy must be discontinued at least 3 weeks or 5 half-lives, whichever is shorter, prior to the first administration of study treatment (dexamethasone, montelukast, or methotrexate).

[0329] Methotrexate is contraindicated in pregnancy, alcoholism, or liver disease, immunodeficiency syndromes, pre-existing blood disorders, and hypersensitivity to methotrexate (MTX).

[0330] NSAIDs, salicylates, TMP, penicillin, warfarin, valproate, proton pump inhibitors, cyclosporine, and cisplatin increase the risk of MTX toxicity in the blood, and aminoglycosides, neomycin, and probenecid reduce MTX absorption.

[0331] Drug interactions: Aspirin, NSAIDs, and steroids: Concomitant use may elevate and prolong serum methotrexate levels, potentially leading to increased toxicity.

[0332] Proton pump inhibitors: Concomitant use may increase and prolong serum methotrexate levels, potentially leading to increased toxicity. Oral antibiotics Hepatotoxins Theophylline Folic acid and antifolates Mercaptopurine Nitrous oxide

[0333] Methotrexate is highly bound to plasma proteins, so any drug that displaces methotrexate from proteins can increase its blood levels.

[0334] Montelukast cohort Montelukast is contraindicated in patients with a history of hypersensitivity to the drug or its components. Caution should be exercised with phenylalanine-containing preparations in patients with phenylketonuria (PKU).

[0335] Lazertinib and IV amivantamab The following concomitant medications and therapies are prohibited during the study: Any chemotherapy, anticancer treatment (other than lazertinib and IV amivantamab), or experimental therapy.

[0336] Concomitant use of medications, herbal supplements, and / or foods with known strong inducing or inhibitory effects on CYP3A4 / A5 activity should be avoided. Drugs that are strong inhibitors of CYP3A4 activity must be discontinued for an appropriate period prior to administration of lazertinib.

[0337] Lazertinib is an inhibitor of P-glycoprotein (P-gp), multi-drug resistance protein 4 (MRP4), Breast Cancer Resistance Protein (BCRP), and Organic Cation Transporter 1 (OCT1). Therefore, coadministration of medications, herbal supplements, and / or food that are substrates of P-gp, MRP4, BCRP, or OCT1 is not recommended.

[0338] Lazertinib has the potential for reversible and time-dependent inhibition of CYP3A4. Concomitant use of CYP34A substrate drugs must be discontinued prior to administration of lazertinib.

[0339] Efficacy assessment The primary objective is to evaluate the efficacy of methotrexate, montelukast, or dexamethasone prophylaxis prior to lazertinib and IV amivantamab infusion to reduce the initial dose of IRR. The primary endpoint is the rate of IRR occurring on Day 1 of Cycle 1 after administration of lazertinib and IV amivantamab combination therapy. Signs and symptoms of IRR may include chills, dyspnea, flushing, nausea, chest discomfort, vomiting, tachycardia, hypotension, and / or fever.

[0340] During IV amivantamab infusion, subjects should be clinically monitored at regular intervals (including evaluation before the start of the infusion). Vital signs should be measured within 30 minutes prior to IV amivantamab administration. On Day 1 of Cycle 1, vital signs should also be measured 2 hours ± 15 minutes after IV amivantamab administration. Monitoring should include measurement of pulse / heart rate, blood pressure, temperature, respiratory rate, and oxygen saturation.

[0341] Secondary endpoints were the proportion and severity of individual AEs related to IRR signs and symptoms (chills, dyspnea, flushing, nausea, chest discomfort, vomiting, tachycardia, hypotension, fever) defined by the NCI CTCAE Criteria, version 5.0 during Cycle 1 Day 1, the proportion and severity of these AEs on subsequent doses up to 3 months, the severity of infusion-related reactions, the incidence of other AEs, and the median duration of infusion times for pre-amivantamab infusion medications, IV amivantamab infusion, and post-amivantamab infusion medications, investigator-assessed tumor response, and duration of response.

[0342] This study does not measure background anticancer therapy (IV amivantamab and lazertinib), but assessment of response to solid tumors will be performed according to RECIST v1.1 criteria (European Journal of Cancer 45(2009)228-247).

[0343] Safety assessment Safety of study treatment (methotrexate, montelukast, and dexamethasone) will be assessed by physical examination, laboratory tests, vital signs, electrocardiograms, monitoring of adverse events (AEs), and concomitant medication use.

[0344] Safety of background anticancer therapy (IV amivantamab and lazertinib) will be assessed by physical examination, laboratory tests, vital signs, electrocardiogram, monitoring of adverse events (AEs), and concomitant medication use.

[0345] There will be active safety surveillance during the first 3 months of treatment and through the end of the study, and passive safety surveillance during the open label period where sites will be able to follow subjects for disease assessment and safety via local care.

[0346] statistical methods The primary hypothesis of this study is that the incidence of IV amivantamab IRRs on Day 1 of Cycle 1 will be reduced through prophylaxis with dexamethasone, methotrexate, or montelukast.

[0347] In this study, the null hypothesis that the true IRR rate is ≥0.67 will be tested against the one-sided alternative for each prevention cohort.

[0348] For sample size determination, the Simon two-stage design (Simon, 1989) will be used for each cohort separately. Each cohort will be allowed to be expanded.

[0349] The primary endpoint is the proportion of IRR occurring on Day 1 of Cycle 1 after administration of lazertinib and IV amivantamab combination therapy. The primary analysis of IRR will occur after the last subject has received their first infusion or at the end of the study, whichever occurs first. The treated subject population will be used for the primary analysis. IRR rates will be estimated for cohorts along with 95% confidence intervals.

[0350] Secondary endpoints were the rate and severity of individual AE signs and symptoms of IRR (chills, dyspnea, flushing, nausea, chest discomfort, vomiting, tachycardia, hypotension, fever) occurring on Day 1 of Cycle 1 and on subsequent doses of IV amivantamab up to 3 months, the severity of infusion-related reactions, the incidence of other adverse events, the rate of IRR after subsequent doses, median infusion times for amivantamab pre-infusion medications, IV amivantamab infusion, and amivantamab post-infusion medications, and investigator-assessed ORR and duration of response.

[0351] A secondary endpoint of ORR with confirmed best overall response will occur approximately 12 weeks after the last subject receives their first infusion or at the end of the study, whichever occurs first. ORR is defined as the proportion of subjects achieving either a complete response (CR) or partial response (PR) as defined by investigator assessment using RECIST v1.1. Observed ORRs will be presented for each cohort with two-sided exact 95% confidence intervals, as appropriate.

[0352] Duration of response was estimated using the Kaplan-Meier method and was calculated as the time from initial response of CR or PR to progressive disease (PD) or death from underlying disease, whichever occurred first, for subjects who achieved CR or PR only.

Claims

1. 1. A pharmaceutical composition comprising an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody for use in a method of reducing the incidence or severity of infusion-related reactions (IRRs) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, comprising: The method comprises: a) dexamethasone, b) montelukast, or c) methotrexate, to said subject.

2. The antibody a) a first domain that specifically binds to EGFR, comprising the amino acid sequences of heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2, and LCDR3 of SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively; b) a second domain that specifically binds c-Met, comprising the amino acid sequences of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NOs: 7, 8, 9, 10, 11, and 12, respectively; 2. The pharmaceutical composition of claim 1, comprising:

3. 3. The pharmaceutical composition of claim 2, wherein the first domain comprises a heavy chain variable region (VH) of SEQ ID NO: 13 and a light chain variable region (VL) of SEQ ID NO: 14, and the second domain comprises a VH of SEQ ID NO: 15 and a VL of SEQ ID NO:

16.

4. The pharmaceutical composition of claim 3 , wherein the antibody is of the IgG1 isotype.

5. 5. The pharmaceutical composition of claim 4, wherein 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.

6. The pharmaceutical composition of claim 5 , wherein the antibody is an isolated bispecific antibody.

7. 6. The pharmaceutical composition of claim 5, wherein the bispecific antibody is amivantamab.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the antibody is administered at a dose of about 1,050 mg, about 1,400 mg, about 1,600 mg, or about 2,240 mg.

9. 9. The pharmaceutical composition of claim 8, wherein the antibody is administered at a dose of about 1,400 mg.

10. 9. The pharmaceutical composition of claim 8, wherein the antibody is administered at a dose of about 1,050 mg.

11. 9. The pharmaceutical composition of claim 8, wherein the antibody is administered at a dose of about 1,600 mg.

12. 9. The pharmaceutical composition of claim 8, wherein the antibody is administered at a dose of about 2,240 mg.

13. The pharmaceutical composition of any one of claims 1 to 7, wherein the antibody is administered once a week or once every two weeks.

14. 14. The pharmaceutical composition of claim 13, wherein the antibody is administered once a week for the first four weeks, then once every two weeks.

15. The pharmaceutical composition of any one of claims 1 to 7, wherein the antibody is administered as a monotherapy.

16. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the subject treated with the anti-EGFR / c-Met antibody is further administered one or more chemotherapeutic agents.

17. 17. The pharmaceutical composition of claim 16, wherein the one or more chemotherapeutic agents comprises a tyrosine kinase inhibitor (TKI).

18. 18. The pharmaceutical composition of claim 17, wherein the one or more chemotherapeutic agents comprises lazertinib.

19. 18. The pharmaceutical composition of claim 17, wherein the one or more chemotherapeutic agents comprises osimertinib.

20. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein methotrexate is administered 3 to 7 days prior to the administration of the anti-EGFR / c-Met antibody.

21. 21. The pharmaceutical composition of claim 20, wherein methotrexate is administered at a dose of 25 mg.

22. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein montelukast is administered daily starting 4 days prior to said administration of said anti-EGFR / c-Met antibody.

23. 23. The pharmaceutical composition of claim 22, wherein the montelukast is administered five times.

24. 24. The pharmaceutical composition of claim 23, wherein montelukast is administered at a dose of 10 mg.

25. 21. The pharmaceutical composition of claim 20, further comprising administering IV dexamethasone on days 1 and 2 of administration of the anti-EGFR / c-Met antibody, wherein said administration of dexamethasone is 45 to 60 minutes before said administration of the anti-EGFR / c-Met antibody.

26. 26. The pharmaceutical composition of claim 25, wherein the IV dexamethasone is administered at a dose of 10 mg.

27. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein oral dexamethasone is administered one day prior to the administration of the anti-EGFR / c-Met antibody.

28. 28. The pharmaceutical composition of claim 27, wherein the oral dexamethasone is administered at a total daily dose of 8 mg.

29. 28. The pharmaceutical composition of claim 27, further comprising administering IV dexamethasone on days 1 and 2 of administration of the anti-EGFR / c-Met antibody, wherein the IV dexamethasone is administered at a dose of 10-20 mg.

30. 8. The pharmaceutical composition of any one of claims 1 to 7, further comprising premedicating with one or more of an antihistamine, an antipyretic, or a glucocorticoid.

31. 31. The pharmaceutical composition of claim 30, wherein the premedication comprises diphenhydramine.

32. 32. The pharmaceutical composition of claim 31, wherein the diphenhydramine is administered in a dose of 25 to 50 mg.

33. 31. The pharmaceutical composition of claim 30, wherein the premedication comprises acetaminophen.

34. 34. The pharmaceutical composition of claim 33, wherein the acetaminophen is administered in a dose of 650 to 1,000 mg.