Methods for reducing dermatologic adverse events in patients treated with EGFR / met bispecific antibodies

Abstract

The present invention relates to methods of reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody and EGFR tyrosine kinase inhibitor, comprising (a) administering an antibiotic(s); (b) administering an antiseptic(s); and (c) administering a non-comedogenic moisturizer to the subject.

Description

Methods for Reducing Dermatologic Adverse Events in Patients Treated with EGFR / MET Bispecific AntibodiesREFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0001] This application claims priority to U.S. Provisional Application No. 63 / 829,037, filed June 24, 2025, U.S. Provisional Application No. 63 / 809,517, filed May 21, 2025, U.S.Provisional Application No. 63 / 803,087, filed May 9, 2025, U.S. Provisional Application No. 63 / 757,091, filed February 11, 2025, U.S. Provisional Application No. 63 / 749,044, filed January 24, 2025, U.S. Provisional Application No. 63 / 682,756, filed August 13, 2024, and U.S.Provisional Application No. 63 / 682,755, filed August 13, 2024, the disclosures of each of which are hereby incorporated by reference in their entireties.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The sequence listing of the present application is submitted electronically via The United States Patent and Trademark Center Patent Center as an XML formatted sequence listing with a file name “JBI6939WOPCTl_SequenceListing.xml”, creation date of August 8, 2025, and a size of 19,873 bytes. This sequence listing submitted is part of the specification and is herein incorporated by reference in its entirety.FIELD OF THE INVENTION

[0003] The present invention relates to methods of reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody and an EGFR-tyrosine kinase inhibitor, comprising administering (a) antibiotics; (b) antiseptics; and (c) non- comedogenic moisturizer to the subject.BACKGROUND

[0004] Amivantamab is a bispecific epidermal growth factor receptor (EGFR)-directed and hepatocyte growth factor receptor (c-MET)-directed antibody FDA approved for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations. Lazertinib is a central nervous system (CNS)-penetrating third-generation EGFR tyrosine kinase inhibitor. Amivantamab and lazertinib administration significantly improves progression-free survival rates in treatment-naive patients with EDGF-mutatedadvanced non-small cell lung cancer (Cho et al., 2023, Ann Oncol, 34:S1306), however both amivantamab and lazertinib are independently associated with dermatologic adverse events (DAEs), which impact patient quality of life (QoL) and reduce patient adherence. DAEs are typically treated with topical / systemic corticosteroids and / or systemic antibiotics, but are not always effective.

[0005] Thus, there is a need for improved combinations of therapeutics that would reduce the DAEs in patients treated with EGFR / c-Met bispecific antibodies, such as amivantamab, and EGFR tyrosine kinase inhibitors, such as lazertinib.SUMMARY

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

[0007] In one aspect, the disclosure provides a method of reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject treated with an anti-cancer therapy, wherein the anti-cancer therapy comprises an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, comprising: a) administering an antibiotic; and b) administering a non-com edogenic moisturizer to the subject.

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

[0009] In some embodiments, the method further comprises at least one of: a) administering an antiseptic; or b) administering a zinc salt to the subject. In some embodiments, the antibody is administered to the subject at a dose of about 1,050 mg to about 4,640 mg. In some embodiments, the antibody is administered intravenously (IV) to the subject once a week for the first 4 weeks and then once every 2 weeks. In some embodiments, the antibody is administered subcutaneously (SC) to the subject once a week for the first 4 weeks and then once every 4 weeks. In some embodiments, the antibody is administered on a 28-day cycle.

[0010] In some embodiments, the antibody is administered as a monotherapy. In some embodiments, the method further comprises administering to the subject at least additional one anti-cancer therapy. In some embodiments, the at least one additional anti-cancer therapy comprises at least one EGFR tyrosine kinase inhibitor (TKI) or at least one chemotherapeutic composition. In some embodiments, the at least one EGFR TKI comprises lazertinib, osimertinib, capmatinib, or mobocertinib. In some embodiments, the at least one chemotherapeutic composition comprises: a) folinic acid; b) 5-fluorourcacil; and c) oxaliplatin or irinotecan.

[0011] In some embodiments, the subject has a cancer selected from the group consisting of: colorectal cancer (CRC), non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), gastric cancer, esophageal cancer, and head and neck cancer.

[0012] In some embodiments, step a) comprises: i) administering to the subject an oral antibiotic for about 12 weeks followed by administering to the subject a topical antibiotic; or ii) administering to the subject an oral antibiotic for about 12 weeks at a first dose followed by administering to the subject the oral antibiotic at a second dose for about 12 weeks.

[0013] In some embodiments, the oral antibiotic is doxycycline or minocycline. In some embodiments, the oral antibiotic is administered to the subject at a dose of about 100 mg twice daily for about 12 weeks followed by a dose of 50 mg or 100 mg once daily for about 12 weeks.

[0014] In some embodiments, the topical antibiotic comprises about 1% (w / v) clindamycin. In some embodiments, the topical antibiotic is administered to the scalp of the subject once a day.

[0015] In some embodiments, the topical antiseptic comprises about 4% (w / v) chlorhexidine. In some embodiments, the method comprises administering the topical antiseptic to the fingernails and toenails of the subject once a day

[0016] In some embodiments, the zinc salt comprises zinc gluconate. In some embodiments, the zinc salt is orally administered to the subject at a dose of about 70 mg or 140 mg once a day.

[0017] In some embodiments, step b) comprises administering the non-comedogenic moisturizer to the face and skin of the subject at least once a day. In some embodiments, the non- comedogenic moisturizer is selected from the group consisting of VANICREAM™ Daily Facial Moisturizer, SHANI DARDEN® Hydration Peptide Cream, Neutrogena® Hydroboost Water Boost Cream, CeraVe® Ultra-Light Moisturizing Lotion, humane® Oil-Free Moisturizer, ELTA MD® AM Therapy, TATCHA® The Water Cream, FARMACY® Daily Greens, LA ROCHE- POSAY® Toleriane Double Repair Moisturizer, DIEUX® Air Angel, KIEHL’s® Ultra FacialOil-Free Gel Cream, LA ROCHE-POSAY® LIPIKAR® Daily Repair Moisturizing Lotion, LAROCHE-POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Cream, Dr. Jart+® Ceramidin™ Body Lotion, and Charlotte Tilbury® Magic Water Cream.

[0018] In some embodiments, the method further comprises administering to the subject at least one of: a) a beta blocker and a corticosteroid if the subject develops a scalp dermatologic adverse event of interest (DAE); b) a topical antiseptic alone, or in combination with a topical beta blocker or a topical Janus kinase (JAK) inhibitor, if the subject develops paronychia; c) a topical corticosteroid or topical immunosuppressant if the subject develops a body DAE; or d) a topical corticosteroid or topical immunosuppressant if the subject develops a facial DAE.

[0019] In some embodiments, the beta blocker of a) is propranolol. In some embodiments, the corticosteroid of a) comprises a 0.05% clobetasol shampoo.

[0020] In some embodiments, a) comprises at least one of: i) orally administering the beta blocker to the subject in a dose of about 30 mg daily until complete resolution of the scalp DAE; or ii) topically administering the corticosteroid to the scalp of the subject once daily until at least the final day the antibody is administered to the subject.

[0021] In some embodiments, the topical antiseptic of b) is a topical solution comprising about 4% (w / v) chlorhexidine. In some embodiments, the topical beta blocker of b) is a topical solution comprising about 0.5% (w / v) timolol. In some embodiments, the topical JAK inhibitor of b) is a topical cream comprising 1.5% ruxolitinib solution.

[0022] In some embodiments, b) comprises at least one of: i) administering the topical antiseptic to the hands and feet of the subject once daily until at least the final day the antibody is administered to the subject; ii) administering the topical beta blocker to the paronychia of the subject twice daily until at least the final day the antibody is administered to the subject; or iii) if the paronychia has not been completely resolved after 4 weeks of administering the topical antiseptic, administering the topical JAK inhibitor to the paronychia of the subject twice daily, until complete resolution of the paronychia or up to 12 weeks, whichever occurs first, beginning 4 weeks after the first administration of the topical antiseptic.

[0023] In some embodiments, the topical corticosteroid of c) or d) is a cream comprising 0.1% (w / v) betamethasone. In some embodiments, the topical immunosuppressant of c) or d) is a topical cream comprising 1.5% ruxolitinib or a topical ointment comprising 0.1% tacrolimus.

[0024] In some embodiments, c) comprises at least one of: i) administering the topical corticosteroid to the affected area of the body of the subject once daily until complete resolution of the body DAE; or ii) administering the topical immunosuppressant to the affected area of thebody of the subject twice daily until complete resolution of the body DAE or up to 12 weeks, whichever occurs first.

[0025] In some embodiments, d) comprises at least one of: i) administering the topical corticosteroid to the face of the subject once daily until complete resolution of the facial DAE or up to 2 weeks, whichever occurs first; ii) if the facial DAE has not been completely resolved after 2 weeks of administering the topical corticosteroid, administering the topical immunosuppressant to the face of the subject twice daily until complete resolution of the paronychia or up to 11 weeks, whichever occurs first, beginning 2 weeks after the first administration of the topical corticosteroid; or iii) administering the topical immunosuppressant to the face of the subject twice daily until complete resolution of the body DAE or up to 12 weeks, whichever occurs first.

[0026] The supportive care medications described herein, including any pre-treatment or post-treatment medications, and combinations thereof, are administered in connection with an anti-EGFR / c-MET bispecific antibody described herein, including amivantamab, in any scenario wherein the anti-EGFR / c-MET bispecific antibody is administered to a subject in need thereof, including as a monotherapy or non-fixed dose or fixed combination therapy and irrespective of the route of administration, including by intravenous or subcutaneous route.BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The following detailed description of embodiments of the invention will be better understood when read in conjunction with the appended drawing. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawing.

[0028] Figure 1 depicts a schematic representation of a study design for comparing enhanced and standard of care (SoC) dermatologic management (DM).

[0029] Figure 2 depicts a schematic representation of participants in a COCOON study. Of the 246 participants screened for eligibility, 99 were assigned to the COCOON DM arm and 100 participants were assigned to the SoC DM arm.

[0030] Figure 3A and Figure 3B depict representative incidence of Grade >2 dermatologic adverse events of interest (DAEIs) in the first 12 weeks after initiation of treatment with amivantamab and lazertinib. Figure 3A depicts total DAEIs, DAEIs excluding paronychia, and paronychia. Figure 3B depicts scalp localized DAEIs, facial DAEIs, and body DAEIs.

[0031] Figure 4 depicts representative distribution of Grade >2 DAEIs in the first 12 weeks by predefined subgroup. CI, Confidence Interval; ECOG, Eastern Cooperative Oncology Group.

[0032] Figure 5 A and Figure 5B depict representative incidence of Grade >2 DAEIs in the first six months after initiation of treatment with amivantamab and lazertinib. Figure 5A depicts total DAEIs, DAEIs excluding paronychia, and paronychia. Figure 5B depicts scalp localized DAEIs, facial DAEIs, and body DAEIs.

[0033] Figure 6 depicts representative response rates in subjects receiving COCOON DM or SoC DM.

[0034] Figure 7 depicts a representative Kaplan-Meier distribution of time to first occurrence of a Grade >2 DAEI.

[0035] Figure 8 depicts representative incidence and severity of individual DAEIs. TEAE, Treatment-Emergent Adverse Event.

[0036] Figure 9 depicts representative changes from baseline Skindex-16 total scores in the first 12 months of treatment. C, Cycle; D, Day; e.g., C1D15, Cycle 1 Day 15.

[0037] Figure 10A through Figure 10C depict representative changes from baseline in Skindex-16 subscales for the first 12 months of treatment. Figure 10A depicts patient-reported outcomes pertaining to dermatologic-related quality of life observed in the Postbaseline Functioning Subscale. Figure 10B depicts patient-reported outcomes pertaining to dermatologic- related quality of life observed in the Postbaseline Emotional Subscale. Figure 10C depicts patient-reported outcomes pertaining to dermatologic-related quality of life observed in the Postbaseline Symptom Subscale. SE, Standard Error.

[0038] Figure 11 A and Figure 1 IB depict representative proportions of patients with dermatologic symptoms on Patient’s Global Impression-Severity (PGI-S). Figure 11A depicts representative patient-reported rash, skin condition, and nail infection symptoms at Cycle 3 Day 15. Figure 11A depicts representative patient-reported rash, skin condition, and nail infection symptoms at Cycle 7 Day 1.

[0039] Figure 12 depicts representative changes from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Core 30 (EORTC-QLC-C30) Score in the first 12 months after initiation of treatment with amivantamab and lazertinib.

[0040] Figure 13 depicts a schematic representation of a study design for comparing modified enhanced dermatologic management and early invention with patients receiving subcutaneous (SC) amivantamab and oral lazertinib. PO, orally; QD, once daily; QW, weekly; Q4W, every four weeks; FID, three times per day.

[0041] Figure 14 depicts a schematic representation of a substudy design.

[0042] Figure 15 depicts schematic representation of a study design for comparing reactive enhanced and standard of care (SoC) dermatologic management.DETAILED DESCRIPTIONDefinitions

[0043] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as though fully set forth.

[0044] It is to be understood that the terminology used herein is for describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0045] Although any methods and materials similar or equivalent to those described herein may 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 will be used.

[0046] When a list is presented, unless stated otherwise, 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” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0047] 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.

[0048] The conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0049] The transitional terms “comprising,” “consisting essentially of,” and “consisting of’ are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “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 a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of’ and “consisting essentially of.”

[0050] ‘About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.

[0051] The term “antibody” or “antibodies” is meant 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 configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity.

[0052] “Specific binding” or “specifically binds” or “specifically binding” or “binds” refer to an antibody binding to an antigen or an epitope within the antigen with greater affinity than for other antigens. Typically, the antibody binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 5x10'8M or less, for example about 1x10'9M or less, about IxlO'10M or less, about IxlO'11M or less, or about IxlO'12M or less, typically with the KD that is at least one hundred-fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein). The dissociation constant may be measured using known protocols.Antibodies that bind to the antigen or the epitope within the antigen may, however, have crossreactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno) or Pan troglodytes (chimpanzee, chimp). While a monospecific antibody binds one antigen or one epitope, a bispecific antibody binds two distinct antigens or two distinct epitopes.

[0053] “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. CDRs may be defined using various delineations such as Kabat (Wu et al. (1970) J ExpMed 132: 211-50) (Kabat etal., Sequences ofProteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia etal. (1987) J Mol Biol 196: 901-17), IMGT (Lefranc et al. (2003) Dev Comp Immunol 27 : 55-77) and AbM (Martin and Thornton (1996) J Bmol Biol 263: 800-15). The correspondence between the various delineations and variable region numbering are described (see e.g., Lefranc et al. (2003) Dev Comp Immunol 27: 55-77; Honegger and Pluckthun, (2001) J Mol Biol 309:657-70; International ImMunoGeneTics (IMGT) database; Web resources, http: / / www_imgt_org). Available programs such as abYsis by UCL Business PLC may be used to delineate CDRs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification.

[0054] ‘Full-length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0055] “Antigen binding fragment” refers to a portion of an immunoglobulin molecule that binds an antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the VL, Fab, F(ab’)2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3- FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3. VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. W01998 / 44001, WO1988 / 01649, WO1994 / 13804 and W01992 / 01047.

[0056] ‘Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C- terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.

[0057] ‘Humanized antibodies” refers to antibodies in which the antigen binding sites are derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Humanized antibodies may include intentionally introduced mutations in the framework regions so that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.

[0058] ‘Human antibodies” refers to antibodies having heavy and light chain variable regions in which both the framework and the antigen binding site are derived from sequences of human origin. If the antibody contains a constant region or a portion of the constant region, the constant region is also derived from sequences of human origin. Antibodies in which antigen binding sites are derived from a non-human species are not included in the definition of “human antibody.”

[0059] A human antibody comprises heavy or light chain variable regions that are derived from sequences of human origin if the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Nonlimiting example systems include human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci. A human antibody typically contains amino acid differences when compared to the human germline or rearranged immunoglobulin sequences due to, for example, naturally occurring somatic mutations, intentional substitutions in the framework or antigen binding site, and substitutions introduced during cloning or VDJ recombination in non-human animals. Typically, a human antibody is at least 80% identical in amino acid sequence to an amino acid sequence encoded by a human germline or rearranged immunoglobulin gene. 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, a human antibody may contain consensusframework sequences derived from human framework sequence analyses (see, e.g., Knappik et al., J. Mol. Biol. 296:57-86 (2000)), or synthetic HCDR3 incorporated into human immune- globulin gene libraries displayed on phage (see, e.g., Shi et al., J. Mol. Biol. 397:385-96 (2010) and Int. Pat. Publ. No. W02009 / 085462).

[0060] “Bispecific” refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific antibody may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.

[0061] “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 specifically binding EGFR and c-Met are typically VH / V pairs, and the bispecific anti-EGFR / c-Met antibody is monovalent in terms of binding to EGFR and c-Met.

[0062] ‘Isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides, polypeptides vectors or viruses) which have been substantially separated and / or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step. “Isolated” refers to a molecule that is substantially free of other cellular material and / or chemicals and encompasses molecules that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

[0063] Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (X), based on the amino acid sequences of their constant domains.

[0064] ‘Low fucose” or “low fucose content” as used in the application refers to antibodies with fucose content of about between 1%-15%.

[0065] ‘Normal fucose” or ‘normal fucose content” as used herein refers to antibodies with fucose content of about over 50%, typically about over 80% or over 85%.

[0066] ‘Recombinant” refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.

[0067] Carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the antibody of the invention is administered. Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as 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 increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives. Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in e.g., Remington: The Science and Practice of Pharmacy, 21stEdition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, See especially pp. 958-989.

[0068] “Dosage” refers to the information of the amount of the therapeutic or the drug to be taken by the subject and the frequency of the number of times the therapeutic is to be taken by the subject. “Dose” refers to the amount or quantity of the therapeutic or the drug to be taken each time.

[0069] “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.

[0070] Co-administration,” “administration with,” “administration in combination with,” “in combination with,” or the like, encompass administration of the selected therapeutics or drugs to a single patient, and are intended to include treatment regimens in which the therapeutics or drugs are administered by the same or different route of administration or at the same or different time.

[0071] ‘Fixed combination” refers to a single pharmaceutical composition comprising two or more compounds.

[0072] ‘Non-fixed combination” refers to separate pharmaceutical compositions, wherein each comprises at least one compound. The at least one compound or unit dosage forms can be administered as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the subject.

[0073] “Antagonist” or “inhibitor” refers to a molecule that, when bound to a cellular protein, suppresses at least one reaction or activity that is induced by a natural ligand of the protein. A molecule is an antagonist when the at least one reaction or activity is suppressed 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 reaction or activity suppressed in the absence of the antagonist (e.g., negative control), or when the suppression is statistically significant when compared to the suppression in the absence of the antagonist.

[0074] Treat”, “treating” or “treatment” of a disease or disorder such as cancer refers to accomplishing at least one of the following: reducing the severity and / or duration of the disorder, inhibiting worsening of symptoms characteristic of the disorder being treated, limiting or preventing recurrence of the disorder in subjects that have previously had the disorder, or limiting or preventing recurrence of symptoms in subjects that were previously symptomatic for the disorder.

[0075] ‘Prevent,” “preventing,” “prevention,” or “prophylaxis” of a disease or disorder means preventing that a disorder occurs in subject.

[0076] “Responsive,” “responsiveness,” or “likely to respond” refers to any kind of improvement or positive response, such as alleviation or amelioration of at least one symptom, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.

[0077] “Subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. The terms “subject” and “patient” are used interchangeably herein.

[0078] Cancer” refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread) to other areas of a patient’s body.

[0079] ‘EGFR or c-Met expressing cancer” refers to cancer that has detectable expression of EGFR or c-Met or has EGFR or c-Met mutation or amplification. EGFR or c-Met expression,amplification and mutation status can be detected using know methods, such as sequencing, next generation sequencing, fluorescent in situ hybridization, immunohistochemistry, flow cytometry or western blotting.

[0080] “Epidermal growth factor receptor” or “EGFR” refers to the human EGFR (also known as HER1 or ErbBl (Ullrich et al., Nature 309:418-425, 1984) having the amino acid sequence shown in GenBank accession number NP 005219, as well as naturally- occurring variants thereof.

[0081] “Hepatocyte growth factor receptor” or “c-Mef ’ as used herein refers to the human c-Met having the amino acid sequence shown in GenBank Accession No: NP_001120972 and natural variants thereof.

[0082] “Newly diagnosed” refers to a subject who has been diagnosed with EGFR or c-Met expressing cancer but has not yet received treatment for CRC ( .g., mCRC).

[0083] “Refractory” refers to a disease that does not respond to a treatment. A refractory disease can be resistant to a treatment before or at the beginning of the treatment, or a refractory disease can become resistant during a treatment.

[0084] “Relapsed” refers to the return of a disease or the signs and symptoms of a disease after a period of improvement after prior treatment with a therapeutic.

[0085] “Diagnosing” or “diagnosis” refers to methods to determine if a subject is suffering from 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 prior diagnosed disease or condition, i.e., stratifying a patient population on likelihood to respond to treatment. Diagnosis is typically performed by a physician based on the general guidelines for the disease to be diagnosed or other criteria that indicate a subject is likely to respond to a particular treatment.

[0086] “Biological sample” refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present within a subject. Exemplary samples are biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cystic fluid, tear drops, feces, sputum, mucosal secretions of the secretory tissues and organs, vaginal secretions, ascites fluids, fluids of the pleural, pericardial, peritoneal, abdominal and other body cavities, fluids collected by bronchial lavage, synovial fluid, liquid solutions contacted with a subject or biological source, for example, cell and organ culture medium including cell or organ conditioned medium, lavage fluids and the like, tissue biopsies, tumor tissue biopsies, tumor tissue samples, fine needle aspirations, surgically resected tissue, organ cultures or cell cultures.Methods of the Disclosure

[0087] In one aspect, the disclosure provides a method of reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, comprising: a) administering an antibiotic; b) administering a topical antiseptic; and c) administering a non- comedogenic moisturizer. In some embodiments, the disclosure provides a method of reducing occurrence of DAEs in a subject treated with an EGFR tyrosine kinase inhibitor (TKI), comprising: a) administering an antibiotic; b) administering a topical antiseptic; and c) administering a non-comedogenic moisturizer. In some embodiments, the disclosure provides a method of reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject treated with an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody and an EGFR TKI, comprising: a) administering an antibiotic; b) administering a topical antiseptic; and c) administering a non-comedogenic moisturizer.

[0088] In one aspect, the disclosure provides a method of reducing occurrence and / or severity of dermatologic adverse events (DAEs) in a subject comprising administering to the subject a prophylactic treatment. In some embodiments, the DAE is a DAE of interest (DAEI). In some embodiments, the disclosure provides a method of reducing occurrence and / or severity of DAEs in a subject treated with an anti-EGFR / c-Met antibody, comprising administering to the subject a prophylactic treatment. In some embodiments, the method comprises administering to the subject: a) an antibiotic; b) a non-comedogenic moisturizer; and c) a zinc salt. In some embodiments, the disclosure provides a method of reducing occurrence or severity of DAEs in a subject treated with an anti-EGFR / c-Met antibody and an anti-cancer therapy, comprising administering to the subject: a) an antibiotic; b) a non-comedogenic moisturizer; and c) a zinc salt.

[0089] In one aspect, the disclosure provides a method of reducing the severity of a DAE in a subject, comprising administering to the subject an early intervention once a DAE has been identified. In some embodiments, the disclosure provides a method of reducing the severity of a DAE in a subject treated with an anti-EGFR / c-Met antibody comprising administering to the subject : a) a beta blocker and a topical corticosteroid if the DAE is a scalp DAE; b) a topical antiseptic with or without a beta blocker when the DAE is paronychia; c) a topical steroid if the DAE is a body DAE; and / or d) a topical steroid with or without an immunosuppressant. In one aspect, the disclosure provides a method of reducing the severity of a DAE in a subject treated with an anti-EGFR / c-Met antibody and an anti-cancer therapy, comprising administering to the subject: a) a beta blocker and a topical corticosteroid if the DAE is a scalp DAE; b) a topicalantiseptic with or without a beta blocker when the DAE is paronychia; c) a topical steroid if the DAE is a body DAE; and / or d) to a topical steroid with or without an immunosuppressant.

[0090] In one aspect, the disclosure provides a method of reducing occurrence and / or severity of dermatologic adverse events of interest (DAEs) in a subject comprising administering to the subject a prophylactic treatment and an early intervention once a DAE has been detected. In some embodiments, the disclosure provides a method of reducing occurrence and / or severity of DAEs in a subject treated with an anti-EGFR / c-Met antibody, comprising i) administering to the subject: a) an antibiotic; b) a non-comedogenic moisturizer; and c) a zinc salt; and ii) when a DAE occurs, administering to the subject: a) a beta blocker and a topical corticosteroid if the DAE is a scalp DAE; b) a topical antiseptic with or without a beta blocker when the DAE is paronychia; c) a topical steroid if the DAE is a body DAE; and / or d) to a topical steroid with or without an immunosuppressant. In one aspect, the disclosure provides a method of reducing occurrence and / or severity of DAEs in a subject treated with an anti-EGFR / c-Met antibody and an anti-cancer therapy, comprising i) administering to the subject: a) an antibiotic; b) a non- comedogenic moisturizer; and c) a zinc salt; and ii) when a DAE occurs, administering to the subject: a) a beta blocker and a topical corticosteroid if the DAE is a scalp DAE; b) a topical antiseptic with or without a beta blocker when the DAE is paronychia; c) a topical steroid if the DAE is a body DAE; and / or d) to a topical steroid with or without an immunosuppressant.

[0091] An adverse reaction or adverse event (AE) is any untoward medical occurrence in a patient or a subject to whom EGFR / c-Met bispecific antibody and EGFR tyrosine kinase inhibitor are being administered or were administered. In some embodiments, the AE is a DAE. In some embodiments, the DAEs are selected from the group consisting of rash, dermatitis acneiform, pruritus, skin fissures, acne, folliculitis, erythema, eczema, rash maculo-papular, skin exfoliation, skin lesion, skin irritation, dermatitis, rash erythematous, rash macular, rash popular, rash pruritic, rash pustular, dermatitis contact, dermatitis exfoliative generalized, drug eruption, dyshidrotic eczema, eczema asteatotic, and paronychia.

[0092] In some embodiments, the severity of a DAE is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. 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 related to adverse event. In some embodiments, the severity of a DAE is graded according to the Skindex-16 questionnaire. In some embodiments, the severity of a DAE is graded based on the Patient’s Global Impression-Severity (PGI-S). In some embodiments, the severity of a DAE is gradedbased on the Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Core 30 (EORTC-QLC-C30) Score.

[0093] In some embodiments, the presence of DAEs in a patient or subject is evaluated at any time starting after initiating administration of the EGFR / c-Met bispecific antibody and EGFR tyrosine kinase inhibitor up to 12 weeks after initiating administration. In some embodiments, the presence of DAEs in a patient or subject is evaluated at any time starting after initiating administration of the EGFR / c-Met bispecific antibody and EGFR tyrosine kinase inhibitor up to six months after initiating administration. In some embodiments, the presence of DAEs in a patient or subject is evaluated at any time starting after initiating administration of the EGFR / c-Met bispecific antibody and EGFR tyrosine kinase inhibitor up to 12 months after initiating administration.Anti-EGFR / c-Met Antibodies

[0094] In some embodiments, the anti-EGFR / c-Met antibody is a bispecific antibody. In certain embodiments, the antibody is an isolated antibody. In some embodiments, the antibody is an isolated bispecific antibody.

[0095] In some embodiments, the antibody (e.g., bispecific antibody) comprises a first domain that specifically binds EGFR and a second domain that specifically binds c-Met.EGFR Binding Arm

[0096] In some embodiments, the first domain that specifically binds EGFR comprises: a) heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3 amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; and / or b) light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:4, 5 and 6, respectively.

[0097] In certain embodiments, the first domain that specifically binds EGFR comprises: a) HCDR1, HCDR2, HCDR3 amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; and b) LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively.HCDR1: TYGMH (SEQ ID NO:1)HCDR2: VIWDDGSYKYYGDSVKG (SEQ ID NO:2)HCDR3: DGITMVRGVMKDYFDY (SEQ ID NO: 3)LCDR1 : RASQDISSALV (SEQ ID N0:4)LCDR2: DASSLES (SEQ ID NO: 5)LCDR3: QQFNSYPLT (SEQ ID NO: 6)

[0098] 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 some embodiments, the first domain comprises a VH of SEQ ID NO: 13.

[0099] 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 some embodiments, the first domain comprises a VL of SEQ ID NO: 14.

[0100] As used herein, the term “identical” or “has sequence identity,” refers to the extent to which two amino acid sequences have the same residues at the same positions when the sequences are aligned to achieve a maximal level of identity, expressed as a percentage. For sequence alignment and comparison, typically one sequence is designated as a reference sequence, to which a test sequences are compared. The sequence identity between reference and test sequences is expressed as the percentage of positions across the entire length of the reference sequence where the reference and test sequences share the same amino acid upon alignment of the reference and test sequences to achieve a maximal level of identity. As an example, two sequences are considered to have 70% sequence identity when, upon alignment to achieve a maximal level of identity, the test sequence has the same amino acid residue at 70% of the same positions over the entire length of the reference sequence.

[0101] 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.

[0102] 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.

[0103] In some embodiments, the first domain comprises: a) a VH of SEQ ID NO: 13; and / or b) a VL of SEQ ID NO: 14.

[0104] In some embodiments, the first domain comprises: a) a VH of SEQ ID NO: 13; and b) a VL of SEQ ID NO: 14.VH: QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDD GSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDY FDYWGQGTLVTVSS (SEQ ID NO: 13)VL: AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGV PSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK (SEQ ID NO: 14)

[0105] 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 some embodiments, the first domain comprises a HC1 amino acid sequence of SEQ ID NO: 17.

[0106] 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 some embodiments, the first domain comprises a LC1 amino acid sequence of SEQ ID NO: 18.

[0107] In some embodiments, the first domain comprises:a) a HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17; and / or b) a LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18.

[0108] In some embodiments, the first domain comprises: a) a HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17; and b) a LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18.

[0109] In some embodiments, the first domain comprises: a) a HC1 of SEQ ID NO: 17; and / or b) a LC1 of SEQ ID NO: 18.

[0110] In some embodiments, the first domain comprises: a) a HC1 of SEQ ID NO: 17; and b) a LC1 of SEQ ID NO: 18.HC1 : QVQLVESGGGWQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWD DGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKD YFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSG ALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDI<THTCPPCPAPELLGGPSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVD GVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CI<VSNI<ALPAPIEI<TISI< AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 17)LC1 : AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESG VPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFP PSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSST LTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 18) c-Met binding arm

[0111] In certain embodiments, the second domain that specifically binds c-Met comprises: a) HCDR1, HCDR2, HCDR3 amino acid sequences of SEQ ID NOs:7, 8 and 9, respectively; and / or b) LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs: 10, 11 and 12, respectively.

[0112] In certain embodiments, the second domain that specifically binds c-Met comprises: a) HCDR1, HCDR2, HCDR3 amino acid sequences of SEQ ID NOs:7, 8 and 9, respectively; and b) LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs: 10, 11 and 12, respectively.HCDR1: SYGIS (SEQ ID NO:7)HCDR2: WISAYNGYTNYAQKLQG (SEQ ID NO: 8)HCDR3: DLRGTNYFDY (SEQ ID NO: 9)LCDR1 : RASQGISNWLA (SEQ ID NO: 10)LCDR2: AASSLLS (SEQ ID NO: 11)LCDR3: QQANSFPIT (SEQ ID NO: 12)

[0113] 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 some embodiments, the second domain comprises a VH of SEQ ID NO: 15

[0114] 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 some embodiments, the second domain comprises a VL of SEQ ID NO: 16.

[0115] In some embodiments, the second domain comprises: 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.

[0116] In some embodiments, the second domain comprises: 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.

[0117] In some embodiments, the second domain comprises: a) a VH of SEQ ID NO: 15; and / orb) a VL of SEQ ID NO: 16.

[0118] In some embodiments, the second domain comprises: a) a VH of SEQ ID NO: 15; and b) a VL of SEQ ID NO: 16.VH: QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAY NGYTNYAQKLQGRVTMTTDTS TS TAYMELRSLRSDDTAVYYCARDLRGTNYFD YWGQ GTLVTVSS (SEQ ID NO: 15)VL: DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK (SEQ ID NO: 16)

[0119] 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 some embodiments, the second domain comprises a HC2 amino acid sequence of SEQ ID NO: 19.

[0120] 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 some embodiments, the second domain comprises a LC2 amino acid sequence of SEQ ID NO: 20.

[0121] In some embodiments, the second domain comprises: a) a HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19; and / or b) a LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0122] In some embodiments, the second domain comprises: a) a HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19; andb) a LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0123] In some embodiments, the second domain comprises: a) a HC2 of SEQ ID NO: 19; and / or b) a LC2 of SEQ ID NO:20.

[0124] In some embodiments, the second domain comprises: a) a HC2 of SEQ ID NO: 19; and b) a LC2 of SEQ ID NO:20.HC2: QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAY NGYTNYAQKLQGRVTMTTDTS TS TAYMELRSLRSDDTAVYYCARDLRGTNYFD YWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI< TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CT<VSNI<ALPAPIEI<TISI<AI<GQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 19)LC2: DIQMTQSPS S VS AS VGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAAS SLLS GVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIF PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSS TLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20)

[0125] In some embodiments, the antibody (e.g., bispecific antibody) comprises: a) a first domain that specifically binds EGFR, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:l, 2, 3, 4, 5 and 6, respectively; and / or b) a second domain that specifically binds c-Met, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:7, 8, 9, 10, 11 and 12, respectively.

[0126] In certain embodiments, the antibody (e.g., bispecific antibody) comprises: a) a first domain that specifically binds EGFR, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:l, 2, 3, 4, 5 and 6, respectively; andb) a second domain that specifically binds c-Met, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:7, 8, 9, 10, 11 and 12, respectively.

[0127] In some embodiments, the antibody (e.g., bispecific antibody) comprises: 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.

[0128] In certain embodiments, the antibody (e.g., bispecific antibody) comprises: 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.

[0129] In some embodiments, the antibody (e.g., bispecific antibody) comprises: 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 a VL of SEQ ID NO: 16.

[0130] In some embodiments, the antibody (e.g., bispecific antibody) comprises: 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 a VL of SEQ ID NO: 16.

[0131] In certain embodiments, the antibody (e.g., bispecific antibody) comprises: a) a HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17;b) a LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18; c) a HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19; and / or d) a LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0132] In certain embodiments, the antibody (e.g., bispecific antibody) comprises: a) a HC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 17; b) a LC1 amino acid sequence that is at least 80% identical to SEQ ID NO: 18; c) a HC2 amino acid sequence that is at least 80% identical to SEQ ID NO: 19; and d) a LC2 amino acid sequence that is at least 80% identical to SEQ ID NO:20.

[0133] In certain embodiments, the antibody (e.g., bispecific antibody) comprises: a) a HC1 of SEQ ID NO: 17; b) a LC1 of SEQ ID NO: 18; c) a HC2 of SEQ ID NO: 19; and / or d) a LC2 of SEQ ID NO:20.

[0134] In some embodiments, the antibody (e.g., bispecific antibody) comprises: a) a HC1 of SEQ ID NO: 17; b) a LC1 of SEQ ID NO: 18; c) a HC2 of SEQ ID NO: 19; and d) a LC2 of SEQ ID NO:20.

[0135] 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 IgGl isotype. Some variation exists within the IgGl constant domain (e.g., well-known allotypes), for example, with variation at positions 214, 356, 358, 422, 431, 435 and / or 436 (residue numbering according to the 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 IgGl allotype, such as Glml7, Glm3, Glml, Glm2, Glm27 or Glm28.

[0136] In some embodiments, the antibody is a human antibody.

[0137] In some embodiments, the antibody is amivantamab. Amivantamab is an IgGl anti-EGFR / c-Met bispecific antibody described in U.S. Pat. No. 9,593,164.

[0138] Other anti-EGFR / c-Met antibodies (e.g, bispecific antibodies) may also be used in the methods of the disclosure, for example, by combining publicly available EGFR binding VH / VE domains and c-Met binding VH / VE domains.

[0139] In some embodiments, the antibody (e.g., bispecific antibody) comprises a biantennary glycan structure with a fucose content of between about 1% to about 15% or less than about 20%.

[0140] Antibodies with reduced fucose content can be made using different methods reported to lead to the successful expression of relatively high defucosylated antibodies bearing the biantennary complex- type of Fc oligosaccharides such as control of culture osmolality (Konno et al., Cytotechnology 64(:249-65, 2012), application of a variant CHO line Led 3 as the host cell line (Shields etal., J Biol Chem 277:26733-26740, 2002), application of a variant CHO line EB66 as the host cell line (Olivier et al., MAbs ;2(4), 2010; Epub ahead of print;PMID:20562582), application of a rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introduction of small interfering RNA specifically against the a 1,6-fucosyltrasferase ( FUT8) gene (Mori et al., Biotechnol Bioeng88:901-908, 2004), or co-expression of 0- 1 , 4- A-acetylglucosaminy I transferase III and Golgi a-mannosidase II or a potent alpha-mannosidase I inhibitor, kifunensine (Ferrara et al., J Biol Chem281:5032- 5036, 2006, Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Zhou etal., Biotechnol Bioeng 99:652-65, 2008). In general, lowering fucose content in the glycan of the antibodies potentiates antibody-mediated cellular cytotoxicity (ADCC).Generating Anti-EGFR / c-Met Antibodies

[0141] Anti-EGFR / c-Met antibodies used in the methods of the disclosure may be generated, for example, using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 interface in each half molecule to favor heterodimer formation of two antibody half molecules having distinct specificity either in vitro in cell-free environment or using co-expression. The Fab arm exchange reaction is the result of a disulfide-bond isomerization reaction and dissociation-association of CH3 domains. The heavy chain disulfide bonds in the hinge regions of the parental monospecific antibodies are reduced. The resulting free cysteines of one of the parental monospecific antibodies form an inter heavy-chain disulfide bond with cysteine residues of a second parental monospecific antibody molecule and simultaneously CH3 domains of the parental antibodies release and reform by dissociation-association. The CH3 domains of the Fab arms may be engineered to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody having two Fab arms or half molecules which each bind a distinct epitope, i.e., an epitope on EGFR and an epitope on c-Met. For example, the bispecific antibodies of theinvention may be generated using the technology described in Int. Pat. Publ. No.WO2011 / 131746. Mutations F405L in one heavy chain and K409R in the other heavy chain may be used in case of IgGl antibodies. For IgG2 antibodies, a wild-type IgG2 and a IgG2 antibody with F405L and R409K substitutions may be used. For IgG4 antibodies, a wild-type IgG4 and a IgG4 antibody with F405L and R409K substitutions may be used. To generate bispecific antibodies, first monospecific bivalent antibody and the second monospecific bivalent antibody are engineered to have the aforementioned mutation in the Fc region, the antibodies are incubated together under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide bond isomerization; thereby generating the bispecific antibody by Fab arm exchange. The incubation conditions may optimally be restored to non-reducing. 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 betamercaptoethanol. For example, incubation for at least 90 min 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 from 5-8, for example at pH of 7.0 or at pH of 7.4 may be used.

[0142] Bispecific anti-EGFR / c-Met antibodies used in the methods of the disclosure may also be generated using designs such as the Knob-in-Hole (Genentech), CrossMAbs (Roche) and the electrostatically-matched (Chugai, Amgen, NovoNordisk, Oncomed), the LUZ-Y (Genentech), the Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), and the Biclonic (Merus).

[0143] In the “knob-in-hole” strategy (see, e.g., Inti. Publ. No. WO 2006 / 028936) select amino acids forming the interface of the CH3 domains in human IgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen. After co-expression of the two antibodies, a heterodimer is formed as a result of the preferential interaction of the heavy chain with a “hole” with the heavy chain with a “knob”. Exemplary CH3 substitution pairs forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V.

[0144] CrossMAb technology, in addition to utilizing the “knob-in-hole” strategy to promoter Fab arm exchange utilizes CHI / CL domain swaps in one half arm to ensure correct light chain pairing of the resulting bispecific antibody (see e.g., U.S. Patent No. 8,242,247).

[0145] Other cross-over strategies may be used to generate full length bispecific antibodies of the invention by exchanging variable or constant, or both domains between the heavy chain and the light chain or within the heavy chain in the bispecific antibodies, either in one or both arms. These exchanges include for example VH-CH1 with VL-CL, VH with VL, CH3 with CL and CH3 with CHI as described in Int. Patent Publ. Nos. W02009 / 080254, W02009 / 080251, W02009 / 018386 and W02009 / 080252.

[0146] Other strategies such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues at one CH3 surface and negatively charged residues at a second CH3 surface may be used, as described in US Patent Publ. No. US2010 / 0015133; US Patent Publ. No. US2009 / 0182127; US Patent Publ. No. US2010 / 028637 or US Patent Publ. No. US2011 / 0123532. In other strategies, heterodimerization may be promoted by following substitutions (expressed as modified positions in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): L351 Y_F405 A_Y407 V / T394W, T366I_K392M_T394W / F405 A_Y407 V, T366L K392M_T394W / F405 A_Y407V, L351 Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W as described in U.S. Patent Publ. No. US2012 / 0149876 or U.S. Patent Publ. No. US2013 / 0195849.

[0147] SEEDbody technology may be utilized to generate bispecific antibodies of the invention. SEEDbodies have, in their constant domains, select IgG residues substituted with IgA residues to promote heterodimerization as described in U.S. Patent No. US20070287170.

[0148] Mutations are typically made at the DNA level to a molecule such as the constant domain of the antibody using standard methods.Administration

[0149] The anti-EGFR / c-Met antibody (e.g., bispecific antibody) may be administered in a pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0150] In some embodiments, the pharmaceutical composition comprising the anti-EGFR / c- Met antibody (e.g., bispecific antibody) is administered via an intravenous infusion.

[0151] In some embodiments, the pharmaceutical composition comprising the anti-EGFR / c- Met antibody is administered subcutaneously (SC).

[0152] In some embodiments, the antibody is administered at a dose of about 350 mg to about 4,640 mg. In some embodiments, the antibody is administered at a dose of about 350 mg, about 700 mg, 1,050 mg, about 1,400 mg, about 1,600 mg, about 1,750 mg, about 2,100 mg, about 2,240 mg, about 2,400 mg, about 3,360 mg, about 3,520 mg, or about 4,640 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 350 mg. In certain embodiments, the antibody is administered at a dose of about 700 mg. In certain embodiments, the antibody is administered at a dose of about 1,400 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 1,750 mg. In some embodiments, the antibody is administered at a dose of about 2,100 mg. In some embodiments, the antibody is administered at a dose of about 2,240 mg. In some embodiments, the antibody is administered at a dose of about 2,400 mg. In some embodiments, the antibody is administered at a dose of about 3,360 mg. In some embodiments, the antibody is administered at a dose of about 3,520 mg. In some embodiments, the antibody is administered at a dose of about 4,640 mg.

[0153] In some embodiments, the antibody is administered at a dose of about 350 mg.

[0154] In some embodiments, the antibody is administered at a dose of about 700 mg.

[0155] In some embodiments, the antibody is administered at a dose of about 750 mg.

[0156] In some embodiments, the antibody is administered at a dose of about 800 mg.

[0157] In some embodiments, the antibody is administered at a dose of about 850 mg.

[0158] In some embodiments, the antibody is administered at a dose of about 900 mg.

[0159] In some embodiments, the antibody is administered at a dose of about 950 mg.

[0160] In some embodiments, the antibody is administered at a dose of about 1,000 mg.

[0161] In some embodiments, the antibody is administered at a dose of about 1,100 mg.

[0162] In some embodiments, the antibody is administered at a dose of about 1,150 mg.

[0163] In some embodiments, the antibody is administered at a dose of about 1,200 mg.

[0164] In some embodiments, the antibody is administered at a dose of about 1,250 mg.

[0165] In some embodiments, the antibody is administered at a dose of about 1,300 mg.

[0166] In some embodiments, the antibody is administered at a dose of about 1,350 mg.

[0167] In some embodiments, the antibody is administered at a dose of about 1,400 mg.

[0168] In some embodiments, the antibody is administered at a dose of about 1,500 mg.

[0169] In some embodiments, the antibody is administered at a dose of about 1,600 mg.

[0170] In some embodiments, the antibody is administered at a dose of about 1,700 mg.

[0171] In some embodiments, the antibody is administered at a dose of about 1,800 mg.

[0172] In some embodiments, the antibody is administered at a dose of about 1,900 mg.

[0173] In some embodiments, the antibody is administered at a dose of about 2,000 mg.

[0174] In some embodiments, the antibody is administered at a dose of about 2,100 mg.

[0175] In some embodiments, the antibody is administered at a dose of about 2,200 mg.

[0176] In some embodiments, the antibody is administered at a dose of about 2,240 mg.

[0177] In some embodiments, the antibody is administered at a dose of about 2,300 mg.

[0178] In some embodiments, the antibody is administered at a dose of about 2,500 mg.

[0179] In some embodiments, the antibody is administered at a dose of about 2,750 mg.

[0180] In some embodiments, the antibody is administered at a dose of about 3,000 mg.

[0181] In some embodiments, the antibody is administered at a dose of about 3,250 mg.

[0182] In some embodiments, the antibody is administered at a dose of about 3,500 mg.

[0183] In some embodiments, the antibody is administered at a dose of about 3,520 mg.

[0184] In some embodiments, the antibody is administered at a dose of about 3,750 mg.

[0185] In some embodiments, the antibody is administered at a dose of about 4,000 mg.

[0186] In some embodiments, the antibody is administered at a dose of about 4,250 mg.

[0187] In some embodiments, the antibody is administered at a dose of about 4,500 mg.

[0188] In some embodiments, the antibody is administered at a dose of about 4,640 mg.

[0189] In certain embodiments, the antibody is administered at a dose of 1,050 mg for body weight <80 kg and 1,400 mg for body weight > 80 kg.

[0190] In certain embodiments, the antibody is administered at a dose of 1,400 mg for body weight <80 kg and 1,750 mg for body weight > 80 kg.

[0191] In certain embodiments, the antibody is administered at a dose of 1,600 mg for body weight <80 kg and 2,240 mg for body weight > 80 kg.

[0192] In certain embodiments, the antibody is administered at a dose of 1,750 mg for body weight <80 kg and 2,100 mg for body weight > 80 kg.

[0193] In certain embodiments, the antibody is administered at a dose of 3,520 mg for body weight <80 kg and 4,640 mg for body weight > 80 kg.

[0194] In some embodiments, the antibody is administered twice a week.

[0195] In certain embodiments, the antibody is administered once a week.

[0196] In some embodiments, the antibody is administered once every two weeks.

[0197] In certain embodiments, the antibody is administered once every three weeks.

[0198] In some embodiments, the antibody is administered once every four weeks.

[0199] In certain embodiments, the antibody is administered once a week or once every two weeks. In some embodiments, the antibody is administered once weekly for the first 4 weeks and then every 2 weeks (e.g., Weeks 1, 2, 3, 4, 5, 7, 9, 11, etc.). In some embodiments the antibody is administered once weekly for four weeks and then every 4 weeks (e.g., Weeks 1, 2, 3, 4, 5, 9, 13, etc.). In some embodiments the antibody is administered once weekly for four weeks, not administered for two weeks, and then administered every 3 weeks (e.g., Weeks 1, 2, 3, 4, 7, 10, 13, etc.).

[0200] In some embodiments, the antibody is administered on a 28-day cycle.

[0201] In some embodiments, the antibody is administered on a 21 -day cycle.

[0202] In some embodiments, the first dose is administered over two days (e.g., Week 1, Day1 and Week 1, Day 2). In some embodiments, the first dose is administered over two days, and all subsequent doses are administered on a single day (e.g., Dose 1 : Week 1, Day 1 and Week 1, Day 2; Dose 2: Week 2, Day 1; Dose 3: Week 3, Day 1, etc.).

[0203] In some embodiments, the subject has a body weight of <80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 1,050 mg once weekly for the first 4 weeks and then every 2 weeks on a 28-day cycle (e.g., 1,050 mg on Weeks 1, 2, 3, 4, 5, 7, 9, 11, etc.). In other embodiments, the subject has a body weight of <80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 1,600 mg once weekly for the first 4 weeks and then at a dose of 3,530 mg once every 4 weeks on a 28- day cycle (e.g., 1,600 mg on Weeks 1, 2, 3, and 4 then 3,530 mg on Weeks 5, 9, 13, etc.). In some embodiments, the subject has a body weight of <80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of about 1 ,400 mg once weekly for the first 4 weeks, not administered for two weeks, and then at a dose of 1,750 mg once every 3 weeks on a 21-day cycle (e.g., 1,400 mg on Weeks 1, 2, 3, and 4 then 1,750 mg on Weeks 7, 10, 13, etc.).

[0204] In certain embodiments, the subject has a body weight of >80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 1,400 mg once weekly for the first 4 weeks and then every 2 weeks on a 28-day cycle (e.g., 1,400 mg on Weeks 1, 2, 3, 4, 5, 7, 9, 11, etc.). In other embodiments, the subject has a body weight of >80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 2,240 mg once weekly for the first 4 weeks and then at a dose of 4,640 mg every 4 weeks on a 28-daycycle (e.g., 2,240 mg on Weeks 1, 2, 3, and 4 then 4,640 mg on Weeks 5, 9, 13, etc.). In some embodiments, the subject has a body weight of >80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 1,750 mg once weekly for the first 4 weeks, not administered for two weeks, and then at a dose of 2,100 mg once every 3 weeks on a 21-day cycle (e.g., 1,750 mg on Weeks 1, 2, 3, and 4 then 2,100 mg on Weeks 7, 10, 13, etc.).

[0205] Pharmaceutical compositions comprising 4,460 mg, 3,520 mg, 3,360 mg, 2,400 mg, 2240 mg, 2,100 mg, 1,750 mg, 1,600 mg, 1,400 mg, 1,050 mg, and 700 mg dose of the anti- EGFR / c-Met antibody can be administered in total volumes of about 28 mL, 21 mL and 14 mL, respectively, with 350 mg / 7 mL (50 mg / mL) solution in a single-dose vial. Pharmaceutical compositions comprising 4,640 mg, 3,520 mg, 3,360 mg, 2,400 mg, 2,240 mg, 2,100 mg, 1,750 mg, 1,600 mg dose of the anti-EGFR / c-Met antibody can be administered in total volumes of about 29 mL, 22 mL, 14 mL, and 10 mL, respectively, with 160 mg / mL solution in a single-dose or multi-dose vial.

[0206] Additional information regarding amivantamab can be found, for example, in the prescribing information product insert for RYBREVANT® (amivantamab-vmjw) (www. janssenlabels. com / package- insert / product- monograph / prescribing- information / RYBREVANT- pi. pdf), which is incorporated herein by reference.

[0207] In some embodiments, the antibody is administered as a monotherapy. In some embodiments, the antibody is administered as a non-fixed dose or fixed co-therapy.

[0208] In some embodiments, amivantamab is administered based on body weight. In some embodiments, amivantamab is administered intravenously or subcutaneously. In some embodiments, amivantamab is administered subcutaneously as a co-formulation with recombinant human hyaluronidase. In some embodiments, amivantamab is administered subcutaneously as a co-formulation with the recombinant human hyaluronidase rHuPH20. In some embodiments, amivantamab is administered Q2W, Q3W, or Q4W, or an equivalent thereof. In some embodiments, amivantamab is administered according to a following dose and schedule: intravenous Q2W:intravenous Q3W:subcutaneous Q2W dosing regimen is 1,600 mg (2,240 mg if BW >80 kg) on Cycle 1 Days 1, 8, 15, and 22 then on Days 1 and 15 of each 28-day cycle starting at Cycle 2; subcutaneous Q3W dosing regimen is 1,600 mg (2,240 mg if BW >80 kg) on Cycle 1 Day 1, 2,400 mg (3,360 mg if BW >80 kg) on Cycle 1 Days 8 and 15 and then on Day 1 of each subsequent 21 -day cycle starting at Cycle 2; or subcutaneous Q4W dosing regimen is 1,600 mg (2,240 mg if BW >80 kg) on Cycle 1 Days 1, 8, 15, and 22 then 3,520 mg (4,640 mg if BW >80 kg) on Day 1 of each subsequent 28-day cycle starting at Cycle 2.Additional Therapies

[0209] In certain embodiments, the method further comprises administering to the subject one or more additional anti-cancer therapies. Non-limiting examples of the one or moreadditional therapeutic agents include a T cell expressing chimeric antigen receptor (CAR) (CAR- T cell), a natural killer cell expressing CAR (CAR-NK cell), a macrophage expressing CAR (CAR-M cell), a chemotherapeutic agent, an immune checkpoint inhibitor, a T-cell redirector, radiation therapy, surgery and a standard of care drug. In certain embodiments, the one or more additional therapeutic agents comprises chemotherapy, radiation therapy, surgery, a targeted anti-cancer therapy, a kinase inhibitor, or a combination thereof.

[0210] In some embodiments, the anti-EGFR / c-Met antibody (e.g., bispecific antibody) and the one or more additional anti-cancer therapies (e.g., chemotherapeutic agents) are administered simultaneously. In other embodiments, the antibody and the one or more additional anti-cancer therapies are administered separately (e.g., sequentially).

[0211] For combination therapies, the one or more anti-cancer therapies may be administered using recommended doses and dosages of the anti-cancer therapy.Chemotherapies

[0212] In some embodiments, the one or more additional therapeutic agents comprise one or more chemotherapeutic agents.

[0213] A non- exhaustive list of chemotherapeutic agents considered for use in combination therapies include pemetrexed (Alimta®), anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), leucovorin calcium, melphalan (Alkeran®), 6-mer captopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), 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 (D TIC-Dome®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride forinjection (Hy camptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0214] Example alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Haemanthamine®, Nordopan®, Uracil Nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), tri ethylenemelamine (Hemel®, Hexylen®, Hexastat®), Demethyldopan®, Desmethyldopan®, triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine (DTIC-Dome®). Additional example alkylating agents include, without limitation, Oxaliplatin (Eloxatin®); Melphalan (also known as L-PAM, L- sarcolysin, and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexylen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Temozolomide (Temodar® and Temodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®-AQ);Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexylen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HC1 (Treanda®).

[0215] Anti-cancer therapies that may be administered in combination with the anti-EGFR / c- Met antibody (e.g., bispecific antibody) in the methods of the disclosure include any one or more of the chemotherapeutic drugs or other anti-cancer therapeutics known to those of skill in the art. Chemotherapeutic agents are chemical compounds useful in the treatment of cancer and include growth inhibitory agents or other cytotoxic agents and include 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 cyclosphosphamide (CYTOXAN®); alkyl sulfonates suchas busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as 5-FU, pemetrexed, and methotrexate; 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; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2’, 2”-trichlorotri ethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; members of taxoid or taxane family, such as paclitaxel (TAXOL®docetaxel (TAXOTERE®) and analogues thereof; 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 inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; inhibitors of receptor tyrosine kinases and / or angiogenesis, including sorafenib (NEXAVAR® ), sunitinib (SUTENT® ), pazopanib (VOTRIENT™), toceranib(PALLADIA™), vandetamb (ZACTIMA™), cediramb (RECENTIN®), regorafemb (BAY 73- 4506), axitinib (AG013736), lestaurtinib (CEP-701), erlotinib (TARCEVA®), gefitinib (IRES SA®), afatmib (BIBW 2992), lapatmib (TYKERB®), neratmib (HKI-272), and the like, and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)- imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (FARESTON®); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Other conventional cytotoxic chemical compounds as those disclosed in Wiemann et al., 1985, in Medical Oncology (Calabresi et al, eds.), Chapter 10, McMillan Publishing, are also applicable to the methods of the present invention.

[0216] In some embodiments, the one or more chemotherapeutic agents comprise folinic acid (leucovorin, FOL), fluorouracil (5-FU, F) and oxaliplatin (Eloxatin, OX). FOLFOX, e.g., FOLFOX6, for example, mFOLFOX6, a chemotherapy regimen for treatment of colorectal cancer, is known to those skilled in the art. Additional information regarding FOLFOX can be found, for example, in de Gramont et al., J Clin Oncol. 18(16):2938-47 (2000), Tournigand et al., J Clin Oncol. 22(2):229-37 (2004), Goldberg et al., J Clin Oncol. 22(l):23-30 (2004), Tsai et al., Springerplus. 5(1): 1318 (2016), Neugut et al., Clin Colorectal Cancer 18(2): 133-40 (2019) and Sobrero et al., Journal of Clinical Oncology 36(15):1478-85 (2018), which are incorporated herein by reference.

[0217] In some embodiments, the one or more chemotherapeutic agents comprise FOLFOX. In some embodiments, FOLFOX comprises folinic acid, 5-fluorouracil, and oxaliplatin. In some embodiments, the oxaliplatin is administered at a dose of about 85 mg / m2In some embodiments, the leucovorin is a racemic mixture of L- and D-folinic acid (leucovorin). In some embodiments, the folinic acid is L-leucovorin (levoleucovorin). In some embodiments, the folinic acid is administered at a dose between 200 mg / m2and 400 mg / m2. In some embodiments, the folinic acid is leucovorin, and the leucovorin is administered at a dose of about 400 mg / m2. In some embodiments, the folinic acid is levoleucovorin, and the levoleucovorin is administered at a dose of about 200 mg / m2. In some embodiments, the fluorouracil is administered at a dose of about 2,800 mg / m2.

[0218] In certain embodiments, the one or more chemotherapeutic agents comprise folinic acid (leucovorin, FOL), fluorouracil (5-FU, F) and irinotecan (Camptosar, IRI). FOLFIRI, achemotherapy regimen for treatment of colorectal cancer, is known to those skilled in the art. Additional information regarding FOLFIRI can be found, for example, in Tournigand et al., J Clin Oncol. 22(2):229-37 (2004), Kamnerdsupaphon et al., J Med Assoc Thai. 90(10):2121-7 (2007), Kirstein et al., Oncologist 19(11 ): 1156-68 (2014), Chen et al., Medicine (Baltimore) 95(46): e5221 (2016), which are incorporated herein by reference.

[0219] In some embodiments the one or more chemotherapeutic agents comprise FOLFIRI. In some embodiments, FOLFIRI comprises folinic acid, fluorouracil, and irinotecan. In some embodiments, the irinotecan is administered at a dose of about 180 mg / m2. In some embodiments, the folinic acid is a racemic mixture of L- and D-folinic acid (leucovorin). In some embodiments, the folinic acid is L-folinic acid (levoleucovorin). In some embodiments, the folinic acid is administered at a dose between 200 mg / m2and 400 mg / m2. In some embodiments, the folinic acid leucovorin, and the leucovorin is administered at a dose of about 400 mg / m2. In some embodiments, the folinic acid is levoleucovorin, and the levoleucovorin is administered at a dose of about 200 mg / m2. In some embodiments, the fluorouracil is administered at a dose of about 2,800 mg / m2.

[0220] In some embodiments, the one or more chemotherapeutic agents (e.g., FOLFOX or FOLFIRI) are administered once every two weeks. In some embodiments, the one or more chemotherapeutic agents (e.g., FOLFOX or FOLFIRI) are administered on a 28-day cycle. In some embodiments, the one or more chemotherapeutic agents (e.g., FOLFOX or FOLFIRI) are administered on Days 1 and 15 of the Cycle.

[0221] In some embodiments, the one or more chemotherapeutic agents comprise carboplatin and pemetrexed. In some embodiments, the carboplatin is administered at a dose to achieve an area under the curve (AUC) of about 5 mg / mL / min. In some embodiments, the pemetrexed is administered at a dose of about 500 mg / m2. In some embodiments, the carboplatin and pemetrexed are administered once every three weeks. In some embodiments, The carboplatin is administered every three weeks until disease progression or unacceptable toxicity. In some embodiments, the carboplatin is administered every three weeks for up to 12 weeks.EGFR Tyrosine Kinase Inhibitors

[0222] In some embodiments, the subject is being treated with an EGFR tyrosine kinase inhibitor (TKI). Examples of EGFR TKIs include, but are not limited to,

[0223] In some embodiments, the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, dacomitinib, icotinib, nazartinib, osimertinib, lazertinib, aumolertinib,furmonertinib, simotinib, neratinib, almonertinib, olmutinib, mobocertinib, poziotinib, crizotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, sunitinib, pelitinib, AV-412, EXEL-7647, CO-1686, and AZD9291. In some embodiments, the EGFR TKI is lazertinib. In some embodiments, the EGFR TKI is osimertinib. In some embodiments, the TKI is mobocertinib.

[0224] Lazertinib is a 3rd generation EGFR tyrosine kinase inhibitor (TKI); the structure and synthesis of lazertinib is described in U.S. Pat. No. 9, 593,098, which is incorporated by reference herein. The chemical name of the lazertinib free base, which is represented by formula (I) herein, is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-lH-pyrazol-l-yl)pyrimidin-2- ylamino)-4-methoxy-2-morpholinophenyl)acrylamide (referred to herein as lazertinib). The mesylate salt of lazertinib may be represented by formula (II):(II). The mesylate salt of lazertinib represented by formula (II) may also be in a hydrated form (e.g., a monohydrate, etc.).

[0225] Embodiments of lazertinib (e.g., salts, hydrates, and / or crystalline forms) are described in PCT / KR2018 / 004473, which is also incorporated by reference herein.

[0226] According to particular embodiments, lazertinib in the form of a free base has little to no effect on wild-type EGFR, and is a highly selective and irreversible EGFR TKI with strong inhibitory activity against the single mutation of T790M and dual mutations, e.g., it targets the activating EGFR mutations dell9 and L858R, as well as the T790M mutation. In one aspect of the invention, the mutation may be delE746-A750, L858R, or T790M, and it may be dual mutations selected from delE746-A750 / T790M or L858R / T790M.

[0227] An embodiment of the disclosure provides a method of treating a subject having a cancer, comprising administering to the subject a combination therapy, wherein the combination therapy comprises 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):or solvate, hydrate, tautomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is a mesylate salt that is optionally hydrated.

[0228] Pharmaceutically acceptable salt forms include pharmaceutically 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, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. Pharmaceutically acceptable basic / cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.

[0229] A pharmaceutically acceptable acid salt is formed by reaction of the free base form of a compound of Formula (I) with a suitable inorganic or organic acid including, but not limited to, hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2- naphthalenesulfonic, or hexanoic acid. A pharmaceutically acceptable acid addition salt of a compound of Formula (I) can comprise or comprise or be, for example, a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formarate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g., 2- naphthalenesulfonate) or hexanoate salt.

[0230] The free acid or free base forms of the compound of formula (I) may be prepared from the corresponding base addition salt or acid addition salt form, respectively. For example, a compound of the invention in an acid addition salt form may be converted to the corresponding free base form by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0231] The EGFR TKI may be administered in a pharmaceutical composition. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0232] In some embodiments, the pharmaceutical composition comprising the EGFR TKI is delivered orally.

[0233] In some embodiments, the EGFR TKI is administered at a dose of about 100 mg to about 500 mg. In some embodiments, the EGFR TKI is administered at a dose of about 100 mg, about 150 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg. In some embodiments, the EGFR TKI is administered at a dose of about 100 mg. In certain embodiments, the EGFR TKI is administered at a dose of about 200 mg. In certain embodiments, the EGFR TKI is administered at a dose of about 240 mg. In certain embodiments, the EGFR TKI is administered at a dose of about 250 mg.

[0234] In some embodiments, the EGFR TKI is administered at a dose of about 100 mg.

[0235] In some embodiments, the EGFR TKI is administered at a dose of about 150 mg.

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

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

[0238] In some embodiments, the EGFR TKI is administered at a dose of about 250 mg.

[0239] In some embodiments, the EGFR TKI is administered at a dose of about 300 mg.

[0240] In some embodiments, the EGFR TKI is administered at a dose of about 350 mg.

[0241] In some embodiments, the EGFR TKI is administered at a dose of about 400 mg.

[0242] In some embodiments, the EGFR TKI is administered at a dose of about 450 mg.

[0243] In some embodiments, the EGFR TKI is administered at a dose of about 500 mg.

[0244] In some embodiments, the EGFR TKI is administered every other day, once daily, or twice daily. In some embodiments, the EGFR TKI is administered once daily.

[0245] In some embodiments, the EGFR TKI is administered at a dose of 240 mg once daily.

[0246] Pharmaceutical compositions comprising a 240 mg dose of the EGFR TKI can be administered in a pill, capsule, or tablet.

[0247] In some embodiments, the EGFR TKI is administered as a monotherapy. In some embodiments, the EGFR TKI is administered as a co-therapy.Antibody / EGFR TKI Combination Therapy

[0248] In some embodiments, the subject is being treated with a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody an EGFR TKI. In some embodiments, the subject is being treated with amivantamab and an EGFR TKI. In some embodiments, the subject is being treated with a bispecific anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody and lazertinib. In some embodiments, the subject is being treated with amivantamab and lazertinib.

[0249] In some embodiments, the anti-EGFR / c-Met antibody (e.g., bispecific antibody) is administered via an intravenous infusion (IV) and the EGFR TKI is administered orally.

[0250] In some embodiments, the pharmaceutical composition comprising the anti-EGFR / c- Met antibody is administered subcutaneously (SC) and the EGFR TKI is administered orally.

[0251] In some embodiments, the subject has a body weight of <80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered intravenously at a dose of 1,050 mg once weekly for the first 4 weeks and then every 2 weeks on a 28-day cycle and the EGFR TKI (e.g., lazertinib) at a dose of 240 mg daily. In other embodiments, the subject has a body weight of <80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered subcutaneously at a dose of 1,600 mg once weekly for the first 4 weeks and then at a dose of 3,530 mg once every 4 weeks on a 28-day cycle and the EGFR TKI (e.g., lazertinib) at a dose of 240 mg daily.

[0252] In certain embodiments, the subject has a body weight of >80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered intravenously at a dose of 1,400 mg once weekly for the first 4 weeks and then every 2 weeks on a 28-day cycle and the EGFR TKI (e.g., lazertinib) at a dose of 240 mg daily. In other embodiments, the subject has a body weight of >80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered subcutaneously at a dose of 2,240 mg once weekly for the first 4 weeks and then at a dose of 4,640 mg every 4 weeks on a 28-day cycle and the EGFR TKI (e.g., lazertinib) at a dose of 240 mg daily.Antibody / Chemotherapeutic Combination Therapy

[0253] In some embodiments, the subject is being treated with a bispecific anti-EGFR / c-Met antibody and a chemotherapeutic agent. In some embodiments, the subject is being treated with amivantamab and a chemotherapeutic agent. In some embodiments, the subject is being treated with a bispecific anti-EGFR / c-Met antibody and FOLFOX. In some embodiments, the subject is being treated with a bispecific anti-EGFR / c-Met antibody and FOLFIRI. In some embodiments, the subject is being treated with amivantamab and FOLFOX. In some embodiments, the subject is being treated with amivantamab and FOLFIRI.

[0254] In some embodiments, the anti-EGFR / c-Met antibody (e.g., bispecific antibody) is administered via an intravenous infusion (IV) and the chemotherapeutic agent is administered via an IV.

[0255] In some embodiments, the pharmaceutical composition comprising the anti-EGFR / c- Met antibody is administered subcutaneously (SC) and the chemotherapeutic agent is administered via IV.

[0256] In some embodiments, the subject has a body weight (BW) of <80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 1,600 mg once weekly for the first 4 weeks and then every 2 weeks in 28-day cycles. In other embodiments, the subject has a body weight of >80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 2,240 mg once weekly for the first 4 weeks and then every 2 weeks in 28-day cycles. In some embodiments, the antibody is administered once weekly for the first 4 weeks and then on Days 1 and 15 (28 days cycle). In other embodiments, the subject is administered amivantamab SC at a dose of 1,600 mg if the BW is <80 kg, or 2,240 mg if BW is >80 kg, on Days 1, 8, 15, and 22 of Cycle 1 and chemotherapy (e.g., mFOLFOX6, FOLFIRI, etc.) on Days 1 and 15 of Cycle 1 followed by amivantamab SC at a dose of 1,600 mg if the BW is <80 kg, or 2,240 mg if BW is >80 kg, on Days 1 and 15 of Cycle 2+ and chemotherapy (e.g., mFOLFOX6, FOLFIRI, etc.) on Days 1 and 15 of Cycle 2+ (each cycle of 28 days).

[0257] In some embodiments, the subject has a body weight (BW) of less than 80 kg, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 1,600 mg once weekly for the first 4 weeks and then every 2 weeks in 28-day cycles. In some embodiments, the antibody is administered on Cycle 1 Days 1, 8, 15, and 22, and then Cycle 2+ Days 1 and 15 (in 28-day cycles). In some embodiments, the antibody (e.g., bispecific antibody such as amivantamab) is administered via SC injection. In some embodiments, the subject isfurther administered a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is FOLFOX chemotherapy. In some embodiments, FOLFOX chemotherapy is administered to the subject on Days 1 and 15 of each 28-day cycle. In some embodiments, the FOLFOX chemotherapy is mF0LF0X6 chemotherapy. In some embodiments, mF0LF0X6 chemotherapy is administered to the subject on Days 1 and 15 of each 28-day cycle. In some embodiments, the chemotherapeutic agent is FOLFIRI chemotherapy. In some embodiments, FOLFIRI is administered to the subject on Days 1 and 15 of each 28-day cycle.

[0258] In some embodiments, the subject has a body weight (BW) of 80 kg or more, and the antibody (e.g., bispecific antibody such as amivantamab) is administered at a dose of 2,240 mg once weekly for the first 4 weeks and then every 2 weeks in 28-day cycles. In some embodiments, the antibody is administered on Cycle 1 Days 1, 8, 15, and 22, and then Cycle 2+ Days 1 and 15 (in 28-day cycles). In some embodiments, the antibody (e.g., bispecific antibody such as amivantamab) is administered via SC injection. In some embodiments, the subject is further administered a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is FOLFOX chemotherapy. In some embodiments, FOLFOX chemotherapy is administered to the subject on Days 1 and 15 of each 28-day cycle. In some embodiments, the FOLFOX chemotherapy is mFOLFOX6 chemotherapy. In some embodiments, mFOLFOX6 chemotherapy is administered to the subject on Days 1 and 15 of each 28-day cycle. In some embodiments, the chemotherapeutic agent is FOLFIRI chemotherapy. In some embodiments, FOLFIRI is administered to the subject on Days 1 and 15 of each 28-day cycle.Antibiotics

[0259] In some embodiments, the present method comprises administering to a subject an antibiotic. In some embodiments, the method comprises administering to the subject an oral antibiotic. In some embodiments, the method comprises administering to the subject a topical antibiotic. In some embodiments, the method comprises administering to the subject an oral antibiotic for a period of time followed by administering to the subject a topical antibiotic.Oral Antibiotics

[0260] Suitable oral antibiotics include, but are not limited to, tetracycline antibiotics, penicillin antibiotics, cephalosporin antibiotics, carbapenem antibiotics, sulfonamide antibiotics, quinolone antibiotics, macrolide antibiotics, and lincosamide antibiotics.

[0261] In some embodiments, the oral antibiotic is a tetracycline antibiotic. Examples of suitable tetracycline antibiotics include, but are not limited to, tetracycline, chlorotetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, minocycline, rolitetracycline, doxycycline, tigecycline, eravacycline, sarecycline, and omadacycline. In some embodiments, the tetracycline antibiotic is doxycycline, minocycline, or a combination thereof.

[0262] In some embodiments, the oral antibiotic is administered at a dose between about 10 mg and about 500 mg. In some embodiments, the oral antibiotic is administered at a dose of about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg.

[0263] In some embodiments, the oral antibiotic is administered at a dose of about 20 mg.

[0264] In some embodiments, the oral antibiotic is administered at a dose of about 40 mg.

[0265] In some embodiments, the oral antibiotic is administered at a dose of about 50 mg.

[0266] In some embodiments, the oral antibiotic is administered at a dose of about 60 mg.

[0267] In some embodiments, the oral antibiotic is administered at a dose of about 80 mg.

[0268] In some embodiments, the oral antibiotic is administered at a dose of about 100 mg.

[0269] In some embodiments, the oral antibiotic is administered at a dose of about 150 mg.

[0270] In some embodiments, the oral antibiotic is administered at a dose of about 200 mg.

[0271] In some embodiments, the oral antibiotic is administered at a dose of about 250 mg.

[0272] In some embodiments, the oral antibiotic is administered at a dose of about 300 mg.

[0273] In some embodiments, the oral antibiotic is administered at a dose of about 350 mg.

[0274] In some embodiments, the oral antibiotic is administered at a dose of about 400 mg.

[0275] In some embodiments, the oral antibiotic is administered at a dose of about 450 mg.

[0276] In some embodiments, the oral antibiotic is administered at a dose of about 500 mg.

[0277] In some embodiments, the oral antibiotic is administered every other day, once daily, twice daily, three times daily, or four times daily. In some embodiments, the oral antibiotic is administered twice daily.

[0278] In some embodiments, the oral antibiotic is administered at a dose of about 100 mg twice daily (100 mg BID). In some embodiments, the oral antibiotic is administered at a dose of about 100 mg once daily (100 mg QD). In some embodiments, the oral antibiotic is administered at a dose of about 50 mg once daily (50 mg QD).

[0279] In some embodiments, administration of the oral antibiotic to the subject starts before the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the oral antibiotic to the subject starts between one day and about 1 week before the day an anti- epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the oral antibiotic to the subject starts on the same day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject.

[0280] In some embodiments, the oral antibiotic is administered to the subject for between about one week and about 1 year. In some embodiments, the oral antibiotic is administered to the subject for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 42 weeks, about 48 weeks, or about 1 year.

[0281] In some embodiments, the oral antibiotic is administered in a dose of about 100 mg BID for about 12 weeks. In some embodiments, doxycycline or minocycline is orally administered in a dose of about 100 mg BID for about 12 weeks.

[0282] In some embodiments, the oral antibiotic is administered in a dose of about 100 mg QD. In some embodiments, the oral antibiotic is administered in a dose of about 100 mg QD for about 12 weeks. In some embodiments, the oral antibiotic is administered in a dose of about 100 mg BID for about 12 weeks and subsequently administered in a dose of about 100 mg QD for about 12 weeks. In some embodiments, doxycycline or minocycline is orally administered in a dose of about 100 mg BID for about 12 weeks and subsequently administered in a dose of about 100 mg QD for about 12 weeks.

[0283] In some embodiments, the oral antibiotic is administered in a dose of about 50 mg QD. In some embodiments, the oral antibiotic is administered in a dose of about 50 mg QD for about 12 weeks. In some embodiments, the oral antibiotic is administered in a dose of about 50 mg QD for about 14 weeks. In some embodiments, the oral antibiotic is administered in a dose of about 100 mg BID for about 12 weeks and subsequently administered in a dose of about 50 mg QD for about 12 weeks. In some embodiments, the oral antibiotic is administered in a dose of about 100 mg BID for about 12 weeks and subsequently administered in a dose of about 50 mg QD for about 14 weeks. In some embodiments, doxycycline or minocycline is orally administered in a dose of about 100 mg BID for about 12 weeks and subsequently administeredin a dose of about 50 mg QD for about 12 weeks. In some embodiments, doxycycline or minocycline is orally administered in a dose of about 100 mg BID for about 12 weeks and subsequently administered in a dose of about 50 mg QD for about 14 weeks.Topical Antibiotic

[0284] Examples of suitable topical antibiotics include, but are not limited to, tetracycline antibiotics, penicillin antibiotics, cephalosporin antibiotics, carbapenem antibiotics, sulfonamide antibiotics, quinolone antibiotics, macrolide antibiotics, and lincosamide antibiotics. In some embodiments, the oral antibiotic is a lincosamide antibiotic. Examples of suitable lincosamide antibiotics include, but are not limited to, lincomycin, clindamycin, and pirlimycin. In some embodiments, the lincosamide antibiotic is clindamycin.

[0285] In some embodiments, the topical antibiotic is formulated as a topical lotion. In some embodiments, the topical lotion comprises between about 0.1% (w / v) and about 10% (w / v) antibiotic. In some embodiments, the topical lotion comprises about 0.1% (w / v) antibiotic, about 0.2% (w / v) antibiotic, about 0.3% (w / v) antibiotic, about 0.4% (w / v) antibiotic, about 0.5% (w / v) antibiotic, about 0.6% (w / v) antibiotic, about 0.7% (w / v) antibiotic, about 0.8% (w / v) antibiotic, about 0.9% (w / v) antibiotic, about 1% (w / v) antibiotic, about 1.1% (w / v) antibiotic, about 1.2% (w / v) antibiotic, about 1.3% (w / v) antibiotic, about 1.4% (w / v) antibiotic, about 1.5% (w / v) antibiotic, about 1.6% (w / v) antibiotic, about 1.7% (w / v) antibiotic, about 1.8% (w / v) antibiotic, about 1.9% (w / v) antibiotic, about 2% (w / v) antibiotic, about 2.5% (w / v) antibiotic, about 3% (w / v) antibiotic, about 3.5% (w / v) antibiotic, about 4% (w / v) antibiotic, about 4.5% (w / v) antibiotic, about 5% (w / v) antibiotic, about 6% (w / v) antibiotic, about 7% (w / v) antibiotic, about 8% (w / v) antibiotic, about 9% (w / v) antibiotic, or about 10% (w / v) antibiotic.

[0286] In some embodiments, the topical antibiotic is applied to the skin, scalp, face, and / or nails. In some embodiments, the topical antibiotic is applied to the scalp.

[0287] In some embodiments, the topical antibiotic is applied every other day, once a day, twice daily, three times a day, or four times a day. In some embodiments, the topical antibiotic is applied once a day.

[0288] In some embodiments, the topical antibiotic is applied after the subject wakes up. In some embodiments, the topical antibiotic is applied before a meal. In some embodiments, the topical antibiotic is applied after a meal. In some embodiments, the topical antibiotic is applied before the subject goes to bed. In some embodiments, the topical antibiotic is applied after the subject takes a shower / bath.

[0289] In some embodiments, the topical antibiotic, formulated as a 1% topical lotion, is applied to the scalp of the subject before the subject goes to bed. In some embodiments, the topical antibiotic, formulated as a 1% topical lotion, is applied to the scalp of the subject after the subject takes a shower / bath.

[0290] In some embodiments, clindamycin, formulated as a 1% topical lotion, is applied to the scalp of the subject before the subject goes to bed. In some embodiments, clindamycin, formulated as a 1% topical lotion, is applied to the scalp of the subject after the subject takes a shower / bath.

[0291] In some embodiments, the administration of the topical antibiotic to the subject begins before the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the topical antibiotic to the subject starts between one day and about 1 week before the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the topical antibiotic to the subject starts on the same day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the topical antibiotic to the subject starts after the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the topical antibiotic to the subject starts between about 1 day and about 1 year after the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject.

[0292] In some embodiments, the topical antibiotic is administered to the subject once a day starting about 12 weeks after the first administration of the anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody to the subject. In some embodiments, a 1% clindamycin topical lotion is administered to the subject once a day starting about 12 weeks after the first administration of the anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject before bedtime starting about 12 weeks after the first administration of the anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject after the subject takes a shower / bath starting about 12 weeks after the first administration of the anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody to the subject.

[0293] In some embodiments, the topical antibiotic is administered to the subject once a day starting about 12 weeks after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is administered to the subject once a day starting about 12 weeks after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject before bedtime starting about 12 weeks after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject after the subject takes a shower / bath starting about 12 weeks after the first administration of the oral antibiotic to the subject. In some embodiments the topical antibiotic is administered to the subject once a day starting about 12 weeks and ending up to about 52 weeks after the first administration of the oral antibiotic to the subject.

[0294] In some embodiments, the topical antibiotic is administered to the subject once a day starting at about week 13 after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is administered to the subject once a day starting at about week 13 after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject before bedtime starting at about week 13 after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject after the subject takes a shower / bath starting at about week 13 after the first administration of the oral antibiotic to the subject. In some embodiments the topical antibiotic is administered to the subject once a day starting at about week 13 and ending up to about 52 weeks after the first administration of the oral antibiotic to the subject.Oral / Topical Antibiotic Transition

[0295] In some embodiments, an oral antibiotic is administered to the subject for a fixed period of time, after which a topical antibiotic is administered to the subject. In some embodiments, an oral antibiotic is administered to the subject for between about 1 week and about 1 year, after which a topical antibiotic is administered to the subject. In some embodiments, an oral antibiotic is administered to the subject every other day, once a day, twice daily, three times a day, or four times a day for between about 1 week and about 1 year, afterwhich a topical antibiotic is administered every other day, once a day, twice daily, three times a day, or four times a day.

[0296] In some embodiments, an oral antibiotic is administered to a subject for between about 1 week and about 1 year beginning before the day the subject is first administered an anti- epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic is administered to the subject. In some embodiments, an oral antibiotic is administered to a subject for between about 1 week and about 1 year beginning the same day the subject is first administered an anti- epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic is administered to the subject.

[0297] In some embodiments, an oral antibiotic is administered to the subject for about 12 weeks starting the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic is administered to the subject. In some embodiments, an oral antibiotic is administered to the subject twice daily for about 12 weeks starting the day the subject is first administered an anti- epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic is administered to the subject. In some embodiments, an oral antibiotic is administered to the subject at a dose of 100 mg twice daily for about 12 weeks starting the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic is administered to the subject. In some embodiments, doxycycline or minocycline is administered to the subject at a dose of 100 mg twice daily for about 12 weeks starting the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic is administered to the subject.

[0298] In some embodiments, an oral antibiotic is administered to a subject for between about 1 week and about 1 year beginning the day the subject is first administered an anti- epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic is administered to the subject once a day. In some embodiments, an oral antibiotic is administered to a subject for between about 1 week and about 1 year beginning the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic is administered to the scalp of the subject once a day. In some embodiments, an oral antibiotic is administered to a subject for between about 1 week and about 1 year beginning the day thesubject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic, formulated as a 1% (w / v) topical lotion, is administered to the scalp of the subject once a day. In some embodiments, an oral antibiotic is administered to a subject for between about 1 week and about 1 year beginning the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic, formulated as a 1% (w / v) topical lotion, is administered to the scalp of the subject once a day before the subject goes to bed. In some embodiments, an oral antibiotic is administered to a subject for between about 1 week and about 1 year beginning the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic, formulated as a 1% (w / v) topical lotion, is administered to the scalp of the subject once a day after the subject takes a shower / bath. In some embodiments, an oral antibiotic is administered to a subject for between about 1 week and about 1 year beginning the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which clindamycin, formulated as a 1% (w / v) topical lotion, is administered to the scalp of the subject once a day before the subject goes to bed. In some embodiments, an oral antibiotic is administered to a subject for between about 1 week and about 1 year beginning the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which clindamycin, formulated as a 1% (w / v) topical lotion, is administered to the scalp of the subject once a day after the subject takes a shower / bath.

[0299] In some embodiments, an oral antibiotic is administered to the subject twice daily for about 12 weeks starting the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic is administered to the subject daily. In some embodiments, an oral antibiotic is administered to the subject at a dose of 100 mg twice daily for about 12 weeks starting the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which a topical antibiotic, formulated as a 1% (w / v) topical lotion, is administered to the scalp of the subject. In some embodiments, doxycycline or minocycline is administered to the subject at a dose of 100 mg twice daily for about 12 weeks starting the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which clindamycin, formulated as a 1% (w / v) topical lotion, is applied to the scalp of the subject once a day. In someembodiments, doxycycline or minocycline is administered to the subject at a dose of 100 mg twice daily for about 12 weeks starting the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which clindamycin, formulated as a 1% (w / v) topical lotion, is applied to the scalp of the subject once a day before the subject goes to bed. In some embodiments, doxycycline or minocycline is administered to the subject at a dose of 100 mg twice daily for about 12 weeks starting the day the subject is first administered an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody, after which clindamycin, formulated as a 1% (w / v) topical lotion, is applied to the scalp of the subject once a day after the subject goes to bed.

[0300] In some embodiments, the topical antibiotic is administered to the subject once a day starting about 12 weeks after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is administered to the subject once a day starting about 12 weeks after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject before bedtime starting about 12 weeks after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject after the subject takes a shower / bath starting about 12 weeks after the first administration of the oral antibiotic to the subject. In some embodiments the topical antibiotic is administered to the subject once a day starting about 12 weeks and ending up to about 52 weeks after the first administration of the oral antibiotic to the subject.

[0301] In some embodiments, the topical antibiotic is administered to the subject once a day starting at about week 13 after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is administered to the subject once a day starting at about week 13 after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject before bedtime starting at about week 13 after the first administration of the oral antibiotic to the subject. In some embodiments, a 1% clindamycin topical lotion is applied to the scalp of the subject after the subject takes a shower / bath starting at about week 13 after the first administration of the oral antibiotic to the subject. In some embodiments the topical antibiotic is administered to the subject once a day starting at about week 13 and ending up to about 52 weeks after the first administration of the oral antibiotic to the subject. In some embodiments the topical antibiotic is administered to the subject once a day starting at about week 13 and endingup to about 52 weeks (i.e., for about the next 9 months) after the first administration of the oral antibiotic to the subject.Antiseptics

[0302] In some embodiments, the present method comprises administering to a subject a topical antiseptic. Suitable classes of topical antiseptics include diguanides, quaternary ammonium compounds, iodine compounds, halogenated phenol derivatives, quinolone derivatives, silver compounds, cationic surfactants, essential oils, and honeys. Suitable topical antiseptics include, but are not limited to, chlorhexidine, povidone iodine, triclosan, octenidine, benzethonium chloride, benzalkonium chloride, centrimide, methylbenzethonium chloride, cetalkonium chloride, dofanium chloride, demiphen bromide, chloroxylenol, hexachlorophene, polihexadine, tea tree oil, Manuka honey, silver nitrate, silver sulfadiazine, silver chloride, cetylpyridinium chloride, polyhexamethylene biguanide hydrochloride, hydroxyquinoline, dequalinium chloride, and diiodohydroxyguinoline. In some embodiments, the topical antiseptic is chlorhexidine.

[0303] In some embodiments, the topical antiseptic is formulated as a topical solution. In some embodiments, the topical solution comprises between about 0.5% (w / v) and about 50% (w / v) topical antiseptic. In some embodiments, the topical solution comprises about 0.5% (w / v), about 1% (w / v) topical antiseptic, about 1.5% (w / v) topical antiseptic, about 2% (w / v) topical antiseptic, about 2.5% (w / v) topical antiseptic, about 3% (w / v) topical antiseptic, about 3.5% (w / v) topical antiseptic, about 4% (w / v) topical antiseptic, about 4.5% (w / v) topical antiseptic, about 5% (w / v) topical antiseptic, about 6% (w / v) topical antiseptic, about 7% (w / v) topical antiseptic, about 8% (w / v) topical antiseptic, about 9% (w / v) topical antiseptic, about 10% (w / v) topical antiseptic, about 12% (w / v) topical antiseptic, about 14% (w / v) topical antiseptic, about 16% (w / v) topical antiseptic, about 18% (w / v) topical antiseptic, about 20% (w / v) topical antiseptic, about 25% (w / v) topical antiseptic, about 30% (w / v) topical antiseptic, about 40% (w / v) topical antiseptic, or about 50% (w / v) topical antiseptic.

[0304] In some embodiments, the topical antiseptic is applied to the skin, scalp, face, and / or nails. In some embodiments, the topical antiseptic applied to the hands and feet. In some embodiments, the topical antiseptic is applied to the nails.

[0305] In some embodiments, the topical antiseptic is applied every other day, once a day, twice daily, three times a day, or four times a day. In some embodiments, the topical antibiotic is applied once a day.

[0306] In some embodiments, the topical antiseptic is applied before the subject takes a shower / bath. In some embodiments, the topical antiseptic is applied before the subject takes a shower / bath and is washed off in the shower / bath.

[0307] In some embodiments, the topical antiseptic, formulated as a 4% topical solution, is applied to the hands and feet once a day. In some embodiments, the topical antiseptic, formulated as a 4% topical solution, is applied to the hands and feet of the subject once a day before the subject takes a shower / bath and is washed off in the shower / bath.

[0308] In some embodiments, chlorhexidine, formulated as a 4% topical solution, is applied to the hands and feet once a day. In some embodiments, chlorhexidine, formulated as a 4% topical solution, is applied to the hands and feet of the subject once a day before the subject takes a shower / bath and is washed off in the shower / bath.

[0309] In some embodiments, the topical antiseptic, formulated as a 4% topical solution, is applied to the nails once a day. In some embodiments, the topical antiseptic, formulated as a 4% topical solution, is applied to the nails of the subject once a day before the subject takes a shower / bath and is washed off in the shower / bath.

[0310] In some embodiments, chlorhexidine, formulated as a 4% topical solution, is applied to the nails once a day. In some embodiments, chlorhexidine, formulated as a 4% topical solution, is applied to the nails of the subject once a day before the subject takes a shower / bath and is washed off in the shower / bath.

[0311] In some embodiments, the administration of the topical antiseptic to the subject begins before the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the topical antibiotic to the subject starts between one day and about 1 week before the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the topical antibiotic to the subject starts on the same day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the topical antibiotic to the subject starts after the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject.

[0312] In some embodiments, the topical antiseptic is administered as part of an early intervention for a DAE. In some embodiments, the administration of the topical antiseptic to the subject begins in response to the occurrence of a DAE. In some embodiments, the administrationof the topical antiseptic begins in response to occurrence of paronychia. In some embodiments, administration of the topical antiseptic to the subject begins on the day the subject notices the DAE. In some embodiments, administration of the topical antiseptic to the subject begins on the day the subject self-reports a DAE. In some embodiments, administration of the topical antiseptic begins on the day a DAE is identified by a medical professional.Non-Comedogenic Moisturizer

[0313] In some embodiments, the present method comprises administering to a subject a non-comedogenic moisturizer. Exemplary types of ingredients in non-comedogenic moisturizers include prebiotics, probiotics, postbiotics, lipids, peptides, amino acids, vitamins, minerals, humectants, plant extracts, and solvents. Examples of ingredients in non-comedogenic moisturizers include, but are not limited to, shea butter, ceramide 3 (ceramide NP), niacinamide, glycerin, dimethicone, cetearyl alcohol, rapeseed oil, glyceryl stearate, ammonium polyacryloyldimethyl taurate, PEG- 100 stearate, propanediol, Ophiopogon japonicus extract, sorbitan tristearate, dimethiconol, PEG-20 methyl glucose sesquistearate, sodium chloride, mannose, cocamidopropyl betaine, disodium ethylenediaminetetraacetate, capryloyl glycine, caprylyl glycol, citric acid, maltodextrin, xanthan gum, tocopherol, pentaerythrityl tetra-di-t- butyl hydroxyhydrocinnamate, selenium, prebiotics, probiotics, prebiotics, peptides, amino acids, Vitreoscilla filiformis ferment, hyaluronic acid, aloe vera, grape seed extract, moringa, papaya, coconut oil, squalane, and water. In some embodiments, the water is LA ROCHE-POSAY® Prebiotic Thermal Water.

[0314] LA ROCHE-POSAY® Prebiotic Thermal Water comprises minerals, trace elements, and a high concentration of selenium, a natural antioxidant. Ceramide-3 (ceramide NP) is a skinidentical lipid that helps retain moisture and maintain a healthy skin barrier. Shea butter helps restore the skin’s hydrolipidic film and sooth the skin. Niacinamide, a form of vitamin B3, restores the skin’s moisture barrier and reduces irritation and redness. Glycerin is an excellent humectant which helps hydrate the skin by absorbing water from the surrounding environment. Vitreoscilla filiformis ferment is a postbiotic bacterial extract that rebalances the skin microbiome by limiting the growth of S. aureus and decreasing inflammation.

[0315] In some embodiments, the non-comedogenic moisturizer comprises at least one selected from shea butter, ceramide 3 (ceramide NP), niacinamide, glycerin, LA ROCHE- POSAY® Prebiotic Thermal Water, and Vitreoscilla filiformis ferment. In some embodiments, the non-comedogenic moisturizer comprises at least two selected from shea butter, ceramide 3(ceramide NP), niacinamide, glycerin, LA ROCHE-POSAY® Prebiotic Thermal Water, and Vitreoscilla filiformis ferment. In some embodiments, the non-comedogenic moisturizer comprises at least three selected from shea butter, ceramide 3 (ceramide NP), niacinamide, glycerin, LA ROCHE-POSAY® Prebiotic Thermal Water, and Vitreoscilla filiformis ferment. In some embodiments, the non-comedogenic moisturizer comprises at least four selected from shea butter, ceramide 3 (ceramide NP), niacinamide, glycerin, LA ROCHE-POSAY® Prebiotic Thermal Water, and Vitreoscilla filiformis ferment. In some embodiments, the non-comedogenic moisturizer comprises at least five selected from shea butter, ceramide 3 (ceramide NP), niacinamide, glycerin, LA ROCHE-POSAY® Prebiotic Thermal Water, and Vitreoscilla filiformis ferment. In some embodiments, the non-comedogenic moisturizer comprises shea butter, ceramide 3 (ceramide NP), niacinamide, glycerin, LA ROCHE-POSAY® Prebiotic Thermal Water, and Vitreoscilla filiformis ferment.

[0316] Examples of commercially available non-comedogenic moisturizers include, but are not limited to, Neutrogena® Hydroboost Water Boost Cream, Lubriderm® Advanced Therapy Lotion, VANICREAM™ Daily Facial Moisturizer, SHANI DARDEN® Hydration Peptide Cream, CeraVe® Ultra-Light Moisturizing Lotion, humane® Oil-Free Moisturizer, ELTA MD® AM Therapy, TATCHA® The Water Cream, FARMACY® Daily Greens, LA ROCHE- POSAY® Toleriane Double Repair Moisturizer, DIEUX® Air Angel, KIEHL’s® Ultra Facial Oil-Free Gel Cream, LA ROCHE-POSAY® LIPIKAR® Daily Repair Moisturizing Lotion, LA ROCHE-POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Cream, Dr. Jart+® Ceramidin™ Body Lotion, and Charlotte Tilbury® Magic Water Cream. In some embodiments, the non-comedogenic moisturizer is LA ROCHE-POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Cream.

[0317] In some embodiments, the non-comedogenic moisturizer is applied to the face, skin, and / or nailbeds. In some embodiments, the non-comedogenic moisturizer is applied to the face and body.

[0318] In some embodiments, the non-comedogenic moisturizer is applied at least once every other day, at least once a day, at least twice daily, at least three times a day, or at least four times a day. In some embodiments, the non-comedogenic moisturizer is applied at least once a day.

[0319] In some embodiments, the non-comedogenic moisturizer is applied after the subject takes a shower / bath. In some embodiments, the non-comedogenic moisturizer is applied at least once a day, wherein at least one application is after the subject takes a shower / bath.

[0320] In some embodiments, the administration of the non-comedogenic moisturizer to the subject begins before the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the non-comedogenic moisturizer to the subject starts between one day and about 1 week before the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the non-comedogenic moisturizer to the subject starts on the same day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of the non-comedogenic moisturizer to the subject starts after the day an anti- epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject. In some embodiments, administration of LA ROCHE-POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Lotion is applied to the face, skin, and / or nailbeds of the subject at least once daily starting on the day an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody is first administered to the subject.Zinc Salts

[0321] In some embodiments, the present method comprises administering to a subject a zinc salt. In some embodiments, the zinc salt is a bioavailable zinc salt. Examples of suitable bioavailable zinc salts include, but are not limited to, zinc gluconate, zinc citrate, zinc picolinate, zinc acetate, zinc ascorbate, zinc lactate, zinc sulfate, zinc malate, zinc glycinate, zinc nitrate, zinc methionine, and zinc methionine sulfate. In some embodiments, the bioavailable zinc is zinc gluconate.

[0322] In some embodiments, the zinc salt is administered at a dose between about 10 mg and about 1,000 mg. In some embodiments, the zinc salt is administered in a dose between about 20 mg and about 500 mg. In some embodiments, the zinc salt is administered in a dose between about 35 mg and about 210 mg. In some embodiments, the zinc salt is administered in a dose of about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 500 mg, or about 1,000 mg. In some embodiments, the zinc salt is administered in a dose of about 70 mg or about 140 mg.

[0323] In some embodiments, the zinc salt is administered every other day, once daily, twice daily, three times daily, or four times daily. In some embodiments, the zinc salt is administered twice daily.

[0324] In some embodiments, the zinc salt is administered at a dose of about 70 mg once a day (100 mg QD). In some embodiments, the zinc salt is administered at a dose of about 70 mg twice daily (70 mg BID). In some embodiments, the zinc salt is administered at a dose of about 140 mg once a day (140 mg QD).

[0325] In some embodiments, administration of the zinc salt to the subject starts before the day an anti-EGFR / c-Met antibody is first administered to the subject. In some embodiments, administration of the zinc salt to the subject starts between one day and about 1 week before the day an anti-EGFR / c-Met antibody is first administered to the subject. In some embodiments, administration of the zinc salt to the subject starts on the same day an anti-EGFR / c-Met antibody is first administered to the subject.

[0326] In some embodiments, the zinc salt is administered to the subject for at least one week. In some embodiments, the zinc salt is administered for between about one week and about 1 year. In some embodiments, the zinc salt is administered to the subject for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 42 weeks, about 48 weeks, or about 1 year. In some embodiments, the zinc salt is administered until termination of treatment with an anti-EGFR / c-Met antibody.

[0327] In some embodiments, the zinc salt is administered at a specific point in time relative to administration of another compound, composition, and / or treatment. In some embodiments, the zinc salt is administered at a specific point in time relative to administration of an antibiotic. In some embodiments, the zinc salt is administered before or after administration of an antibiotic. In some embodiments, the zinc salt is administered at least about 0.5 hours, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, or at least about 5 hours before or after administration of an antibiotic. In some embodiments, the zinc salt is administered at least 4 hours before or after administration of an antibiotic.

[0328] In some embodiments, zinc gluconate is administered at a dose of about 70 mg or about 140 mg at least 4 hours before or after administration of an antibiotic.Beta Blockers

[0329] In some embodiments, the present method comprises administering to a subject a beta blocker. Suitable beta blockers include, but are not limited to, atenolol, betaxolol, bisoprolol, esmolol, acebutolol, metoprolol, nebivolol, propranolol, carvedilol, timolol, pindolol, penbutolol, sotalol, and labetalol. In some embodiments, the beta blocker comprises propranolol, timolol, or a combination thereof.

[0330] In some embodiments, the beta blocker is administered orally. In some embodiments, propranolol is administered orally. In some embodiments, the orally administered beta blocker is administered at a dose between about 1 mg and about 100 mg. In some embodiments, the orally administered beta blocker is administered at a dose of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, 55 mg, about 60 mg, about 65 mg, about 70 mg, about75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg. In some embodiments, the orally administered beta blocker is administered at a dose of about 30 mg once daily. In some embodiments, about 30 mg propranolol is administered once daily. In some embodiments, about 10 mg propranolol is administered three times daily (10 mg HD).

[0331] In some embodiments, the orally administered beta blocker is administered beginning on the first day a scalp DAE is observed by the subject. In some embodiments, the orally administered beta blocker is administered to the subject starting on the day a DAE is first selfreported by the subject. In some embodiments, the orally administered beta blocker is administered to the subject starting on the day a DAE is identified by a medical professional.

[0332] In some embodiments, the orally administered beta blocker is administered to the subject until complete resolution of a scalp DAE. In some embodiments, the orally administered beta blocker is administered to the subject for a set period of time beyond complete resolution of a scalp DAE. In some embodiments, the orally administered beta blocker is administered to the subject upon recurrence of a scalp DAE after a previous scalp DAE was fully resolved and previous administration was halted.

[0333] In some embodiments, the beta blocker is administered topically. In some embodiments, the topically administered beta blocker is formulated as a topical solution, cream, ointment, lotion, salve, or shampoo. In some embodiments, the topical solution, cream, ointment, lotion, salve, or shampoo comprises between about 0.05% (w / v) and about 5% (w / v) beta blocker. In some embodiments, the solution comprises about 0.05% (w / v), about 0.1% (w / v), about 0.15% (w / v), about 0.2% (w / v), about 0.25% (w / v), about 0.3% (w / v), about 0.35% (w / v), about 0.4%(w / v), about 0.45% (w / v), about 0.5% (w / v), about 0.55% (w / v), about 0.6% (w / v), about 0.65%(w / v), about 0.7% (w / v), about 0.75% (w / v), about 0.8% (w / v), about 0.85% (w / v), about 0.9%(w / v), about 0.95% (w / v), about 1% (w / v), about 1.2% (w / v), about 1.4% (w / v), about 1.6% (w / v), about 1.8% (w / v), about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 3.5% (w / v), about 4% (w / v), about 4.5% (w / v), or about 5% (w / v) beta blocker. In some embodiments, the topical solution, cream, ointment, lotion, salve, or shampoo is a topical solution comprising about 0.5% (w / v) beta blocker. In some embodiments, the topical solution comprises about 0.5% (w / v) timolol.

[0334] In some embodiments, the method comprises administering one, two, three, four, or five drops of a beta blocker solution once a day. In some embodiments, the method comprises administering one, two, three, four, or five drops of a beta blocker solution twice daily. In some embodiments, the method comprises administering one drop of a 0.5% (w / v) beta blocker solution twice daily. In some embodiments, the method comprises administering one drop of a 0.5% (w / v) timolol solution twice daily.

[0335] In some embodiments, the topically administered beta blocker is administered beginning on the first day paronychia is observed by the subject. In some embodiments, the topically administered beta blocker is administered to the subject starting on the day paronychia is first self-reported by the subject. In some embodiments, the topically administered beta blocker is administered to the subject starting on the day paronychia is identified by a medical professional.

[0336] In some embodiments, the topically administered beta blocker is administered to the subject until complete resolution of a paronychia. In some embodiments, the topically administered beta blocker is administered to the subject for a set period of time beyond complete resolution of a paronychia. In some embodiments, the topically administered beta blocker is administered to the subject until cessation of administration of an anti-EGFR / c-Met antibody and / or chemotherapy.Corticosteroids

[0337] In some embodiments, the present method comprises administering to a subject a corticosteroid. Suitable corticosteroids include, but are not limited to, 11 -dehydrocorticosterone, 11 -deoxycorticosterone, 11 -deoxycortisol, 11 -ketoprogesterone, 110-hydroxypregnenolone, 11)3- hydroxyprogesterone, 110,17a, 21 -trihydroxypregnenolone, 17a-hydroxypregnenolone, 17a- hydroxyprogesterone, 18-hydroxy- 11 -deoxycorticosterone, 18-hydroxy corticosterone, 18- hydroxyprogesterone, 21-deoxycortisol, 21-desoxycortisone, 21 -hydroxypregnenolone, alclometasone, aldosterone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisol, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, difluorocortolone, difluprednate, fluclorolone, fludrocortisone, flugestone, flumetasone, fluocinolone, fluocortin, fluocortolone, fluperolone, fluprednidene, fluprednisolone, flurorometholone, fluticasone, formocortal, fluclorolone acetonide, fludroxycortide, flunisolide, fluocinolone acetonide, fluocinonine, halcinonide, halometasone, loteprednol, medrysone, meprednisone, methylprednisolone, mometasone, paramethasone, prebediolone acetate, prednicarbate, prednisolone, prednisone, prednylidene, pregnenolone, progesterone, rimexolone, tixocortol, triamcinolone, and ulobetasol. In some embodiments, the corticosteroid comprises a glucocorticoid. In some embodiments, the glucocorticoid comprises clobetasol, betamethasone, or a combination thereof.

[0338] In some embodiments, the corticosteroid is administered topically. In some embodiments, clobetasol, betamethasone, or a combination thereof is administered topically. In some embodiments, the topically administered corticosteroid is formulated as a topical solution, cream, ointment, lotion, salve, or shampoo. In some embodiments, the topical solution, cream, ointment, lotion, salve, or shampoo comprises between about 0.001% (w / v) and about 5% (w / v) corticosteroid. In some embodiments, the solution comprises about 0.001% (w / v), about 0.002% (w / v), about 0.003 (w / v)%, about 0.004% (w / v), about 0.005% (w / v), about 0.006% (w / v), about 0.007% (w / v), about 0.008% (w / v), about 0.009% (w / v), about 0.01% (w / v), about 0.02% (w / v), about 0.03% (w / v), about 0.04% (w / v), 0.05% (w / v), about 0.1% (w / v), about 0.15% (w / v), about 0.2% (w / v), about 0.25% (w / v), about 0.3% (w / v), about 0.35% (w / v), about 0.4% (w / v), about 0.45% (w / v), about 0.5% (w / v), about 0.55% (w / v), about 0.6% (w / v), about 0.65% (w / v), about 0.7% (w / v), about 0.75% (w / v), about 0.8% (w / v), about 0.85% (w / v), about 0.9% (w / v), about 0.95% (w / v), about 1% (w / v), about 1.2% (w / v), about 1.4% (w / v), about 1.6% (w / v), about 1.8% (w / v), about 2% (w / v), about 2.5% (w / v), about 3% (w / v), about 3.5% (w / v), about 4% (w / v), about 4.5% (w / v), or about 5% (w / v) beta blocker. In some embodiments, the topicalsolution, cream, ointment, lotion, salve, or shampoo comprises about 0.05% (w / v) corticosteroid.In some embodiments, the topical shampoo comprises 0.05% (w / v) clobetasol. In some embodiments, the topical solution, cream, ointment, lotion, salve, or shampoo comprises 0.1% (w / v) corticosteroid. In some embodiments, the topical cream comprises about 0.1% (w / v) betamethasone.

[0339] In some embodiments, the method comprises administering the corticosteroid once, twice, or three times a day. In some embodiments, the method comprises administering the corticosteroid once a day. In some embodiments, the method comprises administering clobetasol once a day. In some embodiments, the method comprises applying a 0.05% (w / v) clobetasol shampoo to the scalp once a day. In some embodiments, the method comprises applying a 0.05% (w / v) clobetasol shampoo to the scalp once a day and rinsing off the shampoo after fifteen minutes. In some embodiments, the method comprises administering betamethasone once a day. In some embodiments, the method comprises administering a 0.1% (w / v) betamethasone cream to the affected area of the body or face once a day.

[0340] In some embodiments, the topically administered corticosteroid is administered beginning on the day a scalp, body, or facial DAE is first observed by the subject. In some embodiments, the topically administered corticosteroid is administered to the subject starting on the day a scalp, body, or facial DAE is first self-reported by the subject. In some embodiments, the topically applied corticosteroid is administered to the subject starting on the day scalp, body, or facial DAE is identified by a medical professional.

[0341] In some embodiments, the topically administered corticosteroid is administered to the subject until complete resolution of a scalp, body, or facial DAE. In some embodiments, the topically administered corticosteroid is administered to the subject until complete resolution of a body DAE. In some embodiments, the topically administered corticosteroid is administered to the subject for a set period of time beyond complete resolution of a scalp, body, or facial DAE. In some embodiments, the topically administered corticosteroid is administered to the subject for a set period of time beyond complete resolution of a scalp DAE. In some embodiments, the topically administered corticosteroid is administered to the subject until cessation of administration of an anti-EGFR / c-Met antibody and / or chemotherapy.

[0342] In some embodiments, the topically applied corticosteroid is administered to the subject only for a fixed period of time. In some embodiments, the topical corticosteroid is administered to the subject for between about 1 day and about 28 days. In some embodiments, the topical corticosteroid is administered to the subject for about 1 day, about 2 days, about 3 days, about 4days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, aboutl9 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days. In some embodiments, the topical corticosteroid is applied to the subject for about 14 days. In some embodiments, the topical corticosteroid is applied to the subject until complete resolution of a facial DAE or about 14 days, whichever occurs first.Immunosuppressant

[0343] In some embodiments, the present method comprises administering to a subject an immunosuppressant. In some embodiments, the immunosuppressant comprises a Janus kinase (JAK) inhibitor, an antimetabolite, calcineurin inhibitors, an immunomodulatory imide drug (IMiD), an mTOR inhibitor, or a combination thereof. Suitable immunosuppressants include, but are not limited to, azathioprine, baricitinib, cyclosporine, lenalidomide, methotrexate, pomalidomide, ruxolitinib, sirolimus, tacrolimus, thalidomide, and voclosporin. In some embodiments, the immunosuppressant comprises a JAK1 / JAK2 inhibitor. In some embodiments, the JAK1 / JAK2 inhibitor comprises ruxolitinib. In some embodiments, the immunosuppressant comprises a calcineurin inhibitor. In some embodiments, the immunosuppressant comprises tacrolimus.

[0344] In some embodiments, the immunosuppressant is administered topically. In some embodiments, tacrolimus is administered topically. In some embodiments, the topically administered immunosuppressant is formulated as a topical solution, cream, ointment, lotion, salve, or shampoo. In some embodiments, the topical solution, cream, ointment, lotion, salve, or shampoo comprises between about 0.01% (w / w) and about 4% (w / w) immunosuppressant. In some embodiments, the topical solution, cream, ointment, lotion, salve, or shampoo comprises about 0.01% (w / w), about 0.02% (w / w), about 0.03% (w / w), about 0.04% (w / w), 0.05% (w / w), about 0.1% (w / w), about 0.15% (w / w), about 0.2% (w / w), about 0.25% (w / w), about 0.3% (w / w), about 0.35% (w / w), about 0.4% (w / w), about 0.45% (w / w), about 0.5% (w / w), about 0.55% (w / w), about 0.6% (w / w), about 0.65% (w / w), about 0.7% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.85% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w), about 1.5% (w / w) about 1.6% (w / w), about 1.7% (w / w), about 1.8% (w / w), about 1.9% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), or about 4% (w / w) immunosuppressant.In some embodiments, the topical solution, cream, ointment, lotion, salve, or shampoo comprises 0.1% (w / w) immunosuppressant. In some embodiments, the topical cream comprises about 0.1% (w / w) tacrolimus. In some embodiments, the topical solution, cream, ointment, lotion, salve, or shampoo comprises 1.5% (w / w) immunosuppressant. In some embodiments, the topical cream comprises about 1.5% (w / w) ruxolitinib.

[0345] In some embodiments, the method comprises administering the immunosuppressant once, twice, or three times a day. In some embodiments, the method comprises administering the immunosuppressant twice daily. In some embodiments, the method comprises administering tacrolimus twice daily. In some embodiments, the method comprises administering a 0.1% (w / w) tacrolimus ointment to the affected area of the face twice daily. In some embodiments, the method comprises administering a 0.1% (w / w) tacrolimus ointment to the affected area of the face twice daily with at least about 8 hours between each application.

[0346] In some embodiments, the topically administered immunosuppressant is administered beginning on the day a facial DAE is first observed by the subject. In some embodiments, the topically administered immunosuppressant is administered to the subject starting on the day a facial DAE is first self-reported by the subject. In some embodiments, the topically applied immunosuppressant is administered to the subject starting on the day facial DAE is identified by a medical professional. In some embodiments, the topical immunosuppressant is administered to the subject only after a prior early intervention treatment has failed to fully resolve a facial DAE.

[0347] In some embodiments, the topically administered immunosuppressant is administered to the subject until complete resolution of a facial DAE. In some embodiments, the topically administered immunosuppressant is administered to the subject for a set period of time beyond complete resolution of a facial DAE. In some embodiments, the topically administered immunosuppressant is administered to the subject for a set period of time beyond complete resolution of a facial DAE. In some embodiments, the topically administered corticosteroid is administered to the subject until cessation of administration of an anti-EGFR / c-Met antibody and / or chemotherapy.

[0348] In some embodiments, the topically applied immunosuppressant is administered to the subject only for a fixed period of time. In some embodiments, the topical immunosuppressant is administered to the subject for between about 1 week and about 24 weeks. In some embodiments, the topical immunosuppressant is administered to the subject for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks.In some embodiments, the topical immunosuppressant is applied to the subject for about 11 weeks. In some embodiments, the topical immunosuppressant is applied to the subject for about 11 weeks only after prior treatment of a facial DAE with a topical corticosteroid for about 14 days has failed to fully resolve the facial DAE.Patient Population

[0349] In some embodiments, the subject who is 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, a non-small cell lung cancer or a small cell lung cancer. In some embodiments, the cancer is a 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.

[0350] In some embodiments, the cancer is the epithelial cell cancer. In some embodiments, the cancer is the breast cancer. In some embodiments, the cancer is the ovarian cancer. In some embodiments, the cancer is the lung cancer. In some embodiments, the cancer is the lung adenocarcinoma. In some embodiments, the cancer is the squamous cell lung cancer. In some embodiments, the cancer is the small cell lung cancer. In some embodiments, the cancer is the colorectal cancer. In some embodiments, the cancer is the anal cancer. In some embodiments, the cancer is the prostate cancer. In some embodiments, the cancer is the kidney cancer. In some embodiments, the cancer is the bladder cancer. In some embodiments, the cancer is the head and neck cancer. In some embodiments, the cancer is the pharynx cancer. In some embodiments, the cancer is the cancer of the nose. In some embodiments, the cancer is the pancreatic cancer. In some embodiments, the cancer is the skin cancer. In some embodiments, the cancer is the oral cancer. In some embodiments, the cancer is the cancer of the tongue. In some embodiments, the cancer is the esophageal cancer. In some embodiments, the cancer is the vaginal cancer. In some embodiments, the cancer is the cervical cancer. In some embodiments, the cancer is the cancer of the spleen. In some embodiments, the cancer is the testicular cancer. In some embodiments, the cancer is the gastric cancer. In some embodiments, the cancer is the cancer of the thymus. Insome embodiments, the cancer is the colon cancer. In some embodiments, the cancer is the thyroid cancer. In some embodiments, the cancer is the liver cancer. In some embodiments, the cancer is the HCC. In some embodiments, the cancer is the PRCC.

[0351] In some embodiments, the cancer is EGFR or c-Met expressing cancer.

[0352] In some embodiments, the cancer is EGFR and c-Met expressing cancer.

[0353] In some embodiments, the cancer is EGFR expressing cancer.

[0354] In some embodiments, the cancer is c-Met expressing cancer.

[0355] In some embodiments, the EGFR and / or c-Met expressing cancer is associated with a wild-type EGFR, an EGFR mutation, an EGFR gene amplification, increased levels of circulating HGF, a wild-type c-Met, a c-Met mutation, a c-Met gene amplification or a mutant KRAS. The EGFR mutation may be an activating mutation such as exon 19 deletion or L858R mutation. In some embodiments, the EGFR mutation is an EGFR exon 19 mutation. In some embodiments, the EGFR mutation is an L858R mutation.

[0356] 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 lead to an increase in at least one biological activity of EGFR, such as elevated tyrosine kinase activity, formation of receptor homodimers and heterodimers, enhanced ligand binding etc. Mutations can be located in any portion of an EGFR gene or regulatory region associated with an EGFR gene and include mutations in exon 18, 19, 20 or 21. Other examples of EGFR activating mutations are known in the art (see e.g., U.S. Pat. Publ. No. US2005 / 0272083). Information about EGFR and other ErbB receptors including receptor homo- and hetero-dimers, receptor ligands, autophosphorylation sites, and signaling molecules involved in ErbB mediated signaling is known in the art (see e.g., Hynes and Lane, Nature Reviews Cancer 5: 341-354, 2005).

[0357] In some embodiments, the EGFR mutation is 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_A750InsHS, delE746_T751InsFPT, delE746_T751InsL, delE746_S752InsIP, delE746_P753InsMS, delE746_T751InsA, delE746_T7511ns APT, delE746_T751InsVA, delE746_S 7521ns V, delE746_P753InsVS, delE746_K754InsGG, delE746_E749, delE746_E749InsP, delL747_E749, delL747_A750InsP, delL747_T751InsP, delL747_T751InsN, delL747_S752InsPT, delL747_P753InsNS, delL747_S752InsPI, delL747_S752, delL747_P753InsS, delL747_K754, delL747_T751InsS,delL747_T751, delL747_P753InsS, delA750_I759InsPT, delT751_I759InsT, delS752_I759, delT751_I759InsN, delT751_D761InsNLY, delS752_I759, delR748-P753, delL747-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 C775 InsX, at least one deletion in EGFR exon 20, or at least one insertion in EGFR exon 20, at least one deletion in EGFR exon 19, or at least one insertion in EGFR exon 19, or any combinations thereof, wherein X refers to any of the naturally occurring amino acids and can be one to seven amino acids long. In some embodiments, the EGFR mutation is L858R. The nomenclature of the mutations is well-known.

[0358] In some embodiments, the EGFR mutation is at least one deletion 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, delE746_T751InsAPT, delE746_T751InsVA, delE746_S752InsV, delE746_P753InsVS, delE746_K754InsGG, delE746_E749, delE746_E749InsP, delL747_E749, delL747_A750InsP, delL747_T751InsP, delL747_T751InsN, delL747_S752InsPT, delL747_P753InsNS, delL747_S752InsPI, delL747_S752, delL747_P753InsS, delL747_K754, delL747_T751InsS, delL747_T751 , delL747_P753InsS, delA750_I759InsPT, delT751_I759InsT, delS752_I759, delT751_I759InsN, delT751_D761InsNLY, delS752_I759, delR748-P753 and delL747-P753insS, delL747-T751.

[0359] Exemplary c-Met mutations include point mutations, deletion mutations, insertion mutations, inversions or gene amplifications that lead to an increase in at least one biological activity of a c-Met protein, such as elevated tyrosine kinase activity, formation of receptor homodimers and heterodimers, enhanced ligand binding etc. Mutations can be located in any portion of the c-Met gene or 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 c-Met exon 14 skipping mutation.

[0360] Methods for detecting EGFR and c-Met mutations or gene amplifications are well known.

[0361] In some embodiments, the subject has been diagnosed with the EGFR mutation prior to administering the therapy comprising an EGFR / c-Met bispecific antibody.

[0362] 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.

[0363] In some embodiments, the subject having the newly diagnosed cancer has at least one EGFR exon 20 mutation. In some embodiments, the subject having the newly diagnosed EGFR or c-Met expressing cancer has at least one EGFR exon 20 mutation. Exon 20 mutations (insertion of at least one amino acid are generally resistant to EGFR tyrosine kinase inhibitors (TKI) (see. e.g. Int. Pat. Publ. No. WO2018 / 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 V774_C775 InsX, wherein X is one to seven amino acids.

[0364] In some embodiments, the subject is EGFR tyrosine kinase inhibitor (TKI) treatment naive.

[0365] In some embodiments, the subject is resistant or relapsed to treatment with a first- generation EGFR TKI.

[0366] In some embodiments, the first-generation EGFR TKI is erlotinib or gefitinib.

[0367] In some embodiments, the subject is resistant or relapsed to treatment with a second- generation EGFR TKI.

[0368] In some embodiments, the second-generation EGFR TKI is afatinib.

[0369] In some embodiments, the subject is resistant or relapsed to treatment with a third generation EGFR TKI.

[0370] In some embodiments, the third generation EGFR TKI is osimertinib.

[0371] In some embodiments, the subject is resistant or has acquired resistance to treatment with a prior anti-cancer therapy.

[0372] In some embodiments, the prior anti-cancer therapy is chemotherapy, a targeted anticancer therapy, or a kinase inhibitor. In some embodiments, the prior anti-cancer therapy is doublet platinum chemotherapy.

[0373] In some embodiments, the TKI is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR or AXL.

[0374] In some embodiments, the TKI is mobocertinib, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib or sunitinib.

[0375] In some embodiments, the subject is resistant or has acquired resistance to an EGFR inhibitor. Exemplary EGFR inhibitors for which cancer may acquire resistance are anti-EGFR antibodies cetuximab (ERBITUX®), pantinumumab (VECTIBIX®), matuzumab, nimotuzumab, small molecule EGFR inhibitors erlotinib (TARCEVA® ), gefitinib (IRESSA®), EKB-569 (pelitinib, irreversible EGFR TKI), pan-ErbB and other receptor tyrosine kinase inhibitors, lapatinib (EGFR and HER2 inhibitor), pelitinib (EGFR and HER2 inhibitor), vandetanib (ZD6474, ZACTIMA™, EGFR, VEGFR2 and RET TKI), PF00299804 (dacomitimb, irreversible pan-ErbB TKI) , CI- 1033 (irreversible pan-erbB 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).Additional Administered Therapeutics

[0376] In certain embodiments, at least one additional therapeutic agent is being administered to the subject. Non-limiting examples of the at least one additional therapeutic agent includes a T cell expressing chimeric antigen receptor (CAR) (CAR-T cell), a natural killer cell expressing CAR (CAR-NK cell), a macrophage expressing CAR (CAR-M cell), a chemotherapeutic agent, an immune checkpoint inhibitor, a T-cell redirector, radiation therapy, surgery, and a standard of care drug. In certain embodiments, the at least one additional therapeutic agent comprises chemotherapy, radiation therapy, surgery, a targeted anti-cancer therapy, a kinase inhibitor, or a combination thereof.

[0377] In some embodiments, the at least one additional therapeutic agent is at least one anticancer therapy. In some embodiments, the at least one additional therapeutic agent comprise at least one chemotherapeutic agent.

[0378] A non- exhaustive list of chemotherapeutic agents considered for use in combination therapies include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), leucovorin calcium, melphalan (Alkeran®), 6- mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 withcarmustine implant (Gliadel®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), 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 (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hy camptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0379] Example alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Haemanthamine®, Nordopan®, Uracil Nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), tri ethylenemelamine (Hemel®, Hexylen®, Hexastat®), Demethyldopan®, Desmethyldopan®, triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine (DTIC-Dome®). Additional example alkylating agents include, without limitation, Oxaliplatin (Eloxatin®); Melphalan (also known as L-PAM, L- sarcolysin, and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexylen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Temozolomide (Temodar® and Temodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®- AQ);Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexylen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine(Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HC1 (Treanda®).

[0380] In some embodiments, the at least one additional therapeutic agent comprises 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 some 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 some 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 or AXL.

[0381] In some embodiments, the kinase inhibitor comprises erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, mobocertinib, poziotinib, criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, sunitinib or a combination thereof. In certain embodiments, the kinase inhibitor is erlotinib. In some 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 some embodiments, the kinase inhibitor is poziotinib. In some embodiments, the kinase inhibitor is criotinib. 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 some embodiments, the kinase inhibitor is regorafenib. In certain embodiments, the kinase inhibitor is pazopanib. In some embodiments, the kinase inhibitor is sorafenib. In some embodiments, the kinase inhibitor is sunitinib. In some embodiments, the kinase inhibitor is mobocertinib.

[0382] In certain embodiments, the at least one prior anti-cancer therapy comprises carboplatin, paclitaxel, gemcitabine, cisplatin, vinorelbine, docetaxel, palbociclib, crizotinib, PD- (L)l axis inhibitor, 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, erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, lazertinib, mobocertinib, poziotinib,criotinib, cabozantinib, capmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib or sunitinib, or any combination thereof.

[0383] Anti-cancer therapies that may be administered in combination with the anti-EGFR / c- Met antibody (e.g., bispecific antibody) in the methods of the disclosure include any at least one of the chemotherapeutic drugs or other anti-cancer therapeutics known to those of skill in the art. Anti-cancer therapeutic agents are chemical compounds useful in the treatment of cancer and include growth inhibitory agents or other cytotoxic agents and include alkylating agents, antimetabolites, anti-microtubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors and the like. Examples of anti-cancer therapys include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites 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; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2’ ,2”-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; members of taxoid or taxane family, such as paclitaxel (TAXOL® docetaxel (TAXOTERE®) and analogues thereof; 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 inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; inhibitors of receptor tyrosine kinases and / or angiogenesis, including sorafenib (NEXAVAR® ), sunitinib (SUTENT® ), pazopamb (VOTRIENT™), toceramb (PALLADIA™), vandetamb (ZACTIMA™), cediramb (RECENTIN®), regorafemb (BAY 73-4506), axitimb (AG013736), lestaurtimb (CEP-701), erlotinib (TARCEVA®), gefitimb (IRESSA®), afatimb (BIBW 2992), lapatinib (TYKERB®), neratinib (HKI-272), and the like, and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (FARESTON®); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Other conventional cytotoxic chemical compounds as those disclosed in Wiemann et al., 1985, in Medical Oncology (Calabresi etal, eds.), Chapter 10, McMillan Publishing, are also applicable to the methods of the present invention.

[0384] In some embodiments, the anti-EGFR / c-Met antibody (e.g., bispecific antibody) and the at least one additional therapeutic agent (e.g., chemotherapeutic agents) is administered simultaneously. In other embodiments, the antibody and the at least one additional therapeutic agent is administered separately (e.g., sequentially).

[0385] For combination therapies, the at least one anti-cancer therapy may be administered using recommended doses and dosages of the anti-cancer therapy.Subjects

[0386] The terms “subject” and “patient” can be used interchangeably herein. “Patient in need thereof’ or “subject in need thereof’ refers to a mammalian subject, preferably human, diagnosed with or suspected of having a disease, to whom will be or has been administered a bispecific anti-EGFR anti-MET antibody according to a method of the invention. “Patient inneed thereof’ or “subject in need thereof’ includes those subjects already with the undesired physiological change or disease well as those subjects prone to have the physiological change or disease.

[0387] In some embodiments, the subject is 18 years of age or older, e.g., 18 to less than 40 years of age, 18 to less than 45 years of age, 18 to less than 50 years of age, 18 to less than 55 years of age, 18 to less than 60 years of age, 18 to less than 65 years of age, 18 to less than 70 years of age, 18 to less than 75 years of age, 40 to less than 75 years of age, 45 to less than 75 years of age, 50 to less than 75 years of age, 55 to less than 75 years of age, 60 to less than 75 years of age, 65 to less than 75 years of age, 60 to less than 75 years of age, 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, 65 years of age or older, 70 years of age or older or 75 years of age or older.

[0388] 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.

[0389] In some embodiments, the subject has been diagnosed with NSCLC 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 some embodiments, the subject is newly diagnosed with NSCLC.

[0390] In certain embodiments, the subject is treatment naive.

[0391] In some embodiments, the subject has received at least one prior anti-cancer therapy. In certain embodiments, the at least one prior anti-cancer therapy comprises at least one chemotherapeutic agent, checkpoint inhibitor, targeted anti-cancer therapy, or kinase inhibitor, or any combination thereof. In some embodiments, the subject is relapsed or resistant to treatment with at least one prior anti-cancer therapy.

[0392] In some embodiments, the subject is resistant or has acquired resistance to an EGFR inhibitor. Exemplary EGFR inhibitors for which cancer may acquire resistance are anti-EGFR antibodies cetuximab (ERBITUX®), pantinumumab (VECTIBIX®), matuzumab, nimotuzumab, small molecule EGFR inhibitors erlotinib (TARCEVA® ), gefitinib (IRESSA®), EKB-569(pelitinib, irreversible EGFR TKI), pan-ErbB and other receptor tyrosine kinase inhibitors, lapatinib (EGFR and HER2 inhibitor), pelitinib (EGFR and HER2 inhibitor), vandetanib (ZD6474, ZACTIMA™, EGFR, VEGFR2 and RET TKI), PF00299804 (dacomitmib, irreversible pan-ErbB TKI) , CI- 1033 (irreversible pan-erbB 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).

[0393] Various qualitative and / or quantitative methods may be used to determine if a subject is resistant, has developed or is susceptible to developing a resistance to treatment with an anticancer therapy. Symptoms that may be associated with resistance to an anti-cancer therapy include a decline or plateau of the well-being of the patient, an increase in the size of a tumor, arrested or slowed decline in growth of a tumor, and / or the spread of cancerous cells in the body from one location to other organs, tissues or cells. Re-establishment or worsening of various symptoms associated with cancer may also be an indication that a subject has developed or is susceptible to developing resistance to an anti-cancer therapy, such as anorexia, cognitive dysfunction, depression, dyspnea, fatigue, hormonal disturbances, neutropenia, pain, peripheral neuropathy, and sexual dysfunction. The symptoms associated with cancer may vary according to the type of cancer. For example, symptoms associated with cervical cancer may include abnormal bleeding, unusual heavy vaginal discharge, pelvic pain that is not related to the normal menstrual cycle, bladder pain or pain during urination, and bleeding between regular menstrual periods, after sexual intercourse, douching, or pelvic exam. Symptoms associated with lung cancer may include persistent cough, coughing up blood, shortness of breath, wheezing chest pain, loss of appetite, losing weight without trying and fatigue. Symptoms for liver cancer may include loss of appetite and weight, abdominal pain, especially in the upper right part of abdomen that may extend into the back and shoulder, nausea and vomiting, general weakness and fatigue, an enlarged liver, abdominal swelling (ascites), and a yellow discoloration of the skin and the whites of eyes (jaundice). One skilled in oncology may readily identify symptoms associated with a particular cancer type.

[0394] Exemplary PD-(L)1 axis inhibitors are antibodies that bind PD-1 such as nivolumab (OPDIVO®), pembrolimumab (KEYTRUDA®), sintilimab, cemiplimab (LIBTAYO®), tripolibamab, tislelizumab, spartalizumab, camrelizumab, dostralimab, genolimzumab orcetrelimab, or antibodies that bind PD-L1, such as PD-L1 antibodies are envafolimab, atezolizumab (TECENTRIQ®), durvalumab (IMFINZI®) and avelumab (BAVENCIO®).

[0395] Marketed antibodies may be purchased via authorized distributor or pharmacy. The amino acid sequences structures of the small molecules can be found from USAN and / or INN submissions by the companies of from CAS registry.Pre-dose Medications

[0396] In some embodiments, the combination treatment, comprising an EGFR / c-Met antibody, also comprises at least one pre-dose medication. In some embodiments, the pre-dose medication comprises antihistamines, antipyretics, glucocorticoids, H2 antagonists, and / or antiemetics. In some embodiments, the pre-dose medication comprises an antihistamine. In some embodiments, the pre-dose medication comprises an antipyretic. In some embodiments, the predose medication comprises a glucocorticoid. In some embodiments, the pre-dose medication comprises an H2 antagonist. In some embodiments, the pre-dose medication comprises an antiemetic. In some embodiments, the at least one pre-dose medication is administered as described in Table 1 or Table 20.Table 1: Pre-Dose Medications* Required at all doses. ’ Required at initial dose (Week 1, Days 1 and 2); optional for subsequent doses.Post-treatment Medications

[0397] In some embodiments, the combination treatment, comprising an EGFR / c-Met antibody, also comprises at least one post-treatment medication. In some embodiments, the posttreatment medication comprises antihistamines, antipyretics, glucocorticoids, opiates, and / or antiemetics. In some embodiments, the post-treatment medication comprises an antihistamine. In some embodiments, the post-treatment medication comprises an antipyretic. In some embodiments, the post-treatment medication comprises a glucocorticoid. In some embodiments, the post-treatment medication comprises an opiate antagonist. In some embodiments, the posttreatment medication comprises an antiemetic. In some embodiments, the at least one posttreatment medication is administered as described in Table 20.Methods for treatments for dermatologic adverse events.

[0398] In some embodiments, ruxolitinib is used to reduce the and / or resolve of a DAE resulting from a treatment comprising administering an anti-EGFR / c-Met antibody alone or in combination with one or more additional anti-cancer therapies. In certain embodiments, ruxolitinib is used to reduce and / or resolve dermatological side effects resulting from a treatment comprising administering amivantamab, with or without Lazertinib, to a patient in need thereof. In certain embodiments, ruxolitinib is used when a patient is experiencing new-onset or persistent dermatological side effects of Grade >2 [excluding paronychia] during treatment with IV or subcutaneous amivantamab, with or without lazertinib. In certain embodiments, ruxolitinib is used in a subject experiencing new-onset or persistent dermatological side effects of Grade >2 of the scalp, face, or body (as defined by NCI CTCAE v5.0 Grading [excluding paronychia]) during treatment with IV or subcutaneous amivantamab, with or without lazertinib. In certain embodiments ruxolitinib can be used by itself or in combination with dermatological management regimens described herein. In certain embodiments, ruxolitinib comprises a ruxolitinib cream. In certain embodiments a ruxolitinib cream comprises a ruxolitinib 1.5% cream. In certain embodiments, a ruxolitinib cream comprises 15 mg of ruxolitinib per gram (1.5%) of cream. In certain embodiments, a ruxolitinib cream is an equivalent cream. In certain embodiments a ruxolitinib cream is used on the skin area, focusing on the inflamed skin and immediately adjacent non-involved area. In certain embodiments a ruxolitinib cream is used on the smallest skin area necessary, focusing on the inflamed skin and immediately adjacent noninvolved area. In certain embodiments, a ruxolitinib cream is used on the skin area until clearance of the lesion or until 12 weeks from first application, whichever occurs first. In certain embodiments, if infection occurs or is suspected, treatment with ruxolitinib should be temporarily discontinued on the affected areas until the infection is cleared, whereupon ruxolitinib is resumed.

[0399] In some embodiments, tacrolimus is used to reduce the and / or resolve of a DAE resulting from a treatment comprising administering an anti-EGFR / c-Met antibody alone or in combination with one or more additional anti-cancer therapies. In certain embodiments, tacrolimus is used to reduce and / or resolve dermatological side effects resulting from a treatment comprising administering amivantamab, with or without lazertinib, to a patient in need thereof. In certain embodiments, tacrolimus is used when a patient is experiencing new-onset or persistent dermatological side effects of Grade >2 [excluding paronychia] during treatment withIV or subcutaneous amivantamab, with or without lazertinib. In certain embodiments, tacrolimus is used in a subject experiencing new-onset or persistent dermatological side effects of Grade >2 of the scalp, face, or body (as defined by NCI CTCAE v5.0 Grading [excluding paronychia]) during treatment with IV or subcutaneous amivantamab, with or without lazertinib. In certain embodiments tacrolimus can be used by itself or in combination with dermatological management regimens described herein. In certain embodiments, tacrolimus comprises a tacrolimus cream. In certain embodiments a tacrolimus cream comprises a tacrolimus 0.1% cream. In certain embodiments, a tacrolimus cream comprises 1 mg of tacrolimus per gram (0.1%) of cream. In certain embodiments, a tacrolimus cream is an equivalent cream. In certain embodiments, a tacrolimus cream is used on the skin area, focusing on the inflamed skin and immediately adjacent non-involved area. In certain embodiments a tacrolimus cream is used on the smallest skin area necessary, focusing on the inflamed skin and immediately adjacent noninvolved area. In certain embodiments, a tacrolimus cream is used on the skin area until clearance of the lesion or until 12 weeks from first application, whichever occurs first. In certain embodiments, a tacrolimus cream is used twice daily. In certain embodiments, a tacrolimus cream is used twice daily and then reduced to once daily. In certain embodiments, a tacrolimus cream is used once daily. In certain embodiments, a tacrolimus cream is used once daily and then reduced to once a day twice weekly (e.g., Monday and Thursday). In certain embodiments, a tacrolimus cream is once a day twice weekly (e.g., Monday and Thursday). In certain embodiments, a tacrolimus cream is once a day twice weekly (e.g., Monday and Thursday) with at least 2 to 3 days between applications. In certain embodiments, if infection occurs or is suspected, treatment with tacrolimus should be temporarily discontinued on the affected areas until the infection is cleared, whereupon tacrolimus is resumed. In certain embodiments, if symptoms do not improve after 8 weeks of treatment, discontinuation of treatment can be considered. In certain embodiments, if symptoms do not improve after 8 weeks of treatment, treatment I discontinued. In certain embodiments, if symptoms do not improve after 8 weeks of treatment, treatment is continued.

[0400] In some embodiments, reactive enhanced dermatologic management is used to reduce the occurrence and / or severity of a DAE resulting from a treatment comprising administering an anti-EGFR / c-Met antibody alone or in combination with one or more additional anti-cancer therapies. In some embodiments, reactive enhanced dermatologic management is used to reduce the occurrence and / or severity of a DAE resulting from a treatment comprising administering amivantamab alone or in combination with one or more additional anti-cancer therapies. In someembodiments, reactive enhanced dermatologic management is used to reduce the occurrence and / or severity of a DAE resulting from a treatment comprising administering amivantamab alone or in combination with one or more chemotherapeutic agents. In some embodiments, reactive enhanced dermatologic management is used to reduce the occurrence and / or severity of a DAE resulting from a treatment comprising administering amivantamab alone or in combination with FOLFOX or FOLFIRI.

[0401] In some embodiments, reactive enhanced dermatologic management is administered when a subject first notices a DAE. In some embodiments, reactive enhanced dermatologic management is administered when a subject first self-reports a DAE. In some embodiments, reactive enhanced dermatologic management is administered when a DAE is first identified by a medical professional. In some embodiments, reactive enhanced dermatologic management is administered for a defined period of time. In some embodiments, reactive enhanced dermatologic management is administered until the DAE has been completely resolved. In some embodiments, reactive enhanced dermatologic management is administered until treatment with an anti- EGFR / c-MET antibody is halted. In some embodiments, enhanced dermatologic management is administered for a defined period of time, until the DAE has been completely resolved, or treatment with an anti-EGFR / c-MET antibody is halted, whichever is shortest.

[0402] In some embodiments, the reactive enhanced dermatologic management is administered in response to a scalp DAE. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises administering a beta blocker and a topical corticosteroid. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering propranolol and topically administering clobetasol. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering 30 mg propranolol once daily and topically administering a shampoo comprising 0.05% (w / v) clobetasol once daily. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering 30 mg propranolol once daily until complete resolution of the scalp DAE and topically administering a shampoo comprising 0.05% (w / v) clobetasol once daily beginning on: a) the day the subject notices the scalp DAE; b) the day the subject self-reports the scalp DAE; or c) the day the scalp DAE is identified by a medical professional. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering 30 mg propranolol once daily until complete resolution of the scalp DAE and topically administering a shampoo comprising 0.05% (w / v) clobetasol once daily at least until the last day the anti-EGFR / c-Met antibody isadministered. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering 30 mg propranolol once daily beginning on: a) the day the subject notices the scalp DAE; b) the day the subject self-reports the scalp DAE; or c) the day the scalp DAE is identified by a medical professional; until complete resolution of the scalp DAE; and topically administering a shampoo comprising 0.05% (w / v) clobetasol once daily beginning on: a) the day the subject notices the scalp DAE; b) the day the subject self-reports the scalp DAE; or c) the day the scalp DAE is identified by a medical professional; until at least the last day the anti-EGFR / c-Met antibody is administered.

[0403] In some embodiments, the reactive enhanced dermatologic management is administered in response to a scalp DAE. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises administering a beta blocker and a topical corticosteroid. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering propranolol and topically administering clobetasol. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering 10 mg propranolol three times daily (TID) and topically administering a shampoo comprising 0.05% (w / v) clobetasol once daily. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering 10 mg propranolol three times daily (TID) until complete resolution of the scalp DAE and topically administering a shampoo comprising 0.05% (w / v) clobetasol once daily beginning on: a) the day the subject notices the scalp DAE; b) the day the subject self-reports the scalp DAE; or c) the day the scalp DAE is identified by a medical professional. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering 10 mg propranolol three times daily (TID) until complete resolution of the scalp DAE and topically administering a shampoo comprising 0.05% (w / v) clobetasol once daily until at least the last day the anti-EGFR / c-Met antibody is administered. In some embodiments, the reactive enhanced dermatologic management for a scalp DAE comprises orally administering 10 mg propranolol three times daily (TID) beginning on: a) the day the subject notices the scalp DAE; b) the day the subject self-reports the scalp DAE; or c) the day the scalp DAE is identified by a medical professional; until complete resolution of the scalp DAE; and topically administering a shampoo comprising 0.05% (w / v) clobetasol once daily beginning on: a) the day the subject notices the scalp DAE; b) the day the subject self-reports the scalp DAE; or c) the day the scalp DAE is identified by a medical professional; until at least the last day the anti-EGFR / c-Met antibody is administered.

[0404] In some embodiments, the reactive enhanced dermatologic management is administered in response to paronychia. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises administering a topical antiseptic and a beta blocker. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises administering a topical antiseptic once daily and a topical beta blocker twice daily. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises administering a topical antiseptic once daily and a topical beta blocker twice daily until at least the last day the anti-EGFR / c-Met antibody is administered. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chi orhexi dine solution and a 0.5% (w / v) timolol solution. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chlorhexidine solution once daily and a 0.5% (w / v) timolol solution twice daily. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chlorhexidine solution once daily and a 0.5% (w / v) timolol solution twice daily beginning on: a) the day the subject notices the paronychia; b) the day the subject self-reports the paronychia; or c) the day the paronychia is identified by a medical professional. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chlorhexidine solution once daily and a 0.5% (w / v) timolol solution until at least the last day the anti-EGFR / c-Met antibody is administered. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chlorhexidine solution once daily and a 0.5% (w / v) timolol solution beginning on: a) the day the subject notices the paronychia; b) the day the subject self-reports the paronychia; or c) the day the paronychia is identified by a medical professional; until at least the last day the anti-EGFR / c-Met antibody is administered.

[0405] In some embodiments, the reactive enhanced dermatologic management for paronychia comprises administering a topical antiseptic, a topical beta blocker, and a topical Janus kinase (JAK) inhibitor. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises administering a topical antiseptic once daily and a topical beta blocker twice daily and, if the paronychia has not been completely resolved within 4 weeks of reactive enhanced dermatologic management, administering a topical JAK inhibitor twice daily. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises administering a topical antiseptic once daily and a topical beta blocker twice daily until at least the last day the anti-EGFR / c-Met antibody is administered and, if the paronychiahas not been completely resolved within 4 weeks of reactive enhanced dermatologic management, administering a topical JAK inhibitor twice daily until the paronychia is completely resolved or for up to 12 weeks, whichever occurs first. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chlorhexidine solution, a 0.5% (w / v) timolol solution, and a 1.5% (w / v) ruxolitinib cream. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chlorhexidine solution once daily and a 0.5% (w / v) timolol solution twice daily and, if the paronychia has not been completely resolved within 4 weeks of reactive enhanced dermatologic management, administering a 1.5% (w / v) ruxolitinib cream twice daily. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chlorhexidine solution once daily and a 0.5% (w / v) timolol solution twice daily beginning on: a) the day the subject notices the paronychia; b) the day the subject self-reports the paronychia; or c) the day the paronychia is identified by a medical professional and, if the paronychia has not been completely resolved within 4 weeks of reactive enhanced dermatologic management, administering a 1.5% (w / v) ruxolitinib cream twice daily beginning 4 weeks after first administration of the chlorhexidine solution and timolol solution. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chlorhexidine solution once daily and a 0.5% (w / v) timolol solution until at least the last day the anti-EGFR / c-Met antibody is administered and, if the paronychia has not been completely resolved within 4 weeks of reactive enhanced dermatologic management, administering a 1.5% (w / v) ruxolitinib cream twice daily beginning 4 weeks after first administration of the chlorhexidine solution and timolol solution until complete resolution of the paronychia or up to 12 weeks, whichever occurs first. In some embodiments, the reactive enhanced dermatologic management for paronychia comprises topically administering a 4% (w / v) chlorhexidine solution once daily and a 0.5% (w / v) timolol solution beginning on: a) the day the subject notices the paronychia; b) the day the subject selfreports the paronychia; or c) the day the paronychia is identified by a medical professional; until at least the last day the anti-EGFR / c-Met antibody is administered and, if the paronychia has not been completely resolved within 4 weeks of reactive enhanced dermatologic management, administering a 1.5% (w / v) ruxolitinib cream twice daily beginning 4 weeks after first administration of the chlorhexidine solution and timolol solution until complete resolution of the paronychia or up to 12 weeks, whichever occurs first.

[0406] In some embodiments, the reactive enhanced dermatologic management is administered in response to a body DAE. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises administering a corticosteroid. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises administering a topical corticosteroid. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering a 0.1% (w / v) betamethasone cream. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering a 0.1% (w / v) betamethasone cream once daily. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering a 0.1% (w / v) betamethasone cream once daily beginning on: a) the day the subject notices the body DAE; b) the day the subject self-reports the body DAE; or c) the day the body DAE is identified by a medical professional. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering a 0.1% (w / v) betamethasone cream once daily until complete resolution of the body DAE. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering a 0.1% (w / v) betamethasone cream once daily. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering a 0.1% (w / v) betamethasone cream once daily beginning on: a) the day the subject notices the body DAE; b) the day the subject self-reports the body DAE; or c) the day the body DAE is identified by a medical professional, until complete resolution of the body DAE.

[0407] In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises administering a topical immunosuppressant. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering a 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment to the affected area of the body twice daily. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment to the affected area of the body twice daily beginning on: a) the day the subject notices the body DAE; b) the day the subject self-reports the body DAE; or c) the day the body DAE is identified by a medical professional. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment to the affected area of the body twice daily until complete resolutionof the body DAE or up to 12 weeks, whichever occurs first. In some embodiments, the reactive enhanced dermatologic management for a body DAE comprises topically administering 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment to the affected area of the body twice daily beginning on: a) the day the subject notices the body DAE; b) the day the subject selfreports the body DAE; or c) the day the body DAE is identified by a medical professional, until complete resolution of the body DAE or up to 12 weeks, whichever occurs first.

[0408] In some embodiments, the reactive enhanced dermatologic management is administered in response to a facial DAE. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises administering a corticosteroid. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises administering a topical corticosteroid. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises topically administering a 0.1% (w / v) betamethasone cream. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises topically administering a 0.1% (w / v) betamethasone cream once daily. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises topically administering a 0.1% (w / v) betamethasone cream once daily beginning on: a) the day the subject notices the facial DAE; b) the day the subject self-reports the facial DAE; or c) the day the facial DAE is identified by a medical professional. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises topically administering a 0.1% (w / v) betamethasone cream once daily for 14 days or until the facial DAE is completely resolved, whichever occurs first. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises topically administering a 0.1% (w / v) betamethasone cream once daily beginning on: a) the day the subject notices the facial DAE; b) the day the subject self-reports the facial DAE; or c) the day the facial DAE is identified by a medical professional until the facial DAE is completely resolved or for 14 days, whichever occurs first. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises administering an immunosuppressant. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises administering a topical immunosuppressant. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises topically administering an immunosuppressant twice daily. In some embodiments, the reactive enhanced dermatologic management for a facial DAE comprises topically administering an immunosuppressant twice daily with at least eight hours between administrations. In some embodiments, the reactive enhanced dermatologic managementcomprises topically administering a 1.5% (w / v) ruxolitinib cream or 0.1% (w / w) tacrolimus ointment. In some embodiments, the reactive enhanced dermatologic management comprises topically administering a 1.5% (w / v) ruxolitinib cream or 0.1% (w / w) tacrolimus ointment twice daily after 14 days of administering 0.1% (w / v) betamethasone cream. In some embodiments, the reactive enhanced dermatologic management comprises topically administering a 1.5% (w / v) ruxolitinib cream or 0.1% (w / w) tacrolimus ointment for about 11 weeks. In some embodiments, the reactive enhanced dermatologic management comprises topically administering a 1.5% (w / v) ruxolitinib cream or 0.1% (w / w) tacrolimus ointment twice daily, with at least eight hours between each administration, for about 11 weeks beginning after 14 days of administering 0.1% (w / v) betamethasone cream.

[0409] In some embodiments, the reactive enhanced dermatologic management for a face DAE comprises administering a topical immunosuppressant. In some embodiments, the reactive enhanced dermatologic management for a face DAE comprises topically administering a 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment. In some embodiments, the reactive enhanced dermatologic management for a face DAE comprises topically administering 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment to the affected area of the face twice daily. In some embodiments, the reactive enhanced dermatologic management for a face DAE comprises topically administering 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment to the affected area of the face twice daily beginning on: a) the day the subject notices the facial DAE; b) the day the subject self-reports the facial DAE; or c) the day the facial DAE is identified by a medical professional until the facial DAE is completely resolved or for 12 weeks, whichever occurs first. In some embodiments, the reactive enhanced dermatologic management for a face DAE comprises topically administering 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment to the affected area of the face twice daily until complete resolution of the face DAE or up to 12 weeks, whichever occurs first. In some embodiments, the reactive enhanced dermatologic management for a face DAE comprises topically administering 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment to the affected area of the face twice daily beginning on: a) the day the subject notices the facial DAE; b) the day the subject self-reports the facial DAE; or c) the day the facial DAE is identified by a medical professional until the facial DAE is completely resolved or for 12 weeks, whichever occurs first.EMBODIMENTSSet A: Enhanced Dermatologic Management1. A method of reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject, wherein the method comprises: a) administering an antibiotic; b) administering a non-comedogenic moisturizer; and c) administering a topical antiseptic, zinc salt, or both; to the subject, and wherein the subject is being treated with an anti-cancer therapy, wherein the anti-cancer therapy comprises an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) bispecific antibody.2. The method of embodiment 1, wherein the antibody comprises: a first domain that specifically binds EGFR, comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:l, 2, 3, 4, 5 and 6, respectively; and a second domain that specifically binds c-Met, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 ammo acid sequences of SEQ ID NOs:7, 8, 9, 10, 11 and 12, respectively.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 IDNO: 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 1-3, wherein the antibody is of the IgGl isotype.5. The method of any one of embodiments 1-4, 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 1-5, 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 1-7, wherein the antibody comprises a biantennary glycan structure with a fucose content of about 1% to about 15% or less than about 20%.9. The method of any one of embodiments 1-8, wherein the antibody is administered at a dose of about 1,050 mg to about 4,640 mg.10. The method of embodiment 9, wherein the antibody is administered at a dose of about 1,050 mg, about 1,400 mg, about 1,600 mg, about 1,750 mg, about 2,100 mg, about 2,240 mg, about 2,400 mg, about 3,360 mg, about 3,520 mg, or about 4,640 mg.11. The method of embodiment 10, wherein the antibody is administered at a dose of about 1,050 mg.12. The method of embodiment 10, wherein the antibody is administered at a dose of about 1,400 mg.13. The method of embodiment 10, wherein the antibody is administered at a dose of about 1,600 mg.14. The method of embodiment 10, wherein the antibody is administered at a dose of about 2,240 mg.15. The method of embodiment 10, wherein the antibody is administered at a dose of about 3,520 mg.16. The method of embodiment 10, wherein the antibody is administered at a dose of about 4,640 mg.17. The method of any one of embodiments 1-16, wherein the antibody is administered once a week, once every two weeks, once every three weeks, or once every four weeks.18. The method of embodiment 17, wherein the antibody is administered once a week for the first 4 weeks and then once every 2 weeks.19. The method of embodiment 18, wherein the antibody is administered intravenously (IV).20. The method of embodiment 17, wherein the antibody is administered once a week for the first 4 weeks and then once every 4 weeks.21. The method of embodiment 20, wherein the antibody is administered subcutaneously (SC).22. The method of embodiment 21, wherein the antibody is administered at a dose of about 1,600 mg or about 2,240 mg once a week for the first 4 weeks and then at a dose of about 3,520 mg or about 4,640 mg once every 4 weeks.23. The method of any one of embodiments 1-22, wherein the antibody is administered on a 28-day cycle.24. The method of any one of embodiments 1-23, wherein the antibody is administered as a monotherapy.25. The method of any one of embodiments 1-23, wherein the subject treated with the anti-EGFR / c-Met antibody is further administered at least one anti-cancer therapy.26. The method of embodiment 18, wherein the at least one anti-cancer therapy comprises at least one tyrosine kinase inhibitor (TKI) or at least one chemotherapeutic composition.27. The method of embodiment 26, wherein the at least one TKI comprises at least one EGFR TKI.28. The method of embodiment 27, the at least one EGFR TKI comprises lazertinib, osimertinib, capmatinib, or mobocertinib.29. The method of embodiment 28, wherein the at EGFR TKI comprises lazertinib.30. The method of embodiment 29, wherein lazertinib is administered at a dose of 240 mg.31. The method of embodiment 30, wherein lazertinib is administered orally once a day.32. The method of any one of embodiments 1-31, wherein subject has non-small cell lung cancer (NSCLC).33. The method of embodiment 32, wherein cancer is associated with EGFR exon 19 deletion.34. The method of embodiment 32 or 33, wherein cancer is associated with L858R mutation.35. The method of any one of embodiments 1-34, wherein the subject is anti -EGFR therapy naive.36. The method of any one of embodiments 1-35, wherein the subject is treatment naive.37. The method of any one of embodiments 1-34, wherein the subject has received prior anti-EGFR therapy.38. The method of any one of embodiments 1-34 and 37, wherein the subject is relapsed or resistant to treatment with at least one prior anti-cancer therapy.39. The method of embodiment 38, wherein prior anti-cancer therapy is an EGFR TKI.40. The method of embodiment 39, wherein the EGFR TKI is osimertinib.41. The method of embodiment 38, wherein the prior anti-cancer therapy comprises a platinum chemotherapy.42. The method of embodiment 26, wherein the at least one chemotherapeutic composition comprises: a) folinic acid, 5 -fluorouracil, and oxaliplatin or irinotecan; or b) carboplatin and pemetrexed.43. The method of any one of embodiments 1-42, wherein the subject is 18 years of age or older.44. The method of any one of embodiments 1-43, wherein step a) comprises: i) administering to the subject an oral antibiotic for about 12 weeks followed by administering to the subject a topical antibiotic; or ii) administering to the subject an oral antibiotic for about 12 weeks at a first dose followed by administering to the subject the oral antibiotic at a second dose for about 12 weeks.45. The method of embodiment 44, wherein the oral antibiotic comprises a tetracycline antibiotic.46. The method of embodiment 44 or 45, wherein the oral antibiotic is doxycycline or minocycline.47. The method of any one of embodiments 44-46, wherein the oral antibiotic is administered to the subject beginning on the day that the anti-cancer therapy is administered for the first time.48. The method of any one of embodiments 44-47, wherein the oral antibiotic is administered at a dose of about 100 mg twice daily for about 12 weeks.49. The method of any one of embodiments 45-48, wherein the oral antibiotic is administered twice daily for about 12 weeks and then administered once daily for about 12 weeks.50. The method of any one of embodiments 45-49, wherein the oral antibiotic is administered at a dose of about 100 mg twice daily for about 12 weeks and then administered at a dose of about 100 mg or about 50 mg once daily for about 12 weeks.51. The method of any one of embodiments 44-50, wherein the topical antibiotic comprises a lincosamides antibiotic.52. The method of any one of embodiments 44-51, wherein the topical antibiotic comprises clindamycin.53. The method of embodiments 44-52, wherein the topical antibiotic is formulated as a topical lotion.54. The method of embodiment 52, wherein the topical lotion comprises about 1% (w / v) topical antibiotic.55. The method of any one of embodiments 44-54, wherein the topical antibiotic is administered once a day.56. The method of any one of embodiments 44-55, wherein the topical antibiotic is applied to the scalp of the subject.57. The method of any one of embodiments 44-55, wherein the topical antibiotic is applied to the subject before the subject goes to bed.58. The method of any one of embodiments 44-55, wherein the topical antibiotic is applied to the subject after the subject takes a bath or shower.59. The method of any one of embodiments 1-58, wherein step c) comprises administering to the non-comedogenic moisturizer to the subject comprises administering to the subject the non-comedogenic moisturizer at least once a day.60. The method of any one of embodiments 1-59, wherein the non-comedogenic moisturizer comprises at least one selected from the group consisting of shea butter, ceramide-3 (ceramide NP), niacinamide, glycerin, dimethicone, cetearyl alcohol, rapeseed oil, glyceryl stearate, ammonium polyacryloyldimethyl taurate, PEG- 100 stearate, propanediol, Ophiopogon japonicus extract, sorbitan tristearate, dimethiconol, PEG-20 methyl glucose sesquistearate, sodium chloride, mannose, cocamidopropyl betaine, disodium ethylenediaminetetraacetate, capryloyl glycine, caprylyl glycol, citric acid, maltodextrin, xanthan gum, tocopherol, pentaerythrityl tetra-di-t-butyl hydroxyhydrocinnamate, selenium, prebiotics, probiotics, prebiotics, peptides, amino acids, Vitreoscilla filiformis ferment, hyaluronic acid, aloe vera, grape seed extract, moringa, papaya, coconut oil, squalane, and water.61. The method of any one of embodiments 1-60, wherein the non-comedogenic moisturizer comprises a ceramide-based moisturizer.62. The method of any one of embodiments 1-61, wherein the non-comedogenic moisturizer is applied to the face and skin of the subject.63. The method of any one of embodiments 1-62, wherein the non-comedogenic moisturizer is selected from the group consisting of VANICREAM™ Daily Facial Moisturizer, SHANI DARDEN® Hydration Peptide Cream, Neutrogena® Hydroboost Water Boost Cream, CeraVe® Ultra-Light Moisturizing Lotion, humane® Oil-Free Moisturizer, ELTA MD® AM Therapy, TATCHA® The Water Cream, FARMACY® Daily Greens, LA ROCHE-POSAY® Toleriane Double Repair Moisturizer, DIEUX® Air Angel, KIEHL’s® Ultra Facial Oil-Free Gel Cream, LA ROCHE-POSAY® LIPIKAR® Daily Repair Moisturizing Lotion, LA ROCHE- POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Cream, Dr. Jart+® Ceramidin™ Body Lotion, and Charlotte Tilbury® Magic Water Cream.64. The method of any one of embodiments 1-63, wherein the non-comedogenic moisturizer is LA ROCHE-POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Cream.65. The method of any one of embodiments 1-64, wherein step c) comprises administering a topical antiseptic to the subject once a day.66. The method of any one of embodiments 1-65, wherein the topical antiseptic comprises a biguanide antiseptic.67. The method of any one of embodiments 1-66, wherein the topical antiseptic is chlorhexidine.68. The method of any one of embodiments 1-67, wherein the topical antiseptic is formulated as a topical solution.69. The method of any one of embodiments 1-68, wherein the topical antiseptic comprises about 4% (w / v) topical antiseptic.70. The method of any one of embodiments 1-69, wherein the topical antiseptic is applied to the fingernails and toenails.71. The method of any one of embodiments 1-70, wherein the topical antiseptic is administered to the subject starting on the day that the anti-cancer therapy is administered to the subject for the first time.72. The method of any one of embodiments 1-71, wherein step c) comprises administering a zinc salt to the subject once daily.73. The method of any one of embodiments 1-72, wherein step c) comprises administering a zinc salt to the subject twice daily74. The method of any one of embodiments 1-73, wherein the zinc salt is a bioavailable zinc salt.75. The method of any one of embodiments 1-74, wherein the zinc salt is zinc gluconate.76. The method of any one of embodiments 1-75, wherein the zinc salt is administered in a dose of about 70 mg.77. The method of any one of embodiments 1-76, wherein the zinc salt is administered to the subject beginning on the day that the anti-cancer therapy is administered for the first time.78. The method of any one of embodiments 1-77, wherein the zinc salt is administered to the subject at least until treatment with the anti-cancer therapy is halted.79. The method of any one of embodiments 1-77, further comprising administering a premedication with at least one of antihistamines, antipyretics, or glucocorticoids.80. The method of embodiment 79, wherein the premedication comprises diphenhydramine.81. The method of embodiment 80, wherein the diphenhydramine is administered at a dose of 25 to 50 mg.82. The method of embodiment 79, wherein the premedication comprises acetaminophen.83. The method of embodiment 82, wherein the acetaminophen is administered at a dose of 650 to 1,000 mg.84. The method of any one of embodiments 1-83, wherein occurrence or severity of dermatologic adverse events of grade >2 was significantly reduced.85. The method of any one of embodiments 1-84, wherein the dermatological adverse events of grade >2 were significantly reduced by about 50%.86. The method of any one of embodiments 1-85, wherein occurrence or severity of dermatologic adverse events of grade >3 was significantly reduced.87. The method of any one of embodiments 1-86, wherein the dermatological adverse events of grade >3 were significantly reduced by about 50%.88. The method of any one of embodiments 1-87, wherein occurrence or severity of scalp dermatologic adverse events of grade >2 was significantly reduced.89. The method of any one of embodiments 1-88, wherein the scalp grade >2 dermatological adverse events were significantly reduced by about 70%.90. The method of any one of embodiments 1-89, wherein occurrence of dose reduction and / or discontinuation of an anti-cancer therapy was reduced.91. The method of any one of embodiments 1-90, wherein the occurrence of dose reduction and / or discontinuation of an anti-cancer therapy was reduced by about 50%.92. The method of any one of embodiments 1-91, wherein the occurrence of grade >2 dermatologic events is reduced by about 40% after 12 weeks of treatment.93. The method of any one of embodiments 1-92, wherein the occurrence of grade >2 dermatologic events involving the skin, with the exception of paronychia, is reduced by about 50% after 12 weeks of treatment.94. The method of any one of embodiments 1-93, wherein the occurrence of grade >2 dermatologic events involving the scalp is reduced by about 50% after 12 weeks of treatment.95. The method of any one of embodiments 1-94, wherein the occurrence of grade >2 dermatologic events involving the face is reduced by about 70% after 12 weeks of treatment.96. The method of any one of embodiments 1-95, wherein the occurrence of grade >2 dermatologic events involving the body is reduced by about 50% after 12 weeks of treatment.97. The method of any one of embodiments 1 -96, wherein the occurrence of grade >2 dermatologic events is reduced by about 20% after six months of treatment.98. The method of any one of embodiments 1-97, wherein the occurrence of grade >2 dermatologic events involving the skin, with the exception of paronychia, is reduced by about 50% after six months of treatment.99. The method of any one of embodiments 1-98, wherein the occurrence of grade >2 dermatologic events involving the scalp is reduced by about 50% after six months of treatment.100. The method of any one of embodiments 1-99, wherein the occurrence of grade >2 dermatologic events involving the face is reduced by about 60% after six months of treatment.101. The method of any one of embodiments 1-100, wherein the occurrence of grade >2 dermatologic events involving the body is reduced by about 40% after six months of treatment.102. The method of any one of embodiments 1-101, wherein the occurrence of grade >3 dermatologic events involving the scalp is reduced by about 90% after six months of treatment.103. The method of any one of embodiments 1-102, wherein the occurrence of grade >3 dermatologic events involving the face is reduced by about 60% after six months of treatment.104. The method of any one of embodiments 1-103, wherein the occurrence of grade >3 dermatologic events involving the body is reduced by about 60% after six months of treatment.105. The method of any one of embodiments 1-104, wherein the method delays the average onset of a grade >2 dermatologic adverse event by about two months.106. The method of any one of embodiments 1-105, wherein: a) occurrence or severity of dermatologic adverse events of grade >2 was significantly reduced by about 50%; b) occurrence or severity of dermatologic adverse events of grade >3 was significantly reduced by about 50%; c) occurrence or severity of scalp dermatologic adverse events of grade >2 was significantly reduced by about 70%; and / ord) occurrence of dose reduction and / or discontinuation of an anti-cancer therapy was reduced by about 50%.107. The method of any one of embodiments 1-106, wherein: a) occurrence of grade >2 dermatologic events is reduced by about 40% after 12 weeks of treatment; b) occurrence of grade >2 dermatologic events involving the skin, with the exception of paronychia, is reduced by about 50% after 12 weeks of treatment; c) occurrence of grade >2 dermatologic events involving the scalp is reduced by about 50% after 12 weeks of treatment; d) occurrence of grade >2 dermatologic events involving the face is reduced by about 70% after 12 weeks of treatment; and / or e) occurrence of grade >2 dermatologic events involving the body is reduced by about 50% after 12 weeks of treatment.108. The method of any one of embodiments 1-107, wherein: a) occurrence of grade >2 dermatologic events is reduced by about 20% after six months of treatment; b) occurrence of grade >2 dermatologic events involving the skin, with the exception of paronychia, is reduced by about 50% after six months of treatment; c) occurrence of grade >2 dermatologic events involving the scalp is reduced by about 50% after six months of treatment; d) occurrence of grade >2 dermatologic events involving the face is reduced by about 60% after six months of treatment; and / or e) occurrence of grade >2 dermatologic events involving the body is reduced by about 40% after six months of treatment.109. The method of any one of embodiments 1-108, wherein: a) occurrence of grade >3 dermatologic events involving the scalp is reduced by about 90% after six months of treatment; b) occurrence of grade >3 dermatologic events involving the face is reduced by about 60% after six months of treatment;c) occurrence of grade >3 dermatologic events involving the body is reduced by about 60% after six months of treatment; and / or d) method delays the average onset of a grade >2 dermatologic adverse event by about two months.110. The method of any one of embodiments 1-109, wherein: a) occurrence or severity of dermatologic adverse events of grade >2 was significantly reduced by about 50%; b) occurrence or severity of dermatologic adverse events of grade >3 was significantly reduced by about 50%; c) occurrence or severity of scalp dermatologic adverse events of grade >2 was significantly reduced by about 70%; d) occurrence of dose reduction and / or discontinuation of an anti-cancer therapy was reduced by about 50%; e) occurrence of grade >2 dermatologic events is reduced by about 40% after 12 weeks of treatment; f) occurrence of grade >2 dermatologic events involving the skin, with the exception of paronychia, is reduced by about 50% after 12 weeks of treatment; g) occurrence of grade >2 dermatologic events involving the scalp is reduced by about 50% after 12 weeks of treatment; h) occurrence of grade >2 dermatologic events involving the face is reduced by about 70% after 12 weeks of treatment; i) occurrence of grade >2 dermatologic events involving the body is reduced by about 50% after 12 weeks of treatment. j) occurrence of grade >2 dermatologic events is reduced by about 20% after six months of treatment; k) occurrence of grade >2 dermatologic events involving the skin, with the exception of paronychia, is reduced by about 50% after six months of treatment; l) occurrence of grade >2 dermatologic events involving the scalp is reduced by about 50% after six months of treatment; m) occurrence of grade >2 dermatologic events involving the face is reduced by about 60% after six months of treatment;n) occurrence of grade >2 dermatologic events involving the body is reduced by about 40% after six months of treatment; o) occurrence of grade >3 dermatologic events involving the scalp is reduced by about 90% after six months of treatment; p) occurrence of grade >3 dermatologic events involving the face is reduced by about 60% after six months of treatment; q) occurrence of grade >3 dermatologic events involving the body is reduced by about 60% after six months of treatment; and / or r) method delays the average onset of a grade >2 dermatologic adverse event by about two months.111. An antibiotic for use in the method of any one of embodiments 1-110.112. Use of an antibiotic in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject according to the method of any one of embodiments 1-110, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.113. Use of an antibiotic in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antiseptic, a zinc salt, or both.114. A non-comedogenic moisturizer for use in the method of any one of embodiments 1- 110.115. Use of a non-comedogenic moisturizer in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject according to the method of any one of embodiments 1-110, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.116. Use of a non-comedogenic moisturizer in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises co-administration of: 1) the medicament, 2) an antibiotic, and 3) an antiseptic, a zinc salt, or both.117. A topical antiseptic for use in the method of any one of embodiments 1-110.118. Use of a topical antiseptic in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject according to the method of any one of embodiments 1-110, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.119. Use of a topical antiseptic in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject, wherein the subject is being treated with an anti- EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises co- administration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.120. A zinc salt for use in the method of any one of embodiments 1-110.121. Use of a zinc salt in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject according to the method of any one of embodiments 1-110, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.122. Use of a zinc salt in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.Set B: Reactive Enhanced Dermatologic Management1. A method of reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject, wherein the method comprises:a) administering an antibiotic; b) administering a non-comedogenic moisturizer; and c) administering a topical antiseptic, zinc salt, or both; to the subject, and wherein the subject is being treated with an anti-cancer therapy, wherein the anti-cancer therapy comprises an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) bispecific antibody.2. The method of embodiment 1, wherein the antibody comprises: a first domain that specifically binds EGFR, comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs:l, 2, 3, 4, 5 and 6, respectively; and a second domain that specifically binds c-Met, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 ammo acid sequences of SEQ ID NOs:7, 8, 9, 10, 11 and 12, respectively.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 IDNO: 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 1-3, wherein the antibody is of the IgGl isotype.5. The method of any one of embodiments 1-4, 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 1-5, 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 1-7, wherein the antibody comprises a biantennary glycan structure with a fucose content of about 1% to about 15% or less than about 20%.9. The method of any one of embodiments 1-8, wherein the antibody is administered at a dose of about 1,050 mg to about 4,640 mg.10. The method of embodiment 9, wherein the antibody is administered at a dose of about 1,050 mg, about 1,400 mg, about 1,600 mg, about 1,750 mg, about 2,100 mg, about 2,240 mg, about 2,400 mg, about 3,360 mg, about 3,520 mg, or about 4,640 mg.11. The method of embodiment 10, wherein the antibody is administered at a dose of about 1,050 mg.12. The method of embodiment 10, wherein the antibody is administered at a dose of about 1,400 mg.13. The method of embodiment 10, wherein the antibody is administered at a dose of about 1,600 mg.14. The method of embodiment 10, wherein the antibody is administered at a dose of about 2,240 mg.15. The method of embodiment 10, wherein the antibody is administered at a dose of about 3,520 mg.16. The method of embodiment 10, wherein the antibody is administered at a dose of about 4,640 mg.17. The method of any one of embodiments 1-16, wherein the antibody is administered once a week, once every two weeks, once every three weeks, or once every four weeks.18. The method of embodiment 17, wherein the antibody is administered once a week for the first 4 weeks and then once every 2 weeks.19. The method of embodiment 18, wherein the antibody is administered intravenously (IV).20. The method of embodiment 17, wherein the antibody is administered once a week for the first 4 weeks and then once every 4 weeks.21. The method of embodiment 20, wherein the antibody is administered subcutaneously (SC).22. The method of embodiment 21, wherein the antibody is administered at a dose of about 1,600 mg or about 2,240 mg once a week for the first 4 weeks and then at a dose of about 3,520 mg or about 4,640 mg once every 4 weeks.23. The method of any one of embodiments 1-22, wherein the antibody is administered on a 28-day cycle.24. The method of any one of embodiments 1-23, wherein the antibody is administered as a monotherapy.25. The method of any one of embodiments 1-23, wherein the subject treated with the anti-EGFR / c-Met antibody is further administered at least one anti-cancer therapy.26. The method of embodiment 18, wherein the at least one anti-cancer therapy comprises at least one tyrosine kinase inhibitor (TKI) or at least one chemotherapeutic composition.27. The method of embodiment 26, wherein the at least one TKI comprises at least oneEGFR TKI.28. The method of embodiment 27, the at least one EGFR TKI comprises lazertinib, osimertinib, capmatinib, or mobocertinib.29. The method of embodiment 28, wherein the at EGFR TKI comprises lazertinib.30. The method of embodiment 29, wherein lazertinib is administered at a dose of 240 mg.31. The method of embodiment 30, wherein lazertinib is administered orally once a day.32. The method of any one of embodiments 1-31, wherein subject has non-small cell lung cancer (NSCLC).33. The method of embodiment 32, wherein cancer is associated with EGFR exon 19 deletion.34. The method of embodiment 32 or 33, wherein cancer is associated with L858R mutation.35. The method of any one of embodiments 1-34, wherein the subject is anti -EGFR therapy naive.36. The method of any one of embodiments 1-35, wherein the subject is treatment naive.37. The method of any one of embodiments 1-34, wherein the subject has received prior anti-EGFR therapy.38. The method of any one of embodiments 1-34 and 37, wherein the subject is relapsed or resistant to treatment with at least one prior anti-cancer therapy.39. The method of embodiment 38, wherein prior anti-cancer therapy is an EGFR TKI.40. The method of embodiment 39, wherein the EGFR TKI is osimertinib.41. The method of embodiment 38, wherein the prior anti-cancer therapy comprises a platinum chemotherapy.42. The method of embodiment 26, wherein the at least one chemotherapeutic composition comprises: a) folinic acid, 5 -fluorouracil, and oxaliplatin or irinotecan; or b) carboplatin and pemetrexed.43. The method of any one of embodiments 1-42, wherein the subject is 18 years of age or older.44. The method of any one of embodiments 1-43, wherein step a) comprises: i) administering to the subject an oral antibiotic for about 12 weeks followed by administering to the subject a topical antibiotic; or ii) administering to the subject an oral antibiotic for about 12 weeks at a first dose followed by administering to the subject the oral antibiotic at a second dose for about 12 weeks.45. The method of embodiment 44, wherein the oral antibiotic comprises a tetracycline antibiotic.46. The method of embodiment 44 or 45, wherein the oral antibiotic is doxycycline or minocycline.47. The method of any one of embodiments 44-46, wherein the oral antibiotic is administered to the subject beginning on the day that the anti-cancer therapy is administered for the first time.48. The method of any one of embodiments 44-47, wherein the oral antibiotic is administered at a dose of about 100 mg twice daily for about 12 weeks.49. The method of any one of embodiments 45-48, wherein the oral antibiotic is administered twice daily for about 12 weeks and then administered once daily for about 12 weeks.50. The method of any one of embodiments 45-49, wherein the oral antibiotic is administered at a dose of about 100 mg twice daily for about 12 weeks and then administered at a dose of about 100 mg or about 50 mg once daily for about 12 weeks.51. The method of any one of embodiments 44-50, wherein the topical antibiotic comprises a lincosamides antibiotic.52. The method of any one of embodiments 44-51, wherein the topical antibiotic comprises clindamycin.53. The method of embodiments 44-52, wherein the topical antibiotic is formulated as a topical lotion.54. The method of embodiment 52, wherein the topical lotion comprises about 1% (w / v) topical antibiotic.55. The method of any one of embodiments 44-54, wherein the topical antibiotic is administered once a day.56. The method of any one of embodiments 44-55, wherein the topical antibiotic is applied to the scalp of the subject.57. The method of any one of embodiments 44-55, wherein the topical antibiotic is applied to the subject before the subject goes to bed.58. The method of any one of embodiments 44-55, wherein the topical antibiotic is applied to the subject after the subject takes a bath or shower.59. The method of any one of embodiments 1-58, wherein step c) comprises administering to the non-comedogenic moisturizer to the subject comprises administering to the subject the non-comedogenic moisturizer at least once a day.60. The method of any one of embodiments 1-59, wherein the non-comedogenic moisturizer comprises at least one selected from the group consisting of shea butter, ceramide-3 (ceramide NP), niacinamide, glycerin, dimethicone, cetearyl alcohol, rapeseed oil, glyceryl stearate, ammonium polyacryloyldimethyl taurate, PEG- 100 stearate, propanediol, Ophiopogon japonicus extract, sorbitan tristearate, dimethiconol, PEG-20 methyl glucose sesquistearate, sodium chloride, mannose, cocamidopropyl betaine, disodium ethylenediaminetetraacetate, capryloyl glycine, caprylyl glycol, citric acid, maltodextrin, xanthan gum, tocopherol, pentaerythrityl tetra-di-t-butyl hydroxyhydrocinnamate, selenium, prebiotics, probiotics, prebiotics, peptides, amino acids, Vitreoscilla filiformis ferment, hyaluronic acid, aloe vera, grape seed extract, moringa, papaya, coconut oil, squalane, and water.61. The method of any one of embodiments 1-60, wherein the non-comedogenic moisturizer comprises a ceramide-based moisturizer.62. The method of any one of embodiments 1-61, wherein the non-comedogenic moisturizer is applied to the face and skin of the subject.63. The method of any one of embodiments 1-62, wherein the non-comedogenic moisturizer is selected from the group consisting of VANICREAM™ Daily Facial Moisturizer, SHANI DARDEN® Hydration Peptide Cream, Neutrogena® Hydroboost Water Boost Cream, CeraVe® Ultra-Light Moisturizing Lotion, humane® Oil-Free Moisturizer, ELTA MD® AM Therapy, TATCHA® The Water Cream, FARMACY® Daily Greens, LA ROCHE-POSAY® Toleriane Double Repair Moisturizer, DIEUX® Air Angel, KIEHL’s® Ultra Facial Oil-Free Gel Cream, LA ROCHE-POSAY® LIPIKAR® Daily Repair Moisturizing Lotion, LA ROCHE- POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Cream, Dr. Jart+® Ceramidin™ Body Lotion, and Charlotte Tilbury® Magic Water Cream.64. The method of any one of embodiments 1-63, wherein the non-comedogenic moisturizer is LA ROCHE-POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Cream.65. The method of any one of embodiments 1-64, wherein step c) comprises administering a topical antiseptic to the subject once a day.66. The method of any one of embodiments 1-65, wherein the topical antiseptic comprises a biguanide antiseptic.67. The method of any one of embodiments 1-66, wherein the topical antiseptic is chlorhexidine.68. The method of any one of embodiments 1-67, wherein the topical antiseptic is formulated as a topical solution.69. The method of any one of embodiments 1-68, wherein the topical antiseptic comprises about 4% (w / v) topical antiseptic.70. The method of any one of embodiments 1-69, wherein the topical antiseptic is applied to the fingernails and toenails.71. The method of any one of embodiments 1-70, wherein the topical antiseptic is administered to the subject starting on the day that the anti-cancer therapy is administered to the subject for the first time.72. The method of any one of embodiments 1-71, wherein step c) comprises administering a zinc salt to the subject once daily.73. The method of any one of embodiments 1-72, wherein step c) comprises administering a zinc salt to the subject twice daily74. The method of any one of embodiments 1-73, wherein the zinc salt is a bioavailable zinc salt.75. The method of any one of embodiments 1-74, wherein the zinc salt is zinc gluconate.76. The method of any one of embodiments 1-75, wherein the zinc salt is administered in a dose of about 70 mg.77. The method of any one of embodiments 1-76, wherein the zinc salt is administered to the subject beginning on the day that the anti-cancer therapy is administered for the first time.78. The method of any one of embodiments 1-77, wherein the zinc salt is administered to the subject at least until treatment with the anti-cancer therapy is halted.79. The method of any one of embodiments 1-78, further comprising administering to the subject: a) a beta blocker and a corticosteroid if the subject develops a scalp dermatologic adverse event of interest (DAE); b) a antiseptic alone or in combination with a beta blocker and / or a Janus kinase (JAK) inhibitor, if the subject develops paronychia; c) a corticosteroid or immunosuppressant if the subject develops a body DAE; and / or d) a corticosteroid or immunosuppressant if the subject develops a facial DAE.80. The method of embodiment 79, a) comprises administering an oral beta blocker.81. The method of embodiment 79 or 80, wherein the beta blocker of a) is administered once daily.82. The method of any one of embodiments 79-81, wherein the beta blocker of a) comprises a nonselective beta blocker.83. The method of any one of embodiments 79-82, wherein the beta blocker of a) is propranolol.84. The method of any one of embodiments 79-83, wherein the beta blocker of a) is administered in a dose of about 30 mg once daily.85. The method of any one of embodiments 79-84, wherein the beta blocker of a) is administered in a dose of about 10 mg three times daily (10 mg TID).86. The method of any one of embodiments 79-85, wherein the beta blocker of a) is administered to the subject beginning on the first day: a) the subject notices the scalp DAE; b) the subject self-reports the scalp DAE; and / or c) a medical provider identifies the scalp DAE.87. The method of any one of embodiments 79-86, wherein the beta blocker of a) is administered until complete resolution of the scalp DAE.88. The method of any one of embodiments 79-87, wherein a) comprises administering to the subject a topical corticosteroid.89. The method of any one of embodiments 79-88, wherein the corticosteroid of a) is administered once daily.90. The method of any one of embodiments 79-89, wherein the corticosteroid of a) comprises a glucocorticoid.91. The method of any one of embodiments 79-90, wherein the corticosteroid of a) comprises a 0.05% (w / v) clobetasol shampoo.92. The method of any one of embodiments 79-91, wherein the corticosteroid of a) is applied to the scalp of the subject for about 15 minutes and rinsed off once daily.93. The method of any one of embodiments 79-92, wherein the corticosteroid of a) is administered to the subject beginning on the first day: a) the subject notices the scalp DAE; b) the subject self-reports the scalp DAE; and / or c) a medical provider identifies the scalp DAE.94. The method of any one of embodiments 79-93, wherein the corticosteroid of a) is administered until at least the last day the anti-cancer therapy is administered.95. The method of any one of embodiments 79-94, wherein b) comprises administering to the subject a topical antiseptic.96. The method of any one of embodiments 79-95, wherein the antiseptic of b) is administered once daily.97. The method of any one of embodiments 79-96, wherein the antiseptic comprises a biguanide antiseptic.98. The method of any one of embodiments 79-97, wherein the antiseptic of b) comprises a 4% (w / v) chlorhexidine solution.99. The method of any one of embodiments 79-98, wherein the antiseptic of b) is applied to the hands and feet once daily.100. The method of any one of embodiments 79-99, wherein the antiseptic of b) is administered to the subject beginning on the first day: a) the subject notices the paronychia; b) the subject self-reports the paronychia; and / or c) a medical provider identifies the paronychia.101. The method of any one of embodiments 79-100, wherein the antiseptic of b) is administered until at least the last day the anti-cancer therapy is administered.102. The method of any one of embodiments 79-101, wherein b) comprises administering to the subject a topical beta blocker.103. The method of any one of embodiments 79-102, wherein the beta blocker of b) is applied twice daily.104. The method of any one of embodiments 79-103, wherein the beta blocker of b) comprises a nonspecific beta blocker.105. The method of any one of embodiments 79-104, wherein the beta blocker of b) solution comprises a 0.5% (w / v) timolol solution.106. The method of any one of embodiments 79-105, wherein a) comprises applying one drop of the topical beta blocker solution to the paronychia twice daily.107. The method of any one of embodiments 79-106, wherein the beta blocker of b) is administered to the subject beginning on the first day: a) the subject notices the paronychia; b) the subject self-reports the paronychia; and / or c) a medical provider identifies the paronychia.108. The method of any one of embodiments 79-107, wherein the beta blocker of b) is administered until at least the last day the anti-cancer therapy is administered.109. The method of any one of embodiments 79-100, wherein b) comprises administering to the subject a topical JAK inhibitor.110. The method of any one of embodiments 79-109, wherein the JAK inhibitor of b) is applied twice daily.111. The method of any one of embodiments 79-110, wherein the JAK inhibitor of b) comprises a JAK1 / JAK2 inhibitor.112. The method of any one of embodiments 79-111, wherein the JAK inhibitor of b) comprises a 1.5% (w / v) ruxolitinib cream.113. The method of any one of embodiments 79-112, wherein the JAK inhibitor of b) is applied to the paronychia twice daily.114. The method of any one of embodiments 79-113, wherein the JAK inhibitor of b) is administered to the subject beginning after 4 weeks of administering the topical antiseptic if the paronychia has not completely resolved.115. The method of any one of embodiments 79-114, wherein the JAK inhibitor of b) is administered to the subject until complete resolution of the paronychia or 12 weeks, whichever occurs first.116. The method of any one of embodiments 79-115, wherein c) comprises administering to the subject a topical corticosteroid.117. The method of any one of embodiments 79-116, wherein the corticosteroid of c) is applied once daily.118. The method of any one of embodiments 79-117, wherein the corticosteroid of c) comprises a glucocorticoid.119. The method of any one of embodiments 79-118, wherein the corticosteroid of c) cream comprises a 0.1% betamethasone cream.120. The method of any one of embodiments 79-119, wherein c) comprises applying a thin layer of a corticosteroid cream to the affected body area once daily.121. The method of any one of embodiments 79-120, wherein the corticosteroid of c) is administered to the subject beginning on the first day: a) the subject notices the body DAE; b) the subject self-reports the body DAE; and / or c) a medical provider identifies the body DAE.122. The method of any one of embodiments 79-121, wherein the corticosteroid of c) is administered until complete resolution of the body DAE.123. The method of any one of embodiments 79-122, wherein c) comprises administering to the subject a topical immunosuppressant.124. The method of any one of embodiments 79-123, wherein the immunosuppressant of c) is applied twice daily.125. The method of any one of embodiments 79-124, wherein the immunosuppressant of c) comprises a JAK1 / JAK2 inhibitor or a calcineurin inhibitor.126. The method of any one of embodiments 79-125, wherein the immunosuppressant of c) comprises a 1.5% (w / v) ruxolitinib cream or a 0.1% tacrolimus ointment.127. The method of any one of embodiments 79-126, wherein c) comprises applying a thin layer of a topical immunosuppressant to the affected body area twice daily.128. The method of any one of embodiments 79-127, wherein the immunosuppressant of c) is administered to the subject beginning on the first day: a) the subject notices the body DAE; b) the subject self-reports the body DAE; and / or c) a medical provider identifies the body DAE.129. The method of any one of embodiments 79-128, wherein the immunosuppressant of c) is administered until complete resolution of the body DAE or for up to 12 weeks, whichever occurs first.130. The method of any one of embodiments 79-129, wherein d) comprises administering to the subject a topical corticosteroid.131. The method of any one of embodiments 79-130, wherein the corticosteroid of d) is applied once daily.132. The method of any one of embodiments 79-131, wherein the corticosteroid of d) comprises a glucocorticoid.133. The method of any one of embodiments 79-132, wherein the corticosteroid of d) comprises a 0.1% betamethasone cream.134. The method of any one of embodiments 79-133, wherein d) comprises applying a thin layer a topical corticosteroid to the affected facial area once daily.135. The method of any one of embodiments 79-134, wherein the corticosteroid of d) is administered to the subject beginning on the first day: a) the subject notices the facial DAE; b) the subject self-reports the facial DAE; and / or c) a medical provider identifies the facial DAE.136. The method of any one of embodiments 79-135, wherein the corticosteroid of d) is administered for about 14 days, or until complete resolution of the facial DAE, whichever occurs first.137. The method of any one of embodiments 79-136, wherein d) further comprises administering to the subject a topical immunosuppressant if the corticosteroid was administered for 14 days and the facial DAE has not been completely resolved.138. The method of embodiment 137, wherein the immunosuppressant of d) is administered twice daily.139. The method of embodiment 137 or 138, wherein the immunosuppressant of d) comprises a JAK1 / JAK2 inhibitor or a calcineurin inhibitor.140. The method of embodiment 137 or 138, wherein the immunosuppressant of d) comprises a 1.5% (w / v) ruxolitinib cream or a 0.1% (w / w) tacrolimus ointment.141. The method of any one of embodiments 137-140, wherein d) comprises administering a thin layer of a topical immunosuppressant to the affected facial area twice daily with at least eight hours between administrations.142. The method of any one of embodiments 137-141, wherein the immunosuppressant of d) is administered to the subject for about 11 weeks or until complete resolution of the facial DAE, whichever occurs first.143. The method of any one of embodiments 79-142, wherein d) comprises administering to a subject a topical immunosuppressant.144. The method of any one of embodiments 79-143, wherein the immunosuppressant of d) comprises a JAK1 / JAK2 inhibitor or a calcineurin inhibitor.145. The method of any one of embodiments 79-144, wherein the immunosuppressant of d) comprises a 1.5% (w / v) ruxolitinib cream or a 0.1% (w / w) tacrolimus ointment.146. The method of any one of embodiments 79-145, wherein d) comprises administering a thin layer of a topical immunosuppressant to the affected facial area twice daily with at least eight hours between administrations.147. The method of any one of embodiments 79-146, wherein the immunosuppressant of d) is administered to the subject until complete resolution of the facial DAE or up to 12 weeks, whichever occurs first.148. The method of any one of embodiments 79-147, further comprising administering a pre-dose medication with at least one of antihistamines, antipyretics, or glucocorticoids before administration of the anti-cancer therapy.149. The method of embodiment 148, wherein the pre-dose medication comprises diphenhydramine.150. The method of embodiment 149, wherein the diphenhydramine is administered at a dose of 25 mg to 50 mg before each administration of the anti-cancer therapy.151. The method of any one of embodiments 148-150, wherein the pre-dose medication comprises acetaminophen.152. The method of embodiment 151, wherein the acetaminophen is administered at a dose of 650 mg to 1,000 mg before each administration of the anti-cancer therapy.153. The method of any one of embodiments 148-152, wherein the glucocorticoid is dexamethasone.154. The method of embodiment 153, wherein the dexamethasone is administered at a dose of about 20 mg before the first administration of the anti-cancer therapy.155. The method of embodiment 153, wherein the dexamethasone is administered at a dose of about 10 mg before any administration of the anti-cancer therapy after the first administration.156. The method of any one of embodiments 148-155, wherein administration of the predose medication further comprises administering of a medication with at least one of an H2 antagonist or antiemetic after each administration of the anti-cancer therapy.157. The method of embodiment 156, wherein the H2 antagonist is ranitidine.158. The method of embodiment 157, wherein the ranitidine is administered at a dose of about 50 mg.159. The method of any one of embodiments 148-158, wherein the antiemetic is ondansetron.160. The method of embodiment 159, wherein the ondansetron is administered at a dose of about 8 mg or about 16 mg.161. The method of any one of embodiments 1-160, wherein the method further comprises administering a post-dose medication comprising at least one of a glucocorticoid, an antihistamine, an antipyretic, an opiate, or an antiemetic.162. The method of embodiment 161, wherein the glucocorticoid is dexamethasone.163. The method of embodiment 162, wherein the dexamethasone is administered at a dose of about 10 mg.164. The method of any one of embodiments 161-163, wherein the antihistamine is diphenhydramine.165. The method of embodiment 164, wherein the diphenhydramine is administered at a dose of between about 25 mg and about 50 mg.166. The method of any one of embodiments 161-165, wherein the antipyretic is acetaminophen.167. The method of embodiment 166, wherein the acetaminophen is administered at a dose of between about 650 mg and about 1,000 mg.168. The method of any one of embodiments 161-167, wherein the opiate is meperidine.169. The method of embodiment 168, wherein the meperidine is administered at a dose of between about 25 mg and about 100 mg.170. The method of any one of embodiments 161-169, wherein the anti emetic is ondansetron.171. The method of embodiment 170, wherein the ondansetron is administered in a dose of between about 8 mg and about 16 mg.172. An antibiotic for use in the method of any one of embodiments 1-171.173. Use of an antibiotic in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject according to the method of any one of embodiments 1-171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.174. Use of an antibiotic in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antiseptic, a zinc salt, or both.175. A non-comedogenic moisturizer for use in the method of any one of embodiments 1- 171.176. Use of a non-comedogenic moisturizer in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject according to the method of any one of embodiments 1-171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.177. Use of a non-comedogenic moisturizer in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises co-administration of: 1) the medicament, 2) an antibiotic, and 3) an antiseptic, a zinc salt, or both.178. A topical antiseptic for use in the method of any one of embodiments 1-171.179. Use of a topical antiseptic in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject according to the method of any one of embodiments 1-171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.180. Use of a topical antiseptic in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises co- administration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.181. A zinc salt for use in the method of any one of embodiments 1-171.182. Use of a zinc salt in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject according to the method of any one of embodiments 1-171, wherein the subject is being treated with an anti -EGFR / c-Met bispecific antibody.183. Use of a zinc salt in the manufacture of a medicament for reducing occurrence or severity of DAEs in a subject, wherein the subject is being treated with an anti -EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.184. A beta blocker for use in the method of any one of embodiments 79-171.185. Use of a beta blocker in the manufacture of a medicament for reducing occurrence or severity of scalp DAEs in a subject according to the method of any one of embodiments 79- 171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.186. Use of a beta blocker in the manufacture of a medicament for reducing occurrence or severity of scalp DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c- Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.187. A corticosteroid for use in the method of any one of embodiments 79-171.188. Use of a corticosteroid in the manufacture of a medicament for reducing occurrence or severity of scalp DAEs in a subject according to the method of any one of embodiments 79- 171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.189. Use of a corticosteroid in the manufacture of a medicament for reducing occurrence or severity of scalp DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c- Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.190. An antiseptic for use in the method of any one of embodiments 79-171.191. Use of an antiseptic in the manufacture of a medicament for reducing occurrence or severity of paronychia in a subject according to the method of any one of embodiments 79-171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.192. Use of an antiseptic in the manufacture of a medicament for reducing occurrence or severity of paronychia in a subject, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.193. A beta blocker use in the method of any one of embodiments 79-171.194. Use of a beta blocker in the manufacture of a medicament for reducing occurrence or severity of paronychia in a subject according to the method of any one of embodiments 79- 171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.195. Use of a beta blocker in the manufacture of a medicament for reducing occurrence or severity of paronychia in a subject, wherein the subject is being treated with an anti-EGFR / c- Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.193. A Janus kinase (JAK) inhibitor use in the method of any one of embodiments 79- 171.194. Use of a JAK inhibitor in the manufacture of a medicament for reducing occurrence or severity of paronychia in a subject according to the method of any one of embodiments 79- 171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.195. Use of a JAK inhibitor in the manufacture of a medicament for reducing occurrence or severity of paronychia in a subject, wherein the subject is being treated with an anti-EGFR / c- Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.196. A corticosteroid for use in the method of any one of embodiments 79-171.197. Use of a corticosteroid in the manufacture of a medicament for reducing occurrence or severity of body DAEs in a subject according to the method of any one of embodiments 79- 171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.198. Use of a corticosteroid in the manufacture of a medicament for reducing occurrence or severity of body DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c- Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.199. An immunosuppressant for use in the method of any one of embodiments 79-171.200. Use of an immunosuppressant in the manufacture of a medicament for reducing occurrence or severity of body DAEs in a subject according to the method of any one of embodiments 79-171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.201. Use of an immunosuppressant in the manufacture of a medicament for reducing occurrence or severity of body DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises co- administration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.202. A corticosteroid for use in the method of any one of embodiments 79-171.203. Use of a corticosteroid in the manufacture of a medicament for reducing occurrence or severity of facial DAEs in a subject according to the method of any one of embodiments 79- 171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.204. Use of a corticosteroid in the manufacture of a medicament for reducing occurrence or severity of facial DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c- Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises coadministration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.205. An immunosuppressant for use in the method of any one of embodiments 79-171.206. Use of an immunosuppressant in the manufacture of a medicament for reducing occurrence or severity of facial DAEs in a subject according to the method of any one of embodiments 79-171, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody.207. Use of an immunosuppressant in the manufacture of a medicament for reducing occurrence or severity of facial DAEs in a subject, wherein the subject is being treated with an anti-EGFR / c-Met bispecific antibody, wherein the reducing occurrence or severity of DAEs comprises co- administration of: 1) the medicament, 2) a non-comedogenic moisturizer, and 3) an antibiotic.SET C: Prophylactic Medicaments1. Use of an antibiotic in the manufacture of a medicament for reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject, wherein the reducing occurrence or severity of DAEs comprises coadministration of the antibiotic in combination with: a) a non-comedogenic moisturizer; and b) an antiseptic, a zinc salt, or both, and wherein the subject is being treated with an anti-cancer therapy, wherein the anti-cancer therapy comprises an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) bispecific antibody.2. The use of embodiment 1, wherein the antibody comprises: a first domain that specifically binds EGFR, comprising heavy chain complementarity determining region 1 (HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5 and 6, respectively; and a second domain that specifically binds c-Met, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NOs: 7, 8, 9, 10, 11 and 12, respectively.3. The use 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 use of any one of embodiments 1-3, wherein the antibody is of the IgGl isotype.5. The use of any one of embodiments 1-4, 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 use of any one of embodiments 1-5, wherein the antibody is an isolated bispecific antibody.7. The use of embodiment 6, wherein the bispecific antibody is amivantamab.8. The use of any one of embodiments 1-7, wherein the antibody comprises a biantennary glycan structure with a fucose content of about 1% to about 15% or less than about 20%.9. The use of any one of embodiments 1-8, wherein the antibody is administered at a dose of about 1,050 mg to about 4,640 mg.10. The use of embodiment 9, wherein the antibody is administered at a dose of about 1,050 mg, about 1,400 mg, about 1,600 mg, about 1,750 mg, about 2,100 mg, about 2,240 mg, about 2,400 mg, about 3,360 mg, about 3,520 mg, or about 4,640 mg.11. The use of embodiment 10, wherein the antibody is administered at a dose of about 1,050 mg.12. The use of embodiment 10, wherein the antibody is administered at a dose of about 1,400 mg.13. The use of embodiment 10, wherein the antibody is administered at a dose of about 1,600 mg.14. The use of embodiment 10, wherein the antibody is administered at a dose of about 2,240 mg.15. The use of embodiment 10, wherein the antibody is administered at a dose of about 3,520 mg.16. The use of embodiment 10, wherein the antibody is administered at a dose of about 4,640 mg.17. The use of any one of embodiments 1-16, wherein the antibody is administered once a week, once every two weeks, once every three weeks, or once every four weeks.18. The use of embodiment 17, wherein the antibody is administered once a week for the first 4 weeks and then once every 2 weeks.19. The use of embodiment 18, wherein the antibody is administered intravenously (IV).20. The use of embodiment 17, wherein the antibody is administered once a week for the first 4 weeks and then once every 4 weeks.21. The use of embodiment 20, wherein the antibody is administered subcutaneously (SC).22. The use of embodiment 21, wherein the antibody is administered at a dose of about 1,600 mg or about 2,240 mg once a week for the first 4 weeks and then at a dose of about 3,520 mg or about 4,640 mg once every 4 weeks.23. The use of any one of embodiments 1-22, wherein the antibody is administered on a 28-day cycle.24. The use of any one of embodiments 1-23, wherein the antibody is administered as a monotherapy.25. The use of any one of embodiments 1-23, wherein the subject treated with the anti- EGFR / c-Met antibody is further administered at least one anti-cancer therapy.26. The use of embodiment 18, wherein the at least one anti-cancer therapy comprises at least one tyrosine kinase inhibitor (TKI) or at least one chemotherapeutic composition.27. The use of embodiment 26, wherein the at least one TKI comprises at least one EGFR TKI.28. The use of embodiment 27, the at least one EGFR TKI comprises lazertinib, osimertinib, capmatinib, or mobocertinib.29. The use of embodiment 28, wherein the at EGFR TKI comprises lazertinib.30. The use of embodiment 29, wherein lazertinib is administered at a dose of 240 mg.31. The use of embodiment 30, wherein lazertinib is administered orally once a day.32. The use of any one of embodiments 1-31, wherein subject has non-small cell lung cancer (NSCLC).33. The use of embodiment 32, wherein cancer is associated with EGFR exon 19 deletion.34. The use of embodiment 32 or 33, wherein cancer is associated with L858R mutation.35. The use of any one of embodiments 1-34, wherein the subject is anti-EGFR therapy naive.36. The use of any one of embodiments 1-35, wherein the subject is treatment naive.37. The use of any one of embodiments 1-34, wherein the subject has received prior anti- EGFR therapy.38. The use of any one of embodiments 1-34 and 37, wherein the subject is relapsed or resistant to treatment with at least one prior anti-cancer therapy.39. The use of embodiment 38, wherein prior anti-cancer therapy is an EGFR TKI.40. The use of embodiment 39, wherein the EGFR TKI is osimertinib.41. The use of embodiment 38, wherein the prior anti-cancer therapy comprises a platinum chemotherapy.42. The use of embodiment 26, wherein the at least one chemotherapeutic composition comprises: a) folinic acid, 5 -fluorouracil, and oxaliplatin or irinotecan; or b) carboplatin and pemetrexed.43. The use of any one of embodiments 1-42, wherein the subject is 18 years of age or older.44. The use of any one of embodiments 1-43, wherein the reducing occurrence or severity of DAEs comprises: i) administration of an oral antibiotic for about 12 weeks followed by administration of a topical antibiotic; or ii) administration of an oral antibiotic for about 12 weeks at a first dose followed by administration of the oral antibiotic at a second dose for about 12 weeks.45. The use of embodiment 45, wherein the oral antibiotic is doxycycline or minocycline.46. The use of embodiment 45 or 46, wherein the oral antibiotic is administered to the subject beginning on the day that the anti-cancer therapy is administered for the first time.47. The use of any one of embodiments 45-47, wherein the oral antibiotic is administered at a dose of about 100 mg twice daily for about 12 weeks.48. The use of any one of embodiments 45-48, wherein the oral antibiotic is administered twice daily for about 12 weeks and then administered once daily for about 12 weeks.49. The use of any one of embodiments 45-49, wherein the oral antibiotic is administered at a dose of about 100 mg twice daily for about 12 weeks and then administered at a dose of about 100 mg or about 50 mg once daily for about 12 weeks.50. The use of any one of embodiments 45-48, wherein the topical antibiotic comprises clindamycin.51. The use of any one of embodiments 45-51, wherein the topical antibiotic is formulated as a topical lotion.52. The use of embodiment 52, wherein the topical lotion comprises about 1% (w / v) topical antibiotic.53. The use of any one of embodiments 51-53, wherein the topical antibiotic is administered once a day.54. The use of any one of embodiments 51-54, wherein the topical antibiotic is applied to the scalp of the subject.55. The use of any one of embodiments 51-55, wherein the topical antibiotic is applied to the subject before the subject goes to bed.56. The use of any one of embodiments 51-56, wherein the topical antibiotic is applied to the subject after the subject takes a bath or shower.57. The use of any one of embodiments 1-57, wherein reducing occurrence or severity of DAEs comprises administration of the non-comedogenic moisturizer at least once a day.58. The use of any one of embodiments 1-58, wherein the non-comedogenic moisturizer comprises at least one selected from the group consisting of shea butter, ceramide-3 (ceramide NP), niacinamide, glycerin, dimethicone, cetearyl alcohol, rapeseed oil, glyceryl stearate, ammonium polyacryloyldimethyl taurate, PEG- 100 stearate, propanediol, Ophiopogon japonicus extract, sorbitan tristearate, dimethiconol, PEG-20 methyl glucose sesquistearate, sodium chloride, mannose, cocamidopropyl betaine, disodium ethylenediaminetetraacetate, capryloyl glycine, caprylyl glycol, citric acid, maltodextrin, xanthan gum, tocopherol, pentaerythrityl tetra- di-t-butyl hydroxyhydrocinnamate, selenium, prebiotics, probiotics, prebiotics, peptides, amino acids, Vitreoscilla filiformis ferment, hyaluronic acid, aloe vera, grape seed extract, moringa, papaya, coconut oil, squalane, and water.59. The use of any one of embodiments 1-59, wherein the non-comedogenic moisturizer is applied to the face and skin of the subject.60. The use of any one of embodiments 1-60, wherein the non-comedogenic moisturizer is selected from the group consisting of VANICREAM™ Daily Facial Moisturizer, SHANI DARDEN® Hydration Peptide Cream, Neutrogena® Hydroboost Water Boost Cream, CeraVe® Ultra-Light Moisturizing Lotion, humane® Oil-Free Moisturizer, ELTA MD® AM Therapy, TATCHA® The Water Cream, FARMACY® Daily Greens, LA ROCHE-POSAY® Tolenane Double Repair Moisturizer, DIEUX® Air Angel, KIEHL’s® Ultra Facial Oil-Free Gel Cream,LA ROCHE-POSAY® LIPIKAR® Daily Repair Moisturizing Lotion, LA ROCHE-POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Cream, Dr. Jart+® Ceramidin™ Body Lotion, and Charlotte Tilbury® Magic Water Cream.61. The use of any one of embodiments 1-60, wherein the non-comedogenic moisturizer is LA ROCHE-POSAY® LIPIKAR® AP+M Triple Repair Moisturizing Cream.62. The use of any one of embodiments 1-61, wherein reducing occurrence or severity of DAEs further comprises coadministration of at least one of: a) a topical antiseptic; or b) a zinc salt.63. The use of embodiment 62, wherein reducing occurrence or severity of DAES comprises administration of a topical antiseptic to the subject once a day.64. The use of embodiment 62 or 63, wherein the topical antiseptic is chlorhexidine.65. The use of any one of embodiments 62-64, wherein the topical antiseptic is formulated as a topical solution.66. The use of any one of embodiments 62-65, wherein the topical antiseptic comprises about 4% (w / v) topical antiseptic.67. The use of any one of embodiments 62-66, wherein the topical antiseptic is applied to the fingernails and toenails.68. The use of any one of embodiments 62-67, wherein the topical antiseptic is administered to the subject starting on the day that the anti-cancer therapy is administered to the subject for the first time.69. The use of any one of embodiments 62-68, wherein step b) comprises administering a zinc salt to the subject once daily.70. The use of any one of embodiments 62-69, wherein step b) comprises administering a zinc salt to the subject twice daily71. The use of any one of embodiments 62-70, wherein the zinc salt is zinc gluconate.72. The use of any one of embodiments 62-71, wherein the zinc salt is administered in a dose of about 70 mg.73. The use of any one of embodiments 62-72, wherein the zinc salt is administered to the subject beginning on the day that the anti-cancer therapy is administered for the first time.74. The use of any one of embodiments 62-73, wherein the zinc salt is administered to the subject at least until treatment with the anti-cancer therapy is halted.75. The use of any one of embodiments 1-74, further comprising administering a premedication with at least one of antihistamines, antipyretics, or glucocorticoids.76. The use of embodiment 75, wherein the premedication comprises diphenhydramine.77. The use of embodiment 76, wherein the diphenhydramine is administered at a dose of 25 to 50 mg.78. The use of embodiment 75, wherein the premedication comprises acetaminophen.79. The use of embodiment 78, wherein the acetaminophen is administered at a dose of 650 to 1,000 mg.80. The use of any one of embodiments 1-79, wherein occurrence or severity of dermatologic adverse events of grade >2 was significantly reduced.81. The use of any one of embodiments 1-80, wherein the dermatological adverse events were significantly reduced by about 50%.82. The use of any one of embodiments 1-81, wherein occurrence or severity of dermatologic adverse events of grade >3 or of grade 3 was significantly reduced.83. The use of any one of embodiments 1-82, wherein the dermatological adverse events were significantly reduced by about 50%.84. The use of any one of embodiments 1-83, wherein occurrence or severity of scalp dermatologic adverse events of grade >2 was significantly reduced.85. The use of any one of embodiments 1-84, wherein the dermatological adverse events were significantly reduced by about 70%.86. The use of any one of embodiments 1-85, wherein occurrence of dose reduction and / or discontinuation of an anti-cancer therapy was reduced.87. The use any one of embodiments 1-86, wherein the occurrence of dose reduction and / or discontinuation of an anti-cancer therapy was reduced by about 50%.88. The use any one of embodiments 1-87, wherein the occurrence of grade >2 dermatologic events is reduced by about 40% after 12 weeks of treatment.89. The use any one of embodiments 1-88, wherein the occurrence of grade >2 dermatologic events involving the skin, with the exception of paronychia, is reduced by about 50% after 12 weeks of treatment.90. The use of any one of embodiments 1-89, wherein the occurrence of grade >2 dermatologic events involving the scalp is reduced by about 50% after 12 weeks of treatment.91. The use of any one of embodiments 1-90, wherein the occurrence of grade >2 dermatologic events involving the face is reduced by about 70% after 12 weeks of treatment.92. The use any one of embodiments 1-91, wherein the occurrence of grade >2 dermatologic events involving the body is reduced by about 50% after 12 weeks of treatment.93. The use of any one of embodiments 1-92, wherein the occurrence of grade >2 dermatologic events is reduced by about 20% after six months of treatment.94. The use of any one of embodiments 1-93, wherein the occurrence of grade >2 dermatologic events involving the skin, with the exception of paronychia, is reduced by about 50% after six months of treatment.95. The use of any one of embodiments 1-94, wherein the occurrence of grade >2 dermatologic events involving the scalp is reduced by about 50% after six months of treatment.96. The use of any one of embodiments 1-95, wherein the occurrence of grade >2 dermatologic events involving the face is reduced by about 60% after six months of treatment.97. The use of any one of embodiments 1-96, wherein the occurrence of grade >2 dermatologic events involving the body is reduced by about 40% after six months of treatment.98. The use of any one of embodiments 1-97, wherein the occurrence of grade >3 dermatologic events involving the scalp is reduced by about 90% after six months of treatment.99. The use of any one of embodiments 1-98, wherein the occurrence of grade >3 dermatologic events involving the face is reduced by about 60% after six months of treatment.100. The use of any one of embodiments 1 -99, wherein the occurrence of grade >3 dermatologic events involving the body is reduced by about 60% after six months of treatment.101. The use of any one of embodiments 1-100, wherein reducing occurrence or severity of DAEs delays the average onset of a grade >2 dermatologic adverse event by about two months.Set D: Reactive Medicaments1. Use of an antibiotic in the manufacture of a medicament for reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject, wherein the subject is being treated with an anti-cancer therapy, wherein the anticancer ther...

Claims

1. CLAIMSWhat is claimed is:

1. A method of reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject, wherein the method comprises: a) administering an antibiotic; b) administering a non-comedogenic moisturizer; and c) administering an antiseptic, a zinc salt, or both; to the subject, and wherein the subject is being treated with an anti-cancer therapy, wherein the anti-cancer therapy comprises an anti-epidermal growth factor receptor (EGFR) / hepatocyte growth factor receptor (c-Met) antibody.

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

3. The method 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 method of claim 1, wherein the antibody is administered intravenously (IV) to the subject.

5. The method of claim 1, wherein the antibody is administered subcutaneously (SC) to the subject.

6. The method of claim 1, wherein the antibody is administered as a monotherapy.

7. The method of claim 1, wherein the method further comprises administering to the subject at least additional one anti-cancer therapy.

8. The method of claim 1, wherein step a) comprises: i) administering to the subject an oral antibiotic for about 12 weeks followed by administering to the subject a topical antibiotic; or ii) administering to the subject an oral antibiotic for about 12 weeks at a first dose followed by administering to the subject the oral antibiotic at a second dose for about 12 weeks.

9. The method of claim 8, wherein the oral antibiotic comprises a tetracycline antibiotic.

10. The method of claim 8, wherein the oral antibiotic is administered to the subject at a dose of about 100 mg twice daily for about 12 weeks followed by a dose of 100 mg once daily for about 12 weeks or a dose of 50 mg once daily for about 14 weeks.

11. The method of claim 8, wherein the topical antibiotic comprises a lincosamides antibiotic.

12. The method of claim 8, wherein the topical antibiotic is administered to the scalp of the subject once a day.

13. The method of claim 1, wherein the antiseptic comprises a diguanide antiseptic.

14. The method of claim 1, wherein the method comprises administering a topical antiseptic to the fingernails and toenails of the subject once a day15. The method of claim 1, wherein the zinc salt comprises a bioavailable zinc salt.

16. The method of claim 1, wherein the zinc salt is orally administered to the subject at a dose of about 70 mg or 140 mg once a day.

17. The method of claim 1, wherein step b) comprises administering the non- comedogenic moisturizer to the face and skin of the subject at least once a day.

18. The method of claim 1, wherein the non-comedogenic moisturizer comprises a ceramide-based moisturizer.

19. The method of claim 1, wherein the method further comprises administering to the subject at least one of: a) a beta blocker and a corticosteroid if the subject develops a scalp dermatologic adverse event of interest (DAE); b) a topical antiseptic alone, or in combination with a topical beta blocker or a topical Janus kinase (JAK) inhibitor, if the subject develops paronychia; c) a topical corticosteroid or topical immunosuppressant if the subject develops a body DAE; or d) a topical corticosteroid or topical immunosuppressant if the subject develops a facial DAE.

20. The method of claim 19, wherein the beta blocker of a) comprises a nonselective beta blocker .

21. The method of claim 19, wherein the corticosteroid of a) comprises a glucocorticoid.

22. The method of claim 19, wherein a) comprises at least one of: i) orally administering the beta blocker to the subject in a dose of about 30 mg daily until complete resolution of the scalp DAE; or ii) topically administering the corticosteroid to the scalp of the subject once daily until at least the final day the antibody is administered to the subject.

23. The method of claim 19, wherein the topical antiseptic of b) comprises a diguanide antiseptic.

24. The method of claim 19, wherein the topical beta blocker of b) comprises a nonselective beta blocker.

25. The method of claim 19, wherein the topical JAK inhibitor of b) comprises a JAK1 / JAK2 inhibitor.

26. The method of claim 19, wherein b) comprises at least one of: i) administering the topical antiseptic to the hands and feet of the subject once daily until at least the final day the antibody is administered to the subject; ii) administering the topical beta blocker to the paronychia of the subject twice daily until at least the final day the antibody is administered to the subject; or iii) if the paronychia has not been completely resolved after 4 weeks of administering the topical antiseptic, administering the topical JAK inhibitor to the paronychia of the subject twice daily, until complete resolution of the paronychia or up to 12 weeks, whichever occurs first, beginning 4 weeks after the first administration of the topical antiseptic.

27. The method of claim 19, wherein the topical corticosteroid of c) or d) comprises a glucocorticoid.

28. The method of claim 19, wherein the topical immunosuppressant of c) or d) comprises a JAK1 / JAK2 inhibitor or a calcineurin inhibitor.

29. The method of claim 19, wherein c) comprises at least one of: i) administering the topical corticosteroid to the affected area of the body of the subject once daily until complete resolution of the body DAE; or ii) administering the topical immunosuppressant to the affected area of the body of the subject twice daily until complete resolution of the body DAE or up to 12 weeks, whichever occurs first.

30. The method of claim 26, wherein d) comprises at least one of: i) administering the topical corticosteroid to the face of the subject once daily until complete resolution of the facial DAE or up to 2 weeks, whichever occurs first; ii) if the facial DAE has not been completely resolved after 2 weeks of administering the topical corticosteroid, administering the topical immunosuppressant to the face of the subject twice daily until complete resolution of the paronychia or upto 11 weeks, whichever occurs first, beginning 2 weeks after the first administration of the topical corticosteroid; or iii) administering the topical immunosuppressant to the face of the subject twice daily until complete resolution of the body DAE or up to 12 weeks, whichever occurs first.

31. A method of reducing occurrence or severity of dermatologic adverse events (DAEs) in a subject, wherein the subject is being treated with an anti-cancer therapy, wherein the anti-cancer therapy comprises amivantamab; and wherein the method comprises: a) orally administering 100 mg doxycycline or minocycline to the subject twice daily for 12 weeks beginning on the first day the anti-cancer therapy is administered to the subject and topically administering 1% clindamycin to the scalp of the subject for 9 months beginning after completion of the oral doxycycline or minocycline; b) topically administering a ceramide-based non-comedogenic moisturizer at least once daily to the face and body of the subject, except the scalp, while the subject is receiving the anti-cancer therapy; and c) topically administering 4% chlorhexidine to the hands and feet of the subject at least once daily, while the subject is receiving the anti-cancer therapy.

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