Combination therapies for the treatment of colorectal cancer

Abstract

Disclosed herein are methods of treating metastatic colorectal cancer (e.g., in the frontline setting) with a bispecific anti-EGFR / c-Met antibody and FOLFIRI or mFOLFOX6.

Description

COMBINATION THERAPIES FOR THE TREATMENT OF COLORECTAL CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of United States Provisional Patent Application No. 63 / 674,612, filed July 23, 2024, the disclosure of which is incorporated herein by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which is being submitted herewith electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 21, 2025, is named 103693_007540_SL.xml and is 19,882 bytes in size.TECHNICAL FIELD

[0003] Disclosed herein are compositions and methods for treating colorectal cancer.BACKGROUND

[0004] Colorectal cancer (CRC) is the third most common cancer worldwide and represents a major global health concern. Approximately two million new cases were reported in 2020, with an estimated 180,000 new diagnoses in North America, 500,000 in Europe, and 1 million in Asia. Significant advances in the understanding of CRC tumor biology, including the identification of genetic alterations, have led to the molecular subtyping of CRC. Molecular profiling includes assessment for the presence of driver mutations, including Kirsten rat sarcoma viral oncogene (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF), and assessment of Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2 / HER-2) amplification or overexpression, as well as determination of mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). Furthermore, tumor sidedness (i.e., left vs. right) is integrated into the management of mCRC patients, especially for the choice of first line therapy. While EGFR-directed antibodies, in conjunction with SoC chemotherapy, have improved initial disease control, almost all patients treated with these therapies will relapse. There remains a need for improved therapies in the frontline treatment of colorectal cancer.SUMMARY

[0005] Disclosed herein are methods of treating left-sided colorectal cancer (CRC) that is wild-type for RAS and BRAF in a subject or a population of subjects not previously administered any prior systemic therapy for the CRC comprising administering to the subject or the population of subjects a therapeutically effective amount of a bispecific anti-EGFR / c-Met antibody comprising a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequences of SEQ ID NO: 3; a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 6; a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequences of SEQ ID NO: 9; and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 12; and FOLFIRI or mFOLFOX6.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosed methods, the drawings show exemplary embodiments of the methods; however, the methods are not limited to the specific embodiments disclosed. In the drawings:

[0007] FIG 1 illustrates the study design for methods of using Amivantamab and FOLFIRI or mFOLFOX6 to treat colorectal cancer.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0008] The disclosed methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.

[0009] Unless specifically stated otherwise, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the disclosed methods are not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement.

[0010] Where a range of numerical values is recited or established herein, the range includes the endpoints thereof and all the individual integers and fractions within the range, and also includes each of the narrower ranges therein formed by all the various possible combinations of those endpoints and internal integers and fractions to form subgroups of the larger group of values within the stated range to the same extent as if each of those narrower ranges was explicitly recited. Where a range of numerical values is stated herein as being greater than a stated value, the range is nevertheless finite and is bounded on its upper end by a value that is operable within the context of the herein disclosure. Where a range of numerical values is stated herein as being less than a stated value, the range is nevertheless bounded on its lower end by a non-zero value. It is not intended that the scope of the methods be limited to the specific values recited when defining a range. All ranges are inclusive and combinable.

[0011] The term “about” when used in reference to numerical ranges, cutoffs, or specific values is used to indicate that the recited values may vary by up to as much as 10% from the listed value. As many of the numerical values used herein are experimentally determined, it should be understood by those skilled in the art that such determinations can, and often times will, vary among different experiments. The values used herein should not be considered unduly limiting by virtue of this inherent variation. Thus, the term “about” is used to encompass variations of ± 10% or less, variations of ± 5% or less, variations of ± 1% or less, variations of ± 0.5% or less, or variations of ± 0. 1% or less from the specified value.

[0012] ‘ ‘In combination with” means that two or more therapeutics can be administered to a subject together in a mixture, concurrently as single agents, or sequentially as single agents in any order.

[0013] ‘ ‘Treat,” “treatment,” and like terms refer to therapeutic treatment, and includes reducing the severity and / or frequency of symptoms, eliminating symptoms and / or the underlying cause of the symptoms, reducing the frequency or likelihood of symptoms and / or their underlying cause, and improving or remediating damage caused, directly or indirectly, by colorectal cancer. Treatment also includes prolonging survival as compared to the expected survival of a subject not receiving treatment.

[0014] As used herein, “administering to said patient” and similar terms indicate a procedure by which, for example, the bispecific anti-EGFR / c-Met antibody and FOLFIRI areinjected into a patient such that target cells, tissues, or segments of the body of the subject are contacted with the bispecific anti-EGFR / c-Met antibody and FOLFIRI. Administering can also indicate oral ingestion of particular drug as described herein.

[0015] As used herein, the phrase “therapeutically effective amount” refers to an amount of the bispecific anti-EGFR / c-Met antibody and an amount of the FOLFIRI, as described herein, effective to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject. Exemplary indicators of a therapeutically effective amount include, for example, improved wellbeing of the patient, reduction of a tumor burden, arrested or slowed growth of a cancer, and / or absence of metastasis of cancer cells to other locations in the body.

[0016] The term “subject” as used herein is intended to mean any animal, in particular, mammals. The methods are applicable to human and nonhuman animals, although preferably used with mice and humans, and most preferably with humans. “Subject” and “patient” are used interchangeably herein.

[0017] “Antibody” refers to all isotypes of immunoglobulins (IgG, IgA, IgE, IgM, IgD, and IgY) including various monomeric, polymeric, and chimeric forms, unless otherwise specified. Specifically encompassed by the term “antibody” are polyclonal antibodies, monoclonal antibodies (mAbs), and antibody-like polypeptides, such as chimeric antibodies and humanized antibodies.

[0018] “Bispecific” and “bispecific antibodies” refer to engineered proteins comprising two antibodies, or antigen-binding domains from two antibodies, that are capable of simultaneously binding two different antigens (targets). Bispecifics can be used to, for example, form a link between T cells and target cells, leading to the activation of T cells and generation of an immunological synapse.

[0019] “Amivantamab” (also known as RYBREVANT® or JNJ 61186372) is a fully human immunoglobulin Gl-based bispecific antibody directed against the EGF and MET receptors, with evidence of preclinical activity against NSCLC tumors with activating EGFR mutations, the T790M and C797S second-site resistance EGFR mutations, overexpressed wildtype EGFR, as well as with activation of the MET pathway. By inhibiting EGFR and MET signaling, either by blocking ligand-induced activation and / or inducing receptor degradation, amivantamab may disrupt these signaling pathways and prevent tumor growth and progression. In addition, the presence of high levels of EGFR and MET on the surface of tumor cells allowsfor targeting of these cells for destruction by immune effector cells, through antibody dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular trogocytosis (ADCT).

[0020] PFS refers to the time from start of treatment, or from the date of randomization, until disease progression or death (due to any cause), whichever comes first, using RECIST vl.l. In some embodiments, PFS refers to the time from the date of randomization, until disease progression or death (due to any cause), whichever comes first. In some embodiments, PFS refers to the time from start of treatment, until disease progression or death (due to any cause), whichever comes first.

[0021] Overall survival refers to the time from start of treatment, or from the date of randomization, until death due to any cause. In some embodiments, overall survival refers to the time from start of treatment, until death due to any cause. In some embodiments, overall survival refers to the time from the date of randomization, until death due to any cause.

[0022] Objective response rate refers to the proportion of subjects in a population of subjects with a confirmed partial response or complete response, as determined using RECIST vl.l criteria.

[0023] Duration of response refers to the time from the date of first documented response (CR or PR, confirmation of response required) until the date of documented progression or death, whichever comes first.

[0024] Progression-free survival after subsequent therapy (PFS2) refers to the time from start of treatment, or from the date of randomization, until the second objective disease progression, after initiation of subsequent systemic anticancer therapy, or death, whichever comes first. In some embodiments, PFS2 refers to the time from start of treatment, until the second objective disease progression, after initiation of subsequent systemic anti cancer therapy, or death, whichever comes first. In some embodiments, PFS2 refers to the time from the date of randomization, until the second objective disease progression, after initiation of subsequent systemic anticancer therapy, or death, whichever comes first.

[0025] Time to treatment failure refers to the time from start of treatment, or from the date of randomization, to discontinuation of therapy for any reason including death, progression, toxicity or initiation of new anti-cancer therapy. In some embodiments, time to treatment failure refers to the time from start of treatment, to discontinuation of therapy for any reason including death, progression, toxicity or initiation of new anti-cancer therapy. In some embodiments, time to treatment failure refers to the time from the date of randomization, to discontinuation of therapy for any reason including death, progression, toxicity or initiation of new anti -cancer therapy.

[0026] “Hyaluronidase” refers to a class of enzymes that degrade hyaluronan. Hyaluronidases are endoglycosidases used to increase the dispersion and absorption of other coadministered drugs when administered subcutaneously (e.g., subcutaneous injections, subcutaneous infusion such as hypodermoclysis). Hyaluronidases include, but are not limited to, bacterial hyaluronidases (EC 4.2.2. 1 or EC 4.2.99.1), hyaluronidases from leeches, other parasites and crustaceans (EC 3.2.1.36), and mammalian-type hyaluronidases (EC 3.2.1.35). Hyaluronidase (recombinant human) has a molecular weight of approximately 61 kDa. Hyaluronidases include those of non-human origin including, but not limited to, murine, canine, feline, leporine, avian, bovine, ovine, porcine, equine, piscine, ranine, bacterial, and any from leeches, other parasites, and crustaceans. Exemplary human hyaluronidases include HYAL1, HYAL2, HYAL3, HYAL4, and PH20. Also included amongst hyaluronidases are soluble hyaluronidases, including, ovine and bovine PH20, and soluble forms of PH20. Exemplary hyaluronidases include those set forth in U.S. Pub. No. 2013 / 0302275, which is incorporated by reference herein, including, for example, hyaluronidases set forth as SEQ ID NOs: 6, 7-31, 69, 70, 71, 72, 856-861, 869-921 from U.S. Pub. No. 2013 / 0302275 (which are incorporated herein by reference), mature forms thereof (lacking the signal sequence), allelic variants thereof, and truncated forms thereof that exhibit hyaluronidase activity, including C-terminal truncated variants that are soluble.

[0027] As used herein, PH20 refers to a type of hyaluronidase that occurs in sperm and is neutral-active.

[0028] Soluble PH20 refers to a polypeptide characterized by its solubility under physiological conditions. Generally, a soluble PH20 lacks all or a portion of a glycophosphatidyl anchor (GPI) attachment sequence, or does not otherwise sufficiently anchor to the cell membrane. For example, a soluble PH20 can be a C-terminally truncated variant of a PH20 lacking a contiguous sequence of amino acids that corresponds to all or a portion of a GPI anchor attachment sequence. Hence, upon expression from a cell, a soluble PH20 is secreted into the medium.

[0029] Soluble human PH20 (sHuPH20) includes human PH20 polypeptides that lack a contiguous sequence of amino acids from the C-terminus of human PH20 that includes all or a portion of the GPI anchor sequence (C-terminally truncated PH20 polypeptides) such that upon expression, the polypeptides are soluble under physiological conditions. For example, soluble human PH20 polypeptides are C-terminally truncated polypeptides of human PH20 in its precursor form or in its mature form lacking the signal sequence, or allelic variants thereof as setforth in SEQ ID NOs: 36-42 herein and as disclosed in U.S. Pub. No. 20130302275 as SEQ ID NOs: 6, 7, and 68-72 of that reference which are incorporated herein by reference.

[0030] U.S. Pub. No. 2004 / 0268425, which is incorporated by reference herein, describes members of the soluble, neutral active Hyaluronidase Glycoprotein family, particularly the human soluble PH-20 Hyaluronidase Glycoproteins (also referred to as sHASEGPs). U.S. Pub. No. 20100143457, which is incorporated herein by reference, describes shorter active soluble PH20 (i.e., 36-469, -470, 471, and longer forms i.e., 36-495 to 36-500) the sequences of which are also incorporated herein by reference.

[0031] Hyaluronidase activity refers to the ability to enzymatically catalyze the cleavage of hyaluronic acid. The United States Pharmacopeia (USP) XXII assay for hyaluronidase determines hyaluronidase activity indirectly by measuring the amount of higher molecular weight hyaluronic acid, or hyaluronan, (HA) substrate remaining after the enzyme is allowed to react with the HA for 30 min at 37 °C (USP XXII-NF XVII (1990) 644-645 United States Pharmacopeia Convention, Inc, Rockville, MD). A Reference Standard solution can be used in an assay to ascertain the relative activity, in units, of any hyaluronidase. In vitro assays to determine the hyaluronidase activity of hyaluronidases, such as PH20, including modified PH20 polypeptides, are known in the art and described herein. Exemplary assays include the microturbidity assay that measures cleavage of hyaluronic acid by hyaluronidase indirectly by detecting the insoluble precipitate formed when the uncleaved hyaluronic acid binds with serum albumin. Reference Standards can be used, for example, to generate a standard curve to determine the activity in Units of the hyaluronidase being tested.

[0032] Specific activity refers to Units of activity per mg protein. The milligrams of hyaluronidase is defined by the absorption of a solution of at 280 nm assuming a molar extinction coefficient of approximately 1.7, in units of M-l cm-1.

[0033] Neutral active refers to the ability of a PH20 polypeptide to enzymatically catalyze the cleavage of hyaluronic acid at neutral pH, such as at a pH between or about between pH 6.0 to pH 7.8.

[0034] Human recombinant DNA-derived hyaluronidase enzyme PH20 (rHuPH20) is a glycosylated single-chain protein produced by CHO cells containing a DNA plasmid encoding residues 36-482 of SEQ ID NO: 36, resulting in a heterogeneous mixture of soluble forms of human hyaluronidase (PH20) that begin at residue 36 and terminate at residues 478, 479, 480, 481, and 482 of SEQ ID NO: 36, including any one of SEQ ID NOs: 31, 35, 34, 33 and 32.

[0035] The methods for subcutaneous formulation and administration of the anti- EGFR / c-Met antibody, such as amivantamab, are described in WO2022224187, which are incorporated herein by reference.

[0036] In some embodiments, the anti-EGFR / c-Met antibody of the invention is coformulated with a hyaluronidase enzyme.

[0037] The composition can comprise an amount of hyaluronidase enzyme that results in an increase in the dispersion of the bispecific antibody during the subcutaneous administration. The hyaluronidase enzyme has no adverse effect on the molecular integrity of the bispecific antibody. Furthermore, the hyaluronidase enzyme merely modifies the delivery of the bispecific antibody to the systemic circulation but does not possess any properties that could provide or contribute to the therapeutic effects of systemically absorbed bispecific antibody. The hyaluronidase enzyme is not systemically bioavailable and does not adversely affect the molecular integrity of the bispecific antibody at the recommended storage conditions of the composition. A number of suitable hyaluronidase enzymes are known. The preferred enzyme is a human hyaluronidase enzyme, such as a soluble human PH20 hyaluronidase, preferably the recombinant human hyaluronidase enzyme product known as rHuPH20. The amino acid sequence of soluble human PH20 hyaluronidases include the soluble human PH20 known as rHuPH20 and available under CAS Registry No. 757971-58-7. Soluble human PH20 hyaluronidases are described in Int’l Pub. No. W02004 / 078140 and U.S. Patent No. 7,767,429 incorporated herein by reference, in their entirety. In some embodiments, soluble hyaluronidases include those whose sequence are set forth in any of SEQ ID NOs: 31-35. Soluble PH20 hyaluronidase, when expressed in a cell, include a signal sequence for trafficking in the cell. Thus, in some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 36. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 32, namely residues 36-482 of wild type human hyaluronidase. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 33. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 34. In some embodiments, the soluble PH20 hyaluronidase comprises rHuPH20 comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 31. In some embodiments, the soluble PH20 hyaluronidases, when expressed in a cell, comprise a mixture of species that can include any one of SEQ ID NOs: 31, 32, 33, 34, and 35 in various abundance. The average molecular weight is 61 kDa.

[0038] rHuPH20 refers to the composition produced upon expression in a cell, such as CHO cell, of nucleic acids that encode residues 36-482 of SEQ ID NO: 36, generally linked to the native or a heterologous signal sequence (residues 1-35 of SEQ ID NO: 36). rHuPH20 is produced by expression of a nucleic acid molecule, such as encoding amino acids 1-482 (set forth in SEQ ID NO: 36) in a mammalian cell. Translational processing removes the 35 amino acid signal sequence. As produced in the culture medium there is heterogeneity at the C-terminus such that the product, designated rHuPH20, includes a mixture of species that can include one or more of the polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO: 36, and some shorter polypeptides, in various abundance. Typically, rHuPH20 is produced in cells, such as CHO cells, for example DG44 CHO cells, that facilitate correct N-glycosylation to retain activity. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 35. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 32. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 33. In some embodiments, the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 34.

[0039] It is to be appreciated that certain features of the disclosed methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0040] As used herein, the singular forms “a,” “an,” and “the” include the plural.

[0041] 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” or “A, B, and / 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.”

[0042] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unlessotherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0043] The term “comprising” is intended to include examples encompassed by the terms “consisting essentially of’ and “consisting of’; similarly, the term “consisting essentially of’ is intended to include examples encompassed by the term “consisting of.”

[0044] Disclosed herein are methods of treating left-sided colorectal cancer (CRC) that is wild-type for RAS and BRAF in a subject or a population of subjects not previously administered any prior systemic therapy for the CRC, the method comprising administering to the subject or the population of subjects a therapeutically effective amount of a bispecific anti- EGFR / c-Met antibody, the antibody comprising a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequences of SEQ ID NO: 3; a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 6; a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequences of SEQ ID NO: 9; and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 12; and FOLFIRI or mFOLFOX6. In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgGl isotype. In some embodiments the bispecific anti-EGFR / c-Met antibody comprises the VH1 comprising the amino acid sequence of SEQ ID NO: 13; the LC1 comprising a variable region 1 (VL1) comprising the amino acid sequence of SEQ ID NO: 14; the HC2 comprising a variable region 2 (VH2) comprising the amino acid sequence of SEQ ID NO: 15; and the LC2 comprising a variable region 2 (VL2) comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments the bispecific anti-EGFR / c-Met antibody comprises the HC1 comprising the amino acid sequence of SEQ ID NO: 17; the LC1 comprising the amino acid sequence of SEQ ID NO: 18; the HC2 comprising the amino acid sequence of SEQ ID NO: 19; and the LC2 comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments the bispecific anti-EGFR / c-Met antibody is amivantamab. In some embodiments the bispecific anti-EGFR / c- Met antibody is a biosimilar of amivantamab.

[0045] In some embodiments, the methods treat a subject. In some embodiments, the methods treat a population of subjects.

[0046] The colorectal cancer (CRC) treated can be unresectable or metastatic colorectal cancer. In some embodiments, the colorectal cancer is unresectable colorectal cancer. In some embodiments, the colorectal cancer is metastatic colorectal cancer. In some embodiments, the colorectal cancer is a primary tumor. The colorectal cancer can be recurrent. For example, the colorectal cancer can be recurrent unresectable colorectal cancer, or recurrent metastatic colorectal cancer. In some embodiments, the colorectal cancer is an adenocarcinoma. In some embodiments, the colorectal cancer is a left-sided CRC. In some embodiments, the colorectal cancer is a primary tumor that involves the splenic flexure, descending colon, sigmoid colon, rectosigmoid, or rectum.

[0047] In some embodiments, the subject has not received agents that target EGFR or agents that target MET. In some embodiments, the population of subjects have not received prior agents that target EGFR or agents that target MET.

[0048] The subject can be wild type for KRAS, NRAS, and BRAF. The population of subjects can be wild type for KRAS, NRAS, and BRAF. In some embodiments, the colorectal cancer is wild type for KRAS, NRAS, and BRAF. In some embodiments, the colorectal cancer is wild type for KRAS / NRAS G12 and G13 and BRAF V600 codons. In some embodiments, the colorectal cancer is wild type for KRAS / NRAS A59, Q61, KI 17, or A146 or BRAF V600. In some embodiments, the colorectal cancer has a silent mutation in KRAS / NRAS A59, Q61, KI 17, or A 146 or BRAF N600.

[0049] The bispecific anti-EGFR / c-Met antibody can be administered in an amount of about 1600 mg to about 2240 mg. In some embodiments, for subjects with a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 1,600 mg. In some embodiments, for subjects with a body weight greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 2,240 mg.

[0050] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered weekly. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered every two weeks. The bispecific anti-EGFR / c-Met antibody can be administered weekly for the first four weeks and every two weeks thereafter. The bispecific anti-EGFR / c-Met antibody can be administered on days 1, 8, 15, and 22 of a first 28-day treatment cycle. After the first 28-day treatment cycle, the bispecific anti-EGFR / c-Met antibody can be administered on days 1 and 15 of each subsequent 28-day treatment cycle, starting in the second 28-day treatment cycle.

[0051] In some embodiments, the bispecific anti-EGFR / c-Met antibody can be administered using alternative dosing regimens.

[0052] In certain embodiments, the alternative dosing regimens are alternative subcutaneous dosing regimens. In certain embodiments, the bispecific anti-EGFR / c-Met antibody can be administered subcutaneously at 1,600 mg if <80 kg BW (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. In certain embodiments, the bispecific anti-EGFR / c-Met antibody can be administered subcutaneously at 1,600 mg if <80 kg BW (2,240 mg if BW >80 kg) on Cycle 1 Days 1, 8, 15, and 22 then 3,520 mg if <80 kg BW (4,640 mg if BW >80 kg) on Day 1 of each subsequent 28- day cycle starting at Cycle 2. In certain embodiments, the bispecific anti-EGFR / c-Met antibody can be administered subcutaneously at 1,600 mg if <80 kg BW (2,240 mg if BW >80 kg) on Cycle 1 Day 1, 2,400 mg if <80 kg BW (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

[0053] In certain embodiments, the alternative dosing regimens are alternative intravenous dosing regimens. In certain embodiments, the bispecific anti-EGFR / c-Met antibody can be administered intravenously according to the following:In certain embodiments, the bispecific anti-EGFR / c-Met antibody can be administered intravenously according to the following:In certain embodiments, the split infusion is administered as 350 mg on Day 1 with the remainder administered on Day 2.

[0054] In some embodiments, the antibody (e.g., bispecific antibody) is administered at a dose of about 140 mg to about 4,640 mg, for example, about 700 mg to about 1,400 mg, about 700 mg to about 1,050 mg, about 1,050 mg to about 1,400 mg, about 1,750 mg to about 2,100 mg, about 1,600 mg to about 2240 mg, about 1,600 mg to about 3,360 mg, or about 2,240 mg to about 3,360 mg.

[0055] In some embodiments, the antibody is administered at a dose of about 700 mg, about 1,050 mg, about 1,400 mg, about 1,750 mg, about 2,100 mg, about 1,600 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 1,400 mg. In particular embodiments, the antibody is administered at a dose of about 700 mg. In some embodiments, the antibody is administered at a dose of about 1,750 mg. In some embodiments, the antibody is administered at a dose of about 1,600 mg. In some embodiments, the antibody is administered at a dose of about 2,100 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.

[0056] In certain embodiments, the antibody is administered at a dose of 1,050 mg for body weigh <80 kg and 1,400 mg for body weight > 80 kg.

[0057] In particular embodiments, the antibody is administered at a dose of 700 mg for body weigh <80 kg and 1,050 mg for body weight > 80 kg.

[0058] In particular embodiments, the antibody is administered at a dose of 1,750 mg for body weigh <80 kg and 2,100 mg for body weight > 80 kg.

[0059] In certain embodiments, the antibody is administered at a dose of 1,600 mg for body weigh <80 kg and 2,240 mg for body weight > 80 kg.

[0060] In certain embodiments, the antibody is administered at a dose of 2,400 mg for body weigh <80 kg and 3,360 mg for body weight > 80 kg.

[0061] In certain embodiments, the antibody is administered at a dose of 3,520 mg for body weigh <80 kg and 4,640 mg for body weight > 80 kg.

[0062] In some embodiments, the antibody is administered twice a week.

[0063] In certain embodiments, the antibody is administered once a week.

[0064] In some embodiments, the antibody is administered once every two weeks.

[0065] In certain embodiments, the antibody is administered once every three weeks.

[0066] In some embodiments, the antibody is administered once every four weeks.

[0067] In certain embodiments, the antibody is administered once a week or once every three weeks. In particular embodiments, the antibody is administered once weekly for the first 3 weeks and then once every 3 weeks.

[0068] The FOLFIRI or mFOLFOX6 can be intravenously administered every two weeks. In some embodiments, the FOLFIRI is intravenously administered every two weeks. In some embodiments, the mFOLFOX6 is intravenously administered every two weeks. The FOLFIRI or mFOLFOX6 can be administered on days 1 and 15 of a first 28-day treatment cycle. In some embodiments, the FOLFIRI is administered on days 1 and 15 of a first 28-day treatment cycle. In some embodiments, the mFOLFOX6 is administered on days 1 and 15 of a first 28-day treatment cycle. After the first 28-day treatment cycle, the FOLFIRI or mFOLFOX6 can be administered on days 1 and 15 of each subsequent 28-day treatment cycle, starting in the second 28-day treatment cycle. In some embodiments, after the first 28-day treatment cycle, the FOLFIRI can be administered on days 1 and 15 of each subsequent 28-day treatment cycle, starting in the second 28-day treatment cycle. In some embodiments, after the first 28-day treatment cycle, the mFOLFOX6 can be administered on days 1 and 15 of each subsequent 28- day treatment cycle, starting in the second 28-day treatment cycle.

[0069] According to an embodiment, a method of treating CRC in a subject (e.g., leftsided CRC that is wild-type for RAS and BRAF in a subject not previously administered any prior systemic therapy for the CRC) comprises administering to the subject a combination regimen comprising (i) amivantamab and (ii) FOLFIRI or mFOLFOX6, in 28-day treatment cycles, according to the schedule shown in the following table:Cycles 2+ refers to Cycle 2 and all subsequent cycles. Also abbreviated to C2+.

[0070] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously. Exemplary subcutaneous formulations that can be used in accordance with the present methods are described in U.S. Publication No. 2022 / 0395573, which is incorporated by reference herein. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered intravenously.

[0071] The herein disclosed methods can provide a prolonged overall survival of the subject compared to a reference subject or a reference population of subjects with left-sided CRC wild type for RAS and BRAF not previously administered any prior systemic therapy for the CRC and administered: cetuximab and FOLFIRI, or cetuximab and mF0LF0X6. In some embodiments, the reference subject or reference population of subjects had received Cetuximab weekly at a dose of 400 mg / m2for the first dose and 250 mg / m2thereafter or once every two weeks at a dose of 500 mg / m2.

[0072] The herein disclosed methods can provide an improvement in median progression free survival (PFS) relative to median PFS of a reference population of subjects with left-sided CRC wild type for RAS and BRAF not previously administered any prior systemic therapy for the CRC and administered: cetuximab and FOLFIRI, or cetuximab and mF0LF0X6.In some embodiments, the PFS is assessed using RECIST vl .l criteria. In some embodiments, the reference subject or reference population of subjects had received Cetuximab weekly at a dose of 400 mg / m2for the first dose and 250 mg / m2thereafter or once every two weeks at a dose of 500 mg / m2.

[0073] The herein disclosed methods can provide an improvement in objective response rate by blinded independent central review (BICR), objective response rate (ORR) as assessed by investigator, duration of response, PFS after first subsequent therapy, disease control rate, time to treatment failure, time to systemic progression, or any combination thereof, wherein the improvement is relative to a reference subject or a reference population of subjects with leftsided CRC wild type for RAS and BRAF not previously administered any prior systemic therapy for the CRC and administered: cetuximab and FOLFIRI, or cetuximab and mF0LF0X6. In some embodiments, the reference subject or reference population of subjects had received Cetuximab weekly at a dose of 400 mg / m2for the first dose and 250 mg / m2thereafter or once every two weeks at a dose of 500 mg / m2.

[0074] As used herein, the term “FOLFIRI” refers to therapeutic regimens that include the drugs leucovorin calcium (folinic acid), fluorouracil, and irinotecan hydrochloride, whether administered individually or together. The regimen can comprise, for example, 180 mg / m2intravenous irinotecan, 400 mg / m2intravenous leucovorin or 200 mg / m2intravenous levoleucovorin, 400 mg / m2intravenous 5 -fluorouracil bolus, and 2,400 mg / m2intravenous 5- fluorouracil.

[0075] As used herein, the term “FOLFOX” refers to therapeutic regimens that include the drugs leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin, whether administered individually or together. Exemplary FOLFOX therapeutic regimens include, but are not limited to, regimens that differ with respect to the dosages and the number of cycles that the drugs are administered during a given period of time, such as FOLFOX-4, FOLFOX-6, modified FOLFOX-6 (mFOLFOX-6), and FOLFOX-7. In some embodiments, the FOLFOX is mFOLFOX6 and comprises, for example, 85 mg / m2intravenous oxaliplatin, 400 mg / m2intravenous leucovorin or 200 mg / m2intravenous levoleucovorin, 400 mg / m2intravenous 5- fluorouracil bolus, and 2,400 mg / m2intravenous 5 -fluorouracil.

[0076] In the herein disclosed methods, the HC1 can comprise a variable region 1 (VH1) comprising the amino acid sequence of SEQ ID NO: 13; the LC1 can comprise a variable region 1 (VL1) comprising the amino acid sequence of SEQ ID NO: 14; the HC2 can comprise a variable region 2 (VH2) comprising the amino acid sequence of SEQ ID NO: 15; and the LC2can comprise a variable region 2 (VL2) comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgGl isotype.

[0077] In the herein disclosed methods, the HC1 can comprise the amino acid sequence of SEQ ID NO: 17; the LC1 can comprise the amino acid sequence of SEQ ID NO: 18; the HC2 can comprise the amino acid sequence of SEQ ID NO: 19; and the LC2 can comprise the amino acid sequence of SEQ ID NO: 20. In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgGl isotype. In some embodiments, the bispecific anti-EGFR / c-Met antibody is amivantamab.

[0078] In the herein disclosed methods, the subject or population of subjects can be administered a glucocorticoid, an antihistamine, and / or an antipyretic prior to the administering of the bispecific anti-EGFR / c-Met antibody. In some embodiments, a glucocorticoid, an antihistamine, and an antipyretic are administered prior to the administering of the bispecific anti-EGFR / c-Met antibody.

[0079] In some embodiments, the glucocorticoid comprises dexamethasone. The dexamethasone can be administered in an amount of about 10 mg. The dexamethasone can be administered orally or intravenously. The dexamethasone can be administered prior to the administering of the bispecific anti-EGFR / c-Met antibody. For intravenous delivery, the dexamethasone can be administered about 45 to about 60 minutes prior to the administering of the bispecific anti-EGFR / c-Met antibody. For oral delivery, the dexamethasone can be administered at least 60 minutes, such as, for example, 60 to 90 minutes, prior to the administering of the bispecific anti-EGFR / c-Met antibody. The dexamethasone can be administered on day 1 of the first 28-day cycle. The dexamethasone can be further administered on day 8 of the first 28-day cycle.

[0080] In some embodiments, the glucocorticoid comprises methylprednisolone. The methylprednisolone can be administered in an amount of about 40 mg. The methylprednisolone can be administered orally or intravenously. The methylprednisolone can be administered prior to the administering of the bispecific anti-EGFR / c-Met antibody. For intravenous delivery, the methylprednisolone can be administered about 45 to about 60 minutes prior to the administering of the bispecific anti-EGFR / c-Met antibody. For oral delivery, the methylprednisolone can be administered a least 60 minutes prior to the administering of the bispecific anti-EGFR / c-Met antibody. The methylprednisolone can be administered on day 1 of the first 28-day cycle. The methylprednisolone can be further administered on day 8 of the first 28-day cycle.

[0081] In some embodiments, the antihistamine comprises diphenhydramine. The diphenhydramine can be administered in an amount of about 25 mg to about 50 mg. Thediphenhydramine can be administered intravenously. The diphenhydramine can be administered prior to the administering of the bispecific anti-EGFR / c-Met antibody. The diphenhydramine can be administered about 15 to about 30 minutes prior to the administering of the bispecific anti- EGFR / c-Met antibody.

[0082] In some embodiments, the antihistamine comprises chlorphenamine. The chlorphenamine can be administered in an amount of about 10 mg. The chlorphenamine can be administered intravenously. The chlorphenamine can be administered prior to the administering of the bispecific anti-EGFR / c-Met antibody. The chlorphenamine can be administered about 15 to about 30 minutes prior to the administering of the bispecific anti-EGFR / c-Met antibody.

[0083] In some embodiments, the antipyretic comprises paracetamol / acetaminophen. The paracetamol / acetaminophen can be administered in an amount of about 650 mg to about 1000 mg. The paracetamol / acetaminophen can be administered orally or intravenously. The paracetamol / acetaminophen can be administered prior to the administering of the bispecific anti- EGFR / c-Met antibody. For intravenous delivery, the paracetamol / acetaminophen be administered about 15 to about 30 minutes prior to the administering of the bispecific anti- EGFR / c-Met antibody. For oral delivery, the paracetamol / acetaminophen can be administered about 30 to about 60 minutes prior to the administering of the bispecific anti-EGFR / c-Met antibody.

[0084] In the herein disclosed methods, the subject or population of subjects can be administered a H2 -antagonist and / or an antiemetic prior to the administering of the bispecific anti-EGFR / c-Met antibody. In some embodiments, an H2 -antagonist and an antiemetic are administered prior to the administering of the bispecific anti-EGFR / c-Met antibody.

[0085] In some embodiments, the H2 -antagonist comprises ranitidine. The ranitidine can be administered in an amount of about 50 mg. The ranitidine can be administered intravenously. The ranitidine can be administered prior to the administering of the bispecific anti- EGFR / c-Met antibody.

[0086] In some embodiments, the antiemetic comprises ondansetron. The ondansetron can be administered in an amount of about 16 mg intravenously. The ondansetron can be administered in an amount of about 8 mg orally. The ondansetron can be administered prior to the administering of the bispecific anti-EGFR / c-Met antibody.SEQUENCES>SEQ ID NO: 1 (HCDR1, EGFR binding arm) TYGMH>SEQ ID NO: 2 (HCDR2, EGFR binding arm)VIWDDGS YKYYGD S VKG>SEQ ID NO: 3 (HCDR3, EGFR binding arm)DGITMVRGVMKDYFDY>SEQ ID NO: 4 (LCDR1, EGFR binding arm)RASQDISSALV>SEQ ID NO: 5 (LCDR2, EGFR binding arm)DASSLES>SEQ ID NO: 6 (LCDR3, EGFR binding arm)QQFNSYPLT>SEQ ID NO: 7 (HCDR1, c-Met binding arm)SYGIS>SEQ ID NO: 8 (HCDR2, c-Met binding arm)WISAYNGYTNYAQKLQG>SEQ ID NO: 9 (HCDR3, c-Met binding arm)DLRGTNYFDY>SEQ ID NO: 10 (LCDR1, c-Met binding arm)RASQGISNWLA>SEQ ID NO: 11 (LCDR2, c-Met binding arm)AASSLLS>SEQ ID NO: 12 (LCDR3, c-Met binding arm)QQANSFPIT>SEQ ID NO: 13 (VH, EGFR binding arm)QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWG QGTLVTVSS>SEQ ID NO: 14 (VL, EGFR binding arm)AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK>SEQ ID NO: 15 (VH, c-Met binding arm)QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTN YAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVS S>SEQ ID NO: 16 (VL, c-Met binding arm)DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK>SEQ ID NO: 17 HC1QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK>SEQ ID NO: 18 LC1AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC>SEQ ID NO: 19 HC2QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK>SEQ ID NO: 20 LC2DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECEMBODIMENTS

[0087] Non-limiting, enumerated embodiments of the present invention are provided below.1. A method of treating left-sided colorectal cancer (CRC) that is wild-type for RAS and BRAF in a subject or a population of subjects not previously administered any prior systemic therapy for the CRC, the method comprising administering to the subject or the population of subjects a therapeutically effective amount of: a bispecific anti-EGFR / c-Met antibody, the antibody comprising a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequences of SEQ ID NO: 3;a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 6; a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequences of SEQ ID NO: 9; and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 12; andFOLFIRI or mFOLFOX6.2. The method of embodiment 1, wherein the colorectal cancer is unresectable or metastatic colorectal cancer.3. The method of any one of the previous embodiments, wherein the subject has not received agents that target EGFR or agents that target MET.4. The method of any one of the previous embodiments, wherein the colorectal cancer is wild type for KRAS, N AS. and BRAF.5. The method of any one of the previous embodiments, wherein the bispecific anti- EGFR / c-Met antibody is administered in an amount of about 1600 mg to about 2240 mg.6. The method of any one of the previous embodiments, wherein for subjects with a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 1,600 mg.7. The method of any one of embodiments 1-5, wherein for subjects with a body weight greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 2,240 mg.8. The method of any one of the previous embodiments, comprising administering the bispecific anti-EGFR / c-Met antibody weekly for the first four weeks and every two weeks thereafter.9. The method of any one of the previous embodiments, comprising administering the bispecific anti-EGFR / c-Met antibody on days 1, 8, 15, and 22 of a first 28-day treatment cycle.10. The method of embodiment 9, comprising, after the first 28-day treatment cycle, administering the bispecific anti-EGFR / c-Met antibody on days 1 and 15 of each subsequent 28- day treatment cycle, starting in the second 28-day treatment cycle.11. The method of any one of the previous embodiments, wherein the FOLFIRI or mFOLFOX6 is intravenously administered every two weeks.12. The method of any one of the previous embodiments, comprising administering the FOLFIRI or mFOLFOX6 on days 1 and 15 of a first 28-day treatment cycle.13. The method of embodiment 12, comprising, after the first 28-day treatment cycle, administering the FOLFIRI or mFOLFOX6 on days 1 and 15 of each subsequent 28-day treatment cycle, starting in the second 28-day treatment cycle.14. The method of any one of the previous embodiments, wherein the bispecific anti- EGFR / c-Met antibody is administered subcutaneously.15. The method of any one of embodiments 1-13, wherein the bispecific anti-EGFR / c- Met antibody is administered intravenously.16. The method of any one of the previous embodiments, wherein the method provides a prolonged overall survival of the subject compared to a reference subject or a reference population of subjects with left-sided CRC wild type for RAS and BRAF not previously administered any prior systemic therapy for the CRC and administered: cetuximab and FOLFIRI, or cetuximab and mFOLFOX6.17. The method of any one of the previous embodiments, wherein the method provides an improvement in median progression free survival (PFS) relative to median PFS of a reference population of subjects with left-sided CRC wild type for RAS and BRAF not previously administered any prior systemic therapy for the CRC and administered: cetuximab and FOLFIRI, or cetuximab and mF0LF0X6.18. The method of any one of the previous embodiments, wherein the method provides an improvement in objective response rate by blinded independent central review (BICR), objective response rate (ORR) as assessed by investigator, duration of response, PFS after first subsequent therapy, disease control rate, time to treatment failure, time to systemic progression, or any combination thereof, wherein the improvement is relative to a reference subject or a reference population of subjects with left-sided CRC wild type for RAS and BRAF not previously administered any prior systemic therapy for the CRC and administered: cetuximab and FOLFIRI, or cetuximab and mF0LF0X6.19. The method of embodiment 17, wherein the PFS is assessed using RECIST vl.l criteria.20. The method of any one of embodiments 16-19, wherein the reference subject or reference population of subjects had received cetuximab weekly at a dose of 400 mg / m2for the first dose and 250 mg / m2thereafter or once every two weeks at a dose of 500 mg / m2.21. The method of any one of the previous embodiments, wherein the FOLFIRI comprises 180 mg / m2intravenous irinotecan, 400 mg / m2intravenous leucovorin or 200 mg / m2intravenous levoleucovorin, 400 mg / m2intravenous 5 -fluorouracil bolus, and 2,400 mg / m2intravenous 5 -fluorouracil.22. The method of any one of the previous embodiments, wherein the mFOLFOX6 comprises 85 mg / m2intravenous oxaliplatin, 400 mg / m2intravenous leucovorin or 200 mg / m2intravenous levoleucovorin, 400 mg / m2intravenous 5 -fluorouracil bolus, and 2,400 mg / m2intravenous 5 -fluorouracil.23. The method of any one of the previous embodiments, wherein:the HC1 comprises a variable region 1 (VH1) comprising the amino acid sequence of SEQ ID NO: 13; the LC1 comprises a variable region 1 (VL1) comprising the amino acid sequence of SEQ ID NO: 14; the HC2 comprises a variable region 2 (VH2) comprising the amino acid sequence of SEQ ID NO: 15; and the LC2 comprises a variable region 2 (VL2) comprising the amino acid sequence of SEQ ID NO: 16.24. The method of any one of the previous embodiments, wherein the bispecific anti- EGFR / c-Met antibody is an IgGl isotype.25. The method of any one of the previous embodiments, wherein: the HC1 comprises the amino acid sequence of SEQ ID NO: 17; the LC1 comprises the amino acid sequence of SEQ ID NO: 18; the HC2 comprises the amino acid sequence of SEQ ID NO: 19; and the LC2 comprises the amino acid sequence of SEQ ID NO: 20.26. The method of any one of the previous embodiments, wherein the bispecific anti- EGFR / c-Met antibody is amivantamab.27. The method of any one of the previous embodiments, comprising administering a glucocorticoid, an antihistamine, or an antipyretic prior to the administering of the bispecific anti-EGFR / c-Met antibody.28. The method of embodiment 27, wherein the glucocorticoid comprises dexamethasone or methylprednisolone, the antihistamine comprises diphenhydramine or chlorphenamine, and the antipyretic comprises paracetamol / acetaminophen.29. The method of any one of the previous embodiments, comprising administering of a H2 -antagonist or an antiemetic prior to the administering of the bispecific anti-EGFR / c-Met antibody.30. The method of embodiment 29, wherein the H2 -antagonist comprises ranitidine, and the antiemetic comprises ondansetron.EXAMPLES

[0088] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments.

[0089] EXAMPLE 1: Amivantamab plus chemotherapy in relapsed / refractory metastatic colorectal cancer: Results from OrigAMI-1, an open-label, phase lb / 2 study (NCT05379595)Study Overview

[0090] The purpose of this study is to assess the anti-tumor activity of amivantamab as a monotherapy (Cohorts A, B, and C), to characterize the safety of amivantamab when added to standard-of care (SoC) chemotherapy in participants with metastatic colorectal cancer (mCRC) (Ph2 cohorts), and to assess the recommended phase 2 combination dose (RP2CD) of amivantamab when added to SoC chemotherapy (Phlb cohorts).

[0091] The study includes up to 28 days screening period, treatment period begins on Cycle 1 Day 1 (C1D1) (for Cohorts A, B, and C) or CID -2 (for Phlb-D, Phlb-E, Cohorts D and E) with the administration of the study treatment and continue as 28-day cycles until the end of treatment visit, up to 30 days after discontinuation of study treatment. The safety of amivantamab as a monotherapy or in addition to SoC chemotherapy is assessed by physical examinations, Eastern Cooperative Oncology Group (ECOG) criteria for performance status (PS), laboratory tests, vital signs, monitoring of adverse events, and concomitant medication usage.Participation Criteria

[0092] Inclusion criteria include the following:• Participant must have been previously diagnosed with histologically or cytologically confirmed unresectable or metastatic adenocarcinoma of the colon or rectum• For Phase 1 dose confirmation cohorts (Cohorts Phlb-D and Phlb-E): Participant must have evaluable disease. For Phase 2 dose expansion cohorts (Cohorts D and E): Participant must have measurable disease according to Response Criteria in Solid Tumors (RECIST) Version 1.1. If only one measurable lesion exists, it may be used for thescreening biopsy as long as baseline tumor assessment scans are performed greater than or equal to (>=) 7 days after the biopsy• Participant must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1• Participant must have a tumor lesion amenable for biopsy and agree to mandatory protocol-defined screening biopsy• A female participant of childbearing potential must have a negative serum pregnancy test at screening and within 72 hours of the first dose of study treatment and must agree to further serum or urine pregnancy tests during the study. Note: Participant must not be pregnant, breastfeeding, or planning to become pregnant while enrolled in this study

[0093] Exclusion criteria include the following:• Participant with identified mutation in Kirsten rat sarcoma viral oncogene (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF), or epidermal growth factor receptor (EGFR) ectodomain, or ERBB2 / HER2 amplification by central circulating tumor deoxyribonucleic acid (ctDNA) testing at screening• Participant with symptomatic or untreated brain metastasis• History or known presence of leptomeningeal disease• Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (for example, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessmentsArms & Interventions

[0094] The study is designed as shown in Table A.Table A: Study DesignPrimary Outcome Measures

[0095] The study’s primary outcome measures include those shown in Table B.Table B: Primary Outcome MeasuresMethods

[0096] OrigAMI-1 (NCT05379595) is assessing the safety and efficacy of ami alone or combined with chemo in pts with refractory RAS / RAF WT mCRC. Eligible pts were WT for KRAS, N AS. BRAF. and EGFR ectodomain by ctDNA testing, without ERBB2 / HER2 amplification. For chemo combination cohorts, pts were treatment-naive for prior anti-EGFR therapy (max 1 prior line). Patients received ami (1050 mg [1400 mg if >80kg]) plus mFOLFOX6 or FOLFIRI. Response was assessed by the investigator per RECIST vl . 1.Results

[0097] As of 8 April 2024, 44 pts were dosed; with 21 receiving ami+FOLFOX and 23 receiving ami+FOLFIRI at a median follow-up of 3.9 and 4.4 months (mo), respectively. Median age (range) was 62 (36-79) y, 70% of pts were male, and the median number prior lines was 1. The most frequent treatment-emergent adverse events (AEs) were rash and neutropenia. The best timepoint response rate was 63% (10 / 16) for ami+FOLFOX and 48% (11 / 23) for ami+FOLFIRI. The median duration of response (DoR) among confirmed responders was not estimable (NE) for ami+FOLFOX and 6.5 mo (95% CI, 5.6-NE) for ami+FOLFIRI. See Table C for additional details.Table C: Summary of efficacy findingsaAs of data cutoff, 5 patients on ami+FOLFOX treatment have not reached their first disease assessment.bDCR (disease control rate) is defined as the percentage of patients achieving a best timepoint response of complete / partial response or stable diseasecAmong confirmed responders.

[0098] Conclusions: Ami+chemo demonstrated encouraging, durable antitumor activity in relapsed / refractory mCRC.

[0099] EXAMPLE 2: A Randomized, Open-label Phase 3 Study of Amivantamab and mFOLFOX6 or FOLFIRI Versus Cetuximab and mFOLFOX6 or FOLFIRI as First- line Treatment in Participants With KRAS / NRAS and BRAF Wild-type Unresectable or Metastatic Left-sided Colorectal Cancer (OrigAML2; 61186372COR3001)

[0100] The primary objective of this study is to compare PFS (as assessed by BICR) in participants treated with amivantamab + mF0LF0X6 or FOLFIRI versus participants treated with cetuximab + mF0LF0X6 or FOLFIRI. Secondary objectives include other measures of efficacy, safety, and PROs.Study Design

[0101] This is a randomized, open-label, active-controlled, parallel-group, multicenter, interventional, Phase 3 study of amivantamab and FOLFIRI or mF0LF0X6 therapy, compared with cetuximab and FOLFIRI or mF0LF0X6, as first-line treatment in in adult participants who have unresectable or metastatic left-sided CRC that is KRAS / NRAS and BRAF wild type. Participants must be treatment-naive in the metastatic setting and must not have received prior anti-EGFR or anti -MET therapy. Approximately 1,000 participants will be randomly assigned in a 1 : 1 ratio (-500 in each treatment group) will be randomized in this study with the following stratification criteria: choice of chemotherapy, limited disease, and prior adjuvant therapy.

[0102] The screening period will be up to 28 days prior to randomization. The treatment period will begin on Cycle 1 Day 1 and continue as 28-day cycles. Participants will receive study treatment until radiographic disease progression by BICR or other discontinuation criteria are met. Participants will then be followed for survival, subsequent anticancer treatment, and disease status.

[0103] Following analysis of the primary endpoint, participants who continue to benefit from study treatment, as determined by the investigator, may continue to receive access to study treatment(s), either via an open-label or long-term extension rollover study or any other post-trial access program, when available and permitted by local regulations.

[0104] Participants will be enrolled into 1 of 2 treatment arms:Arm A: Amivantamab SC (1600 mg for BW <80 kg; 2240 mg for BW >80 kg) + mF0LF0X6 or FOLFIRIArm B: Cetuximab + mF0LF0X6 or FOLFIRI

[0105] Response to treatment and primary objective of PFS will be assessed by BICR according to RECIST vl .1 .TABLE 1: Objectives and EndpointsEstimands

[0106] The primary scientific question of interest is: What is the relative effect of amivantamab + mF0LF0X6 or FOLFIRI compared with cetuximab + mF0LF0X6 or FOLFIRI in prolonging PFS, regardless of treatment discontinuation, curative surgery, or subsequent anticancer therapy, as first-line treatment in adults with unresectable or metastatic left-sided CRC that is KRAS / NRAS and BRAF WT?Hypothesis

[0107] The hypothesis is that the amivantamab and mFOLFOX6 or FOLFIRI combination will demonstrate superior PFS compared with cetuximab and mFOLFOX6 or FOLFIRI combination as first-line treatment in adult participants with KRAS / NRAS and BRAF WT unresectable or metastatic left-sided colorectal cancer.Overall Design

[0108] This is a randomized, open-label, active-controlled, parallel-group, multicenter, interventional, Phase 3 study of amivantamab + mF0LF0X6 or FOLFIRI compared with cetuximab + mF0LF0X6 or FOLFIRI as first-line treatment in adult participants who have unresectable or metastatic left-sided CRC that is KRAS / NRAS and BRAF WT. Participants must be treatment-naive in the metastatic setting and must not have received prior anti-EGFR or anti- MET therapy. A target of approximately 1,000 participants will be randomly assigned in a 1: 1 ratio with the following stratification criteria: choice of chemotherapy, limited disease, and prior adjuvant therapy.

[0109] The study consists of a Screening Period, a Treatment Period, and a Follow-up Period.Screening Period

[0110] The Screening Period starts at the time of the signing of the informed consent form (ICF) and ends with randomization. The ICF must be signed before the first study-related activity is conducted. Screening procedures must be completed within 28 days of randomization. However, screening imaging may occur within 35 days prior to randomization. The Screening Period may be extended to a maximum of 42 days if necessary to receive local biomarker test results without having to screen-fail the participant (screening procedures still must be completed within 28 days of randomization).

[0111] During the screening period, participants will be evaluated for study eligibility. Participants must be diagnosed to have KRAS, NRAS, and BRAF WT disease by local testing prior to randomization. Both tissue-based and blood-based testing is an acceptable method forthe eligibility determination. The local test must at least include KRAS and NRAS G12 and G13 and BRAF V600 codons. Other KRAS / NRAS codons, as well as MSI-H / dMMR status and ERBB2 / HER2 amplification status, should be determined per the local guidelines and standard practice. The local test results must be included in the participant’s study records, and a deidentified copy must also be submitted to the Sponsor. Participants who fail to meet all inclusion criteria, meet at least 1 exclusion criterion, or both may be rescreened if their condition changes. Rescreening must be discussed with and approved by the Sponsor on a case-by-case basis. Participants who are eligible for rescreening must sign a new ICF prior to any additional study activities being performed. The data obtained closest to the first study treatment administration will be used to determine eligibility.Treatment Period

[0112] The Treatment Phase will begin on Cycle 1 Day 1 (C1D1) within 3 days after randomization. The assignment of chemotherapy backbone (ie, mF0LF0X6 or FOLFIRI) is at the discretion of the investigator and must be predetermined prior to randomization and continued throughout the Treatment Period. The administration of the study treatment will continue as 28-day cycles until the EOT visit, approximately 30 days after discontinuation of study treatment. The latest measurements taken before administration of the first study treatment will be defined as baseline values. Study treatment should continue until documented radiographic progression using RECIST vl . 1 confirmed by BICR or another reason for discontinuation of study treatment. The investigator should not discontinue study treatment until confirmation of progression has been received from BICR. If radiographic progression is not confirmed by BICR, the participant should continue to receive study treatment and undergo imaging in accordance with the protocol.Follow-up Period

[0113] Participants who discontinue study treatment for any reason will be followed for survival and subsequent anticancer treatment and any other assessments. Disease status will be assessed every 12 weeks (±14 days) after the last dose of study treatment or disease progression (whichever occurs first), until the end of study, death, lost to follow-up, or withdrawal of consent, whichever comes first. PRO assessments may be collected by telephone or electronic devices and will be discontinued at the end of study, death, lost to follow-up, withdrawal of consent, or at the time a planned interim analysis shows statistical significance for the OS endpoint, whichever occurs first. Survival status and subsequent therapy information maybe obtained by telephone or chart review and may be obtained at a shorter interval than every12 weeks during follow-up if required. Investigators may recontact the participant to obtain longterm follow-up information regarding the participant’s safety or survival status as noted in the ICF. If the information is obtained via telephone contact, written documentation of the communication must be available for review in the source documents. If the participant has died, the date and cause of death will be collected and documented.

[0114] A diagram of the study design is provided in FIG. 1.

[0115] This is an open-label study; therefore, no blinding is applied. An active control (cetuximab and mF0LF0X6 or FOLFIRI) is used as a comparator arm.End of Study

[0116] The end of study / study completion is considered as the last scheduled study assessment for the last participant in the study.Participant Study Completion

[0117] A participant will be considered to have completed the study if the participant (1) died while on study, or (2) was on study (ie, did not meet the criteria for withdrawal from study) at the time of end of study.Study Population

[0118] Screening for eligible participants will be performed within 28 days (35 days for screening imaging and 42 days for results of biomarker analysis) before randomization. The inclusion and exclusion criteria for enrolling participants in this study are described below.TABLE 2: Inclusion Criteria. Each potential participant must satisfy all of the following criteria to be enrolled in the study.TABLE 3: Exclusion Criteria: Any potential participant who meets any of the following criteria will be excluded from participating in the study.

[0119] All study enrollment criteria must have been met at screening. If a participant’s clinical status changes (including any available laboratory results or receipt of additional medical records) after screening but before the first dose of study treatment is given such that the participant no longer meets all eligibility criteria, then the participant must be excluded from participation in the study.Treatments

[0120] For this study, “study treatment” refers to amivantamab SC or cetuximab with chemotherapy backbone (leucovorin or levoleucovorin, 5-FU, and oxaliplatin or irinotecan). Amivantamab SC and cetuximab are considered Investigational Medicinal Products (IMPs), and the components of the chemotherapy backbone are considered Auxiliary Medicinal Products (AxMPs, also known as NIMP). All other study-specified medications are considered concomitant medicationsTABLE 4: Description of treatments

[0121] The amivantamab dosage will be based on the participant’s baseline body weight (BW). Amivantamab will be administered as a manual subcutaneous (SC) injection intothe abdomen. Doses will be administered at alternating locations on the abdomen in the periumbilical area.

[0122] A missed dose is defined as failure to administer study treatment within 3 days of the scheduled dosing date in Cycle 1 (Cl) or failure to administer study treatment within 7 days (or 3 days for weekly cetuximab regimen) of the scheduled dosing date in Cycle 2 (C2) and beyond. If a dose is missed, as defined above, it will not be made up. Administration may resume at the next planned dosing date. All other assessments should be performed relative to actual study treatment administration, not on the originally scheduled administration day.

[0123] Participants in Arm A will receive amivantamab in addition to standard of care (SoC) mF0LF0X6 or FOLFIRI as described in Table 5 or according to the institutional standard. Participants in Arm B will receive cetuximab in addition to SoC mF0LF0X6 or FOLFIRI as described herein or according to the institutional standard. A reduced starting dose of 5-FU should be considered to limit the toxicity for participants with known partial dihydropyrimidine dehydrogenase (DPD) deficiency based on the local guidelines and standard practice. In the absence of serious toxicity, subsequent doses may be increased with careful monitoring. For dose modification, final treatment decisions should depend on clinical judgment, based on local regulations, labeling, and the institutional standard (including but not limited to skipping bolus 5-FU administration). Decisions on study treatment dose modification should be guided by the safety profile of each drug and the likelihood of causality.

[0124] On days when amivantamab or cetuximab and chemotherapy are administered, amivantamab or cetuximab should be administered prior to chemotherapy. In general, administer oxaliplatin 85 mg / m2or irinotecan 180 mg / m2(or per local standard) and leucovorin 400 mg / m2(or levoleucovorin 200 mg / m2) IV over approximately 2 hours at the same time in separate bags (or sequentially according to the institutional SoC), then 5-FU 400 mg / m2IV bolus followed by continuous infusion of 5-FU 2400 mg / m2over approximately 46-48 hours or 1200 mg / m2 / day for 2 days. mFOLFOX6 or FOLFIRI administration should be delayed if the participant experiences absolute neutrophil count (ANC) <1.5 x 109 / L, if the platelet count is <75 x 109 / L, if stomatitis or diarrhea has not recovered to Grade <1, or if fatigue has not recovered to Grade <2. If toxicities related to mFOLFOX6 or FOLFIRI do not recover for more than 8 weeks, mFOLFOX6 or FOLFIRI treatment should be discontinued. When chemotherapy agents are sourced locally, refer to the local prescribing information for each agent for a list of excipients. The body surface area (BSA) of the participant should be calculated by the institutional standard. Continued use of either amivantamab / cetuximab, mFOLFOX6 / FOLFIRI, or components of mFOLFOX6 / FOLFIRI (eg, 5-FU alone, oxaliplatin alone, or irinotecan alone) is permitted afterthe approval from the sponsor when either amivantamab / cetuximab or mF0LF0X6 / F0LFIRI is discontinued.

[0125] Participants undergoing curative resection / surgery should continue to receive study treatments (or part of study treatments) per the investigator’s discretion.

[0126] For participants receiving mFOLFOX6: To prevent the occurrence of accumulative oxaliplatin-induced neurotoxicity, participants may discontinue oxaliplatin after a minimum of 6 cycles at the investigator’s discretion and continue to receive other protocol- specified study medications after consultation with the sponsor.Table 5: Study Treatment Administration Schedule for Amivantamab SC + FOLFIRI or mFOLFOX6a When amivantamab and chemotherapy are administered on the same day, amivantamab should be given prior to chemotherapy.Table 6: Study Treatment Administration Schedule for Cetuximab+FOLFIRI or mFOLFOX6a. When cetuximab and chemotherapy are administered on the same day, cetuximab should be given prior to chemotherapy.Cycle 2+ refers to Cycle 2 and all subsequent cycles. Also abbreviated to C2+.*Cetuximab administration should be completed 1 hour prior to the initiation of F0LFIRI / mF0LF0X6 per the SoC.Dose Modification

[0127] Decisions regarding dose modification of the individual study treatments should be guided by the observed toxicity and the safety profile of each drug.

[0128] Guidance on dose modification and toxicity management for toxicities that may be attributed to amivantamab, cetuximab, or mFOLFOX6 / FOLFIRI is provided below. The safety profile of amivantamab is largely distinct from that associated with chemotherapeutic agents. However, overlapping toxicity should be considered in the evaluation of all AEs.Toxicities Attributed to Amivantamab

[0129] Refer to Error! Reference source not found.Table 7 for guidance on delay and modification of the amivantamab dose based on the toxicity grade of adverse events (AEs). Table 7: Guidance for Amivantamab Dose Delay and Modification for ToxicitiesConsidered Related to Amivantamaba. Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. b. For all toxicities, consider supportive care according to protocol or local standards (if no protocol guidance provided), as appropriate. c. If interruption occurs for more than 1 cycle, contact the sponsor to discuss retreatment. If the participant is benefiting from treatment, study treatments may continue upon consultation with the sponsor. d. Resolution defined as Grade <1 or back to baseline. For hypoalbuminemia, the dose can be resumed without resolution of the event to Grade <1 or baseline and based on the investigator’s clinical judgement. For liver enzyme abnormalities requiring intermption of treatment, a discussion should occur with the sponsor before restarting amivantamab.

[0130] Guidance for stepwise dose modification of amivantamab is outlined in Table8.Table 8: Guidance for Amivantamab Stepwise Dose ReductionTreatment of Administration-related Reactions

[0131] Administration-related reactions (ARRs) have been observed during treatment with amivantamab SC, predominantly with the first exposure on Cycle 1 Day 1 (generally occurring within the first 4 hours after the initial injection). The majority of ARRs have been Grade 1 or 2.

[0132] Participants who experience early symptoms of ARRs, manifesting as fever, chills, rigors, bronchospasm, headache, rash, pruritus, arthralgia, hypo- or hypertension, or other symptoms, must have their amivantamab SC injection interrupted, if ongoing, and the symptoms managed according to the recommendations provided in Table 9. If the ARR occurs while administering the first injection of amivantamab (Cycle 1 Day 1), injection interruption should be considered even with mild symptoms to prevent more severe manifestations of ARRs.Table 9: Management of Administration-related Reactions During Amivantamab SCTreatmenta. Per NCI-CTCAE v5.0.

[0133] Predose and postdose medications, including prophylactic and reactive management recommendations for ARR, are provided.

[0134] A suggested stepwise management of rash is provided in Table 10.Table 10: Suggested Management of Rash During Amivantamab Treatmenta. Per NCI-CTCAE v5.0. b. If amivantamab must be withheld due to toxicity for 2 consecutive doses, then study treatment cannot be restarted without consultation with the sponsor. Participants considered by the investigator and sponsor to be benefiting from treatment may be continued, potentially at a lower dose upon satisfactory resolution of the toxicity. c. Resolution defined as: <Grade 1 non-hematologic toxicity or back to baseline. d. For example, hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream.Toxicities Attributed to Cetuximab

[0135] If an infusion related reaction (IRR) develops later during the infusion or at a subsequent infusion, the following management is recommended:• Grade 1 or 2: Reduce the infusion rate by 50%.• Grade 3 or 4: Immediately and permanently discontinue cetuximab.

[0136] Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, .S', aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis / ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis have been reported. Acneiform rash of any grade occurred in 82%, and severe (Grades 3 and 4) acneiform rash occurred in 10% of patients who received cetuximab (Erbitux USPI; Erbitux SmPC). Recommendations for management of dermatologic toxicities and infectious sequelae are provided in Table 11 .Table 11: Management of Dermatologic Toxicities and Infectious Sequelae During Cetuximab TreatmentToxicities Attributed to mFOLFOX6 or FOLFIRI

[0137] For the dose modification, final treatment decisions should depend on clinical judgment, based on local regulations, labeling, and the institutional standard (including but not limited to skipping bolus 5-FU administration). Decisions on study treatment dose modification should be guided by the safety profile of each drug and the likelihood of causality.

[0138] Dose modifications of chemotherapy will be based on the maximum toxicity experienced during a cycle. Treatment should be delayed until the toxicity resolves to Grade <1 or the baseline status of the participant.

[0139] Participants may have a maximum of 2 dose modifications (Level -2) to each treatment throughout the course of the study for toxicities before the agent should be discontinued. Dose reduction should be based upon the most severe toxicity if multiple toxicities are experienced concurrently. Refer to Table 12 for dose modification guidance.Table 12: Guidance for Chemotherapy Stepwise Dose ReductionLeucovorin dose is always 400 mg / m2 IV given prior to the infusion of 5-FU. If any infusion of 5-FU is to be skipped, leucovorin must also be skipped.Hematologic Toxicities

[0140] Hematologic toxicities are commonly observed with chemotherapy through myelosuppression. The chemotherapy should be given only when the participants have absolute neutrophil count (ANC) >1.5 x 109 / L and platelets >75 x 109 / L on the day of chemotherapy. Table 13 provides the recommended guidance for hematologic toxicities.Table 13: Suggested Management of Hematologic Toxicities

[0141] Table 14 provides recommended guidance for diarrhea.Table 14: Suggested Management of Diarrhea

[0142] Table 15 provides recommended guidance for mucositis.Table 15: Suggested Management of Mucositis

[0143] Table 16 provides recommended guidance for nausea or vomiting. These dose reduction recommendations should be made only if they persist despite optimized antiemetic regimens.Table 16: Suggested Management of Nausea or VomitingNeurotoxicity

[0144] Neuropathy occurs in the majority of participants who receive oxaliplatin. The following guidance is recommended for the neurotoxicity.Grade 2: Interfering with function but not daily activities• Reduce oxaliplatin by 1 dose level for the remainder of the cycle and for subsequent cyclesGrade 3: Pain or functional impairment that interfered with daily activities• Reduce oxaliplatin by 1 dose level for the remainder of the cycle and for subsequent cycles if resolves to Grade <2 between treatments• Reduce oxaliplatin by 1 additional dose level for the remainder of the cycle and for subsequent cycles for recurrent Grade 3 neurotoxicity resolving to Grade <2 between treatments• Discontinue oxaliplatin if persists between treatmentsGrade 4: Persistent impairment that is disabling or life-threatening• Discontinue oxaliplatinFor pharyngo-laryngeal dysesthesiaConsider increasing the duration of oxaliplatin infusion to 6 hours for all subsequent treatments.

[0145] To prevent the occurrence of cumulative oxaliplatin-induced neurotoxicity, participants may discontinue oxaliplatin after a minimum of 6 cycles at the investigator discretion and continue to receive other protocol-specified study medicationsConcomitant Therapy: Pre-infusion and Post-infusion MedicationsPredose Medications for Amivantamab

[0146] Required predose medications and optional predose medications for amivantamab are summarized in Table 17.Table 17: Predose Medications for Amivantamab (Amivantamab + mFOLFOX6 or FOLFIRI Arm)a. If a medication noted in this table is not locally available, a similar medication and dose may be substituted and administered per local guidelines. b. Participants for whom suggested medications are contraindicated should explore alternative medications with their study doctor. If alternative medications are not suitable for the intent above, participants are not required to take the corresponding medication. c. Select 1 from each category. d. Beginning with C1D8, optional predose steroids may be administered prior to amivantamab if clinically indicated for participants who experienced an IRR on C1D1 or C1D2.Postdose Medications for Amivantamab

[0147] Optional post-dose medications may be prescribed and continued for up to 48 hours after any infusion if clinically indicated, at the discretion of the investigator (Table 18). Optional medications can be used prophylactically as clinically indicated. If a medication noted in this table is not locally available, a similar medication and dose may be substituted and administered per local guidelines.Table 18: Optional Postdose Medications for Amivantamab (Amivantamab + mFOLFOX6 or FOLFIRI arm)Pre- and Post-infusion Medication for Cetuximab

[0148] Premedicate with a histamine-1 (Hl) receptor antagonist intravenously 30 to 60 minutes prior to the first dose or subsequent doses of cetuximab, as per the investigator’s discretion. Other pre- and post-infusion medication, such as an H2 antagonist (eg. famotidine), steroids, or antipyretic (eg. acetaminophen) may be administered according to institutional standards.Pre- and Post-infusion Medication for Chemotherapy

[0149] Prior to the administration of chemotherapy, pre-medication with antiemetics, such as serotonin (5HTs) antagonists (ie, ondansetron or granisetron), with or without dexamethasone may be used at the investigator’s discretion or according to institutional standards. Other pre-medications and post-medications should be provided to mitigate chemotherapy toxicities according to the approved label or institutional standards.

[0150] Examples of specific schedules for administration of amivantamab+mF0LF0X6 or FOLFIRI and pre-infusion medications, and cetuximab+mFOLFOX6 or FOLFIRI and pre-infiision medications are shown in Table 19 and Table 20. The schedule of activities (SoA) is shown in Table 21. The intercurrent events and their corresponding strategies are shown in Table 22.Table 19: Suggested Order of Administration When Amivantamab is Given with mFOLFOX6 or FOLFIRIa. Mandatory on C1D1 onlyTable 20: Suggested Order of Administration When Cetuximab is Given with mFOLFOX6 / FOLFIRIProhibited Medications and Therapies

[0151] The following concomitant medications and therapies are prohibited during the study:• Any chemotherapy, systemic anticancer therapy, or experimental therapy (other than study treatments).• Radiotherapy to tumor lesions being assessed for tumor response prior to radiographic progression.• Use of live or live attenuated vaccines during study treatment and for 90 days after completion of study treatment (vaccination is allowed per local guidelines including annual influenza and inactivated SARS-CoV-2 vaccines).TABLE 21: Schedule of Activities (SoA)Response Assessment

[0152] RECIST vl . 1 criteria will be used to assess participant response to treatment: CR, PR, stable disease, progressive disease, or not evaluable (Eisenhauer 2009). Disease assessments will include the chest, abdomen, pelvis, and any other disease location(s). Baseline disease assessments should be performed no more than 35 days prior to randomization. For participants who undergo curative intent surgical resection during the Treatment Period, only preintervention imaging will be used to assess the best oral response of CR, PR, or stable disease. Postintervention tumor assessments will be used to determine the time of PD and where it occurs (eg, recurrence at the site of resection or a distant new lesion).Primary Endpoint / Estimand

[0153] Primary Estimand Scientific Question of Interest: What is the relative effect of amivantamab + mF0LF0X6 or FOLFIRI compared with cetuximab + mF0LF0X6 or FOLFIRI in prolonging PFS, regardless of treatment discontinuation, curative surgery, or subsequent anticancer therapy?• Population: adult participants with unresectable or metastatic left-sided CRC that is KRAS / NRAS and BRAF WT and who are treatment-naive and have not received prior anti- EGFR or anti-MET therapy• Variable: time to event, PFS by BICR• Study treatment: amivantamab + mF0LF0X6 or FOLFIRI (experimental treatment) or cetuximab + mF0LF0X6 or FOLFIRI (control treatment).• Population-level summary: HR of amivantamab + mF0LF0X6 or FOLFIRI versus cetuximab + mF0LF0X6 or FOLFIRI with corresponding confidence intervals (CI). Table 22. Intercurrent events and their corresponding strategies:

[0154] The primary endpoint of PFS is defined as the time from randomization until the date of objective disease progression or death (due to any cause), whichever comes first, based on BICR using RECIST v 1. 1. Participants who have not progressed or have not died at the time of analysis will be censored at their last evaluable RECIST vl.l assessment date. Participants without evaluable baseline or postbaseline disease assessment will be censored at the date of randomization. Participants with documented disease progression or death after 2 or more consecutive missed / unevaluable disease assessments will be censored at the date of last evaluable disease assessment before the missed / unevaluable visits.

[0155] PFS will be analyzed using a log-rank test stratified by choice of chemotherapy (mFOLFOX6 / FOLFIRI), limited disease (yes / no), and prior adjuvant chemotherapy (yes / no). The p-value generated from the stratified log-rank test will be used for the primary hypothesis testing. The HR and its 95% CI will be estimated based on a stratified Cox’s regression model.

[0156] The median PFS with 95% CI will be estimated using Kaplan-Meier method. The Kaplan-Meier PFS curve will also be plotted by treatment group. In addition, PFS rates with 95% CI will be estimated by Kaplan-Meier method at landmarks (eg, 6-month, 12-month, and 18-month) and reported for each treatment group. The number and percentage of participants who had a PFS event or were censored will be reported, and reasons for PFS event and censoring will be summarized.

[0157] To assess homogeneity of the treatment effect on PFS across subgroups, the following prespecified subgroup analyses will be conducted:• Choice of chemotherapy(mFOLFOX6 / FOLFIRI)• Limited disease (yes / no)• Prior adjuvant chemotherapy (yes / no)• ECOG PS at baseline (0, 1)• Age group (<65 years, >65 years; <75 years, >75 years)• Sex• Race• Weight (<80 kg, >80 kg)• Region

[0158] A forest plot of the PFS HRs (along with the 95% Cis) will be produced for each level of the subgroups listed above. The following PFS sensitivity analyses will be conducted:• Unstratified analysis of PFS• PFS analysis censoring for death / progressive disease after start of subsequent anticancer therapy• PFS analysis censoring for death / progressive disease at the date of curative surgery• PFS not censored for missing more than 2 disease evaluations: PFS analysis will be performed considering all progression or death, whichever occur first, as events regardless of missed or unevaluable disease assessments for 2 or more consecutive visits.• PFS based on investigator assessmentSecondary EndpointsOverall Survival

[0159] OS is defined as time from the date of randomization to the date of death due to any cause. Any participant not known to have died at the time of analysis will be censored based on the last recorded date on which the participant was known to be alive. OS will be analyzed using a similar methodology and model as for the primary analysis of PFS.

[0160] If the testing of PFS shows statistical significance, the analysis of OS will be carried out using a total 1-sided alpha of 2.5%. Alpha spending function as implemented by the Lan-DeMets method will be used to determine the statistical boundary for each of the interim and final analyses of OS. Sensitivity analysis using unstratified log-rank test will be performed. In addition, to assess homogeneity of the treatment effect on OS, forest plots will be provided for same prespecified subgroups as for the PFS analysis.

[0161] OS sensitivity analyses adjusting for treatment switching, such as inverse probability of censoring weighting or rank-preserving structural failure time models, may be conducted if a significant number of participants randomized to cetuximab + mF0LF0X6 or FOLFIRI arm subsequentially receive amivantamab as second-line treatment.Objective Response Rate

[0162] ORR is defined as the proportion of randomized participants achieving PR or CR, as determined by BICR using RECIST vl.l criteria.

[0163] ORR and its exact 95% CI will be calculated. ORR will be analyzed using a stratified logistic regression model. The odds ratio of ORR together with its associated 95% CI will be provided.

[0164] For participants who undergo curative intent surgical resection during the treatment phase, only pre-intervention imaging will be used to assess the best oral response of CR, PR, or SD.Duration of Response and Time to Response

[0165] DoR is defined as time from the date of first documented response (CR or PR) until the date of documented progression or death, whichever comes first, for participants who have PR or CR. The end of response should coincide with the date of progression or death from any cause used for the PFS endpoint. If a participant does not progress following a response, then their DoR will be until the PFS censoring time.

[0166] A Kaplan-Meier plot and median DoR with 95% CI (calculated from the Kaplan-Meier estimate) will be presented by treatment group.

[0167] Time to first response will be summarized for all confirmed responders by treatment group using descriptive statistics and frequency statistics by time point.Progression -free Survival After Subsequent Anticancer Systemic Therapy

[0168] PFS2 is defined as the time from randomization until the date of second objective disease progression, after initiation of subsequent systemic anticancer therapy, based on investigator assessment (after that used for PFS) or death, whichever comes first. Participants alive and for whom a second disease progression has not been observed will be censored at the last time known to be alive and without a second disease progression (ie, last disease assessment).

[0169] PFS2 will be analyzed using the similar method as the primary analysis of PFS.Disease Control Rate

[0170] DCR is defined as the percentage of randomized participants achieving CR, PR, or stable disease (with minimum duration of 7 weeks) as defined by BICR using RECIST vl.l .Time to Treatment Failure

[0171] Time to treatment failure is defined as time from randomization to discontinuation of therapy for any reason including death, progression, toxicity, or initiation of new anticancer therapy.Curative Resection (RO) Rate

[0172] Curative resection (RO) rate is defined as the proportion of Full Analysis Set participants (or participants with limited disease at baseline) who underwent curative surgery. The proportion and the 95% CI will be provided.Patient-reported Outcomes

[0173] Compliance and results for each PRO measure will be summarized descriptively by treatment group and by study visit. Change from baseline in EORTC scales, EQ- 5D-5L visual analogue scale, and utility score will be analyzed using mixed models for repeated measures. Time to worsening in EORTC scales will be analyzed using a Kaplan-Meier method and stratified Cox proportional-hazard model.

[0174] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments disclosed herein and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

[0175] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

Claims

What is claimed is:

1. A method of treating left-sided colorectal cancer (CRC) that is wild-type for RAS and BRAF in a subject or a population of subjects not previously administered any prior systemic therapy for the CRC, the method comprising administering to the subject or the population of subjects a therapeutically effective amount of: a bispecific anti-EGFR / c-Met antibody, the antibody comprising a first heavy chain (HC1) comprising a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a HCDR3 comprising the amino acid sequences of SEQ ID NO: 3; a first light chain (LC1) comprising a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 4, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 6; a second heavy chain (HC2) comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, and a HCDR3 comprising the amino acid sequences of SEQ ID NO: 9; and a second light chain (LC2) comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 10, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 12; andFOLFIRI or mFOLFOX6.

2. The method of claim 1, wherein the colorectal cancer is unresectable or metastatic colorectal cancer.

3. The method of any one of the previous claims, wherein the subject has not received agents that target EGFR or agents that target MET.

4. The method of any one of the previous claims, wherein the colorectal cancer is wild type for KRAS, NRAS, and BRAF.

5. The method of any one of the previous claims, wherein the bi specific anti-EGFR / c- Met antibody is administered in an amount of about 1600 mg to about 2240 mg.

6. The method of any one of the previous claims, wherein for subjects with a body weight of less than 80 kg, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 1,600 mg.

7. The method of any one of claims 1-5, wherein for subjects with a body weight greater than or equal to 80 kg, the bispecific anti-EGFR / c-Met antibody is administered in an amount of about 2,240 mg.

8. The method of any one of the previous claims, comprising administering the bi specific anti-EGFR / c-Met antibody weekly for the first four weeks and every two weeks thereafter.

9. The method of any one of the previous claims, comprising administering the bispecific anti-EGFR / c-Met antibody on days 1, 8, 15, and 22 of a first 28-day treatment cycle.

10. The method of claim 9, comprising, after the first 28-day treatment cycle, administering the bispecific anti-EGFR / c-Met antibody on days 1 and 15 of each subsequent 28- day treatment cycle, starting in the second 28-day treatment cycle.

11. The method of any one of the previous claims, wherein the FOLFIRI or mFOLFOX6 is intravenously administered every two weeks.

12. The method of any one of the previous claims, comprising administering the FOLFIRI or mFOLFOX6 on days 1 and 15 of a first 28-day treatment cycle.

13. The method of claim 12, comprising, after the first 28-day treatment cycle, administering the FOLFIRI or mFOLFOX6 on days 1 and 15 of each subsequent 28-day treatment cycle, starting in the second 28-day treatment cycle.

14. The method of any one of the previous claims, wherein the bispecific anti-EGFR / c- Met antibody is administered subcutaneously.

15. The method of any one of claims 1-13, wherein the bispecific anti-EGFR / c-Met antibody is administered intravenously.

16. The method of any one of the previous claims, wherein the method provides a prolonged overall survival of the subject compared to a reference subject or a reference population of subjects with left-sided CRC wild type for RAS and BRAF not previously administered any prior systemic therapy for the CRC and administered: cetuximab and FOLFIRI, or cetuximab and mF0LF0X6.

17. The method of any one of the previous claims, wherein the method provides an improvement in median progression free survival (PFS) relative to median PFS of a reference population of subjects with left-sided CRC wild type for RAS and BRAF not previously administered any prior systemic therapy for the CRC and administered: cetuximab and FOLFIRI, or cetuximab and mF0LF0X6.

18. The method of any one of the previous claims, wherein the method provides an improvement in objective response rate by blinded independent central review (BICR), objective response rate (ORR) as assessed by investigator, duration of response, PFS after first subsequent therapy, disease control rate, time to treatment failure, time to systemic progression, or any combination thereof, wherein the improvement is relative to a reference subject or a reference population of subjects with left-sided CRC wild type for RAS and BRAF not previously administered any prior systemic therapy for the CRC and administered: cetuximab and FOLFIRI, or cetuximab and mF0LF0X6.

19. The method of claim 17, wherein the PFS is assessed using RECIST vl. 1 criteria.

20. The method of any one of claims 16-19, wherein the reference subject or reference population of subjects had received cetuximab weekly at a dose of 400 mg / m2for the first dose and 250 mg / m2thereafter or once every two weeks at a dose of 500 mg / m2.

21. The method of any one of the previous claims, wherein the FOLFIRI comprises 180 mg / m2intravenous irinotecan, 400 mg / m2intravenous leucovorin or 200 mg / m2intravenouslevoleucovorin, 400 mg / m2intravenous 5 -fluorouracil bolus, and 2,400 mg / m2intravenous 5- fluorouracil.

22. The method of any one of the previous claims, wherein the mFOLFOX6 comprises 85 mg / m2intravenous oxaliplatin, 400 mg / m2intravenous leucovorin or 200 mg / m2intravenous levoleucovorin, 400 mg / m2intravenous 5 -fluorouracil bolus, and 2,400 mg / m2intravenous 5- fluorouracil.

23. The method of any one of the previous claims, wherein: the HC1 comprises a variable region 1 (VH1) comprising the amino acid sequence of SEQ ID NO: 13; the LC1 comprises a variable region 1 (VL1) comprising the amino acid sequence of SEQ ID NO: 14; the HC2 comprises a variable region 2 (VH2) comprising the amino acid sequence of SEQ ID NO: 15; and the LC2 comprises a variable region 2 (VL2) comprising the amino acid sequence of SEQ ID NO: 16.

24. The method of any one of the previous claims, wherein the bispecific anti-EGFR / c- Met antibody is an IgGl isotype.

25. The method of any one of the previous claims, wherein: the HC1 comprises the amino acid sequence of SEQ ID NO: 17; the LC1 comprises the amino acid sequence of SEQ ID NO: 18; the HC2 comprises the amino acid sequence of SEQ ID NO: 19; and the LC2 comprises the amino acid sequence of SEQ ID NO: 20.

26. The method of any one of the previous claims, wherein the bispecific anti-EGFR / c- Met antibody is amivantamab.

27. The method of any one of the previous claims, comprising administering a glucocorticoid, an antihistamine, or an antipyretic prior to the administering of the bispecific anti-EGFR / c-Met antibody.

28. The method of claim 27, wherein the glucocorticoid comprises dexamethasone or methylprednisolone, the antihistamine comprises diphenhydramine or chlorphenamine, and the antipyretic comprises paracetamol / acetaminophen.

29. The method of any one of the previous claims, comprising administering of a H2 - antagonist or an antiemetic prior to the administering of the bispecific anti-EGFR / c-Met antibody.

30. The method of claim 29, wherein the H2 -antagonist comprises ranitidine, and the antiemetic comprises ondansetron.

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