WO2026022733A1 - Polythérapies pour le traitement du cancer colorectal - Google Patents

Polythérapies pour le traitement du cancer colorectal

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Publication number
WO2026022733A1
WO2026022733A1 PCT/IB2025/057473 IB2025057473W WO2026022733A1 WO 2026022733 A1 WO2026022733 A1 WO 2026022733A1 IB 2025057473 W IB2025057473 W IB 2025057473W WO 2026022733 A1 WO2026022733 A1 WO 2026022733A1
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seq
amino acid
egfr
acid sequence
administered
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Robert SCHNEPP
Ryota IWASAWA
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Janssen Biotech Inc
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Janssen Biotech Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific

Definitions

  • compositions and methods for treating colorectal cancer are disclosed herein.
  • CRC Colorectal cancer
  • 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).
  • KRAS Kirsten rat sarcoma viral oncogene
  • NRAS neuroblastoma RAS viral oncogene homolog
  • BRAF v-raf murine sarcoma viral oncogene homolog B
  • ERBB2/HER-2 Erb-B2 Receptor Tyrosine Kinase 2
  • dMMR mismatch repair deficiency
  • MSI-H microsatellite instability
  • 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 (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
  • FIG 1 illustrates the study design for methods of using amivantamab and FOLFIRI to treat colorectal cancer.
  • Left-sided CRC is defined as a primary tumor that involves the splenic flexure, descending colon, sigmoid colon, rectosigmoid, or rectum.
  • Right-sided CRC is defined as a primary tumor that arises from the cecum, the ascending colon, or the transverse colon.
  • 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.
  • 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.
  • 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.
  • “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.
  • 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.
  • administering to said patient and similar terms indicate a procedure by which, for example, the bispecific anti-EGFR/c-Met antibody and FOLFIRI are injected 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Amivantamab (also known as RYBREVANT® or JNJ 61186372) is a fully human immunoglobulin G1 -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.
  • amivantamab may disrupt these signaling pathways and prevent tumor growth and progression.
  • the presence of high levels of EGFR and MET on the surface of tumor cells allows for targeting of these cells for destruction by immune effector cells, through antibody dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular trogocytosis (ADCT).
  • ADCC antibody dependent cellular cytotoxicity
  • ADCT antibody-dependent cellular trogocytosis
  • 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.
  • 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.
  • 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.
  • 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.
  • Progression-free survival after subsequent therapy 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.
  • PFS2 refers to the time from start of treatment, until the second objective disease progression, after initiation of subsequent systemic anticancer therapy, or death, whichever comes first.
  • 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.
  • 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. .
  • 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.
  • 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.
  • “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.
  • 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
  • PH20 refers to a type of hyaluronidase that occurs in sperm and is neutral-active.
  • Soluble PH20 refers to a polypeptide characterized by its solubility under physiological conditions.
  • 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.
  • GPI glycophosphatidyl anchor
  • 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.
  • GPI glycophosphatidyl anchor
  • Soluble human PH20 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.
  • 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 set forth 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.
  • 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.
  • Hyaluronidase activity refers to the ability to enzymatically catalyze the cleavage of hyaluronic acid.
  • USP United States Pharmacopeia
  • 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.
  • 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.
  • 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.
  • Human recombinant DNA-derived hyaluronidase enzyme PH20 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.
  • the methods for subcutaneous formulation and administration of the anti- EGFR/c-Met antibody are described in WO2022224187, which are incorporated herein by reference.
  • the anti-EGFR/c-Met antibody of the invention is coformulated with a hyaluronidase enzyme.
  • 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.
  • 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 IntT Pub. No. W02004/078140 and U.S. Patent No. 7,767,429 incorporated herein by reference, in their entirety.
  • 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.
  • the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 36.
  • the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 32, namely residues 36-482 of wild type human hyaluronidase.
  • the amino acid sequence of the soluble PH20 hyaluronidase comprises SEQ ID NO: 33.
  • 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.
  • 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.
  • rHuPH20 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.
  • rHuPH20 is produced in cells, such as CHO cells, for example DG44 CHO cells, that facilitate correct N-glycosylation to retain activity.
  • the hyaluronidase is a soluble human PH20 (rHuPH20) comprising the amino acid sequence of SEQ ID NO: 35.
  • 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.
  • HC1 a first heavy chain
  • HCDR1 a heavy chain complementarity determining region 1
  • LCDR3 a first light chain
  • LC1 a light chain complementarity determining region 1
  • LCDR2 a LCDR2 comprising the amino acid sequence of SEQ ID NO: 5
  • LCDR3 a second heavy chain
  • the bispecific anti-EGFR/c-Met antibody is an IgGl isotype.
  • 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.
  • 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.
  • the bispecific anti-EGFR/c- Met antibody is amivantamab.
  • the bispecific anti-EGFR/c-Met antibody is a biosimilar of amivantamab.
  • the methods treat a subject. In some embodiments, the methods treat a population of subjects.
  • the colorectal cancer (CRC) treated can be unresectable or metastatic colorectal cancer.
  • the colorectal cancer is unresectable colorectal cancer.
  • the colorectal cancer is metastatic colorectal cancer.
  • the colorectal cancer can be recurrent.
  • the colorectal cancer can be recurrent unresectable colorectal cancer, or recurrent metastatic colorectal cancer.
  • the colorectal cancer is an adenocarcinoma.
  • the colorectal cancer is an adenocarcinoma. Of the colon or rectum.
  • the subject progressed on or after treatment with the fluoropyrimidine-based chemotherapy.
  • the subject has received or been intolerant to at least one, but no more than one line of the fluoropyrimidine-based chemotherapy for metastatic colorectal cancer with documented radiographic disease progression on or after the line of chemotherapy.
  • the population of subjects progressed on or after treatment with the fluoropyrimidine-based chemotherapy.
  • the population of subjects has received or been intolerant to at least one, but no more than one line of the fluoropyrimidine-based chemotherapy for metastatic colorectal cancer with documented radiographic disease progression on or after the line of chemotherapy.
  • the subject has not received prior irinotecan -based chemotherapy, agents that target EGFR, or agents that target MET.
  • the population of subjects have not received prior irinotecan-based chemotherapy, agents that target EGFR, or agents that target MET.
  • the subject can be wild type for KRAS, NRAS, and BRAF.
  • the population of subjects can be wild type for KRAS, NRAS, and BRAF.
  • the colorectal cancer is wild type for KRAS, NRAS, and BRAF
  • the colorectal cancer is wild type for KRAS/NRAS G12 and G13 an BRAF V600 codons.
  • the colorectal cancer is wild type for KRAS/NRAS A59, Q61, KI 17, or A146 or BRAF V600.
  • the colorectal cancer has a silent mutation in KRAS/NRAS A59, Q61, KI 17, or A146 o BRAF V600.
  • 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.
  • 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.
  • the antibody e.g., bispecific antibody
  • the 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.
  • 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.
  • 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.
  • 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.
  • the antibody is administered at a dose of 700 mg for body weigh ⁇ 80 kg and 1,050 mg for body weight > 80 kg.
  • 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.
  • 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.
  • 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.
  • 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.
  • the antibody is administered twice a week.
  • the antibody is administered once a week.
  • the antibody is administered once every two weeks.
  • the antibody is administered once every three weeks.
  • the antibody is administered once every four weeks.
  • 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.
  • the bispecific anti-EGFR/c-Met antibody can be administered using alternative dosing regimens.
  • the alternative dosing regimens are alternative subcutaneous dosing regimens.
  • 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.
  • 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.
  • 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
  • the alternative dosing regimens are alternative intravenous dosing regimens.
  • the bispecific anti-EGFR/c-Met antibody can be administered intravenously according to the following:
  • the bispecific anti-EGFR/c-Met antibody can be administered intravenously according to the following:
  • the split infusion is administered as 350 mg on Day 1 with the remainder administered on Day 2.
  • the FOLFIRI is intravenously administered every two weeks.
  • the FOLFIRI can be administered on days 1 and 15 of a first 28-day treatment cycle. 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.
  • a method of treating CRC in a subject comprises administering to the subject a combination regimen comprising (i) amivantamab and (ii) FOLFIRI, in 28-day treatment cycles, according to the schedule shown in the following table: a.
  • a combination regimen comprising (i) amivantamab and (ii) FOLFIRI, in 28-day treatment cycles, according to the schedule shown in the following table: a.
  • amivantamab and chemotherapy are administered on the same day, amivantamab should be given prior to chemotherapy.
  • Cycles 2+ - refers to Cycle 2 and all the subsequent cycles. Also abbreviated to C2+.
  • 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.
  • the bispecific anti-EGFR/c-Met antibody is administered intravenously.
  • 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 CRC wild type for RAS and BRAF previously treated with fluoropyrimidine-based chemotherapy and administered: cetuximab and FOLFIRI, or bevacizumab and FOLFIRI.
  • the reference subject or reference population of subjects had received Cetuximab weekly at a dose of 400 mg/m 2 for the first dose and 250 mg/m 2 thereafter or once every two weeks at a dose of 500 mg/m 2 . In some embodiments, the reference subject or reference population of subjects had received Bevacizumab every two weeks at a dose of 5 mg/kg or 10 mg/kg.
  • 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 CRC wild type for RAS and BRAF previously treated with fluoropyrimidine-based chemotherapy and administered: cetuximab and FOLFIRI, or bevacizumab and FOLFIRI.
  • the PFS is assessed using RECIST vl. l criteria.
  • the reference subject or reference population of subjects had received Cetuximab weekly at a dose of 400 mg/m 2 for the first dose and 250 mg/m 2 thereafter or once every two weeks at a dose of 500 mg/m 2 .
  • the reference subject or reference population of subjects had received Bevacizumab every two weeks at a dose of 5 mg/kg or 10 mg/kg.
  • 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 systematic progression, or any combination thereof, wherein the improvement is relative to a reference subject or a reference population of subjects with CRC wild type for RAS and BRAF previously treated with fluoropyrimidine-based chemotherapy and administered: cetuximab and FOLFIRI, or bevacizumab and FOLFIRI.
  • BICR blinded independent central review
  • ORR objective response rate
  • the reference subject or reference population of subjects had received Cetuximab weekly at a dose of 400 mg/m 2 for the first dose and 250 mg/m 2 thereafter or once every two weeks at a dose of 500 mg/m 2 . In some embodiments, the reference subject or reference population of subjects had received Bevacizumab every two weeks at a dose of 5 mg/kg or 10 mg/kg.
  • 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/m 2 intravenous irinotecan, 400 mg/m 2 intravenous leucovorin or 200 mg/m 2 intravenous levoleucovorin, 400 mg/m 2 intravenous 5 -fluorouracil bolus, and 2,400 mg/m 2 intravenous 5- fluorouracil.
  • 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 LC2 can comprise a variable region 2 (VL2) comprising the amino acid sequence of SEQ ID NO: 16.
  • the bispecific anti-EGFR/c-Met antibody is an IgGl isotype.
  • 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.
  • the bispecific anti-EGFR/c-Met antibody is an IgGl isotype. In some embodiments, the bispecific anti-EGFR/c-Met antibody is amivantamab.
  • 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.
  • a glucocorticoid, an antihistamine, and an antipyretic are administered prior to the administering of the bispecific anti-EGFR/c-Met antibody.
  • 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.
  • the dexamethasone can be administered about 45 to about 60 minutes prior to the administering of the bispecific anti-EGFR/c-Met antibody.
  • 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.
  • 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.
  • the methylprednisolone can be administered about 45 to about 60 minutes prior to the administering of the bispecific anti-EGFR/c-Met antibody.
  • 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.
  • the antihistamine comprises diphenhydramine.
  • the diphenhydramine can be administered in an amount of about 25 mg to about 50 mg.
  • the diphenhydramine 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.
  • 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.
  • 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.
  • the paracetamol/acetaminophen 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.
  • the paracetamol/acetaminophen can be administered about 30 to about 60 minutes prior to the administering of the bispecific anti-EGFR/c-Met antibody.
  • 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.
  • an H2 -antagonist and an antiemetic are administered prior to the administering of the bispecific anti-EGFR/c-Met antibody.
  • 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.
  • 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.
  • a method of treating colorectal cancer (CRC) that is wild-type for RAS and BRAF in a subject or a population of subjects previously treated with fluoropyrimidine-based chemotherapy 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 first heavy
  • the bispecific anti-EGFR/c-Met antibody is administered in an amount of about 1,600 mg.
  • 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 systematic progression, or any combination thereof, wherein the improvement is relative to a reference subject or a reference population of subjects with CRC wild type for RAS and BRAF previously treated with fluoropyrimidine-based chemotherapy and administered: cetuximab and FOLFIRI, or bevacizumab and FOLFIRI.
  • BICR blinded independent central review
  • ORR objective response rate
  • glucocorticoid comprises dexamethasone or methylprednisolone
  • the antihistamine comprises diphenhydramine or chlorphenamine
  • the antipyretic comprises paracetamol/acetaminophen.
  • EXAMPLE 1 A Randomized, Open-label Phase 3 Study of Amivantamab + FOLFIRI Versus Cetuximab/Bevacizumab + FOLFIRI in Participants With KRAS/NRAS and BRAF Wild-type Recurrent, Unresectable or Metastatic Colorectal Cancer Who Have Received Prior Chemotherapy (OrigAMI-3; 61186372COR3002)
  • the primary objective of this study is to compare PFS (as assessed by BICR) and OS in participants treated with amivantamab + FOLFIRI versus participants treated with cetuximab or bevacizumab (investigator’s choice) + FOLFIRI. Secondary objectives include other measures of efficacy, safety, and PROs.
  • the study will aim to enroll a participant population that is geographically reflective of the overall incidence/prevalence of this disease.
  • a target of approximately 700 participants will be randomly assigned in a 1 : 1 ratio with the following stratification criteria: investigator’s choice for control, primary tumor location, duration of first-line therapy, and prior anti-VEGF therapy.
  • 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. Participant safety and study conduct will be monitored throughout the study.
  • participant 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.
  • the term “study treatment” throughout this example refers to amivantamab SC + chemotherapy backbone (5-FU, leucovorin or levoleucovorin, and irinotecan) or cetuximab/bevacizumab + chemotherapy backbone (5-FU, leucovorin or levoleucovorin, and irinotecan).
  • amivantamab + FOLFIRI will demonstrate superior PFS or OS compared with cetuximab or bevacizumab (investigator’s choice) + FOLFIRI as second-line treatment in adult participants with KRAS/NRAS and BRAF WT recurrent, unresectable or metastatic colorectal cancer who have received prior chemotherapy.
  • the study will aim to enroll a participant population that is geographically reflective of the overall incidence/prevalence of this disease.
  • a target of approximately 700 participants will be randomly assigned in a 1 : 1 ratio with the following stratification criteria: investigator’s choice for control, primary tumor location, duration of first-line therapy, and prior anti-VEGF therapy.
  • the study consists of a Screening Period, a Treatment Period, and a Follow-up Period.
  • the Screening Period starts at the time of the signing of the 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. Imaging obtained as standard of care before signing the ICF but within 28 days of randomization may be used for the screening assessment.
  • the local biomarker test data should be either available or pending the results at the time of signing the ICF. If local biomarker testing is not performed as part of the local standard, investigator should contact the sponsor for approval to undergo biomarker testing during the screening period before presenting ICF to the participant.
  • Participants who fail to meet all the inclusion criteria, meet at least 1 exclusion criterion, or both may be rescreened once 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.
  • the Treatment Period will begin on Cycle 1 Day 1 within 3 days after randomization. Participants will be randomly assigned to study treatment in a 1 : 1 ratio (Arm A: amivantamab + FOLFIRI or Arm B: cetuximab or bevacizumab [investigator’s choice] + FOLFIRI arm). The assignment of either cetuximab or bevacizumab in the control arm 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 frequency of study site visits and details of the procedures performed are outlined in the SoA (Table 24).
  • Study treatment should continue until documented radiographic progression using RECIST vl.l 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.
  • Investigators may recontact the participant to obtain long-term 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.
  • 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 treatment” refers to amivantamab or cetuximab/bevacizumab with chemotherapy backbone (leucovorin or levoleucovorin, 5-FU, and irinotecan).
  • chemotherapy backbone leucovorin or levoleucovorin, 5-FU, and irinotecan.
  • IMPs Investigational Medicinal Product
  • AxMPs Auxiliary Medicinal Product
  • All other study-specified medications are considered concomitant medications
  • the amivantamab dosage will be based on the participant’s baseline body weight (BW).
  • a missed dose is defined as failure to administer study treatment within 3 days of the scheduled dosing date in Cycle 1 or failure to administer study treatment within 7 days (or 3 days for weekly cetuximab regimen) of the scheduled dosing date in Cycle 2 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 in the SoA should be performed relative to actual study treatment administration, not on the originally scheduled administration day.
  • Participants in Arm A will receive amivantamab in addition to standard of care (SoC) FOLFIRI as described in Table 5 or according to the institutional standard.
  • Participants in Arm B will receive cetuximab or bevacizumab (investigator’s choice) in addition to SoC FOLFIRI as described in Table 7 and Table 8, respectively, or according to the institutional standard.
  • Patients who had severe toxicity attributed to 5 -fluorouracil during first-line therapy must be tested for dihydropyrimidine dehydrogenase (DPD) deficiency.
  • DPD dihydropyrimidine dehydrogenase
  • a reduced starting dose of 5 -fluorouracil should be considered to limit the toxicity for participants with known partial DPD deficiency based on the local guidelines and standard practice.
  • amivantamab, cetuximab, or bevacizumab should be administered prior to chemotherapy.
  • administer irinotecan 180 mg/m 2 (or per local standard) and leucovorin 400 mg/m 2 (or levoleucovorin 200 mg/m 2 ) IV over approximately 2 hours at the same time in separate bags (or sequentially according to the institutional SoC) then 5-FU 400 mg/m 2 IV bolus followed by continuous infusion of 5-FU 2400 mg/m 2 over approximately 46-48 hours or 1200 mg/m 2 /day for 2 days.
  • FOLFIRI administration should be delayed if the participant experiences absolute neutrophil count (ANC) ⁇ 1.5* 10 9 /L, if the platelet count is ⁇ 75* 10 9 /L, if stomatitis or diarrhea has not recovered to Grade ⁇ 1, or if fatigue has not recovered to Grade ⁇ 2. If toxicities related to FOLFIRI do not recover for more than 8 weeks, FOLFIRI treatment should be discontinued.
  • the body surface area (BSA) of the participant should be calculated by the institutional standard.
  • amivantamab/cetuximab/bevacizumab FOLFIRI
  • components of FOLFIRI eg, 5-FU alone or irinotecan alone
  • Participants undergoing curative resection/surgery should continue to receive study treatments (or part of study treatments) per the investigator’s discretion and should consult with the medical monitor prior to discontinuation of study treatment.
  • Table 5 Study Treatment Administration Schedule for Amivantamab SC +FOLFIRI a When amivantamab and chemotherapy are administered on the same day, amivantamab should be given prior to chemotherapy.
  • bevacizumab and chemotherapy are administered on the same day, bevacizumab should be given prior to chemotherapy.
  • AEs adverse events
  • Table 11 Suggested Management of Rash During Amivantamab Treatment a. 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.
  • IRRs Severe infusion-related reactions
  • anaphylactic reactions may commonly occur, in some cases with fatal outcomes.
  • Infusion reactions of any grade occurred in 8.4%, and severe (Grades 3 and 4) infusion reactions occurred in 2.2% of patients who received cetuximab.
  • the infusion should be stopped for that day. A careful benefit/risk assessment should be undertaken, including consideration whether the participant may have preformed IgE antibodies before a subsequent infusion is given.
  • Table 12 Management of Dermatologic Toxicities and Infectious Sequelae During
  • ILD interstitial lung disease
  • 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.
  • 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 14 for dose modification guidance.
  • FU is to be skipped, leucovorin must also be skipped.
  • Hematologic toxicities are commonly observed with chemotherapy through myelosuppression.
  • the chemotherapy should be given only when the participants have ANC >1.5> ⁇ 10 9 /L and platelets >75* 10 9 /L on the day of chemotherapy.
  • Table 15 provides the recommended guidance for hematologic toxicities. Table 15: Suggested Management of Hematologic Toxicities
  • Table 16 provides recommended guidance for diarrhea.
  • fable 17 provides recommended guidance for mucositis.
  • f able 18 provides recommended guidance for nausea or vomiting. Note that these dose reduction recommendations should be made only if they persist despite optimized antiemetic regimens.
  • Optional postdose medications may be prescribed and continued for up to
  • H2 receptor antagonist Premedicate with a histamine-1 (Hl) receptor antagonist IV 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 such as an H2 antagonist (eg, famotidine), steroids, or antipyretic (eg, acetaminophen) may be administered according to institutional standards.
  • an H2 antagonist eg, famotidine
  • steroids e.g, famotidine
  • antipyretic e.g, acetaminophen
  • pre-medication with antiemetics such as serotonin (5HT3) antagonists (ie, ondansetron or granisetron), with or without dexamethasone, may be used at the investigator’s discretion or according to institutional standards.
  • antiemetics such as serotonin (5HT3) antagonists (ie, ondansetron or granisetron)
  • 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 toxi cities according to the approved label or institutional standards.
  • Table 23 Suggested Order of Administration When Bevacizumab is Given with FOLFIRI a. May be administered according to institutional standards.
  • Radiotherapy to tumor lesions being assessed for tumor response prior to radiographic progression.
  • SoA (Table 24) summarizes the frequency and timing of efficacy, PRO, PK, immunogenicity, biomarker, and safety measurements applicable to this study. TABLE 24: Schedule of Activities (So A)
  • 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 28 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 SD.
  • 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).
  • Frequency of disease assessments should follow as described in the SoA (Table 24) until disease progression as determined by BICR during the treatment period. Timing is relative to randomization; if an assessment is delayed, subsequent assessments should occur according to the original schedule. If an assessment is performed outside of the scheduled visit and the participant has not progressed, every attempt should be made to perform the subsequent assessment at their scheduled visit timepoint. Any other area at which new disease is suspected should also be imaged. Response will be assessed by BICR for central confirmation.
  • CT scan of the chest, abdomen, pelvis, and any other disease location(s) should be performed with both an IV contrast agent and oral contrast. Participants not able to undergo CT scans with IV contrast (eg, due to allergy or renal insufficiency) may have non-contrast CT of the thorax and contrast enhanced MRI of the abdomen and pelvis. MRI can also be used to evaluate sites of disease that cannot be adequately imaged using CT. Identical methodology (CT scan with contrast agent or MRI) should be used for disease assessment at baseline and throughout the study. Techniques other than CT or MRI may be used based upon investigator’s judgment, local SoC, and RECIST vl .1 guidelines for the use of these alternative techniques. For example, bone scintigraphy may be used to identify bone lesions at screening or new bone lesions during treatment, but bone lesions will not be considered target lesions.
  • 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 vl .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.
  • the treatment effect of the amivantamab + FOLFIRI combination therapy, compared with (investigator’s choice) bevacizumab/cetuximab + FOLFIRI combination therapy, on PFS will be analyzed using a log-rank test stratified by primary tumor location (left versus right), duration of first-line therapy ( ⁇ 6 months, >6 months), and prior anti-VEGF therapy (yes/no).
  • the p-value generated from the stratified log-rank test will be used for the first primary hypothesis testing with an initial allocation of 0.1% alpha (0.001, 1 -sided) for PFS; however, if OS is significant, then the p-value will be compared with 0.025 (1-sided alpha of 2.5%).
  • the HR and its 95% CI will be estimated based on a stratified Cox’s regression model with treatment as the sole explanatory variable.
  • the median PFS with 95% CI will be estimated using Kaplan -Mei er method.
  • the Kaplan-Meier PFS curve will also be plotted by treatment group.
  • 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 aPFS event or were censored will be reported, and reasons for PFS event and censoring will be summarized.
  • 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
  • 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.
  • OS will be analyzed using a similar methodology and model as for the primary analysis of PFS using an initial allocation of 2.4% alpha (1-sided). However, 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.
  • OS sensitivity analyses adjusting for treatment switching may be conducted if a significant number of participants who randomized to bevacizumab or cetuximab (investigator’s choice) + FOLFIRI arm subsequentially receive amivantamab as second-line treatment.
  • ORR is defined as the proportion of randomized participants achieving PR or CR, as determined by BICR using RECIST vl .1 criteria.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.
  • 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.
  • Time to first response will be summarized for all confirmed responders by treatment group using descriptive statistics and frequency statistics by time point.
  • 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).
  • PFS2 will be analyzed using the similar method as the primary analysis of PFS.
  • 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 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 is defined as the proportion of Full Analysis Set participants (or participants with metastasis in liver only status at baseline) who underwent curative surgery. The proportion and the 95% CI will be provided.

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Abstract

L'invention concerne des méthodes de traitement du cancer colorectal métastatique (par exemple, dans le cadre de la seconde ligne) avec un anticorps bispécifique anti-EGFR/c-Met et FOLFIRI.
PCT/IB2025/057473 2024-07-23 2025-07-23 Polythérapies pour le traitement du cancer colorectal Pending WO2026022733A1 (fr)

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