CN113840601A - Combination therapy using bispecific anti-EGFR/c-Met antibodies and third generation EGFR tyrosine kinase inhibitors - Google Patents
Combination therapy using bispecific anti-EGFR/c-Met antibodies and third generation EGFR tyrosine kinase inhibitors Download PDFInfo
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Abstract
The present invention relates to combination therapies using bispecific anti-EGFR/c-Met antibodies and third generation EGFR tyrosine kinase inhibitors.
Description
Cross Reference to Related Applications
This application claims priority to U.S. provisional application serial No. 62/847,605 filed on day 5, month 14 of 2019 and U.S. provisional application serial No. 62/847,563 filed on day 5, month 14 of 2019. The disclosure of each of the above applications is incorporated herein by reference in its entirety.
Electronically submitted reference sequence Listing
This application contains a sequence listing electronically submitted via EFS-Web as an ASCII formatted sequence listing with a file name of "jb iota6093usnp1seqilist. txt" and a creation date of 2020, 4, 30 and a size of 22 kb. This sequence listing, filed via EFS-Web, is part of this specification and is incorporated herein by reference in its entirety.
Technical Field
The present invention relates to combination therapies using bispecific anti-EGFR/c-Met antibodies and third generation EGFR tyrosine kinase inhibitors.
Background
The separate roles of both EGFR and c-Met receptors in cancer are well established, making these targets attractive for combination therapy. Both receptors signal through the same ERK and AKT survival and anti-apoptotic pathways and are often upregulated as resistance mechanisms for either single agent treatment; thus, combined inhibition of this pair of receptors may limit the possibility of compensatory pathway activation, thereby acting synergistically to inhibit tumor growth-promoting signaling and improve overall clinical efficacy.
Relapse or resistance to existing therapeutics is common. Thus, there is a need for improved therapeutics or combinations of therapeutics and patient stratification biomarkers to develop more effective treatments for diseases such as EGFR or c-Met positive cancers.
Disclosure of Invention
Embodiments of the present disclosure provide methods of treating a subject having an EGFR-or c-Met expressing cancer comprising administering to the subject a combination therapy, wherein the combination therapy comprises a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof. According to a particular embodiment, the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is the mesylate salt of lacitinib.
Embodiments of the present disclosure provide pharmaceutical combinations comprising (1) a bispecific anti-EGFR/c-Met antibody comprising: a first domain that binds EGFR comprising HCDR1 of SEQ ID NO. 1, HCDR2 of SEQ ID NO. 2, HCDR3 of SEQ ID NO. 3, LCDR1 of SEQ ID NO. 4, LCDR2 of SEQ ID NO. 5, and LCDR3 of SEQ ID NO. 6; and a second domain that binds c-Met, the second domain comprising HCDR1 of SEQ ID NO. 7, HCDR2 of SEQ ID NO. 8, HCDR3 of SEQ ID NO. 9, LCDR1 of SEQ ID NO. 10, LCDR2 of SEQ ID NO. 11, and LCDR3 of SEQ ID NO. 12; and (2) Lazetinib, or a pharmaceutically acceptable salt thereof (e.g., the mesylate salt of Lazetinib).
Drawings
Figure 1 shows the effect of JNJ-61186372 monotherapy or combination with laquinimod or ocitinib on body weight of H1975 xenograft bearing nude mice.
FIG. 2 shows the mean tumor volume (mm) of H1975 xenograft-bearing nude mice treated with JNJ-61186372 monotherapy or in combination with Lazetinib or Oxititinib3)。
Figure 3 shows a KapZan-Meier plot of the percentage of animals remaining in H1975 xenograft-bearing mice treated with JNJ-61186372 monotherapy or in combination with lacitinib or axitinib.
FIG. 4 shows the effect of JNJ-61186372 monotherapy or in combination with Lazetinib or Oxitinib on body weight in H1975-HGF xenograft-bearing nude mice.
FIG. 5 shows the mean tumor volume (mm) on days post tumor implantation for H1975-HGF xenograft-bearing nude mice treated with JNJ-61186372 monotherapy or in combination with Lazetinib or Oxititinib3)。
Figure 6 shows a Kaplan-Meier plot of the percentage of animals remaining in H1975-HGF xenograft-bearing mice treated with JNJ-61186372 monotherapy or in combination with lacitinib or axitinib.
Detailed Description
Definition of
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if fully set forth herein.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.
When a list is provided, it is to be understood that each individual element of the list, and each combination of elements in the list, is a separate embodiment, unless otherwise indicated. For example, a list of embodiments presented as "A, B or C" will be understood to include embodiments "a", "B", "C", "a or B", "a or C", "B or C" or "A, B or C".
"about" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular assay, result, or embodiment, "about" means within one standard deviation, or up to a range of 5% (whichever is greater), according to common practice in the art, unless otherwise explicitly stated in the examples or elsewhere in the specification.
"about once per week" or "once per week" means administered once over a period of about one week. About a week means 7 days ± 2 days, i.e., 5 days to 9 days. Thus, the frequency of administration "about once a week" may be once every 5 days, once every 6 days, once every 7 days, once every 8 days, or once every 9 days.
By "about once every two weeks" is meant administration once over a period of about two weeks. About two weeks means 14 days ± 2 days, i.e. 12 to 16 days. Thus, the frequency of administration "about once every two weeks" may be once every 12 days, once every 13 days, once every 14 days, once every 15 days, or once every 16 days.
As used in this specification and the appended claims, the singular forms "a", "an", "the" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.
The connecting term "and/or" between a plurality of enumerated elements is understood to encompass both individual and combined options. For example, where two elements are connected by "and/or," a first option means that the first element applies without the second element. The second option means that the second element is applied without the first element. A third option refers to the suitability of using the first and second elements together. Any of these options is understood to fall within the meaning and thus meet the requirements of the term "and/or" as used herein. Parallel applicability of more than one option is also understood to fall within the meaning and thus meet the requirements of the term "and/or".
An "antagonist" or "inhibitor" refers to a molecule that, when bound to a cellular protein, inhibits at least one response or activity induced by the natural ligand of the protein. The molecule is an antagonist when at least one response or activity is inhibited to at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the at least one response or activity that is inhibited in the absence of the antagonist (e.g., a negative control), or when the inhibition is statistically significant compared to the inhibition in the absence of the antagonist.
"antibody" refers broadly to and includes immunoglobulin molecules, including in particular monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies, and chimeric monoclonal antibodies), antigen binding fragments, multispecific antibodies such as bispecific, trispecific or tetraspecific antibodies, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies, and any other modified configuration of an immunoglobulin molecule comprising an antigen binding site with the desired specificity. A "full-length antibody" comprises two Heavy Chains (HC) and two Light Chains (LC) interconnected by disulfide bonds, and multimers thereof (e.g., IgM). Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (consisting of domains CH1, hinge, CH2, and CH 3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions, termed Complementarity Determining Regions (CDRs) with intervening Framework Regions (FRs). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR 4. Immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG and IgM, based on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified into isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG 4. The light chain of an antibody of any vertebrate species can be assigned to one of two completely different types, κ and λ, based on the amino acid sequence of its constant domains.
An "antigen-binding fragment" refers to the antigen-binding portion of an immunoglobulin molecule. The antigen-binding fragment may be a synthetic, enzymatically obtainable or genetically engineered polypeptide and comprises VH, VL, VH and VL, Fab, F (ab')2, Fd and Fv fragments, domain antibodies (dabs) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, HCDR1, HCDR2 and/or HCDR3, and LCDR1, LCDR2 and/or LCDR 3. The VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs, wherein in the case where the VH and VL domains are expressed from separate single chain antibody constructs, the VH/VL domains may pair intramolecularly or intermolecularly to form a monovalent antigen binding site, such as single chain fv (scfv) or diabodies; for example, as described in International patent publications WO1998/44001, WO1988/01649, WO1994/13804 and WO 1992/01047.
"bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may be cross-reactive to other relevant antigens, e.g. to the same antigen from other species (homologues), such as humans or monkeys, e.g. cynomolgus macaque (cynomolgus, cyno) or chimpanzee (Pan troglodytes), or may bind to an epitope shared between two or more different antigens.
By "bispecific anti-EGFR/c-Met antibody" or "bispecific EGFR/c-Met antibody" is meant a bispecific antibody having a first domain that specifically binds EGFR and a second domain that specifically binds c-Met. The domains that specifically bind to EGFR and c-Met are typically a VH/VL pair. Depending on the structure, the bispecific antibody may be monovalent, bivalent, or multivalent in binding to EGFR and c-Met; that is, there may be one or more domains that bind EGFR and one or more domains that bind c-Met.
"biological sample" refers to a collection of similar fluids, cells, or tissues isolated from a subject, as well as fluids, cells, or tissues present in a subject. Exemplary samples are biological fluids such as blood, serum and serosal fluids, plasma, lymph, urine, saliva, cyst fluid, tears, excreta, sputum, mucosal secretions of secreted tissues and organs, vaginal secretions, ascites, pleural fluid, pericardial fluid, peritoneal fluid and other bodily cavity fluids, fluids collected from bronchial lavage, synovial fluid, liquid solutions in contact with a subject or biological source (e.g., cells and organ culture media (including cell or organ conditioned media), lavage fluids, etc.), tissue biopsies, tumor tissue samples, fine needle aspirates, surgically excised tissues, organ cultures, or cell cultures.
"complementarity determining regions" (CDRs) are regions of an antibody that bind antigen. CDRs may be defined using various delineations, such as Kabat (Wu et al, (1970) J Exp Med 132:211-50) (Kabat et al, "Sequences of Proteins of Immunological Interest", 5 th edition, Public Health Service, National Institutes of Health, Bethesda, Md.,1991), Chothia (Chothia et al, (1987) JMol Biol 196:901-17), IMGT (Lefranc et al, (2003) Dev Comp Immunol27:55-77) and AbM (Martin and Thornton, (1996) JBmol Biol 263: 800-15). The correspondence between the various delineations and the variable region numbering is described (see e.g., Lefranc et al, (2003) Dev Comp Immunol27: 55-77; Honegger and Pluckthun, (2001) JMol Biol 309: 657-70; International Immunogenetics (IMGT) database; Web resources, http:// www _ IMGT _ org). Available programs (such as abYsis of UCL Business PLC) can be used to delineate CDRs. As used herein, the terms "CDR," "HCDR 1," "HCDR 2," "HCDR 3," "LCDR 1," "LCDR 2," and "LCDR 3" include CDRs defined by any of the above methods (Kabat, Chothia, IMGT, or AbM), unless the specification expressly indicates otherwise.
The transitional terms "comprising," "consisting essentially of … …," and "consisting of … …" are intended to imply their accepted meanings in patent parlance; that is, (i) "comprising" is synonymous with "including", "containing", or "characterized by", and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) "consisting of … …" excludes any element, step, or ingredient not specified in the claims; and (iii) "consisting essentially of … …" limits the scope of the claims to the specified materials or steps "and materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. Also provided are embodiments described by the phrase "comprising" (or equivalents thereof), such as those embodiments described independently by "consisting of … …" and "consisting essentially of … …".
"cancer" refers to abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, metastasize (spread) to other areas of the patient's body.
"co-administration," with.
"diagnosis" refers to a method of determining whether a subject has a given disease or condition or is likely to develop a given disease or condition in the future or is likely to respond to treatment of a previously diagnosed disease or condition (i.e., stratifying a patient population according to the likelihood of responding to treatment). Diagnosis is typically performed by a physician based on general guidelines for the disease to be diagnosed or other criteria indicating that the subject is likely to respond to a particular treatment.
"dosing regimen" refers to information on the amount of therapeutic agent or drug to be taken by a subject and the frequency of times that the subject has taken the therapeutic agent.
"dosage" refers to the amount or quantity of a therapeutic agent or drug to be administered per time.
"EGFR-or c-Met-expressing cancer" refers to a cancer that has detectable expression of EGFR or c-Met or has mutation or amplification of EGFR or c-Met. EGFR or c-Met expression, amplification and mutation status can be detected using known methods such as sequencing, fluorescence in situ hybridization, immunohistochemistry, flow cytometry or western blotting using tumor biopsy or blood samples. Expression can also be detected by sequencing circulating tumor dna (ctdna).
"epidermal growth factor receptor" or "EGFR" refers to human EGFR (also known as HER1 or ErbB1(Ullrich et al, Nature 309:418-425,1984)) having the amino acid sequence set forth in GenBank accession NP-005219, as well as naturally occurring variants thereof.
"fucose content" refers to the amount of fucose monosaccharide in the sugar chain at Asn297 in the antibody preparation.
As used herein, "hepatocyte growth factor receptor" or "c-Met" refers to human c-Met and its native variants having the amino acid sequence set forth in GenBank accession No. NP _ 001120972.
"human antibody" refers to an antibody that is optimized to have a minimal immune response when administered to a human subject. The variable regions of human antibodies are derived from human immunoglobulin sequences. If the human antibody comprises a constant region or a portion of a constant region, the constant region is also derived from a human immunoglobulin sequence. If the variable regions of a human antibody are obtained from a system using human germline immunoglobulins or rearranged immunoglobulin genes, the human antibody comprises heavy and light chain variable regions that are "derived" from sequences of human origin. Exemplary systems of this type are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals, such as mice or rats carrying human immunoglobulin loci. Due to differences between the systems used to obtain human antibodies and human immunoglobulin loci, the introduction of somatic mutations or deliberate introduction of substitutions into the framework or CDRs, or both, "human antibodies" typically comprise amino acid differences compared to immunoglobulins expressed in humans. Typically, the amino acid sequence of a "human antibody" has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence encoded by a human germline or rearranged immunoglobulin gene. In some cases, a "human antibody" can comprise a consensus framework sequence derived from human framework sequence analysis (e.g., as described in Knappik et al, (2000) J Mol Biol 296: 57-86); or binding to synthetic HCDR 3in a human immunoglobulin gene library displayed on phage (e.g., described in Shi et al, (2010) J Mol Biol 397:385-96 and international patent publication WO 2009/085462). An antibody in which at least one CDR is derived from a non-human species is not included in the definition of "human antibody".
"isolated" refers to a homogeneous population of molecules (such as synthetic polynucleotides, polypeptides, vectors, or viruses) that have been substantially separated from and/or purified from other components of the system in which the molecules are produced (such as recombinant cells), as well as a homogeneous population of proteins that have been subjected to at least one purification or isolation step. "isolated" refers to a molecule that is substantially free of other cellular material and/or chemicals, and encompasses molecules that are isolated to a higher degree of purity (such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity).
By "low fucose" or "low fucose content" is meant that the fucose content of the antibody is between about 1% to 15%.
"monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known changes such as removal of the C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind to an epitope. Bispecific monoclonal antibodies bind to two different epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, such as bispecific, monovalent, bivalent, or multivalent.
"newly diagnosed" refers to a subject diagnosed with a cancer, such as an EGFR-or c-Met-expressing cancer, but who has not received treatment for the cancer.
"Normal fucose" or "normal fucose content" refers to an antibody having a fucose content of greater than about 50%, typically greater than about 80%, or greater than about 85%.
By "pharmaceutical composition" or "pharmaceutical combination" is meant a composition comprising the active ingredients, such as the bispecific EGFR/c-Met antibody, and one or more pharmaceutically acceptable carriers, or a third-generation EGFR tyrosine kinase inhibitor, such as laquinimod, or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, wherein each of the active ingredients is intended to be administered to a patient in combination or sequentially or simultaneously.
By "pharmaceutically acceptable carrier" or "excipient" is meant an ingredient of the pharmaceutical composition other than the active ingredient that is not toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, stabilizers, or preservatives. Pharmaceutically acceptable carriers include, but are not limited to, diluents, disintegrants, or glidants; or diluents, disintegrants, wetting agents, glidants or lubricants.
"prevention" of a disease or disorder means preventing the disorder from occurring in a subject.
"recombinant" refers to DNA, antibodies and other proteins that are prepared, expressed, formed or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.
"refractory" refers to a disease that is not alleviated by treatment. Refractory diseases can be resistant to treatment before or at the beginning of treatment, or refractory diseases can become resistant during treatment.
"recurrence" refers to the recurrence of disease or signs and symptoms of disease after a period of improvement following prior treatment with a therapeutic agent.
"response," "responsiveness," or "likely response" refers to any type of amelioration or positive response, such as alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilization (i.e., not worsening) of the disease state, prevention of disease spread, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
"solvates" and "hydrates" are solvent addition forms that the compounds of the present invention are capable of forming, whereby the multicomponent compound comprises a host molecule (e.g., a compound of formula (I) or a salt thereof) and a guest molecule (water ("hydrate") or another solvent ("solvate") incorporated into the structure.
By "specifically binds" or "binds" is meant that the antibody binds to an antigen or epitope within an antigen with a higher affinity than to other antigens. Typically, the antibody is administered at about 5X 10-8M or less (e.g., about 1X 10)-9M or less, about 1X 10-10M or less, about 1X 10-11M or less or about 1X 10-12M or less) equilibrium dissociation constant (K)D) Binding to or an epitope within an antigen, typically the KDK for binding of the antibody to a non-specific antigen (e.g. BSA, casein)DAt most one hundredth. The dissociation constant can be measured using known protocols. However, antibodies that bind to an antigen or an epitope within an antigen may have cross-reactivity to other related antigens, e.g. to the same antigen from other species (homologous), such as humans or monkeys, e.g. Macaca fascicularis (cynomolgus, cyno) or chimpanzees (chimpanzee, chimp.
"subject" includes any human or non-human animal. "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, and the like. The terms "subject" and "patient" are used interchangeably herein.
The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversion by recombination of some of the bonding electrons.
"therapeutically effective amount" means an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. The therapeutically effective amount may vary depending on the following factors: such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improving the health of a patient.
"treatment" of a disease or disorder, such as cancer, refers to the achievement of one or more of the following: reducing the severity and/or duration of a disorder, inhibiting worsening of symptoms characteristic of the disorder being treated, limiting or preventing recurrence of a disorder in a subject previously suffering from a disorder, or limiting or preventing recurrence of symptoms in a subject previously suffering from symptoms of a disorder.
In the context of EGFR Tyrosine Kinase Inhibitors (TKIs), "untreated" refers to a subject who has not been treated with an EGFR TKI.
"humanized antibody" refers to antibodies in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Humanized antibodies may comprise substitutions in the framework such that the framework may not be an exact copy of the expressed human immunoglobulin or human immunoglobulin germline gene sequence.
"1 st generation EGFR tyrosine kinase inhibitor" (1 st generation TKI) refers to reversible EGFR inhibitors such as gefitinib and erlotinib, which are effective in the first-line treatment of NSCLC carrying EGFR activating mutations such as the deletion of exon 19 and exon 21L858R mutations.
"generation 2 EGFR tyrosine kinase inhibitor" (generation 2 TKI) refers to covalent irreversible EGFR inhibitors such as afatinib and dacomitib, which are effective in the first line treatment of NSCLC carrying EGFR activating mutations such as the deletion of exon 19 and exon 21L858R mutations.
"3 rd generation EGFR tyrosine kinase inhibitor" (3 rd generation TKI) refers to a covalent irreversible EGFR inhibitor such as axitinib and lacitinib that is selective for EGFR activating mutations such as exon 19 and exon 21L858R deletion, alone or in combination with the T790M mutation and has less inhibitory activity against wild-type EGFR.
Methods of the present disclosure
NSCLC is typically driven by activating mutations in the EGFR kinase domain, most commonly an in-frame deletion of exon 19 or an L858R mutation of exon 21. Most patients with these activating EGFR mutations initially respond to first generation EGFR TKIs, such as gefitinib and erlotinib; however, drug resistance limits the response to an average duration of less than 1 year (Kobayashi et al, New Engl J Med, 2005, vol 352, No. 8, pp 786-. Secondary mutations T790M in EGFR have been identified in about 50% of EGFR-mutant NSCLC patients with resistant disease (Chen et al, Pathol Oncol Res, Vol.15, No. 4, p.651-658; Jeffers et al, J Mol Med (Berl)., 1996, Vol.74, No. 9, p.505-513; Pao et al, PLoS Med, 2005, Vol.2, No. 3, p. 73; Sequist et al, Sci Transl Med, 2011, Vol.3, No. 75, p.75 ra 26). This mutation results in EGFR kinase with increased affinity for adenosine triphosphate, thereby reducing the potency of reversible TKIs (Yun et al, Proc natl acadsi usa, 2008, vol 105, 6, p 2070, 2075). In addition, resistant tumors can activate the c-Met pathway by MET gene amplification, increased expression of c-Met protein, and/or increased expression of the c-Met ligand HGF (Engelman et al, Science, 2007, vol. 316, 5827, p. 1039-. Stimulation of the c-Met pathway provides an alternative mechanism to activate the phosphatidylinositol-3 kinase/Akt signaling pathway, thereby bypassing TKI blockade of EGFR and promoting cancer cell survival. These two mechanisms occur simultaneously in 5% to 33% of NSCLC patients resistant to EGFR TKI (Bean et al, Proc Natl Acad Sci USA, 2007, Vol 104, vol 52, p 20932-20937).
JNJ-61186372(JNJ-372) is a bispecific anti-EGFR/c-Met antibody that inhibits both EGFR and c-Met signaling by blocking ligand-induced activation and by inducing receptor degradation, and is described in U.S. patent 9,593,164, which is incorporated herein by reference. In addition, the presence of high levels of EGFR and c-Met on the surface of tumor cells enables immune effector cells to be targeted for destruction by Fc-mediated effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). JNJ-372 is defined by the following amino acid sequence: the EGFR-binding domain comprises heavy chain complementarity determining region 1 of SEQ ID NO:1(HCDR 1), HCDR2 of SEQ ID NO:2, HCDR3 of SEQ ID NO:3, light chain complementarity determining region 1 of SEQ ID NO:4(LCDR 1), LCDR2 of SEQ ID NO:5, and LCDR3 of SEQ ID NO: 6; the c-Met binding domain comprises HCDR1 of SEQ ID NO. 7, HCDR2 of SEQ ID NO. 8, HCDR3 of SEQ ID NO. 9, LCDR1 of SEQ ID NO. 10, LCDR2 of SEQ ID NO. 11, and LCDR3 of SEQ ID NO. 12; the EGFR binding domain comprises the heavy chain variable domain of SEQ ID NO 13 (VH) and the light chain variable domain of SEQ ID NO 14 (VL); the c-Met binding domain comprises the VH of SEQ ID NO. 15 and the VL of SEQ ID NO. 16; the antibody comprises the first heavy chain of SEQ ID NO 17 (HC1), the first light chain of SEQ ID NO 18 (LC1), the second heavy chain of SEQ ID NO 19 (HC2), and the second light chain of SEQ ID NO 20 (LC 2).
1(HCDR1, EGFR binding arm)
TYGMH
2(HCDR2, EGFR binding arm)
VIWDDGSYKYYGDSVKG
3(HCDR3, EGFR binding arm)
DGITMVRGVMKDYFDY
4(LCDR1, EGFR binding arm)
RASQDISSALV
5(LCDR2, EGFR binding arm)
DASSLES
6(LCDR3, EGFR binding arm)
QQFNSYPLT
7(HCDR1, c-Met binding arm)
SYGIS
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
12(LCDR3, c-Met binding arm)
QQANSFPIT
SEQ ID NO 13(VH, EGFR binding arm)
QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS
14(VL, EGFR binding arm)
AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK
15(VH, c-Met binding arm)
QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS
[ SEQ ID NO:16(VL, c-Met binding arm)
DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK
>SEQ ID NO:17HC1
QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>SEQ ID NO:18LC1
AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
>SEQ ID NO:19HC2
QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
>SEQ ID NO:20LC2
DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Lacitinib is a third generation EGFR Tyrosine Kinase Inhibitor (TKI); the structure and synthesis of Lazetinib is described in U.S. Pat. No. 9,593,098, which is incorporated herein by reference. The chemical name of the free base of laquinimod represented by formula (I) herein is N- (5- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-ylamino) -4-methoxy-2-morpholinophenyl) acrylamide (referred to herein as laquinimod). The mesylate salt of Lazetinib may be represented by formula II:
embodiments of Lazetinib (e.g., salts and crystalline forms) are described in PCT/KR2018/004473, also incorporated herein by reference.
According to particular embodiments, the free base form of lacitinib has little effect on wild-type EGFR and is a highly selective and irreversible EGFR TKI with strong inhibitory activity against single and double mutations of T790M; for example, it targets the activating EGFR mutations del19 and L858R, as well as the T790M mutation. In one aspect of the invention, the mutation may be del E746-A750, L858R or T790M, and it may be a double mutation selected from del E746-A750/T790M or L858R/T790M.
Embodiments of the present disclosure provide methods of treating a subject having cancer comprising administering to the subject a combination therapy, wherein the combination therapy comprises a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
Embodiments of the present disclosure also provide methods of treating a subject having an EGFR-or c-Met expressing cancer comprising administering to the subject a combination therapy, wherein the combination therapy comprises a therapeutically effective amount of an isolated bispecific anti-EGFR/c-Met antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
Embodiments of the present disclosure provide pharmaceutical combinations comprising a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for use as a medicament, in particular for use as a medicament in a subject.
Embodiments of the present disclosure provide pharmaceutical combinations comprising a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular for use in the treatment of cancer in a subject.
Embodiments of the present disclosure provide pharmaceutical combinations comprising a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for use in the treatment of an EGFR or c-Met expressing cancer, in particular for use in the treatment of an EGFR or c-Met expressing cancer in a subject.
Embodiments of the present disclosure provide for the use of a combination comprising a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of cancer, in particular for the treatment of cancer in a subject.
Embodiments of the present disclosure provide for the use of a combination comprising a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of an EGFR or c-Met expressing cancer, in particular for the treatment of an EGFR or c-Met expressing cancer in a subject.
Embodiments of the present disclosure provide pharmaceutical combinations comprising a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
Embodiments of the present disclosure provide products comprising a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, as a combined preparation for simultaneous, separate or sequential use in the treatment of cancer, in particular in the treatment of cancer in a subject.
Embodiments of the present disclosure provide products comprising a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, as a combined preparation for simultaneous, separate or sequential use in the treatment of an EGFR-or c-Met-expressing cancer, in particular in the treatment of an EGFR-or c-Met-expressing cancer in a subject.
Embodiments of the present disclosure provide isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibodies, particularly therapeutically effective amounts of isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibodies, for use in combination with a compound of formula (I), particularly in combination with a therapeutically effective amount of a compound of formula (I),
or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in particular for use in the treatment of cancer in a subject.
Embodiments of the present disclosure provide isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibodies, particularly therapeutically effective amounts of isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibodies, for use in combination with a compound of formula (I), particularly in combination with a therapeutically effective amount of a compound of formula (I),
or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for use in the treatment of an EGFR or c-Met expressing cancer, in particular for use in the treatment of an EGFR or c-Met expressing cancer in a subject.
In each embodiment, the bispecific anti-EGFR/c-Met antibody and the latticinib compound, or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, can be administered simultaneously (e.g., as part of the same pharmaceutical composition, or in separate pharmaceutical compositions) or at different times, as described herein.
Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic salts/anionic salts or basic salts/cationic salts. Pharmaceutically acceptable acid/anion salts include acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, etonate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, p-hydroxyacetaminophenylarsonate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, mucate, naphthalenesulfonate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, calcium edetate, picrate, acetate, or salt, and/diphosphate, acetate, and/or a salt, Hypoacetates, succinates, sulfates, bisulfates, tannates, tartrates, theachlorates, tosylates and triethiodide salts. Pharmaceutically acceptable basic/cationic salts include sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine, and triethanolamine salts.
Pharmaceutically acceptable acid salts are formed by reacting the free base form of the compound of formula (I) with a suitable inorganic or organic acid including, but not limited to, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, maleic acid, formic acid, acetic acid, propionic acid, fumaric acid, citric acid, tartaric acid, lactic acid, benzoic acid, salicylic acid, glutamic acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalenesulfonic acid (such as 2-naphthalenesulfonic acid) or hexanoic acid. Pharmaceutically acceptable acid addition salts of compounds of formula (I) may include or be, for example, hydrobromide, hydrochloride, sulphate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulphonate, benzenesulphonate, methanesulphonate, ethanesulphonate, naphthalenesulphonate (e.g. 2-naphthalenesulphonate) or hexanoate.
The free acid or free base form of the compounds of formula (I) may be prepared from the corresponding base addition salt or acid addition salt form, respectively. For example, a compound of the invention in acid addition salt form can be converted to the corresponding free base form by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The compounds of the present invention in base addition salt form can be converted to the corresponding free acids by treatment with a suitable acid (e.g., hydrochloric acid, etc.).
In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises: a first domain that binds EGFR comprising heavy chain complementarity determining region 1 of SEQ ID NO:1(HCDR 1), HCDR2 of SEQ ID NO:2, HCDR3 of SEQ ID NO:3, light chain complementarity determining region 1 of SEQ ID NO:4(LCDR 1), LCDR2 of SEQ ID NO:5, and LCDR3 of SEQ ID NO: 6; and a second domain that binds c-Met, the second domain comprising HCDR1 of SEQ ID NO. 7, HCDR2 of SEQ ID NO. 8, HCDR3 of SEQ ID NO. 9, LCDR1 of SEQ ID NO. 10, LCDR2 of SEQ ID NO. 11, and LCDR3 of SEQ ID NO. 12.
In some embodiments, the first domain that binds EGFR comprises the heavy chain variable region (VH) of SEQ ID NO:13 and the light chain variable region (VL) of SEQ ID NO:14, and the second domain that binds c-Met comprises the VH of SEQ ID NO:15 and the VL of SEQ ID NO: 16.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is an IgG1 isotype. There are variations (e.g., well known allotypes) within the constant domain of IgG1, where the variations are located at positions 214, 356, 358, 422, 431, 435 or 436 (residue numbering according to EU numbering) (see, e.g., IMGT Web resources; IMGT repertoires (IG and TR); proteins and alleles; allotypes). The bispecific anti-EGFR/c-Met antibody may be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m 28. The amino acid sequence of the constant domain of exemplary IgG1 is shown in SEQ ID NO 21.
IgG1 constant domain (SEQ ID NO:21)
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
In some embodiments, the bispecific anti-EGFR/c-Met antibody comprises HC1 of SEQ ID NO 17, LC1 of SEQ ID NO 18, HC2 of SEQ ID NO 19, and LC2 of SEQ ID NO 20.
In some embodiments, the bispecific anti-EGFR/c-Met antibody has a double-branched glycan structure with a fucose content of between about 1% to about 15%.
In some embodiments, the bispecific anti-EGFR/c-Met antibody has a double-branched glycan structure with a fucose content of between about 1% to about 15%, e.g., 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
The relative amount of fucose is the percentage of fucose-containing structures relative to all sugar structures. These can be characterized and quantified by a variety of methods, such as: 1) MALDI-TOF using N-glycosidase F treated samples (e.g., complex structures, mixed structures, and oligomeric and high mannose structures), as described in international patent publication WO 2008/0775462; 2) by enzymatic release of Asn297 glycans, followed by derivatization and detection/quantification by HPLC (UPLC) and/or HPLC-MS with fluorescence detection (UPLC-MS); 3) performing an intact protein analysis on the native or reduced mAb with or without treatment of Asn297 glycan with Endo S or other enzymes that cleave between a first GlcNAc monosaccharide and a second GlcNAc monosaccharide, leaving a fucose attached to the first GlcNAc; 4) the mabs were digested into component peptides by enzymatic digestion (e.g., trypsin or endopeptidase Lys-C), followed by separation, detection and quantification by HPLC-MS (UPLC-MS); 5) mAb oligosaccharides were separated from mAb protein by specific enzymatic deglycosylation at Asn297 with PNGase F. The oligosaccharides thus released can be fluorescently labelled, isolated and identified by various complementary techniques which allow: performing fine characterization on the glycan structure by comparing experimental mass with theoretical mass by using matrix-assisted laser desorption ionization (MALDI) mass spectrometry; determination of the degree of sialylation by ion exchange hplc (glycosep c); isolating and quantifying the oligosaccharide form by normal phase hplc (glycocep n) according to hydrophilic standards; and separating and quantifying oligosaccharide by high performance capillary electrophoresis laser induced fluorescence (HPCE-LIF).
The ability of an antibody to induce ADCC can be enhanced by engineering its oligosaccharide component. Human IgG1 or IgG3 are N-glycosylated with most glycans in the well-known double-branched G0, G0F, G1, G1F, G2, or G2F forms at Asn 297. Antibodies produced by unengineered CHO cells typically have a glycan fucose content of about at least 85%. Removal of core fucose from the dual-branched complex oligosaccharides can enhance antibody-dependent cell-mediated cytotoxicity (ADCC) of the antibody via improved Fc γ RIIIa binding without altering antigen binding or complement-dependent cytotoxicity (CDC) activity. Antibodies with reduced fucose content can be prepared using different methods reported to result in successful expression of relatively high defucosylated antibodies with dual-branched complex-type Fc oligosaccharides, such as controlling the culture osmolality (Konno et al, Cytotechnology, Vol.64, p.249-265, 2012), using the variant CHO cell line Lec13 as host cell line (Shields et al, J Biol Chem, Vol.277, p.26733-26740, 2002), using the variant CHO cell line EB66 as host cell line (Olivier et al, MAbs, 2(4), 2010; Epub ahead of print; PMID:20562582), using the large mouse hybridoma cell line YB2/0 as host cell line (Shinkawa et al, J Biol Chem, p.278, p.66-3473, p.2003), introducing small interfering RNA transferase specific for the alpha-1, 6-fucosyltransferase (FURII 8) gene (Monkan RNA-3473, 2003), biotechnol Bioeng, Vol.88, p.901-908, 2004), or co-expressing β -1, 4-N-acetylglucosaminyltransferase III and golgi α -mannosidase II or a potent α -mannosidase I inhibitor, kifunensine (Ferrara et al, Biotechnol Bioeng, Vol.93, p.851-861, 2006, Xhou et al, Biotechnol Bioeng 99:652-65, 2008).
In some embodiments, the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is represented by a compound of formula (II)
Solvates, hydrates or tautomers thereof. In some embodiments, the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is represented by a compound of formula (II)
In some embodiments, the cancer is a cancer that expresses EGFR or c-Met.
In some embodiments, the cancer is a cancer that expresses EGFR and c-Met.
In some embodiments, the cancer is an EGFR-expressing cancer.
In some embodiments, the cancer is a cancer that expresses c-Met.
In some embodiments, the EGFR-or c-Met-expressing cancer is associated with wild-type EGFR, EGFR mutation, EGFR gene amplification, elevated levels of circulating HGF, wild-type c-Met, c-Met mutation, c-Met gene amplification, or mutant KRAS. The EGFR mutation may be an activating mutation, such as an exon 19 deletion or L858R mutation.
Exemplary EGFR mutations, such as EGFR activating mutations, that may be associated with cancer include point mutations, deletion mutations, insertion mutations, inversions, or gene amplifications that result in an increase in at least one biological activity of EGFR (such as increased tyrosine kinase activity, receptor homodimer and heterodimer formation, enhanced ligand binding, etc.). The mutation may be located in the EGFR gene or any part of the regulatory region associated with the EGFR gene, and includes a mutation of exon 18, 19, 20 or 21. Other examples of EGFR activating mutations are known in the art (see, e.g., U.S. patent publication US 2005/0272083). Information on EGFR and other ErbB receptors, including receptor homodimers and heterodimers, receptor ligands, autophosphorylation sites, and signaling molecules involved in ErbB-mediated signaling, is known in the art (see, e.g., Hynes and Lane, Nature Reviews Cancer 5:341-354, 2005).
In some embodiments, the EGFR mutations are E709K, L718Q, L718V, G719A, G719X, G724X, G724S, I744T, E746K, L747S, E749Q, A750P, A755V, V765M, C775Y, T790M, L792H, L792V, G796, G79R, G796C, C Insid7S, T854S, L36858S, L861S, E746-A750, delE746_ T751 Instron 76KV _ InsdelP 751, InsdelL delI 74753, InsdelP delP 747626, InsdelP 751, InsdelP 74767, InsdelP 751, InsdelP 747636767, InsdelP 751, InsdelP 74769, InsdelP 751, InsdelP 7636767, InsdelP 751, L3, InsdelP 751, Insdes74767, InsdelP 751, Insdes74767, Insdes74768, InsdesP 751, Insdesp 3, Insdes74767, Insdesp 3, InsdelP 751, Insdesp 3, Insdes74767, InsdelP 751, Insdesp 3, Insdes74768, Insdesp 3, s768_ V769 instx, V769_ D770 instx, D770_ N771 instx, N771_ P772 instx, P772_ H773 instx, H773_ V774 instx, V774_ C775 instx, one or more deletions of EGFR exon 20, or one or more insertions of EGFR exon 20, one or more deletions of EGFR exon 19, or one or more insertions of EGFR exon 19, or any combination thereof, wherein X refers to any of the naturally occurring amino acids and can be one to seven amino acids in length. The nomenclature of mutations is well known.
In some embodiments, the EGFR mutation is one or more deletions of exon 19 or L858R or any combination thereof. Exemplary exon 19 deletions are del E746-A750, del E746_ T751InsKV, del E746_ A750InsHS, del E746_ T751InsFPT, del E746_ T751InsL, del E746_ S752InsIP, del E746_ P753InsMS, del E746_ T751InsA, del E746_ T751InsAPT, del E746_ T751InsVA, del E746_ S752InsV, del E746_ P753InsVS, del E746_ K754InsGG, del E746_ E749InsP, del L747_ E749, del L747_ A750InsP, del L747_ T751InsP, del L747_ S Insins, del L747_ P753Insns, del L747_ P753Insns 753 NS, PI 747_ S752, PI 747_ T7 _ S747, I75S 753I, del E I75S 753I, I74S 753I, and delL 751I.
Exemplary c-Met mutations include point mutations, deletion mutations, insertion mutations, inversions, or gene amplifications that result in an increase in at least one biological activity of the c-Met protein (such as increased tyrosine kinase activity, receptor homodimer and heterodimer formation, enhanced ligand binding, etc.). The mutation may be located in any part of the c-Met gene or regulatory region associated with the gene, such as in the kinase domain of c-Met. Exemplary c-Met mutations are at residue positions N375, V13, V923, R175, V136, L229, S323, R988, S1058/T1010 and E168 or exon 14 skipping mutations.
In some embodiments, the c-Met mutation is a c-Met exon 14 skip mutation.
Methods for detecting EGFR and c-Met mutations or gene amplification are well known.
In some embodiments, the cancer is a KRAS mutation. Exemplary KRAS mutations include G12V, G12C, or G12A substitutions.
In some embodiments, the subject is diagnosed with an EGFR mutation prior to administration of the combination therapy.
In some embodiments, the subject has a newly diagnosed cancer.
In some embodiments, the subject has a newly diagnosed EGFR-or c-Met expressing cancer.
In some embodiments, the subject has a newly diagnosed cancer that expresses EGFR and c-Met.
In some embodiments, the subject has a newly diagnosed EGFR-expressing cancer.
In some embodiments, the subject has a newly diagnosed c-Met expressing cancer.
In some embodiments, a subject with a newly diagnosed cancer has one or more EGFR exon 20 mutations. In some embodiments, a subject with a newly diagnosed EGFR-or c-Met expressing cancer has one or more EGFR exon 20 mutations. Exon 20 mutations (insertions of one or more amino acids) are typically resistant to EGFR Tyrosine Kinase Inhibitors (TKIs) (see, e.g., international patent publication WO 2018/094225). Exemplary exon 20 mutations include M766_ a767 insfa, S768_ V769 insva, P772_ H773InsNS, D761_ E762 instx, a763_ Y764 instx, Y764_ Y765 instx, M766_ a767 instx, a767_ V768 instx, S768_ V769 instx, V769_ D770 instx, D770_ N771 instx, N771_ P772 instx, P772_ H773 instx, H773_ V774 instx, and V774_ C775 instx, where X is one to seven amino acids.
In some embodiments, the subject is resistant to treatment with bosutinib.
In some embodiments, the subject has not been treated with a Tyrosine Kinase Inhibitor (TKI).
In some embodiments, the subject has not received treatment with an EGFR Tyrosine Kinase Inhibitor (TKI).
In some embodiments, the subject is resistant to treatment with a first generation EGFR TKI or will relapse.
In some embodiments, the first generation EGFR TKI is erlotinib or gefitinib.
In some embodiments, the subject is resistant to treatment with a second generation EGFR TKI or will relapse.
In some embodiments, the second generation EGFR TKI is afatinib.
In some embodiments, the subject is resistant to treatment with a third generation EGFR TKI or will relapse.
In some embodiments, the third generation EGFR TKI is ocitinib.
In some embodiments, the subject is resistant to or has acquired resistance to treatment with a prior anti-cancer therapy.
In some embodiments, the prior anti-cancer therapy is chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.
In some embodiments, the TKI is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL.
In some embodiments, the TKI is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, oxitinib, poetinib, critinib, cabozantinib, camatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.
In some embodiments, the subject is resistant to or has acquired resistance to an EGFR inhibitor. An exemplary EGFR inhibitor to which cancer may acquire resistance is the anti-EGFR antibody cetuximabPanitumumabMatuzumab, nimotuzumab, small molecule EGFR inhibitor erlotinibGefitinibEKB-569 (pelitinib, irreversible EGFR TKI), pan ErbB and other receptor tyrosine kinase inhibitors, lapatinib (EGFR and HER2 inhibitors), pelitinib (EGFR and HER2 inhibitors), vandetanib (ZD6474, ZACTIMA)TMEGFR, VEGFR2 and RET TKI), PF00299804 (Dacotinib, irreversible pan-ErbB TKI), CI-1033 (irreversible pan-erbB TKI), Afatinib (BIBW2992, RET TKI),Irreversible pan-ErbB TKI), AV-412 (dual EGFR and ErbB2 inhibitors), EXEL-7647(EGFR, ErbB2, GEVGR and EphB4 inhibitors), CO-1686 (irreversible mutant-selective EGFR TKI), AZD9291 (irreversible mutant-selective EGFR TKI) and HKI-272 (lenatinib, irreversible EGFR/ErbB2 inhibitors).
Various qualitative and/or quantitative methods can be used to determine whether a subject is resistant to treatment with an anti-cancer therapy or has developed or is predisposed to developing resistance to such treatment. Symptoms that may be associated with resistance to anticancer therapy include a decrease or stasis in the patient's health status, an increase in the size of the tumor, a suppression or slowing of the decrease in tumor growth, and/or the spread of cancer cells from one location to other organs, tissues, or cells in the body. Reconstitution or worsening of various symptoms associated with cancer may also be indicative of: the subject has developed or is predisposed to developing resistance to anticancer therapy, such as anorexia, cognitive dysfunction, depression, dyspnea, fatigue, hormonal imbalance, neutropenia, pain, peripheral neuropathy, and sexual dysfunction. The symptoms associated with cancer may vary depending on the type of cancer. For example, symptoms associated with cervical cancer can include abnormal bleeding, abnormally large amounts of vaginal secretions, pelvic pain not associated with normal menstrual cycles, bladder pain or pain during urination, and bleeding between normal menstrual periods, after sexual intercourse, irrigation, or pelvic examination. Symptoms associated with lung cancer may include persistent cough, hemoptysis, shortness of breath, chest pain from wheezing, loss of appetite, involuntary weight loss, and fatigue. Symptoms of liver cancer may include loss of appetite and weight, abdominal pain (especially the upper right portion of the abdomen that may extend to the back and shoulders), nausea and vomiting, general weakness and fatigue, increased liver, abdominal swelling (ascites), and white yellowing of the skin and eyes (jaundice). The oncological technician can readily identify the symptoms associated with a particular cancer type.
In some embodiments, the cancer is non-small cell lung cancer (NSCLC), epithelial cell cancer, breast cancer, ovarian cancer, lung adenocarcinoma, squamous cell lung cancer, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, gastric cancer, thymus cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary Papillary Renal Cell Carcinoma (PRCC). In some embodiments, the cancer is metastatic cancer.
In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is an epithelial cell cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the cancer is squamous cell lung cancer. In some embodiments, the cancer is small cell lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is anal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is renal cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is a head and neck cancer. In some embodiments, the cancer is pharyngeal cancer. In some embodiments, the cancer is a nasal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is a skin cancer. In some embodiments, the cancer is an oral cancer. In some embodiments, the cancer is tongue cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is a vaginal cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is a cancer of the spleen. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is a thymus carcinoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is HCC. In some embodiments, the cancer is PRCC.
In some embodiments, NSCLC includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. In some embodiments, the cells of NSCLC have an epithelial phenotype. In some embodiments, the NSCLC has acquired resistance to treatment with one or more EGFR inhibitors.
In NSCLC, specific mutations in the EGFR gene are associated with a high response rate (70-80%) to EGFR tyrosine kinase inhibitors (EGFR-TKI). Deletion of 5 amino acids in exon 19 or the point mutation L858R in EGFR correlated with EGFR-TKI sensitivity (Nakata and Gotoh, Expert Opin Ther Targets 16:771-781,2012). These mutations allow ligand-independent activation of EGFR kinase activity. Activating EGFR mutations occur in 10-30% of NSCLC patients and are significantly more common in eastern Asians, women, never-smokers and patients with adenocarcinoma histology (Janne and Johnson Clin Cancer Res 12(14Suppl):4416s-4420s, 2006). EGFR gene amplification is also strongly associated with response following EGFR-TKI treatment (Capupzzo et al, J Natl Cancer Inst 97:643-55, 2005). EGFR exon 20 insertion has been associated with EGFR TKI resistance.
Although most NSCLC patients with EGFR mutations initially responded to EGFR TKI treatment, virtually all patients acquired resistance that prevented a durable response. 50-60% of patients acquire resistance due to the second site mutation in the kinase domain of EGFR (T790M). Almost 60% of all tumors that become resistant to EGFR tyrosine kinase inhibitors increase c-Met expression, amplify the c-Met gene, or increase its unique known ligand, HGF (Turke et al, Cancer Cell,17:77-88,2010).
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 200mg/kg and about 2000 mg/kg.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 350mg/kg and about 1400 mg/kg.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered in an amount of about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 680mg, about 690mg, about 700mg, about 740mg, about 720mg, about 730mg, about 750mg, About 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1010mg, about 1020mg, about 1030mg, about 1040mg, about 1050mg, about 1060mg, about 1070mg, about 1080mg, about 1090mg, about 1100mg, about 1110mg, about 1120mg, about 1330mg, about 1140mg, about 1150mg, about 1160mg, about 1170mg, about 1180mg, about 1190mg, about 1200mg, about 1210mg, about 1220mg, about 1230mg, about 1240mg, about 1250mg, about 1260mg, about 1270mg, about 1280mg, about 1290mg, about 1310mg, about 1380mg, about 1410mg, about 1380mg, about 1370mg, about 1410mg, about 1380mg, about 1370mg, about 1380mg, about 1410mg, about 1380mg, about 1370mg, about 1410mg, about 1370mg, about 10mg, about 1370mg, about 10mg, About 1430mg, about 1440mg, about 1450mg, about 1460mg, about 1470mg, about 1480mg, about 1490mg, about 1500mg, about 1510mg, about 1520mg, about 1530mg, about 1540mg, about 1550mg, about 1560mg, about 1570mg, about 1580mg, about 1590mg, about 1600mg, about 1610mg, 1620mg, about 1630mg, about 1640mg, about 1650mg, about 1660mg, about 1670mg, about 1680mg, about 1690mg, about 1700mg, about 1710mg, about 1720mg, about 1730mg, about 1740mg, about 1750mg, about 1760mg, about 1770mg, about 1800mg, about 1790mg, about 1810mg, about 1820mg, about 1830mg, about 1840mg, about 1940mg, about 1860mg, about 1870mg, about 1910mg, about 890mg, about 1961880 mg, about 1951880 mg, about 19510 mg, about 1920mg, about 1950mg, about 19310 mg, about 1930mg, about 19310 mg, about 1990mg, about 1920mg, about 980mg, about 1920mg or about 1850 mg.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 350mg, about 700mg, about 1050mg, or about 1400 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 350 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050 mg. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400 mg.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered once weekly.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered once every two weeks.
In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), mesylate salt of laquinimod) is administered in a dose of between about 20mg and about 320 mg. The dosage of a compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof as described herein refers to the amount of free base of the compound of formula (I) in a dosage. For example, according to embodiments wherein the dose comprises the mesylate salt of laquinimod (compound of formula (II)), the dose refers to the amount of the free base of laquinimod (compound of formula (I)); for example, as shown in table 1, mg/dose:
table 1.
In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 40mg and about 320 mg. In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 80mg and about 320 mg. In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 160mg and about 320 mg. In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 240mg and about 320 mg. In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 20mg and about 240 mg. In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 40mg and about 240 mg. In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 80mg and about 240 mg. In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 100mg and about 300 mg. In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 160mg and about 240 mg. In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 100mg and about 300 mg.
In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), mesylate salt of lacitinib) is administered at a dose of at least about 20mg, at least about 40mg, at least about 60mg, at least about 80mg, at least about 100mg, at least about 120mg, at least about 140mg, at least about 160mg, at least about 180mg, at least about 200mg, at least about 220mg, at least about 240mg, at least about 260mg, at least about 280mg, at least about 300mg, or at least about 320 mg.
In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), mesylate salt of lacitinib) is administered at a dose of about 20mg, about 30mg, about 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, or about 320 mg.
In some embodiments, the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), a mesylate salt of laquinimod) is administered once daily.
In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), mesylate salt of lacitinib) is administered at a dose of between about 20mg and about 320mg per day (e.g., about 240mg per day).
In some embodiments, a compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof (e.g., a compound of formula (II), mesylate salt of laquinimod) is administered at a dose of between about 160mg and about 240mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 200mg and about 2000mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at any one of the doses described herein, e.g., at a dose of between about 20mg and about 320mg per day (e.g., about 240mg per day).
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 200mg and about 2000mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (II) or a solvate, hydrate, or tautomer thereof is administered at any one of the doses described herein, e.g., at a dose of between about 20mg and about 320mg per day (e.g., about 240mg per day).
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 350mg and about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at any one of the doses described herein, e.g., at a dose of between about 160mg and about 240mg per day (e.g., about 240mg per day).
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 350mg and about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (II) or a solvate, hydrate, or tautomer thereof is administered at any one of the doses described herein, e.g., at a dose of between about 160mg and about 240mg per day (e.g., about 240mg per day).
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700mg per week for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at any one of the doses described herein, e.g., at a dose of about 160mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700mg per week for four weeks and once every two weeks thereafter, and the compound of formula (II) or a solvate, hydrate, or tautomer thereof is administered at any one of the doses described herein, e.g., at a dose of about 160mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at any one of the doses described herein, e.g., at a dose of about 160mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (II) or a solvate, hydrate, or tautomer thereof is administered at any one of the doses described herein, e.g., at a dose of about 160mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at any one of the doses described herein, e.g., at a dose of about 160mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (II) or a solvate, hydrate, or tautomer thereof is administered at any one of the doses described herein, e.g., at a dose of about 160mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700mg per week for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at any one of the doses described herein, e.g., at a dose of about 240mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700mg per week for four weeks and once every two weeks thereafter, and the compound of formula (II) or a solvate, hydrate, or tautomer thereof is administered at any one of the doses described herein, e.g., at a dose of about 240mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at any one of the doses described herein, e.g., at a dose of about 240mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (II) or a solvate, hydrate, or tautomer thereof is administered at any one of the doses described herein, e.g., at a dose of about 240mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at any one of the doses described herein, e.g., at a dose of about 240mg per day.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (II) or a solvate, hydrate, or tautomer thereof is administered at any one of the doses described herein, e.g., at a dose of about 240mg per day.
According to particular embodiments, the methods of treating a patient with the combination of laquinimod JNJ-61186372 or with the combination of laquinimod JNJ-61186372 as described herein are effective in reducing tumor volume in the patient according to the dosing regimen described herein (e.g., as described above and in example 3) (see, e.g., example 4). Such effects can be observed, for example, in NSCLC patients diagnosed with EGFR T790M negative disease after development after TKI generation 1, and in patients progressing after TKI generation 3 therapy.
In some embodiments, the subject is homozygous for phenylalanine at position 158 of CD16, or heterozygous for valine and phenylalanine at position 158 of CD 16.
A subject homozygous for phenylalanine at position 158 of CD16 has the Fc γ RIIIa-158F/F genotype. Subjects who are heterozygous for valine and phenylalanine at position 158 of CD16 have the fcyriiia-158F/V genotype. CD16 is also known as Fc γ receptor IIIa (Fc γ RIIIa) or low affinity immunoglobulin γ Fc region receptor III-a isoform. The valine/phenylalanine (V/F) polymorphism at residue 158 of Fc γ RIIIa protein has been shown to affect the affinity of Fc γ RIIIa for human IgG. Receptors with Fc γ RIIIa-158F/F or Fc γ RIIIa-158F/V polymorphisms exhibit reduced Fc binding and therefore reduced ADCC as compared to Fc γ RIIIa-158V/V. Bispecific anti-EGFR/c-Met antibodies with reduced fucose content may be more effective in treating patients with Fc γ RIIIa-158F/F or Fc γ RIIIa-158F/V genotypes. The patient can be analyzed for Fc γ RIIIa polymorphisms using conventional methods.
In some embodiments, the subject is further administered a third anti-cancer therapy.
In some embodiments, the third anti-cancer therapy is chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.
In some embodiments, the kinase inhibitor is an inhibitor of EGFR, c-Met, HER2, HER3, HER4, VEGFR, or AXL. In some embodiments, the kinase inhibitor is an inhibitor of EGFR. In some embodiments, the kinase inhibitor is an inhibitor of c-Met. In some embodiments, the kinase inhibitor is an inhibitor of HER 2. In some embodiments, the kinase inhibitor is an inhibitor of HER 3. In some embodiments, the kinase inhibitor is an inhibitor of HER 4. In some embodiments, the kinase inhibitor is an inhibitor of VEGFR. In some embodiments, the kinase inhibitor is an inhibitor of AXL.
In some embodiments, the kinase inhibitor is erlotinib, gefitinib, lapatinib, vandetanib, afatinib, oxitinib, britinib, cabozantinib, camatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.
In some embodiments, the kinase inhibitor is erlotinib. In some embodiments, the kinase inhibitor is gefitinib. In some embodiments, the kinase inhibitor is lapatinib. In some embodiments, the kinase inhibitor is vandetanib. In some embodiments, the kinase inhibitor is afatinib. In some embodiments, the kinase inhibitor is oxitinib. In some embodiments, the kinase inhibitor is bosutinib. In some embodiments, the kinase inhibitor is critinib. In some embodiments, the kinase inhibitor is cabozantinib. In some embodiments, the kinase inhibitor is carbamatinib. In some embodiments, the kinase inhibitor is axitinib. In some embodiments, the kinase inhibitor is lenvatinib. In some embodiments, the kinase inhibitor is nintedanib. In some embodiments, the kinase inhibitor is regorafenib. In some embodiments, the kinase inhibitor is pazopanib. In some embodiments, the kinase inhibitor is sorafenib. In some embodiments, the kinase inhibitor is sunitinib.
The anti-cancer therapies that can be administered in combination with the bispecific anti-EGFR/c-Met antibody and the lacitinib in the methods of the present disclosure include any one or more of chemotherapeutic drugs or other anti-cancer therapeutics known to those of skill in the art. Chemotherapeutic agents are chemical compounds useful in the treatment of cancer and include growth inhibitors or other cytotoxic agents, and include alkylating agents, antimetabolites, antimicrotubule inhibitors, topoisomerase inhibitors, receptor tyrosine kinase inhibitors, angiogenesis inhibitors, and the like. Examples of chemotherapeutic agents include: alkylating agents, such as thiotepa and cyclophosphamideAlkyl sulfonates such as busulfan, endosulfan, and azinam; aziridines such as benzodidopa (benzodipa), carboquone (carboquone), metridopa (meteedopa), and ulidopa (uredopa); ethyleneimine and methylmelamine, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide (triethylenephosphoramide), triethylenethiophosphorylamide (triethylenephosphoramide), and trimethylolmelamine (trimethylemelamine); nitrogen mustards (nitrosgen mustards), such as chlorambucil, chlorambucil (chlorenaphazine), cholorophosphamide (cholorophosphamide), estramustine (estramustine), ifosfamide, mechlorethamine hydrochloride (mechlorethamine oxide hydrochloride), melphalan, neomustard (novembichin), benzene mustard cholesterol (phenesterine), prednimustine (prednimustine), trofosfamide (trofosfamide), uracil mustard (uracilmustard); nitrosoureas (nitroureas) such as carmustine, chlorourethrine, fotemustine (fotemustine), lomustine (lomustine), nimustine (nimustine), ramustine (ranimustine); antibiotics, such as aclacinomysins, actinomycins, anthranomycin, azaserine, bleomycin, actinomycin, calicheamicin, carabicin, carminomycinin), carcinomycin (carzinophilin), chromomycin, dactinomycin, daunorubicin, dirobicin (detoubicin), 6-diaza-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marijumycin (marcellomomycin), mitomycins (mitomycins), mycophenolic acid (mycophenolic acid), norramycin (nogalamycin), olivomycin (olivomycin), pelomycin (polyplomycin), potfiromycin, puromycin (puromycin), triiron doxorubicin (quelamycin), rodobicin (rodorubicin), streptonigrosins (streptonigrin), streptozotocin, tubercidin (tubidin), ubenimex (enn), restatin (nobitin), zorubicin (staubicin); antimetabolites such as methotrexate and 5-FU; folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine (fludarabine), 6-mercaptopurine, thiamiprine (thiamiprine), thioguanine; pyrimidine analogs such as ancitabine (ancitabine), azacitidine (azacitidine), 6-azauridine (azauridine), carmofur (carmofur), cytarabine, dideoxyuridine (dideoxyuridine), doxifluridine (doxifluridine), enocitabine (enocitabine), floxuridine; androgens such as carotinone (calusterone), dromostanolone propionate, epitioandrostanol (epitiostanol), mepiquitane (mepiquitane), testolactone (testolactone); anti-adrenal species such as aminoglutethimide, mitotane, trostane (trilostane); folic acid supplements such as folinic acid (frilic acid); acetoglucurolactone (acegultone); (ii) an aldophosphamide glycoside; aminolevulinic acid (aminolevulinic acid); amsacrine; bestrabuucil; bisantrene; edatrexae; desphosphamide (defofamide); dimecorsine (demecolcine); diazaquinone; elfornitine; ammonium etitanium acetate; etoglut (etoglucid); gallium nitrate; a hydroxyurea; lentinan (lentinan); lonidamine (lonidamine); mitoguazone (mitoguzone); mitoxantrone; mopidanol (mopidanmol); diaminenitracridine (nitrarine); pentostatin (pentostatin); methionine mustard (phenamett); pirarubicin (pirarubicin); podophyllotonic acid(podophyllic acid); 2-ethyl hydrazide; procarbazine;razoxane (rizoxane); sizofuran (sizofiran); helical germanium (spirogermanium); tenuazonic acid (tenuazonic acid); triimine quinone (triaziquone); 2, 2', 2 "-trichlorotriethylamine; urethane (urethan); vindesine; dacarbazine; mannomustine (mannomustine); dibromomannitol (mitobronitol); dibromodulcitol (mitolactol); pipobromane (pipobroman); a polycytidysine; cytarabine (arabine) ("Ara-C"); cyclophosphamide; thiotepa; novel taxanes or members of the taxane family, e.g. paclitaxel (TDocetaxel) And the like; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; catharanthine removal; nuantro (novantrone); (ii) teniposide; daunomycin; aminopterin (aminopterin); (ii) Hirodad; ibandronate (ibandronate); CPT-11; topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoic acid; epothilones (esperamicins); capecitabine; inhibitors of receptor tyrosine kinases and/or angiogenesis, including sorafenibSunitinibPazopanib (VOTRIENT)TM) Toxicillin (PALLADIA)TM) Vandetanib (ZACTIMA)TM) XidinibRegorafenib (BAY73-4506), axitinib (AG013736), lestaurtinib (CEP-701), erlotinibGefitinibAfatinib (BIBW 2992), lapatinibNeratinib (HKI-272), and the like, and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Also included in this definition are anti-hormonal agents, such as anti-estrogenic agents, for modulating or inhibiting the effects of hormones on tumors, including, for example, tamoxifen, raloxifene, aromatase inhibiting 4(5) -imidazole, 4-hydroxyttamoxifen, trovaxifene, keoxifene, LY117018, onapristone, and toremifeneAnd antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and a pharmaceutically acceptable salt, acid or derivative of any of the above. Other conventional cytotoxic chemical compounds such as those disclosed in Wiemann et al, 1985, Medical Oncology (edited by Calabresi et al), Chapter 10, McMillan Publishing, are also suitable for use in the methods of the present invention.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered prior to administration of the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered prior to administration of the compound of formula (II) or a solvate, hydrate, or tautomer thereof.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered after administration of the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered after administration of the compound of formula (II) or a solvate, hydrate, or tautomer thereof.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered one or more times after administration of the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered one or more times after the compound of formula (II) or a solvate, hydrate, or tautomer thereof.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered two, three, four, five, six, seven, eight, nine, ten or more times after the administration of the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered two, three, four, five, six, seven, eight, nine, ten or more times after administration of the compound of formula (II) or a solvate, hydrate or tautomer thereof.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered intermittently after the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered intermittently after the compound of formula (II) or solvate, hydrate, or tautomer thereof is administered.
The length of time between administration of the bispecific anti-EGFR/c-Met antibody and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, or the compound of formula (II) or a solvate, hydrate, or tautomer thereof, or the third anti-cancer therapy may be several minutes (such as about 1 minute, 2 minutes, 5 minutes, 10 minutes, 30 minutes, or 60 minutes) or several hours (such as about 2 hours, 4 hours, 6 hours, 10 hours, 12 hours, 24 hours, or 36 hours) or such as about 2 days, 4 days, 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, 56 days or more.
The bispecific anti-EGFR/c-Met antibody and the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof or a third anti-cancer agent may be administered as a pharmaceutical composition.
The bispecific anti-EGFR/c-Met antibody and the compound of formula (II) or a solvate, hydrate, or tautomer thereof, or the third anti-cancer agent, can be administered as a pharmaceutical composition.
The bispecific anti-EGFR/c-Met antibody can be formulated as a pharmaceutical composition comprising the bispecific anti-EGFR/c-Met antibody and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be one or more diluents, adjuvants, excipients, vehicles, and the like. Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable origin, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine can be used to formulate bispecific anti-EGFR/c-Met antibodies. These solutions are sterile and generally free of particulate matter. They may be sterilized by well-known conventional sterilization techniques, such as filtration.
In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered by intravenous injection. In some embodiments, the bispecific anti-EGFR/c-Met antibody is administered by subcutaneous injection.
In some embodiments, the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, or the compound of formula (II) or a solvate, hydrate or tautomer thereof, is administered as an oral formulation, such as, for example, a solid oral formulation such as a powder, capsule and tablet.
For solid oral formulations such as powders, capsules and tablets such as, for example, for a compound of formula (I) or a compound of formula (II), suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral formulations may also be coated with substances such as sugars or with enteric coatings to regulate the primary site of absorption. For parenteral administration, the carrier may include sterile water, and other excipients may be added to increase solubility or preservative properties. Injectable suspensions or solutions may also be prepared using water-based carriers along with suitable additives. Suitable vehicles and formulations, including other human proteins (e.g., human serum albumin), are described, for example, in Remington: The Science and Practice of Pharmacy, 21 st edition, Troy, D.B. eds, Lipincott Williams and Wilkins, Philadelphia, PA 2006, part 5, Pharmaceutical Manufacturing, page 691-.
The composition may contain pharmaceutically acceptable auxiliary substances as necessary to approximate physiological conditions, such as pH adjusting and buffering agents, stabilizing agents, thickening agents, lubricants, and coloring agents, and the like. The concentration of the bispecific anti-EGFR/c-Met antibody in the pharmaceutical formulation can vary from less than about 0.5% by weight, typically to at least about 1% to as much as 15%, 20%, 30%, 40% or 50% by weight, and can be selected based primarily on the desired dose, fluid volume, viscosity, etc., depending on the particular mode of administration selected. Pharmaceutical compositions comprising solid forms may comprise from about 0.1mg to about 2000mg (such as about 1mg, about 5mg, about 10mg, about 25mg, about 50mg, about 100mg, about 150mg, about 200mg, about 300mg, about 500mg, about 600mg or about 1000mg) of the active ingredient.
The mode of administration may be any suitable route of delivery of the antibody to the host, such as parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (buccal, intranasal, intravaginal, rectal), using formulations in the form of tablets, capsules, solutions, powders, gels, granules; and contained in syringes, implant devices, osmotic pumps, cassettes, micropumps; or other means known in the art as understood by the skilled artisan. Site-specific administration can be achieved, for example, by: intratumoral, parenteral, intrabronchial, intraabdominal, intracapsular, intracartilaginous, intracavitary, intracerebroventricular, intracolic, intracervical, intragastric, intrahepatic, intracardiac, intraosteal, intrapelvic, intrapericardiac, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrarectal, intrarenal, intraretinal, intraspinal, intrasynovial, intrathoracic, intrauterine, intravascular, intravesical, intralesional, vaginal, rectal, buccal, sublingual, intranasal, or transdermal delivery.
The invention will now be described with reference to the following specific, non-limiting examples.
Example 1 combination of JNJ-372 with Lazetinib shows swelling in the H1975 human Lung cancer xenograft model
Tumor cell killing
The objective of this study was to evaluate the antitumor activity of JNJ-372 in combination with third generation TKI lacitinib and ocitinib in H1975 human lung xenografts with activating EGFR (L858R) and second site resistant EGFR (T790M) mutations, as well as in H1975-HGF xenografts in which the c-Met pathway is activated by autocrine overexpression of human HGF (c-Met ligand).
Method
Female athymic nude mice (Crl: NU (Ncr) -Foxn1nu, Charles River) are nine weeks old and have a Body Weight (BW) range of 19.0 grams to 27.2 grams (g) at the start of treatment. Animals were fed free-drinking water (reverse osmosis, 1ppm Cl) and NIH 31 modified and irradiated laboratory diet consisting of 18.0% crude protein, 5.0% crude fat and 5.0% crude fiber. Mice were housed in an Enrich-o' cobs irradiated in static microasolators with 12 hour light cycle, 20 ℃ to 22 ℃ (68 ° F to 72 ° F) and 40% to 60% humidityTMExperimental animal bedding. All studies followed the guidelines for laboratory animal care and use, recommendations for constraints, feeding, surgical procedures, feed and fluid regulation, and veterinary care.
Tumor cell culture
NCI-H1975 cells were grown to mid-log phase in RPMI 1640 medium containing 10% fetal bovine serum, 2mM glutamine, 100 units/mL penicillin G sodium, 25. mu.g/mL gentamicin, and 100. mu.g/mL streptomycin sulfate. Tumor cells were cultured in tissue culture flasks in a humidified incubator at 37 ℃ in an atmosphere of 5% CO2 and 95% air.
In vivo implantation and tumor growth
On the day of implantation, NCI-H1975 cells were harvested during log phase growth and cultured at 5X 107The concentration of individual cells/mL was resuspended in Phosphate Buffered Saline (PBS). By mixing 5X 10 of each animal6An NCI-H1975 cell (0.1mL suspension) was subcutaneously implanted into the right abdominal cavity of each test animal to initiate xenografting, and when the tumor volume approached 150mm3To 200mm3Monitoring the tumor at the target range. After fifteen days, animals were sorted into bins by measuring the calculated tumor volume with a vernier caliper based on tumor width and length (to the nearest mm). Animals were then heuristically sorted among treatment groups, balancing the distribution of small to large size tumor volumes between group assignments. The remaining animals were subjectively placed to minimize the standard error of tumor volume between groups until the number of animals assigned to each cohort met the protocol design. Each tumor volume was 108mm3To 288mm3Resulting in a group mean tumor volume of 206mm for all groups3To 209mm3. Tumor size (in mm 3) was calculated using the following formula:
tumor volume ═ w2×l)/2
Where w is the width of the tumor and l is the length of the tumor (in mm). Tumor weight is assumed to be 1mg corresponding to 1mm3Is estimated.
Test article
JNJ-372 (also known as CNTO4424 or HH80) and isotype control were administered at 1mg/mL PBS, resulting in a dose of 10 mg/kg. Oxitinib powder was suspended at 1mg/mL in 20% (w/v) hydroxypropyl β cyclodextrin (20% HPBCD) in deionized water and magnetically stirred for 15min to produce a uniformly dispersed suspension. Lazetinib (also known as JNJ-70080595, JNJ-595 or YH-CNT) powder was suspended at 1.17mg/mL in 0.5% (w/v) methylcellulose (0.5% MC, vehicle) in deionized water to provide an active dose of 10 mg/kg. All dosing solutions were formulated to provide the prescribed mg/kg dose in a dosing volume of 10 mL/kg.
Treatment of
Female athymic nude mice (n-10/group) were used in this study. When SC tumors reach about 100mm3To 300mm3Treatment was started at size and dosing was started according to the treatment plan summarized in table 2. JNJ-372, isotype control antibody, oxitinib and lacitinib (also known as JNJ-595) were administered at 10mg/kg (effective concentration). JNJ-372 was IP administered twice weekly for 3 weeks, and oxitinib and lacitinib were administered orally daily for 21 days. The control group was orally dosed with vehicle daily for 21 days, and isotype control antibody was IP dosed twice weekly for 3 weeks. Body weight and tumor volume of mice were monitored until day 95 and tumor volume reached 2,000mm in the individual3Euthanasia was performed at the time or at the end of the study.
Table 2.
Calculation and data analysis
The relative body weights of individual mice were calculated using the following formula: (W/W0) × 100, where "W" represents the body weight on a particular day, and "W0" represents the body weight at the start of treatment. Body weight is graphically represented as the mean% ± SEM of initial body weight.
Tumor volume data are graphically represented as mean tumor volume ± SEM. Tumor volume was calculated using the formula: tumor volume (mm)3) (D × D2)/2; where "D" represents a larger diameter and "D" represents a smaller diameter tumor, as determined by caliper measurements.
The% TGI is defined as the difference between the mean tumor burden of the treated and control groups and is calculated as% Δ TGI ═ ([ (TVc-TVc0) - (TVt-TVt0)]V (TVc-TVc 0)). times.100, where "TVc" is the mean tumor burden for a given control group, "TVc 0" is the mean initial tumor burden for a given control group, "TVt" is the mean tumor burden for a treatment groupTumor burden, and "TVt 0" is the average initial tumor burden of the treated group. When the thickness reaches more than or equal to 2,000mm3At the maximum tumor volume or when adverse clinical signs were noted, animals were removed from the study. CR was defined as complete response (complete tumor regression) where tumors were not measurable on the last day of analysis.
Tumor volume and body weight data were represented graphically using Prism software (GraphPad, version 7). Statistical significance of all pairwise comparisons was evaluated on the last day of the study when at least eight mice were retained in each group. When p.ltoreq.0.05, the difference between the groups was considered significant. Statistical significance of tumor volume and body weight was calculated using linear mixed effects analysis in R software version 3.4.2 (using Shiny application version 3.3 developed internally by Janssen's), with treatment and time as fixed effects and animals as random effects. If the respective longitudinal response trajectory is not linear, a logarithmic transformation (base 10) is performed. Information derived from this model was used to make pairwise treatment comparisons with control or all treatment groups.
Survival data was plotted and analyzed using GraphPad Prism 7.04 adapted for Windows with day 1 as the treatment start date. Log rank (Mantel-Cox) analysis included data for all animals in the group, except those assessed as non-treatment-related (NTR) deaths. Two-tailed statistical analysis was performed at a significance level P of 0.05. The statistical test was not adjusted for multiple comparisons. When p.ltoreq.0.05, the difference between the groups was considered significant.
Results
Body weight
The tolerability of JNJ-372 monotherapy or in combination with either TKI could not be assessed in these studies because JNJ-372 did not bind to mouse EGFR or c-Met. In line with this, JNJ-372 monotherapy did not cause significant weight loss compared to the control group in H1975 xenograft-bearing nude mice at day 29 (figure 1). Treatment with either oxitinib or lacitinib, as monotherapy or in combination with JNJ-372, resulted in some transient weight loss in the H1975 model with no weight gain compared to controls (p < 0.05). There was no significant difference in weight loss for the combination of oxitinib or lacitinib plus JNJ-372 when compared to oxitinib or lacitinib monotherapy. One animal from each group treated with the combination of Lazetinib, JNJ-372 and JNJ-372 plus Lazetinib was euthanized at day 21, day 43 and day 71, respectively, due to negative clinical signs; however, it is not clear whether this is due to tumor burden or treatment.
Therapeutic effect
In study H1975, monotherapy treatment with JNJ-372, Latitinib, or Oxitinib induced a significant TGI (86%, 112%, and 111%, respectively) of H1975 xenografts at day 28 (p ≦ 0.0003) compared to controls. On day 28, the combination of JNJ-372 plus lacitinib or ocitinib resulted in 112% TGI compared to controls (p < 0.0001). In addition, the combination of JNJ-372 plus Oxecitinib showed a statistically significant TGI (p.ltoreq.0.03) compared to either monotherapy and resulted in one animal with CR. The combination of JNJ-372 plus lacitinib showed significant TGI (p <0.0001) compared to single agent JNJ-372 treatment, with no significant tendency for longer delay in tumor regrowth compared to lacitinib monotherapy. The combination of JNJ-372 plus lacitinib resulted in 7 of 10 mice with CR compared to 1 of 10 mice treated with lacitinib alone. The combination of JNJ-372 plus Laratinib or Oxitinib resulted in a statistically significant survival advantage (p ≦ 0.0003) compared to controls. The combination of JNJ-372 plus Laratinib showed a statistically significant survival advantage (p ≦ 0.0344) compared to single agent JNJ-372 and single agent Laratinib treatments. The combination of JNJ-372 plus ocitinib showed a statistically significant survival advantage (p <0.0001) compared to the single agent JNJ-372 treatment, and the survival advantage had a non-significant trend compared to the single agent ocitinib treatment.
Table 3 shows the tumor growth inhibition p-values in the H1975 xenograft model. FIG. 2 shows the average of days post tumor implantation for H1975 xenograft-bearing nude mice treated with JNJ-372 monotherapy or in combination with Lazetinib or OxitinibMean tumor volume (mm)3). Figure 3 shows a Kaplan-Meier plot of the percentage of animals remaining in H1975 xenograft-bearing mice treated with JNJ-372 monotherapy or in combination with lacitinib or axitinib. Table 4 shows the survival statistics p-values in the H1975 xenograft model.
Table 3.
Treatment of | Control | Lazetinib | Oxititinib | JNJ-372 |
Lazetinib | <0.0001 | - | - | - |
Oxititinib | <0.0001 | - | - | - |
JNJ-372 | 0.0003 | - | - | - |
Lazetinib + JNJ-372 | <0.0001 | 0.1606 | - | <0.0001 |
Oxitinib + JNJ-372 | <0.0001 | - | 0.0307 | <0.0001 |
Table 4.
Treatment of | Control | Lazetinib | Oxititinib | JNJ-372 |
Lazetinib | 0.0022 | - | - | - |
Oxititinib | 0.0037 | - | - | - |
JNJ-372 | 0.0582 | - | - | - |
Lazetinib + JNJ-372 | 0.0002 | 0.0344 | - | <0.0001 |
Oxitinib + JNJ-372 | 0.0005 | - | 0.1259 | <0.0001 |
Example 2 JNJ-372 with Lazetinib or Ohrschib in H1975-HGF in a human Lung cancer xenograft model
Combination of tinib shows tumor cell killing
Experimental design As described in example 1, except that H1975 cells (H1975-HGF cells) stably transfected to express Hepatocyte Growth Factor (HGF) were used in this study and are hereinafter referred to as H1975-HGF-CNTs. The cells were cultured in RPMI 1640 medium containing 2mM L-glutamine (Invitrogen, catalog No. 11875-127). The medium was supplemented with 10% heat-inactivated fetal bovine serum and 2 μ g/mL puromycin. Puromycin is used as a selective agent in cell culture systems. At 37 ℃ in 5% CO2And 9Cells were cultured in tissue culture flasks in a humidified incubator in an atmosphere of 5% air.
Results
Body weight
In studies with H1975-HGF, on day 28, JNJ-372 monotherapy treatment did not induce significant weight loss compared to controls in mice bearing H1975-HGF tumors (fig. 4). Treatment with either oxitinib or lacitinib resulted in some transient weight loss as monotherapy or in combination with JNJ-372, and no weight gain compared to the control group (p < 0.05). There was no significant difference in weight loss for the combination of oxitinib or lacitinib plus JNJ-372 when compared to oxitinib or lacitinib monotherapy, respectively. Due to negative clinical signs, one mouse in the ositinib and JNJ-372 monotherapy groups and two mice in the group treated with the JNJ-372 garamitinib combination were found dead or euthanized at day 51, day 53, day 70 and day 36, respectively; however, it is not clear whether this is due to tumor burden or treatment.
The treatment groups are shown in table 2.
Therapeutic effect
In studies with H1975-HGF, monotherapy with JNJ-372 or lacitinib resulted in 70% and 75% TGI of H1975-HGF xenografts, respectively (p ═ 0.0059 and p ═ 0.0030, respectively), compared to day 28 controls.
On day 28, treatment with ositinib resulted in a statistically insignificant 57% TGI (p ═ 0.0651) compared to controls. On day 28 of treatment, the combination of JNJ-372 plus lacitinib or ocitinib resulted in 109% or 108% TGI compared to control, respectively (p < 0.0001). In addition, the combination of JNJ-372 plus lacitinib or ocitinib resulted in a significant TGI compared to JNJ-372 or to the corresponding TKI monotherapy (p < 0.0001). Finally, JNJ-372 plus lacitinib resulted in 3 of 10 mice with CR, while the lacitinib monotherapy resulted in 2 of 10 with CR. JNJ-372 plus Oxecitinib produced 4 CR's in 10 mice. The combination of JNJ-372 plus lacitinib or ocitinib resulted in a statistically significant survival advantage (p <0.0001) compared to controls. The combination of JNJ-372 plus Laratinib showed a statistically significant survival advantage (p ≦ 0.0131) compared to single agent JNJ-372 and single agent Laratinib treatments. The combination of JNJ-372 plus ocitinib showed a statistically significant survival advantage (p <0.0001) compared to single agent JNJ-372 and single agent ocitinib treatment.
Table 5 shows the p-value of tumor growth inhibition in the H1975-HGF xenograft model. FIG. 5 shows the mean tumor volume (mm) on days post tumor implantation for H1975-HGF xenograft-bearing nude mice treated with JNJ-372 monotherapy or in combination with Lazetinib or Oxitinib3). Figure 6 shows a Kaplan-Meier plot of the percentage of animals remaining in H1975-HGF xenograft-bearing mice treated with JNJ-372 monotherapy or in combination with lacitinib or axitinib. Table 6 shows the statistical p-values for survival in the H1975-HGF xenograft model.
Table 5.
Treatment of | Control | Lazetinib | Oxititinib | JNJ-372 |
Lazetinib | 0.0030 | - | - | - |
Oxititinib | 0.0651 | - | - | - |
JNJ-372 | 0.0059 | - | - | - |
Lazetinib + JNJ-372 | <0.0001 | <0.0001 | - | <0.0001 |
Oxitinib + JNJ-372 | <0.0001 | - | <0.0001 | <0.0001 |
Table 6.
Treatment of | Control | Lazetinib | Oxititinib | JNJ-372 |
Lazetinib | <0.0001 | - | - | - |
Oxititinib | <0.0001 | - | - | - |
JNJ-372 | <0.0001 | - | - | - |
Lazetinib + JNJ-372 | <0.0001 | 0.0131 | - | 0.0004 |
Oxitinib + JNJ-372 | <0.0001 | - | <0.0001 | <0.0001 |
Conclusion
The aim of these studies was to evaluate the antitumor activity of JNJ-372 in combination with third generation EGFR TKI Oxititinib and Lazetinib in H1975 and H1975-HGF human NSCLC tumors.
In both the H1975 and H1975-HGF xenograft models, the combination of JNJ-372 with either oxitinib or lacitinib showed enhanced antitumor efficacy (by increasing TGI and/or CR) compared to JNJ-372 and the corresponding TKI monotherapy treatment. Some transient weight loss was observed with either oxitinib or lacitinib treatment. The tolerability of the JNJ-372 plus TKI combination could not be assessed because JNJ-372 did not bind to mouse EGFR or c-MET.
Overall, data from both the H1975 and H1975-HGF models suggest that combination treatment with TKI plus JNJ-61186372 may provide superior antitumor activity compared to TKI monotherapy and may be considered for further study in a clinical setting.
Example 3: study 61186372EDI 1001: JNJ-61186372 (human bispecific EGFR and c-Met antibodies) in
Phase 1 first human open label dose escalation study in subjects with advanced non-small cell lung cancer
The study was a first human open label multicenter 2 part phase 1 dose escalation study to evaluate safety and PK, establish a recommended phase 2 dose (RP2D) and recommended phase 2 combination dose (RP2CD) regimen, and evaluate the primary efficacy of JNJ-61186372 as monotherapy and in combination with lazatinib in subjects >18 years with advanced NSCLC. The study goals and endpoints are shown in table 7.
Table 7.
Research and design summaryIn a state of being immersed in
The study was a first human open label multicenter 2 part phase 1 dose escalation study to evaluate safety and PK, establish a recommended phase 2 dose (RP2D) and recommended phase 2 combination dose (RP2CD) regimen, and evaluate the primary efficacy of JNJ-61186372 as monotherapy and in combination with lazatinib in subjects >18 years with advanced NSCLC.
Part 1 JNJ-61186372 monotherapy and combination dose escalation: the MTD (or maximum administered dose [ MAD if MTD is not defined) and RP2D regimens of JNJ-61186372 monotherapy, as well as RP2CD of JNJ-61186372 and the combination of lacitinib, will be determined using traditional 3+3 design in subjects with advanced NSCLC. The total number of subjects enrolled in each dose increment will depend on the dose level at which the MTD or MAD is reached and whether a widening of the dose cohort is indicated. To collect additional safety and PK data at dose, additional subjects may be enrolled into dose cohorts that have been proven safe by SET, with up to 20 subjects per dose cohort. Additional subjects may be enrolled into a country-specific part 1 dose cohort to define safety and PK (if required by their respective health authorities).
For JNJ-61186372 and lacitinib combination dose escalation, the RP2CD of JNJ-61186372 and lacitinib will be determined using a strategy studied from a previous antibody and TKI combination adapted in subjects with EGFR-mutated NSCLC, where the target dose of each agent in RP2CD is the same as RP2D of each agent as monotherapy. The total number of subjects enrolled into the combination dose escalation will depend on the number of dose levels tested and the dose cohort that reached RP2CD, and whether dose cohort escalation is required to determine RP2 CD. As in monotherapy dose escalation, additional country/region specific combination cohorts may be recruited to define safety and PK if their respective health authorities require it.
Part 2 JNJ-61186372 monotherapy and combination dose escalation: recruitment to cohorts a to D of part 2 was initiated after the treatment of JNJ-61186372 monotherapy RP2D regimen was identified in part 1. Up to about 120 subjects with advanced NSCLC who had previously diagnosed activating EGFR mutations, measurable disease, and disease progression after prior systemic anti-cancer treatment for their disease will be initially enrolled into the RP2D protocol identified during part 1. The purpose of cohorts a to D, part 2, was to better characterize the safety and PK of JNJ-61186372 and to explore clinical activity within a molecularly defined tumor subgroup. In cohorts C and D, SET may recommend that up to an additional 70 subjects be recruited each based on safety and efficacy data. In addition, SET may limit recruitment to subpopulations if clinical benefit is demonstrated in a molecularly defined population within a cohort.
Once RP2CD was identified for the combination of JNJ-61186372 and lacitinib in part 1 combination dose escalation, the safety, PK and preliminary efficacy data available will be communicated to relevant health authorities before part 2 combination cohort E expansion begins. Approximately 25 subjects with advanced EGFR mutations in NSCLC will be enrolled to further characterize the safety, tolerability, and primary efficacy of the combination. The subject will be an advanced disease that has not received treatment, or will progress after a previous line of treatment with erlotinib, gefitinib, afatinib or after a first or second line of treatment with a third generation EGFR TKI.
General study
For both part 1 and part 2, the study was divided into 3 cycles. During the screening period, subject eligibility will be determined 28 days prior to the first administration of the study drug. The treatment period will extend from the first dose of study drug to 30 days after the last dose of study drug. The follow-up period will begin at the end of the treatment period and continue with subject survival and follow-up of subsequent anti-cancer treatments until the end of the study. Subjects who permanently discontinued all study treatments for any reason other than radiologic disease progression or withdrawal of consent will continue to follow the schedule for disease assessment until radiologic progression is confirmed or a new anti-cancer treatment is initiated, whichever occurred first.
The study will be conducted in an outpatient setting. Subjects will be on pre-designated days to study center for study drug administration and study evaluation (e.g., adverse event monitoring, physical examination, concomitant drug use, laboratory evaluation, and collection of PK samples). If desired, more frequent field visits may be scheduled based on emerging security observations. For sections 1 and 2 of the study, safety monitoring will be the same and include assessment of adverse events and laboratory abnormalities, which will be ranked according to NCI CTCAE (version 4.03). Other safety measures include monitoring vital signs, Electrocardiogram (ECG), and physical examination. In parts 1 and 2 of the study, additional safety assessments will be performed on those subjects who received the combination of JNJ-61186372 and lacitinib, such as chest X-ray and LVEF assessments (echocardiogram or MUGA). The overall safety of JNJ-61186372 as monotherapy and in combination with laquinimod was evaluated by the safety evaluation group (SET).
Anti-tumor activity will be assessed by clinical response according to response assessment criteria in solid tumors (RECIST v1.1) (Eisenhauer et al, Eur J Cancer, vol 45, 2, p 228-. The investigator will evaluate the disease site by radiographic, physical examination and other procedures as needed, and all results will be recorded in a Case Report Form (CRF). In section 2, if new or modified RP2D or RP2CD has been selected by SET, intra-subject dose escalation may be allowed in subjects with non-progressive disease (see section 3.5).
Population of subjects
In this study, subjects with advanced NSCLC will be enrolled because these tumors may potentially respond to treatment with JNJ-61186372. In addition, all subjects will either progress in previous therapy or will not be eligible or will reject all other currently available approved treatment options and will require additional effective therapy.
In part 1 (dose escalation) of the study, subjects with advanced NSCLC will be enrolled. For only partial 1 combination dose escalation, subjects must be diagnosed with EGFR exon 19del or L858R activating mutations and either not treated with TKI for advanced disease, or progressed following first line treatment with first or second generation TKIs, or treated with third generation TKIs in first or second line settings and not eligible for enrollment in cohort C. The total number of subjects enrolled will depend on the dose level to reach the MTD or MAD and whether a dose cohort enlargement is indicated.
In part 2 (dose escalation) of this study, up to about 145 subjects with advanced NSCLC previously diagnosed as activating EGFR mutations and prior treatment of measurable disease will be initially enrolled into one of 5 different cohorts, as defined by:
queue A: subjects with prior treatment, EGFR-driven tumor progression
Queue B: subjects with previously treated, EGFR independent tumor progression
Queue C: subjects with documented alterations in EGFR or c-Met that mediate resistance to prior treatment with a third generation TKI (e.g., axitinib), or in the case of primary exon 20ins disease, prior treatment with a TKI with known activity in exon 20ins disease (e.g., bosutinib). This change must be confirmed by previous characterization, using local laboratory testing of equivalent tumor tissues prior to screening, until a centralized test is performed with properly validated ctDNA or NGS of tumor tissues. Once performed, all subjects will be assessed collectively for eligibility based on EGFR and c-Met characterization of tumor samples obtained during the screening period, or with equivalent tumor tissue obtained prior to the screening period but after treatment with the most recent systemic anti-cancer therapy.
Queue D: a subject previously diagnosed as having an activating EGFR exon 20 insertion mutation.
Queue E (combination of JNJ-61186372 and lacitinib): subjects with advanced EGFR-mutant NSCLC characterized by exon 19del or L858R sensitivity activating mutations.
In cohorts C and D, the SET may recommend each recruiting up to an additional 70 subjects based on the results of the provisional monitoring. Subjects whose EGFR mutation was not confirmed in the central laboratory could be replaced. Due to changes in standard of care and overlap of target populations, cohorts a and B will be further withheld after cohorts C and D are opened. Approximately 25 subjects will be enrolled in combination cohort E to further characterize the safety, tolerability, and primary efficacy of the combination of JNJ-61186372 and lacitinib at RP2 CD.
JNJ-61186372 and Lazetinib combination
PK profiles for monotherapy RP2D (1050/1400 mg for JNJ-61186372 and 240mg for lacitinib) and both JNJ-61186372 and lacitinib have been established by their respective FIH dose escalation studies, where LTD of either compound was not observed at doses higher than their respective RP2D (1400 mg for JNJ-61186372 and 320mg for lacitinib). The safety and initial efficacy of these two agents in the EGFR-mutated NSCLC population was based on the clinical experience of approximately 100 subjects in each study, including those enrolled into an expanded cohort at their corresponding RP 2D. In addition, both agents have shown clinical activity in the target population at an initial dose below their corresponding RP2D (700 mg for JNJ-61186372 and 240mg for lacitinib), making it possible to maintain therapeutic efficacy if the safety of the combination requires either agent at a dose below its monotherapy RP 2D.
Rationale for dose and regimen selection
The doses to be explored in the combination study (table 8) were selected based on the currently available clinical safety, tolerability, efficacy and clinical PK observed in the FIH study of the two drugs as described above, taking into account the potential overlapping toxicity profile and the predicted lack of expected DDI. The starting dose of JNJ-61186372 was set at a dose level one dose lower (700/1050mg) than its monotherapy RP2D, while the initial dose of lacitinib was set at its RP2D (240 mg). Table 8 describes the dose levels expected to be explored in the combination study.
Table 8.
Additional and/or intermediate dosage levels may be added during the course of the study. To better understand safety, PK or PD, queues may be added at any dose level below MTD.
Dose level-1 represents the dose-taper cohort or treatment dose for patients requiring dose reduction from the starting dose level.
Although the target dose of both JNJ-61186372 and lacitinib combinations was consistent with their RP2D as monotherapy (1050/1400 mg and 240mg, respectively), higher doses could be sought if the changing exposure data indicated that higher doses were required to achieve equivalent target PK exposures. If the changing exposure data indicates that a higher dose than level 2 is required to achieve the exposure observed at monotherapy RP2D of either agent (table 8), the rationale for combining safety, PK and efficacy data, and the next suggested dose cohort level, will be communicated to the relevant health authorities before the next cohort begins.
Combined administration schedule
In the current monotherapy dosing regimen, the lacitinib is administered as daily oral therapy, while JNJ-61186372 is administered intravenously weekly during cycle 1, and then every other week thereafter starting on cycle 2 day 1.
The first dose of JNJ-61186372 was administered as a split dose over 2 days (i.e., cycle 1 day [350mg ] and cycle 1 day 2 [ remaining dose ]) to mitigate the risk of infusion-related reactions, one of the more common toxicities associated with JNJ-61186372, occurring primarily at the first (C1D1) administration. In addition, only this first administration currently requires pre-steroid drug administration.
The administration of latatinib will begin before the start of JNJ-61186372, no more than 2 hours before the start of the first dose of JNJ-61186372 on day 1 of cycle 1, and continue daily thereafter in the same order.
The combination regimen will be administered in a 28 day cycle, starting with a first dose of JNJ-61186372 and lacitinib. The first 28-day cycle (cycle 1) of the combination regimen should include 4 weeks of JNJ-61186372 and 28 doses of laquinimod, while cycle 2 and all subsequent cycles will include 2 two weeks of JNJ-61186372 and 28 days of laquinimod.
Subject selection
Screening of eligible subjects will be performed within 28 days prior to the first administration of study medication.
Inclusion and exclusion criteria for enrollment of subjects in this study are described in the 2 subsections below. Subjects must meet all these criteria to be eligible for study participation, and the sponsor will not be awarded exceptions to these criteria. However, if there is a question of the inclusion or exclusion criteria below, the researcher should consult an appropriate sponsor representative before the subject is recruited.
Inclusion criteria
Each potential subject must meet all of the following criteria that will be entered into the study.
1. The subject must be a legal age of 18 years old or more and meet the jurisdiction in which the study is conducted.
2. The subject must have histologically or cytologically confirmed metastatic or unresectable NSCLC. The subject must progress after receiving prior treatment for metastatic disease, be ineligible or reject all other currently available treatment options. In the event that the subject rejects the currently available treatment regimen, this must be documented in the study record.
3. For only part 1 combination dose escalation: the subject must be diagnosed as having an EGFR exon 19del or L858R activating mutation, and
not treated with TKI for advanced disease, or
Progression after first-line treatment with first-generation (erlotinib or gefitinib) or second-generation (afatinib) TKIs or
Have been treated with a third generation TKI (e.g., ocitinib) in a first-line or second-line environment, and are not eligible for enrollment in cohort C.
For section 2 only: the subject must also have previously diagnosed diseases that activate EGFR mutations (including inhibitor sensitive major mutations such as exon 19 deletions and L858R [ cohorts C and E ], and commercially available TKI-resistant mutations such as exon 20 insertions [ cohorts C and D ]). Laboratory (or equivalent) tests certified by CLIA are required to document EGFR mutation eligibility.
4. For part 1: the subject must have an appreciable disease.
For section 2: the subject must have a measurable disease according to RECIST v 1.1.
5. For section 2:
queues A and B: after treatment with commercial EGFR inhibitors, the subject's disease must have recently progressed. Exceptions are: in subjects diagnosed with mutations associated with resistance from the de novo EGFR inhibitor (e.g., exon 20 insertion), only prior treatment with platinum-based combination chemotherapy is required.
And C, queue C: subjects must have documented that EGFR or c-Met alterations mediate resistance to prior treatment with third generation TKIs (e.g., axitinib), or in the case of primary exon 20ins disease, prior treatment with TKIs having known activity in exon 20ins disease (e.g., bosutinib), and these alterations must be confirmed by prior characterization using local laboratory testing of equivalent tumor tissues prior to screening until properly validated ctDNA or NGS of tumor tissues are obtained for centralized testing. Once performed, all subjects will be assessed collectively for eligibility based on EGFR and c-Met characterization of tumor samples obtained during the screening period, or with equivalent tumor tissue obtained prior to the screening period but after treatment with the most recent systemic anti-cancer therapy.
And a queue D: the subject must have been previously diagnosed with EGFR exon 20 insertion.
Queue E (combination of JNJ-61186372 and lacitinib): the subject must be diagnosed as having an EGFR exon 19del or L858R activating mutation, and
not treated with TKI for advanced disease, or
Progression after first-line treatment with first-generation (erlotinib or gefitinib) or second-generation (afatinib) TKIs or
Progression after treatment with a third generation TKI (e.g., ocitinib) in a first-line or second-line environment, and no eligibility to enroll in cohort C.
6. The subject must have an ECOG performance status of 0 or 1.
7. The subject must have the following organ and bone marrow functions:
hemoglobin is more than or equal to 10g/dL
ANC≥1.5×109/L
Platelet not less than 75X 109/L
AST and ALT ≤ 3 × ULN (upper limit of normal)
Total bilirubin is less than or equal to 1.5 × ULN; subjects with Gilbert syndrome may be enrolled if the bound bilirubin is within normal limits
Serum creatinine<1.5 × ULN or, if available, calculated or measured creatinine clearance>50mL/min/1.73m2
The subject must meet the above laboratory criteria but no history of red blood cell infusion, platelet infusion or G-CSF support within 7 days prior to the test date.
8. Prior to enrollment, women must be:
a. no fertility potential: early stage of first menstrual period; postmenopausal (>45 years of age, amenorrhea for at least 12 months); permanent infertility (e.g., bilateral salpingemphraxis [ which includes tubal ligation to local regulations ], hysterectomy, bilateral salpingectomy, bilateral ovariectomy); or otherwise be incapable of becoming pregnant,
b. having fertility potential and implementing a fertility control method, in compliance with local regulations regarding the use of contraceptive methods for subjects involved in clinical studies, as follows:
1) complete abstinence was performed (when this was consistent with the subject's preferred and usual lifestyle), which was defined as avoiding sexual intercourse during the entire study period (including up to 6 months after the last dose of study drug administration). Regular abstinence (calendar, symptomatic, post-ovulatory) is not considered an acceptable method of contraception.
Or
2) With a single partner receiving vasectomy
Or
3) 2 methods of contraception were performed, including a high-efficiency method (i.e., oral, injectable, or implantable hormonal methods of contraception; the placement of an intrauterine device [ IUD ] or intrauterine system [ IUS ], and a second method (e.g., condom containing spermicidal foam/gel/membrane/cream/suppository or occlusive cap containing spermicidal foam/gel/membrane/cream/suppository [ diaphragm or cervical/domed cap ])
Subjects must agree to continue contraception throughout the study and continue for 6 months after the last dose of study medication.
Note that: if fertility potential changes after the study is initiated (e.g., a woman with inactive anisotropic behavior becomes active, and a woman in the early trimester experiences an initial tide), the woman must begin an efficient method of birth control, as described above.
9. Women of child bearing age must have negative serum (beta-human chorionic gonadotropin [ beta-hCG ]) at the time of screening.
10. Women must agree that eggs (ova, oocytes) must not be donated for reproductive-assisted purposes during the study and within 6 months after receiving the last dose of study agent.
11. Sexually active men with women of reproductive age must agree to use condoms containing spermicidal foam/gel/film/cream/suppository, and their partners must also implement highly effective methods of contraception (i.e. methods of contraception determined using oral, injectable or implantable hormones; placement of intrauterine devices [ IUDs ] or intrauterine systems [ IUSs ]).
If the subject is resected of vas deferens, he must still use a condom (with or without spermicide), but not require his female partner to use a contraceptive.
Subjects also had to donate sperm during the study and within 6 months after receiving the last dose of study drug.
12. The subject must be willing and able to comply with the contraband and restrictions prescribed in the protocol.
13. Each subject must sign an Informed Consent Form (ICF) indicating that he or she knows the purpose and procedure of the study, is willing to participate in the study, including the requirement to provide information during the follow-up period.
14. Subjects eligible for part 2 must agree to perform a pre-treatment tumor biopsy (or submit equivalent archival material) and a tumor biopsy at the time of disease progression, as well as a corresponding blood sample for ctDNA analysis. For subjects in cohort C, equivalent pre-treatment tumor tissue must be collected after treatment with the most recent prior systemic anti-cancer therapy.
Exclusion criteria
Any potential subjects meeting any of the following criteria will be excluded from participation in the study.
1. The subject suffers from uncontrolled complications including, but not limited to, poorly controlled hypertension or diabetes, persistent or active infections or psychiatric/social conditions that will limit compliance with research requirements.
2. Prior to the first administration of JNJ-61186372, the subject had received chemotherapy, targeted cancer therapy, immunotherapy, or treatment with a investigational anti-cancer agent for 2 weeks or 4 half-lives (whichever is longer). For agents with long half-lives, the maximum required time from the last dose is 4 weeks. The toxicity of the prior anti-cancer therapy should have resolved to baseline levels or grade 1 or less (except for alopecia [ any grade ], < grade 2 peripheral neuropathy and < grade 2 hypothyroidism, which are stable in hormone replacement).
Combination dose escalation for part 1: any previous treatment with systemic anti-cancer immunotherapy, including but not limited to anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents.
For section 2 only:
queues A and B: previous treatments for metastatic disease with chemotherapy were not allowed unless the tumor mutation carried de novo resistance to EGFR TKI (e.g., exon 20 insertion).
And C, queue C: metastatic disease (not including maintenance therapy) has previously been treated with more than 2-line cytotoxic chemotherapy.
And a queue D: previous treatment with EGFR TKIs active on EGFR exon 20 insertion (such as bosutinib).
Queue E (combination of JNJ-61186372 and lacitinib): any previous treatment with systemic anti-cancer immunotherapy, including but not limited to anti-PD-1, anti-PD-L1, and anti-CTLA-4 agents.
Note that: local radiotherapy for palliative purposes must be completed at least 7 days prior to treatment with JNJ-61186372.
3. A subject having an untreated brain metastasis. Patients who were clinically stable and asymptomatic for at least 2 weeks prior to study treatment, and who stopped or received low dose corticosteroid therapy (≦ 10mg prednisone or equivalent) for at least 2 weeks who had undergone treatment metastasis are suitable. Exceptions are: subjects with asymptomatic untreated brain metastases (each less than 1cm in diameter) may be eligible to receive JNJ-61186372 and lacitinib combination therapy in part 1 combination up-dosing or part 2 combination extended cohort E.
4. Subjects had a history of malignancy other than the disease studied within 3 years prior to screening (with the exception of squamous cell carcinoma of the skin and basal cell carcinoma, carcinoma of the cervix in situ, or malignancy considered curative by the investigator's opinion and in line with the medical inspector of the sponsor or having minimal risk of recurrence within one year of screening).
5. The subject has a history of clinically significant cardiovascular disease, including but not limited to:
deep vein thrombosis or pulmonary embolism diagnosed within 1 month or within 6 months prior to the first dose of study drug: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft or any acute coronary syndrome. Clinically insignificant thrombosis, such as non-obstructive catheter related clots, is not excluded.
Prolonged QTcF interval >480 milliseconds or clinically significant arrhythmias or electrophysiological diseases (e.g., placement of an implantable cardioverter defibrillator or atrial fibrillation of cardiac rhythm runaway).
Uncontrolled (persistent) hypertension: systolic blood pressure >180 mmHg; diastolic pressure >100mmHg
Congestive heart failure was defined as New York Heart Association (NYHA) grades III-IV (appendix 2) or hospitalization with CHF within 6 months on day 1 of the study (any NYHA grade)
Pericarditis/clinically significant pericardial effusion
Myocarditis
Baseline LVEF ejection scores were below the lower normal limit (LLN), as assessed by screening echocardiography or multi-gated acquisition (MUGA) scans.
6. The subject has leptomeningeal disease.
7. Subjects are known to be allergic, hypersensitive or intolerant to JNJ-61186372 or its excipients.
8. Subjects had received study medication (including study vaccine, but not including anti-cancer therapy [ see exclusion criteria 2]) or used invasive study medical devices within 6 weeks prior to the planned first dose of study medication.
9. Subjects were pregnant or lactating women, or women scheduled to become pregnant during enrollment into the study or within 6 months after the last dose of study medication.
10. Subjects were males who were scheduled to give birth to children during enrollment into the study or within 6 months after the last dose of study medication.
11. The subject has or will have any of the following:
a. invasive surgical procedures to access the body cavity within 4 weeks prior to day 1 of cycle 1 or without complete recovery. Thoracentesis (if desired) and percutaneous biopsy of baseline tumor tissue samples can be performed less than 4 weeks prior to day 1 of cycle 1, so long as the subject has sufficiently recovered from surgery prior to the first dose of study drug, as clinically judged by the investigator;
b. significant traumatic injury within 3 weeks before the start of day 1 of cycle 1 (all wounds must heal completely before day 1);
c. any medical condition requiring complete wound healing capacity and would be expected to compromise the subject's safety if the wound healing capacity is severely reduced during study medication administration;
d. major surgery is expected at the time of administration of the study dose or within 6 months after the last dose of study drug.
12. Subjects with any condition that the investigator deems to be ineligible for optimal benefit (e.g., impaired health) by the subject or to potentially prevent, limit, or confound the assessment specified by the protocol for participation in the present study.
13. Any survey site personnel directly related to the study.
14. The subject has a history of hepatitis b surface antigen (HBsAg) or hepatitis c antibody (anti-HCV) positivity or other clinically active infectious liver disease, or is tested positive for HBsAg or anti-HCV at the time of screening.
Note that: subjects with a history of hepatitis c, who have completed antiviral therapy, and who subsequently demonstrate the absence of serum hcv rna at screening are allowed to participate.
15. The subject has a history of being positive for Human Immunodeficiency Virus (HIV) antibodies, or is tested positive for HIV at the time of screening.
16. The subject has any serious underlying medical or psychiatric disorder (e.g., alcohol or drug abuse), dementia or altered mental state or any problem that would impair the subject's ability to receive or tolerate treatment with the study site program, understand the ability to agree with an informed consent or the researcher deems it to be an impediment to the subject's participation in the study or confound the results of the study.
17. A history of Interstitial Lung Disease (ILD), including drug-induced ILD or radiation pneumonitis that require treatment with prolonged steroids or other immunosuppressive agents over the past 2 years.
Toxicity monitoring and dose modification
Toxicity monitoring of subjects receiving combination JNJ-61186372 and latticine therapy will be the same as subjects receiving monotherapy JNJ-61186372, with additional assessments of 1) chest X-rays at baseline and at the end of cycle 1, and 2) LVEF again at baseline and after 6 weeks.
In cases where a reduced dose is deemed necessary, it should be done as outlined in table 9.
Table 9.
Security assessment
The safety of JNJ-61186372 as monotherapy or in combination with laquinimod would be assessed by physical examination, Eastern Cooperative Oncology Group (ECOG) standards for physical performance status, laboratory tests, vital signs, electrocardiograms, monitoring of adverse events, and concomitant drug use. Additional chest X-ray and LVEF assessments will be performed on those subjects receiving JNJ-61186372 and lacitinib combination therapy. Adverse events that occurred between the signing of informed consent and 30 days after the last dose of study medication were recorded. The severity of adverse events will be assessed using the national cancer institute general terminology standard for adverse events (NCI CTCAE) version 4.03. Survival follow-up will be performed on all subjects until the end of the study. Subjects who discontinue study treatment in addition to disease progression or withdrawal of consent due to follow-up will continue to be assessed for disease until disease progression is documented by imaging or the subject begins a new cancer treatment. Data will also be collected on the anti-cancer therapies administered after the study.
Pharmacokinetic evaluation
Blood samples will be collected from all subjects for measurement of serum JNJ-61186372 and plasma lacitinib concentrations for PK analysis. The PK profile for JNJ-61186372 will be based on serum concentration data obtained from time points before and after the first dose administration and the fifth dose administration. Blood samples of sparse PKs will also be obtained after all other doses have been administered. Pharmacokinetic parameters of the individual will be estimated and descriptive statistics for each dose level will be calculated.
Evaluation of immunogenicity
Blood samples will be collected and analyzed for antibodies against JNJ-61186372 using a validated immunoassay. Serum samples were screened for antibodies binding to JNJ-61186372 and serum titers were determined from positive samples. All samples collected for immune response analysis will be evaluated for concentration of JNJ-61186372 in serum to ensure proper interpretation of immune response data. Other immunogenicity assays may be performed to further characterize any generated immune response. The incidence of antibodies against JNJ-61186372 will be summarized for all subjects receiving at least one study drug administration.
Pharmacodynamic and biomarker evaluation
Blood samples collected at screening and during the study will be analyzed for circulating tumor dna (ctdna) to evaluate molecular changes at baseline for cohort assignment, to follow response to treatment, and to understand resistance mechanisms to JNJ-61186372. In addition, blood samples will be collected for PD assessment. Tumor tissue collected after screening, treatment and after progression (within about 30 days of disease progression documented) can be assessed for biomarkers associated with cancer. Analysis of these tumor tissue samples will help to understand the molecular biology of the tumor, the efficacy observed with JNJ-61186372, and the mechanisms of resistance achieved to JNJ-61186372. These samples can also be used to confirm ctDNA test results.
Efficacy analysis
The primary efficacy analysis for ORR with confirmed optimal overall response will be performed approximately 16 weeks after the last subject received the first infusion or at the end of the study, whichever occurred first. The data cutoff will be communicated to the research center. All treatment analysis sets will be used for primary efficacy analysis. When all subjects were discontinued from study medication, any additional data would be reported to the appropriate health authorities in the CSR appendix.
With respect to cohorts a and B, all efficacy analyses will be considered descriptive due to the limited number of subjects and the limited nature of the study.
For queue C and queue D, a temporary monitoring will be performed.
The Overall Response Rate (ORR) is defined as the proportion of subjects in all treatment analysis sets (or response evaluable analysis sets for interim monitoring) in each extended cohort (part 2) defined by RECIST v1.1 that achieve a full response (CR) or Partial Response (PR). The observed ORR, along with its two-sided 95% confidence intervals, will be presented for each cohort and dose level as appropriate.
The following bayesian method will be used as the sensitivity analysis. The first criterion ensures that ORR should be better than the clinically least effective threshold (50%), and the second criterion is to ensure control of type I error of 0.2.
P (true ORR is equal to or more than 50% | observed ORR, n is 100) ≥ 0.5; a posterior probability of at least 0.5 of a true ORR of not less than 50%
P (true ORR > 30% | observed ORR, n ═ 100) ≥ 0.8; a posterior probability of at least 0.8 for a true ORR > 30%
Using bayesian efficacy, the second criterion was met at the end of each cohort, and preliminary evidence of antitumor activity could be declared if the number of responses confirmed in each cohort C and cohort D was at least 34 out of 100 subjects.
Clinical Benefit Rate (CBR) is defined as the percentage of subjects defined by RECIST v1.1 who achieved a complete or partial response or a persistent stable disease (duration of at least 6 months). The observed ORR and CBR together with their two-sided 95% confidence intervals will be presented for each cohort and dose level as appropriate.
Event endpoint times including Progression Free Survival (PFS), duration of response (DAR), time to failure of treatment (TTF), and Overall Survival (OS) will be estimated using the Kaplan-Meier method. DOR will be calculated as the time from the initial response of CR or PR to Progressive Disease (PD) or death due to underlying disease, whichever occurs first, only for subjects who achieve CR or PR. PFS is defined as the time from the first infusion of study drug to PD or death for any reason. TTF is defined as the time from the first infusion of the study drug to discontinuation of treatment for any reason (including disease progression, treatment toxicity, death) and will be used to capture the clinical benefit of the patient to continue treatment beyond that defined by RECIST v 1.1. OS was defined as the time from the first infusion of study drug to death for any reason. For the endpoint time endpoint, the Kaplan-Meier estimate will be presented graphically, and the median time of the event, along with the corresponding 95% Ci, will be obtained from the Kaplan-Meier estimate.
Examples4. Clinical results
The combination of latatinib and JNJ-61186372 was explored in a phase 1 study in a combination dose escalation cohort (section 1, see example 3). After no Dose Limiting Toxicity (DLT) was observed in the dose cohort evaluated, a 240mg dose of laquinimod (oral; once daily) and 1050mg (subject <80kg)/1400mg (subject >80kg) of JNJ61186372 (cycle 1 weekly IV; cycle 2 twice weekly) were identified as safe and tolerable. Open part 2 expanded cohort (cohort E, see example 3) to further characterize the safety, tolerability and primary efficacy of this combination in 40 subjects with EGFR-mutated NSCLC who progressed in ocitinib. At the same time, an additional part 1 cohort of untreated NSCLCs having EGFR-mutations was evaluated to confirm the dose in this population, and subsequently expanded to 20 subjects to further characterize the safety and tolerability of the combination in subjects not previously exposed to anti-EGFR therapy. A total of 36 subjects were treated with the combination of lacitinib JNJ-61186372 in phase 1 study (34 subjects in part 1 and 2 subjects in the subject expanded cohort (cohort E)). The most common Adverse Events (AEs) were consistent with the toxicities associated with EGFR inhibition in subjects treated with this combination and included skin rash, acne-like dermatitis, paronychia, stomatitis, pruritus and diarrhea, and were similar to AEs observed with other approved EGFR TKIs. In the initial 26 subjects combined dose escalation, evidence of clinical activity was observed in the majority of subjects, defined as tumor response or shrinkage as assessed by the investigators of the study, including subjects who did not meet demand, subjects who developed EGFR T790M negative disease following TKI treatment generation 1, and subjects who progressed following TKI treatment generation 3. These results show the activity of this combination in subjects who currently have no approved targeted therapy.
Detailed description of the preferred embodiments
The following clauses describe specific embodiments of the present invention.
1) A pharmaceutical combination comprising a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for use in the treatment of EGFR-or c-Met expressing cancers.
2) The pharmaceutical combination for use according to embodiment 1, wherein the bispecific anti-EGFR/c-Met antibody comprises: a first domain that binds EGFR comprising heavy chain complementarity determining region 1 of SEQ ID NO:1(HCDR 1), HCDR2 of SEQ ID NO:2, HCDR3 of SEQ ID NO:3, light chain complementarity determining region 1 of SEQ ID NO:4(LCDR 1), LCDR2 of SEQ ID NO:5, and LCDR3 of SEQ ID NO: 6; and a second domain that binds c-Met, said second domain comprising HCDR1 of SEQ ID NO. 7, HCDR2 of SEQ ID NO. 8, HCDR3 of SEQ ID NO. 9, LCDR1 of SEQ ID NO. 10, LCDR2 of SEQ ID NO. 11, and LCDR3 of SEQ ID NO. 12.
3) The pharmaceutical combination for use according to embodiment 2, wherein said first domain that binds EGFR comprises the heavy chain variable region (VH) of SEQ ID NO:13 and the light chain variable region (VL) of SEQ ID NO:14 and said second domain that binds c-Met comprises the VH of SEQ ID NO:15 and the VL of SEQ ID NO: 16.
4) The pharmaceutical combination for use according to any one of embodiments 1 to 3, wherein the bispecific anti-EGFR/c-Met antibody is of IgG1 isotype.
5) The pharmaceutical combination for use according to any one of embodiments 1 to4, wherein the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain of SEQ ID NO:17 (HC1), a first light chain of SEQ ID NO:18 (LC1), a second heavy chain of SEQ ID NO:19 (HC2) and a second light chain of SEQ ID NO:20 (LC 2).
6) The pharmaceutical combination for use according to any one of embodiments 1 to 5, wherein the bispecific anti-EGFR/c-Met antibody has a double branched glycan structure with a fucose content of between about 1% to about 15%.
7) The pharmaceutical combination for use according to any one of embodiments 1 to 6, wherein the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is represented by a compound of formula (II)
8) The pharmaceutical combination for use according to any one of embodiments 1 to 6, wherein the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is N- (5- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-ylamino) -4-methoxy-2-morpholinophenyl) acrylamide.
9) The pharmaceutical combination for use according to any one of embodiments 1 to 8, wherein the EGFR-or c-Met-expressing cancer is associated with wild-type EGFR, EGFR mutation, EGFR gene amplification, elevated levels of circulating HGF, wild-type c-Met, c-Met mutation, c-Met gene amplification or mutant KRAS.
10) The pharmaceutical combination for use according to embodiment 9, wherein the EGFR mutation is E709K, L718Q, L718V, G719A, G719X, G724X, G724S, I744T, E746K, L747S, E749Q, a750P, a755V, V765M, C775Y, T790M, L792H, L792V, G796S, G796 79 796R, G755 796C, C797S, T854I, L858P, L858R, L861X, del E746-a750, del E746 — T751 inski 751, del E746 — T751, del E746 — instil 751, instel 74746, instel 74417, instel 7441 41 41752, instel 74e 7441 751, instel 7441 41 751, instel 7490, instel 751, instel 74e 417, instel 7490, instel 751, instel 74e 746L 751, instel 747, instel 7490, instel 751, instel 747, instel 7490, instel 751, instel 3, InsTP753insS、delL747-T751、M766_A767InsA、S768_V769InsSVA、P772_H773InsNS、D761_E762InsX1-7、A763_Y764InsX1-7、Y764_Y765 InsX1-7、M766_A767InsX1-7、A767_V768 InsX1-7、S768_V769 InsX1-7、V769_D770 InsX1-7、D770_N771 InsX1-7、N771_P772 InsX1-7、P772_H773 InsX1-7、H773_V774 InsX1-7、V774_C775 InsX1-7One or more deletions of EGFR exon 20, or one or more insertions of EGFR exon 20, one or more deletions of EGRF exon 19, or one or more insertions of EGFR exon 19, or any combination thereof, wherein X is any amino acid.
11) The pharmaceutical combination for use according to embodiment 10, wherein the EGFR mutation is the one or more deletions of exon 19 or L858R or any combination thereof.
12) The pharmaceutical combination for use according to embodiment 9, wherein the c-Met mutation is c-
The Met exon 14 skipping mutation.
13) The pharmaceutical combination for use according to embodiment 9, wherein the mutant KRAS
With a G12V, G12C, or G12A substitution.
14) The pharmaceutical combination for use according to any one of embodiments 1 to 13, wherein the subject has been diagnosed with the EGFR mutation prior to administration of the combination therapy.
15) The pharmaceutical combination for use according to any one of embodiments 1 to 14, wherein the subject has a newly diagnosed cancer expressing EGFR or c-Met.
16) The pharmaceutical combination for use according to any one of embodiments 1 to 15, wherein the subject has not received treatment with an EGFR Tyrosine Kinase Inhibitor (TKI).
17) The pharmaceutical combination for use according to any one of embodiments 1 to 15, wherein the subject is resistant to treatment with a first generation EGFR TKI or will relapse.
18) The pharmaceutical combination for use according to embodiment 17, wherein the first generation EGFR TKI is erlotinib or gefitinib.
19) The pharmaceutical combination for use according to any one of embodiments 1 to 14, wherein the subject is resistant to treatment with a second generation EGFR TKI or will relapse.
20) The pharmaceutical combination for use according to embodiment 19, wherein the second generation EGFR TKI is afatinib.
21) The pharmaceutical combination for use according to any one of embodiments 1 to 14, wherein the subject is resistant to treatment with a third generation EGFR TKI or will relapse.
22) The pharmaceutical combination for use according to embodiment 21, wherein the third generation EGFR TKI is ocitinib.
23) The pharmaceutical combination for use according to any one of embodiments 1 to 22, wherein the EGFR-or c-Met expressing cancer is non-small cell lung cancer (NSCLC), epithelial cell cancer, breast cancer, ovarian cancer, lung cancer, squamous cell lung cancer, lung adenocarcinoma, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, head and neck cancer, pharynx cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, stomach cancer, thymus cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary Papillary Renal Cell Carcinoma (PRCC).
24) The pharmaceutical combination for use according to embodiment 23, wherein the cancer is NSCLC.
25) The pharmaceutical combination for use according to any one of embodiments 1 to 23, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 200mg and about 2000 mg.
26) The pharmaceutical combination for use according to embodiment 25, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 350mg and about 1400 mg.
27) The pharmaceutical combination for use according to embodiment 26, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 350mg, about 700mg, about 1050mg or about 1400 mg.
28) The pharmaceutical combination for use according to any one of embodiments 1 to 27, wherein the bispecific anti-EGFR/c-Met antibody is administered once weekly.
29) The pharmaceutical combination for use according to any one of embodiments 1 to 27, wherein the bispecific anti-EGFR/c-Met antibody is administered biweekly.
30) The pharmaceutical combination for use according to any one of embodiments 1 to 29, wherein the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered in a dose of between about 20mg and about 320 mg.
31) The pharmaceutical combination for use according to embodiment 30, wherein the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered at a dose of about 160mg or about 240 mg.
32) The pharmaceutical combination for use according to any one of embodiments 1 to 31, wherein the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered once daily.
33) The pharmaceutical combination for use according to any one of embodiments 1 to 24, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 350mg and about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered at a dose of between about 160mg and about 240mg daily.
34) The pharmaceutical combination for use according to embodiment 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered at a dose of about 160mg daily.
35) The pharmaceutical combination for use according to embodiment 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered at a dose of about 160mg daily.
36) The pharmaceutical combination for use according to embodiment 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered at a dose of about 160mg daily.
37) The pharmaceutical combination for use according to embodiment 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered at a dose of about 240mg daily.
38) The pharmaceutical combination for use according to embodiment 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered at a dose of about 240mg daily.
39) The pharmaceutical combination for use according to embodiment 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is administered at a dose of about 240mg daily.
40) The pharmaceutical combination for use according to any one of embodiments 1 to 39, wherein the bispecific anti-EGFR/c-Met antibody is administered after administration of the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
41) The pharmaceutical combination for use according to embodiment 40, wherein the bispecific anti-EGFR/c-Met antibody is administered one or more times after administration of the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
42) The pharmaceutical combination for use according to embodiment 41, wherein the bispecific anti-EGFR/c-Met antibody is administered two, three, four, five, six, seven, eight, nine, ten or more times after administration of the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
43) The pharmaceutical combination for use according to any one of embodiments 1 to 42, wherein the subject is homozygous for phenylalanine at position 158 of CD16 or heterozygous for valine and phenylalanine at position 158 of CD 16.
44) The pharmaceutical combination for use according to any one of embodiments 1 to 43, further comprising administering a third anti-cancer therapy.
45) The pharmaceutical combination for use according to embodiment 44, wherein the third anti-cancer therapy is chemotherapy, a targeted anti-cancer therapy or a kinase inhibitor.
46) A pharmaceutical combination of a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
47) The pharmaceutical combination of embodiment 46, wherein the isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody is a bispecific anti-EGFR/c-Met antibody comprising: a first domain that binds EGFR comprising HCDR1 of SEQ ID NO. 1, HCDR2 of SEQ ID NO. 2, HCDR3 of SEQ ID NO. 3, LCDR1 of SEQ ID NO. 4, LCDR2 of SEQ ID NO. 5, and LCDR3 of SEQ ID NO. 6; and a second domain that binds c-Met, said second domain comprising HCDR1 of SEQ ID NO. 7, HCDR2 of SEQ ID NO. 8, HCDR3 of SEQ ID NO. 9, LCDR1 of SEQ ID NO. 10, LCDR2 of SEQ ID NO. 11, and LCDR3 of SEQ ID NO. 12.
48) The pharmaceutical combination according to embodiment 46 or 47, wherein the compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is Lazetinib.
49) The pharmaceutical combination according to embodiment 46 or 47, wherein the compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is Lazetinib mesylate.
50) The pharmaceutical combination according to any one of embodiments 46 to 49, comprising between about 350mg and about 1400mg of the bispecific EGFR/c-Met antibody and between about 160mg and about 240mg of the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
51) The pharmaceutical combination according to embodiment 47, wherein the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is N- (5- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-ylamino) -4-methoxy-2-morpholinophenyl) acrylamide.
52) The pharmaceutical combination according to any one of embodiments 46 to 51, wherein the pharmaceutical combination is a non-fixed combination.
53) The pharmaceutical combination according to any one of embodiments 46 to 52, wherein the first domain of the bispecific anti-EGFR/c-Met antibody that binds EGFR comprises the VH of SEQ ID NO 13 and the VL of SEQ ID NO 14; and said second domain that binds c-Met comprises the VH of SEQ ID NO. 15 and the VL of SEQ ID NO. 16.
54) The pharmaceutical combination according to any one of embodiments 46 to 53, wherein the bispecific anti-EGFR/c-Met antibody comprises HC1 of SEQ ID NO 17, LC1 of SEQ ID NO 18, HC2 of SEQ ID NO 19 and LC2 of SEQ ID NO 20.
55) An isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody for use in combination with a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, for use in the treatment of an EGFR or c-Met expressing cancer, in particular for use in the treatment of an EGFR or c-Met expressing cancer in a subject.
56) The isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody for use according to embodiment 55, wherein the isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody is a bispecific anti-EGFR/c-Met antibody comprising: a first domain that binds EGFR comprising HCDR1 of SEQ ID NO. 1, HCDR2 of SEQ ID NO. 2, HCDR3 of SEQ ID NO. 3, LCDR1 of SEQ ID NO. 4, LCDR2 of SEQ ID NO. 5, and LCDR3 of SEQ ID NO. 6; and a second domain that binds c-Met, said second domain comprising HCDR1 of SEQ ID NO. 7, HCDR2 of SEQ ID NO. 8, HCDR3 of SEQ ID NO. 9, LCDR1 of SEQ ID NO. 10, LCDR2 of SEQ ID NO. 11, and LCDR3 of SEQ ID NO. 12.
57) The isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody for use according to embodiment 55 or 56, wherein the compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is Lazetinib.
58) The isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody for use according to embodiment 55 or 56, wherein the compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is Lazetinib mesylate.
59) The isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody for use according to any one of embodiments 55 to 58, comprising between about 350mg and about 1400mg of the bispecific EGFR/c-Met antibody and between about 160mg and about 240mg of the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
60) The isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody for use according to any one of embodiments 55 to 59, wherein the first domain of the bispecific anti-EGFR/c-Met antibody that binds EGFR comprises the VH of SEQ ID NO 13 and the VL of SEQ ID NO 14; and said second domain that binds c-Met comprises the VH of SEQ ID NO. 15 and the VL of SEQ ID NO. 16.
61) The isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody for use according to any one of embodiments 55 to 60, wherein the bispecific anti-EGFR/c-Met antibody comprises HC1 of SEQ ID NO:17, LC1 of SEQ ID NO:18, HC2 of SEQ ID NO:19 and LC2 of SEQ ID NO: 20.
Claims (54)
1. A method of treating a subject having an EGFR-or c-Met-expressing cancer comprising administering to the subject a combination therapy, wherein the combination therapy comprises a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the bispecific anti-EGFR/c-Met antibody comprises: a first domain that binds EGFR comprising heavy chain complementarity determining region 1 of SEQ ID NO:1(HCDR 1), HCDR2 of SEQ ID NO:2, HCDR3 of SEQ ID NO:3, light chain complementarity determining region 1 of SEQ ID NO:4(LCDR 1), LCDR2 of SEQ ID NO:5, and LCDR3 of SEQ ID NO: 6; and a second domain that binds c-Met, said second domain comprising HCDR1 of SEQ ID NO. 7, HCDR2 of SEQ ID NO. 8, HCDR3 of SEQ ID NO. 9, LCDR1 of SEQ ID NO. 10, LCDR2 of SEQ ID NO. 11, and LCDR3 of SEQ ID NO. 12.
3. The method of claim 2, wherein the first domain that binds EGFR comprises the heavy chain variable region (VH) of SEQ ID NO:13 and the light chain variable region (VL) of SEQ ID NO:14, and the second domain that binds c-Met comprises the VH of SEQ ID NO:15 and the VL of SEQ ID NO: 16.
4. The method of any one of claims 1 to4, wherein the bispecific anti-EGFR/c-Met antibody is of the IgG1 isotype.
5. The method of any one of claims 1 to 5, wherein the bispecific anti-EGFR/c-Met antibody comprises a first heavy chain of SEQ ID NO 17 (HC1), a first light chain of SEQ ID NO 18 (LC1), a second heavy chain of SEQ ID NO 19 (HC2), and a second light chain of SEQ ID NO 20 (LC 2).
6. The method of any one of claims 1 to 5, wherein the bispecific anti-EGFR/c-Met antibody has a double-branched glycan structure with a fucose content of between about 1% to about 15%.
8. The method according to any one of claims 1 to 6, wherein the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is N- (5- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-ylamino) -4-methoxy-2-morpholinophenyl) acrylamide.
9. The method of any one of claims 1 to 8, wherein the EGFR-or c-Met-expressing cancer is associated with wild-type EGFR, EGFR mutation, EGFR gene amplification, elevated levels of circulating HGF, wild-type c-Met, c-Met mutation, c-Met gene amplification, or mutant KRAS.
10. The method according to claim 9, wherein the EGFR mutation is E709K, L718Q, L718V, G719A, G719X, G724X, G724S, I744T, E746K, L747S, E749Q, a750P, a755V, V765M, C775Y, T790M, L792H, L792V, G796S, C797S, T854S, L858S, L861S, del E746-a750, del E746_ T InsKV, del E746_ a750InsHS, del E746_ T instt, del E _ T instil, instil 746_ S752, ip 746_ P752, ms _ E, fpe _ E751, flt 751, instel 74dele _ E746_ E746_ E, instil _ E751, instil 746_ E746, instil 746_ E _nsPT、delL747_P753InsNS、delL747_S752InsPI、delL747_S752、delL747_P753InsS、delL747_K754、dekL747_T751InsS、dekL747_T751、delL747_P753InsS、delA750_I759InsPT、delT751_I759InsT、delS752_I759、delT751_I759InsN、delT751_D761InsNLY、delS752_I759、delR748-P753、delL747-P753insS、delL747-T751、M766_A767InsA、S768_V769InsSVA、P772_H773InsNS、D761_E762InsX1-7、A763_Y764InsX1-7、Y764_Y765 InsX1-7、M766_A767InsX1-7、A767_V768 InsX1-7、S768_V769 InsX1-7、V769_D770 InsX1-7、D770_N771 InsX1-7、N771_P772 InsX1-7、P772_H773 InsX1-7、H773_V774 InsX1-7、V774_C775 InsX1-7One or more deletions of EGFR exon 20, or one or more insertions of EGFR exon 20, one or more deletions of EGRF exon 19, or one or more insertions of EGFR exon 19, or any combination thereof, wherein X is any amino acid.
11. The method of claim 10, wherein the EGFR mutation is the one or more deletions of exon 19 or L858R or any combination thereof.
12. The method of claim 9, wherein the c-Met mutation is a c-Met exon 14 skip mutation.
13. The method of claim 9, wherein the mutant KRAS has a G12V, G12C, or G12A substitution.
14. The method of any one of claims 1 to 13, wherein the subject has been diagnosed with the EGFR mutation prior to administration of the combination therapy.
15. The method of any one of claims 1 to 14, wherein the subject has a newly diagnosed cancer that expresses EGFR or c-Met.
16. The method of any one of claims 1 to 15, wherein the subject has not received treatment with an EGFR Tyrosine Kinase Inhibitor (TKI).
17. The method of any one of claims 1 to 15, wherein the subject is resistant to treatment with a first generation EGFR TKI or will relapse.
18. The method of claim 17, wherein the first generation EGFR TKI is erlotinib or gefitinib.
19. The method of any one of claims 1 to 14, wherein the subject is resistant to treatment with a second generation EGFR TKI or will relapse.
20. The method of claim 19, wherein the second generation EGFR TKI is afatinib.
21. The method of any one of claims 1 to 14, wherein the subject is resistant to or will relapse with a third generation EGFR TKI treatment.
22. The method of claim 21, wherein the third generation EGFR TKI is ocitinib.
23. The method of any one of claims 1 to 22, wherein the EGFR-or c-Met-expressing cancer is non-small cell lung cancer (NSCLC), epithelial cell cancer, breast cancer, ovarian cancer, lung cancer, squamous cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, colorectal cancer, anal cancer, prostate cancer, kidney cancer, bladder cancer, cancer of the head and neck, pharynx cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, gastric cancer, thymus cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary Papillary Renal Cell Carcinoma (PRCC).
24. The method of claim 23, wherein the cancer is the NSCLC.
25. The method of any one of claims 1 to 23, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 200mg and about 2000 mg.
26. The method of claim 25, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 350mg and about 1400 mg.
27. The method of claim 26, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 350mg, about 700mg, about 1050mg, or about 1400 mg.
28. The method of any one of claims 1 to 27, wherein the bispecific anti-EGFR/c-Met antibody is administered once weekly.
29. The method of any one of claims 1 to 27, wherein the bispecific anti-EGFR/c-Met antibody is administered biweekly.
30. The method of any one of claims 1-29, wherein the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 20mg and about 320 mg.
31. The method of claim 30, wherein the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 160mg or about 240 mg.
32. The method of any one of claims 1 to 31, wherein the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered once daily.
33. The method of any one of claims 1 to 24, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of between about 350mg and about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of between about 160mg and about 240mg daily.
34. The method of claim 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 160mg daily.
35. The method of claim 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 160mg daily.
36. The method of claim 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 160mg daily.
37. The method of claim 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 700mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 240mg daily.
38. The method of claim 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1050mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 240mg daily.
39. The method of claim 33, wherein the bispecific anti-EGFR/c-Met antibody is administered at a dose of about 1400mg weekly for four weeks and once every two weeks thereafter, and the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof is administered at a dose of about 240mg daily.
40. The method of any one of claims 1 to 39, wherein the bispecific anti-EGFR/c-Met antibody is administered after administration of the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
41. The method of claim 40, wherein the bispecific anti-EGFR/c-Met antibody is administered one or more times after administration of the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
42. The method of claim 41, wherein the bispecific anti-EGFR/c-Met antibody is administered two, three, four, five, six, seven, eight, nine, ten or more times after administration of the compound of formula (I) or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof.
43. The method of any one of claims 1 to 42, wherein the subject is homozygous for phenylalanine at position 158 of CD16, or heterozygous for valine and phenylalanine at position 158 of CD 16.
44. The method of any one of claims 1 to 43, further comprising administering a third anti-cancer therapy to the subject.
45. The method of claim 44, wherein the third anti-cancer therapy is chemotherapy, a targeted anti-cancer therapy, or a kinase inhibitor.
46. A pharmaceutical combination of a therapeutically effective amount of an isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody and a therapeutically effective amount of a compound of formula (I)
Or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
47. The pharmaceutical combination of claim 46, wherein the isolated bispecific anti-Epidermal Growth Factor Receptor (EGFR)/hepatocyte growth factor receptor (c-Met) antibody is a bispecific anti-EGFR/c-Met antibody comprising: a first domain that binds EGFR comprising HCDR1 of SEQ ID NO. 1, HCDR2 of SEQ ID NO. 2, HCDR3 of SEQ ID NO. 3, LCDR1 of SEQ ID NO. 4, LCDR2 of SEQ ID NO. 5, and LCDR3 of SEQ ID NO. 6; and a second domain that binds c-Met, said second domain comprising HCDR1 of SEQ ID NO. 7, HCDR2 of SEQ ID NO. 8, HCDR3 of SEQ ID NO. 9, LCDR1 of SEQ ID NO. 10, LCDR2 of SEQ ID NO. 11, and LCDR3 of SEQ ID NO. 12.
50. The pharmaceutical combination according to any one of claims 46 to 49, comprising between about 350mg and about 1400mg of the bispecific EGFR/c-Met antibody and between about 160mg and about 240mg of the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.
51. The pharmaceutical combination according to any one of claims 46 to 50, wherein the compound of formula (I) or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof is N- (5- (4- (4- ((dimethylamino) methyl) -3-phenyl-1H-pyrazol-1-yl) pyrimidin-2-ylamino) -4-methoxy-2-morpholinophenyl) acrylamide.
52. The pharmaceutical combination according to any one of claims 46 to 51, wherein the pharmaceutical combination is a non-fixed combination.
53. The pharmaceutical combination of any one of claims 46 to 52, wherein the first domain of the bispecific anti-EGFR/c-Met antibody that binds EGFR comprises the VH of SEQ ID NO 13 and the VL of SEQ ID NO 14; and said second domain that binds c-Met comprises the VH of SEQ ID NO. 15 and the VL of SEQ ID NO. 16.
54. The pharmaceutical combination of any one of claims 46 to 53, wherein the bispecific anti-EGFR/c-Met antibody comprises HC1 of SEQ ID NO 17, LC1 of SEQ ID NO 18, HC2 of SEQ ID NO 19 and LC2 of SEQ ID NO 20.
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PCT/IB2020/054594 WO2020230091A1 (en) | 2019-05-14 | 2020-05-14 | Combination therapies with bispecific anti-egfr/c-met antibodies and third generation egfr tyrosine kinase inhibitors |
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Citations (4)
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CN102014913A (en) * | 2008-03-06 | 2011-04-13 | 健泰科生物技术公司 | Combination therapy with C-MET and EGFR antagonists |
US20140141000A1 (en) * | 2012-11-21 | 2014-05-22 | Janssen Biotech, Inc. | Bispecific EGFR/C-Met Antibodies |
CN107098975A (en) * | 2012-11-21 | 2017-08-29 | 詹森生物科技公司 | With reference to the molecule of EGFR and C MET type III fibronectin domains |
WO2018194356A1 (en) * | 2017-04-21 | 2018-10-25 | Yuhan Corporation | Salt of an aminopyridine derivative compound, a crystalline form thereof, and a process for preparing the same |
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US7595378B2 (en) * | 2001-06-13 | 2009-09-29 | Genmab A/S | Human monoclonal antibodies to epidermal growth factor receptor (EGFR) |
SG10201800757TA (en) * | 2010-04-20 | 2018-02-27 | Genmab As | Heterodimeric antibody fc-containing proteins and methods for production thereof |
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CN102014913A (en) * | 2008-03-06 | 2011-04-13 | 健泰科生物技术公司 | Combination therapy with C-MET and EGFR antagonists |
US20140141000A1 (en) * | 2012-11-21 | 2014-05-22 | Janssen Biotech, Inc. | Bispecific EGFR/C-Met Antibodies |
CN107098975A (en) * | 2012-11-21 | 2017-08-29 | 詹森生物科技公司 | With reference to the molecule of EGFR and C MET type III fibronectin domains |
WO2018194356A1 (en) * | 2017-04-21 | 2018-10-25 | Yuhan Corporation | Salt of an aminopyridine derivative compound, a crystalline form thereof, and a process for preparing the same |
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EP3968985A1 (en) | 2022-03-23 |
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BR112021022828A2 (en) | 2022-04-12 |
AU2020275272A1 (en) | 2021-12-02 |
JP2022531980A (en) | 2022-07-12 |
IL287962A (en) | 2022-01-01 |
MA55978A (en) | 2022-03-23 |
KR20220010731A (en) | 2022-01-26 |
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