Dosing regimen for therapies comprising bispecific antiegfr / c-met antibodies

Abstract

Methods of treating a cancer expressing an epidermal growth factor receptor (EGFR) or expressing a hepatocyte growth factor receptor (c-Met) in a subject in need thereof are provided. These methods comprise administering to a subject a therapy comprising an isolated bispecific anti-EGFR / c-Met antibody wherein a dose comprising about 1400 mg to 2100 mg is administered once every 21 day cycle.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480058334.6 (22) Application Date 2024.07.03 (30) Priority Data 18 / 222093 2023.07.14 US (85) PCT International Application Entering National Phase Date 2026.03.12 (86) PCT International Application Application Data PCT / IB2024 / 056510 2024.07.03 (87) PCT International Application Publication Data WO2025 / 017409 EN 2025.01.23 (71) Applicant: Jensen Biotechnology Co., Ltd. Address: Pennsylvania, USA (72) Inventor: R. Nobleauch (74) Patent Agency: China Patent Agency (Hong Kong) Ltd. 72001 Patent Attorney Yu Miaopeng Chang (51) Int.Cl. C07K 16 / 28 (2006.01) A61K 39 / 395 (2006.01) A61K 31 / 5377 (2006.01) A61K 33 / 243 (2006.01) A61P 35 / 00 (2006.01) A61P 35 / 04 (2006.01) (54) Invention Title Dosing Regimen for Therapies Containing Bispecific Anti-EGFR / c-Met Antibodies (57) Abstract Provides a method for treating cancers expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met) in subjects of need. These methods include administering a therapy to the subject containing isolated bispecific anti-EGFR / c-Met antibodies, wherein a dose of approximately 1400 mg to 2100 mg is administered once every 21 days. Claims (2 pages), Description (51 pages), Sequence Listing (electronic publication), Drawings (4 pages) CN 121843963 A 2026.04.10 CN 1 21 84 39 63 A 1. A method for treating a subject with cancer expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), the method comprising administering to the subject an isolated bispecific anti-EGFR / c-Met antibody, said isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, the first domain comprising the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the heavy chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 5.6. LCDR3, wherein the second 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, at a dose of about 1400 mg to 2100 mg, administered once every 21 days. 2. The method of claim 1, wherein the method further comprises administering a third-generation EGFR tyrosine kinase inhibitor (TKI). 3. The method of claim 2, wherein the third-generation EGFR TKI has formula (I): (I). 4. The method of claim 3, wherein the third-generation EGFR TKI is administered at a dose of 240 mg daily. 5. The method of claim 1, wherein the initial dose of the bispecific anti-EGFR / c-Met antibody is a divided dose administered over two consecutive days, wherein if the subject weighs less than 80 kg, the antibody is administered at a dose of approximately 350 mg on day 1 (D1) of the first cycle and at a dose of approximately 1050 mg on day 2 (D2) of the first cycle; or if the subject weighs 80 kg or more, the antibody is administered at a dose of approximately 350 mg on day 1 of the first cycle and at a dose of approximately 1400 mg on day 2 of the first cycle. 6. The method of claim 1, wherein the method further comprises an initial cycle (cycle 1) comprising administering the bispecific antibody once weekly for three weeks at a dose of approximately 1400 mg if the subject weighs less than 80 kg, or at a dose of approximately 1750 mg if the subject weighs 80 kg or more. 7. The method of claim 6, wherein the method further comprises a second cycle (second cycle), the second cycle comprising administering the bispecific antibody every three weeks at a dose of about 1400 mg if the subject weighs less than 80 kg, or at a dose of about 1750 mg if the subject weighs 80 kg or more. 8. The method of claim 1, wherein the method comprises administering the bispecific antibody every three weeks at a dose of about 1750 mg if the subject weighs less than 80 kg, or at a dose of about 2100 mg if the subject weighs 80 kg or more. 9. The method of claim 1, wherein the method further comprises one or more platinum-containing chemotherapeutic agents. 10. The method of claim 9, wherein the one or more chemotherapeutic agents comprise pemetrexed and / or carboplatin. Claims 1 / 2 pages 2 CN 121843963 A11. The method of claim 9, wherein the one or more chemotherapeutic agents are pemetrexed and carboplatin administered on day 1 of each 21-day cycle. 12. The method of claim 9, wherein the one or more chemotherapeutic agents are pemetrexed at a dose of about 500 mg / m² and carboplatin administered to achieve an area under the curve (AUC) of 5. 13. The method of claim 9, wherein the one or more chemotherapeutic agents are pemetrexed at a dose of about 500 mg / m² and carboplatin AUC 5 administered on day 1 of each cycle up to and including the fourth cycle (cycle 4), and wherein pemetrexed is administered on day 1 of each subsequent cycle at a dose of about 500 mg / m². 14. The method of claim 1, wherein the first domain of the bispecific anti-EGFR / c-Met antibody binds to EGFR, and the second domain binds to c-Met. 15. The method of claim 14, wherein the first domain binding 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 binding c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16. 16. The method of claim 15, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype. 17. The method of claim 15, wherein the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20. 18. The method of claim 15, wherein the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15%. 19. The method of claim 3, wherein the compound of formula (I) or its solvate, hydrate, tautomer, or pharmaceutically acceptable salt is lazazetinib mesylate represented by the compound of formula (II): (II). 20. The method of claim 19, wherein the compound of formula (I) or its solvate, hydrate, tautomer, or pharmaceutically acceptable salt is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide. 21. The method of claim 1, wherein the cancer expressing EGFR or c-Met is lung cancer. 22. The method of claim 21, wherein the cancer is non-small cell lung cancer (NSCLC).Claims 2 / 2 Page 3 CN 121843963 A Dosing regimen for a therapy comprising a bispecific anti-EGFR / c-Met antibody

[0001] Electronically submitted reference sequence listing The sequence listing of this application is submitted electronically as an XML formatted sequence listing, named "JBI6724WOPCT1SEQLIST.xml", created on July 2, 2024, and is 21 kilobytes (KB) in size. This submitted sequence listing is part of this specification and is incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to methods for treating a subject with cancer expressing epidermal growth factor receptor (EGFR) or expressing hepatocyte growth factor receptor (c-Met). These methods include administering to a subject a therapy comprising an isolated bispecific anti-EGFR / c-Met antibody, wherein a dose comprising about 1400 mg to 2100 mg is administered once every 21 days. Background Art

[0003] The roles of epidermal growth factor receptors (EGFR, ErbB1, or HER1) and hepatocyte growth factor receptors (c-Met) in cancer have been well established, making them attractive targets for combination therapies. Both receptors signal via the same ERK and AKT survival and anti-apoptotic pathways and are often upregulated as resistance mechanisms to single-agent therapy. Furthermore, relapse or resistance to existing therapeutic agents is common. Therefore, there is a need for improved therapeutic agents or combinations of treatments for the effective treatment of diseases such as EGFR- and / or c-Met-positive cancers. Summary of the Invention

[0004] To meet these needs, this disclosure provides methods for treating cancers expressing epidermal growth factor receptor (EGFR) or expressing hepatocyte growth factor receptor (c-Met) in subjects of need.

[0005] The method of the present invention includes administering to a subject an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, the first domain comprising the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and the second domain comprising the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, the LCDR1 of SEQ ID NO: 10, the LCDR2 of SEQ ID NO: 11, and the LCDR3 of SEQ ID NO: 12.LCDR3 of 12, at a dose of approximately 1400 mg to 2100 mg, is administered once every 21 days.

[0006] In some embodiments, the method further includes administration of a third-generation EGFR tyrosine kinase inhibitor (TKI).

[0007] In some embodiments, the third-generation EGFR TKI has the formula (I): (I). Specification 1 / 51 page 4 CN 121843963 A

[0008] In some embodiments, the third-generation EGFR TKI is administered at a dose of 240 mg per day.

[0009] In some embodiments, the initial dose of the bispecific anti-EGFR / c-Met antibody is a divided dose administered over two consecutive days, wherein if the subject weighs less than 80 kg, the antibody is administered at a dose of approximately 350 mg on day 1 (D1) of the first cycle and at a dose of approximately 1050 mg on day 2 (D2) of the first cycle; or if the subject weighs 80 kg or more, the antibody is administered at a dose of approximately 350 mg on day 1 of the first cycle and at a dose of approximately 1400 mg on day 2 of the first cycle.

[0010] In some embodiments, the method further includes an initial cycle (cycle 1) comprising administering the bispecific antibody once weekly for three weeks at a dose of approximately 1400 mg if the subject weighs less than 80 kg, or at a dose of approximately 1750 mg if the subject weighs 80 kg or more.

[0011] In some embodiments, the method further includes a second cycle (cycle 2) comprising administering the bispecific antibody every three weeks at a dose of about 1400 mg if the subject weighs less than 80 kg, or at a dose of about 1750 mg if the subject weighs 80 kg or more.

[0012] In some embodiments, the method comprises administering the bispecific antibody every three weeks at a dose of about 1750 mg if the subject weighs less than 80 kg, or at a dose of about 2100 mg if the subject weighs 80 kg or more.

[0013] In some embodiments, the method further comprises one or more platinum-containing chemotherapeutic agents. In some embodiments, the one or more chemotherapeutic agents include pemetrexed and / or carboplatin. In some embodiments, the one or more chemotherapeutic agents are pemetrexed and carboplatin administered on day 1 of each 21-day cycle. In some embodiments, one or more chemotherapeutic agents are administered as pemetrexed at a dose of about 500 mg / m² and carboplatin to achieve an area under the curve (AUC) of 5. In some embodiments, one or more chemotherapeutic agents are administered as pemetrexed at a dose of about 500 mg / m² and carboplatin AUC administered on day 1 of each cycle up to and including the fourth cycle (cycle 4).5, wherein pemetrexed is administered at a dose of approximately 500 mg / m² on day 1 of each subsequent cycle.

[0014] In some embodiments, the first domain of the bispecific anti-EGFR / c-Met antibody binds to EGFR, and the second domain binds to c-Met.

[0015] In some embodiments, the first domain binding to 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 binding to c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0016] In some embodiments, the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

[0017] In some embodiments, the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0018] In some embodiments, the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0019] In some embodiments, the compound of formula (I) or its solvates, hydrates, tautomers, or pharmaceutically acceptable salts are lazertinib mesylate represented by the compound of formula (II): Specification 2 / 51 pages 5 CN 121843963 A (II).

[0020] In some embodiments, the compound of formula (I) or its solvates, hydrates, tautomers, or pharmaceutically acceptable salts are N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

[0021] In some embodiments, the cancer expressing EGFR or c-Met is lung cancer.

[0022] In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0023] In some embodiments, the cancer is NSCLC. In some embodiments, the NSCLC is advanced or metastatic EGFR-mutant NSCLC. According to some embodiments, a subject with advanced or metastatic EGFR-mutant NSCLC has failed prior treatment with an EGFR TKI. Brief Description of the Drawings

[0024] Figure 1 is a diagram depicting an overview of the study.

[0025] Figure 2 is a diagram depicting the dosing synchronization of amivantamab and chemotherapy in the LACP cohort.

[0026] Figures 3A to 3C show the C-trough values ​​of etanercept measured on day 8 of cycle 1 (Figure 3A), day 15 of cycle 1 (Figure 3B), and day 22 of cycle 1 (Figure 3C).

[0027] Figures 4A to 4B show the C-trough values ​​of etanercept measured on day 1 of cycle 2 (Figure 4A) and day 15 of cycle 2 (Figure 4B).

[0028] Figure 5 shows the best change (%) of the target lesion SoD (total lesion diameter) relative to baseline in patients treated with etanercept in combination with chemotherapy (carboplatin and pemetrexed). Detailed Description

[0029] The methods disclosed herein can be more readily understood by taking into account the accompanying drawings, which form a part of this disclosure, and by referring to the following detailed description. It should be understood that the methods disclosed herein are not limited to the specific methods described and / or shown herein, and the terminology used herein is used only to describe specific embodiments by way of example and is not intended to limit the methods protected by the claims.

[0030] It should be understood that certain features of the methods disclosed herein are described in the context of individual embodiments for clarity, but may also be provided in combination in a single embodiment. Conversely, various features of the methods disclosed herein are described in the context of individual embodiments for brevity, but may also be provided separately or in any sub-combination.

[0031] As defined herein, the terms “sequence” and “amino acid sequence” mean the succession or sequence of amino acids described by a series of letters using standard nomenclature. Amino acids may comprise unmodified and / or modified amino acids. Specification 3 / 51 pages 6 CN 121843963 A

[0032] As used herein, the terms “individual,” “patient,” and “subject” are used interchangeably to refer to a member of any animal species, including but not limited to birds, humans, and other primates, as well as other mammals, including commercially relevant mammals or animal models such as mice, rats, monkeys, cattle, pigs, horses, sheep, cats, and dogs. Preferably, the subject is a human.

[0033] As used herein, the term "treatment," etc., refers to a method or step taken to alleviate or reduce the number, severity, and / or frequency of one or more symptoms of a disease in a subject. As used herein, "treatment" may include prevention, management, preventive treatment, and / or suppression or reduction of the number, severity, and / or frequency of one or more symptoms of a disease in a subject.

[0034] As used herein, the terms "comprising," "having," "including," and "characterized" are interchangeable, inclusive, open-ended, and do not exclude additional, unlisted elements or method steps. Any statement herein regarding the term "comprising," particularly in the description of the components of a composition or the elements of an apparatus, should be interpreted as follows:This is to be understood as encompassing compositions and methods that are substantially composed of and comprised of the stated components or elements.

[0035] As used in the claims herein, the phrase “composed of” excludes any element, step, or component not specified in the claim. As used in the claims herein, the phrase “composed of” limits the scope of the claim to the specified materials or steps and materials or steps that do not substantially affect one or more essential and novel features of the claimed invention.

[0036] It will be readily understood and appreciated by those skilled in the art that, depending on the environment in which the compound or composition is placed, the compounds and compositions disclosed herein may have certain atoms (e.g., N, O, or S atoms) in a protonated or deprotonated state. Thus, as used herein, the structures disclosed herein contemplate that certain functional groups (e.g., OH, SH, or NH) may be protonated or deprotonated. The disclosure herein is intended to cover the disclosed compounds and compositions regardless of their protonated state based on the environment (such as pH), as will be readily understood by those skilled in the art. Accordingly, compounds having unstable protons or basic atoms described herein should also be understood to represent the salt form of the corresponding compound. The compounds described herein may be in the form of a free acid, a free base, or a salt. Pharmaceutically acceptable salts of the compounds described herein should be understood to be within the scope of this invention.

[0037] As used herein, when referring to a connection between two compounds or molecules, the terms “connected” or “conjugated” mean that the two compounds or molecules are connected by a covalent bond. Unless otherwise stated, the terms “connected” and “conjugated” as used herein may refer to a connection between a first compound and a second compound, with or without any intermediate atoms or groups of atoms.

[0038] As used herein, the term “including” is used to mean the phrase “including but not limited to” and is used interchangeably with that phrase. Unless the context clearly indicates otherwise, the term “or” is used herein to mean the term “and / or” and is used interchangeably with that term.

[0039] “About” means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value was measured or determined, i.e., limitations of the measurement system. In the context of a particular measurement, result, or implementation, unless otherwise expressly stated in the implementation or elsewhere in the specification, “about” means within one standard deviation or a range of up to 5% (whichever is greater) according to convention in the art.

[0040] “About once a week” or “once a week” means administration once every about a week. About a week means 7 days ± 2 days, i.e., 5 to 9 days. Therefore, the dosing frequency of “about once a week” can be once every five days, once every six days, once every seven days, once every eight days, or once every nine days.

[0041] "Approximately every three weeks" means administration once every three weeks. Approximately three weeks is 21 days ± two days, that is, 19 to 23 days. Therefore, the dosing frequency of "approximately every three weeks" can be once every 19 days, once every 20 days, once every 21 days, once every 22 days, or once every 23 days.

[0042] "Antagonist" or "inhibitor" means a molecule that, when bound to a cellular protein, inhibits at least one reaction or activity induced by the protein's natural ligand. A molecule is an antagonist when at least one reaction or activity is inhibited by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than the inhibition of at least one reaction or activity in the absence of an antagonist (e.g., a negative control), or when the inhibition is statistically significant compared to the inhibition in the absence of an antagonist.

[0043] “Antibody” broadly refers to and includes immunoglobulin molecules, specifically including monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies, and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific antibodies, trispecific antibodies, tetraspecific antibodies, etc.), dimer, tetramer, or multimer antibodies, single-chain antibodies, domain antibodies, and any other modified conformation of an immunoglobulin molecule containing an antigen-binding site with desired specificity. A “full-length antibody” comprises two heavy chains (HC) and two light chains (LC) linked by disulfide bonds, and their polymers (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists 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, called complementarity-determining regions (CDRs), interspersed with framework regions (FRs). Each VH and VL consists of three CDR and four FR fragments, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be designated into five major types based on the amino acid sequence of their heavy chain constant domain, namely IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequence of their constant domain, the antibody light chain of any vertebrate species can be designated into one of two completely different types, namely κ and λ.

[0044] "Antigen-binding fragment" refers to the part of an immunoglobulin molecule that binds to an antigen. The antigen-binding fragment can be a combination of...A polypeptide that is synthesized, enzymatically obtainable, or genetically engineered, and includes fragments of VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv, domain antibody (dAb) consisting of a VH domain or a VL domain, shark variable IgNAR domain, humped VH domain, and a minimal recognition unit consisting of amino acid residues of CDRs of a mimic antibody, such as FR3-CDR3-FR4, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs. Where the VH and VL domains are expressed by separate single-chain antibody constructs, the VH / VL domains can be paired intramolecularly or intermolecularly to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or bivalent antibodies; as described, for example, in International Patent Publications WO1998 / 44001, WO1988 / 01649, WO1994 / 13804 and WO1992 / 01047.

[0045] “Bispecific” refers to an antibody that specifically binds to two different antigens or two different epitopes within the same antigen. Bispecific antibodies may have cross-reactivity with other related antigens, for example, cross-reactivity with the same antigen from other species (homologous) (such as humans or monkeys, e.g., cynomolgus macaques (cyno) or chimpanzees), or may bind to epitopes shared between two or more different antigens.

[0046] A “bispecific anti-EGFR / c-Met antibody” or “bispecific EGFR / c-Met antibody” refers to a bispecific antibody having a first domain that specifically binds to EGFR and a second domain that specifically binds to 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 polyvalent in binding to EGFR and c-Met; that is, it may have one or more domains that bind to EGFR and one or more domains that bind to c-Met.

[0047] A “biological sample” refers to a collection of fluid-like, cell-like, or tissue-like material isolated from a subject, as well as fluid-like, cell-like, or tissue-like material present in the subject. Exemplary samples are biological fluids, such as blood, serum and serous fluid, plasma, lymph, urine, saliva, cystic fluid, tears, excretions, sputum, mucosal secretions of secretory tissues and organs, vaginal secretions, ascites, pleural fluid, pericardial fluid, peritoneal fluid, peritoneal fluid and other body cavity fluids, fluids collected by bronchoalveolar lavage fluid, synovial fluid, and liquid solutions that come into contact with the subject or biological sources (e.g., cell and organ culture media (including cell or organ conditioned media)).Irrigation fluid, etc.), tissue biopsy material, tumor tissue biopsy material, tumor tissue sample, fine needle aspirate, surgically removed tissue, organ culture or cell culture.

[0048] The "complementarity-determining region" (CDR) is the antibody region that binds to the antigen. CDR can be defined using various descriptions, such as Kabat (Wu et al., (1970) J Exp Med 132: 211-50) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al., (1987) J Mol Biol 196: 901-17), IMGT (Lefranc et al., (2003) Dev Comp Immunol 27: 55-77) and AbM (Martin and Thornton (1996) J Bmol Biol 263: 800-15). The correspondence between various depictions and variable region numbers is described (see, for example, Lefranc et al., (2003) Dev Comp Immunol 27: 55-77; Honegger and Pluckthun, (2001) J Mol Biol 309:657-70; International ImMunoGeneTics (IMGT) database; Web resource, http: / / www_imgt_org). Available programs (such as abYsis of UCL Business PLC) can be used to depict CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2”, and “LCDR3” include CDRs as defined by any of the above methods (Kabat, Chothia, IMGT, or AbM).

[0049] “Cancer” refers to the 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.

[0050] Terms such as “co-administered,” “administered together with,” “administered in combination with,” “combined with,” and “combination therapy” encompass the administration of two or more therapeutic agents to a single patient and are intended to include treatment regimens in which these therapeutic agents are administered via the same or different routes of administration or at the same or different times.

[0051] “Diagnosis” means determining whether a subject has a given disease or condition or whether it is likely to develop into one in the future.A method for identifying a disease or condition or whether a patient is likely to respond to treatment of a previously diagnosed disease or condition (i.e., stratifying a patient population based on the likelihood of responding to treatment). Diagnosis is typically made by a physician based on general guidelines for the disease to be diagnosed or other criteria indicating a subject's likely response to a particular treatment.

[0052] "Dosing regimen" refers to information about the amount of therapeutic agent or drug to be taken by the subject and the frequency of the number of times the subject will take the therapeutic agent.

[0053] "Dosage" refers to the amount or quantity of therapeutic agent or drug to be taken each time.

[0054] "Therapeutic effective dose" refers to the amount that effectively achieves the desired therapeutic outcome at the required dose and time period. Therapeutic effective dose can vary depending on factors such as an individual's disease state, age, sex, and weight, and the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in an individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved patient health.

[0055] "Cancer expressing EGFR or c-Met" refers to cancer with detectable EGFR or c-Met expression or with EGFR or c-Met mutations or amplifications. 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).

[0056] “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 shown in GenBank accession number NP_005219, and its naturally occurring variants. Specification 6 / 51 pages 9 CN 121843963 A

[0057] As used herein, “hepatocyte growth factor receptor” or “c-Met” refers to human c-Met and its naturally occurring variants having the amino acid sequence shown in GenBank accession number NP_001120972.

[0058] A “human antibody” is an antibody optimized to have a minimal immune response when administered to a human subject. The variable region of a human antibody is derived from a human immunoglobulin sequence. If a human antibody contains a constant region or a portion of a constant region, that constant region is also derived from a human immunoglobulin sequence. If the variable region of a human antibody is obtained using a system that uses human germline immunoglobulins or rearranged immunoglobulin genes, the human antibody contains heavy chain and light chain variable regions “derived” from human-origin sequences. Exemplary systems of this kind include human immunoglobulin gene libraries displayed on bacteriophages and transgenic nonhuman animals, such as mice or rats carrying human immunoglobulin loci. Because the methods used to obtain human antibodies and human immunoglobulin loci...Differences between systems, the introduction of somatic mutations, or the intentional substitution of components in the framework or CDR, or both, mean that "human antibodies" typically contain amino acid differences compared to immunoglobulins expressed in humans. Generally, 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 with the amino acid sequence encoded by human germline immunoglobulin genes or rearranged immunoglobulin genes. In some cases, a “human antibody” may comprise a common frame sequence obtained from human frame sequence analysis (e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86); or a synthetic HCDR3 bound to a human immunoglobulin gene library displayed on a bacteriophage (e.g., as described in Shi et al., (2010) J Mol Biol 397:385-96 and International Patent Publication No. WO2009 / 085462). The definition of “human antibody” does not include antibodies with at least one CDR derived from a non-human species.

[0059] “Isolated” means a homogeneous population of molecules (such as synthetic polynucleotides, polypeptide carriers, or viruses) that have been substantially isolated and / or purified from other components of the system that produces the molecules (such as recombinant cells), as well as proteins that have undergone at least one purification or isolation step. "Separated" means molecules that are substantially free of other cellular material and / or chemicals, and encompasses molecules separated to higher purities (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).

[0060] "Fucose content" refers to the amount of fucose monosaccharide within the glycan chain at Asn297 in the antibody formulation.

[0061] "Low fucose" or "low fucose content" means that the fucose content of the antibody is between 1% and 15%.

[0062] "Normal fucose" or "normal fucose content" means that the fucose content of the antibody is greater than about 50%, usually greater than about 80%, or greater than about 85%.

[0063] A “pharmaceutically acceptable carrier” or “excipient” refers to a component in a pharmaceutical composition other than the active ingredient, which is non-toxic to the subject. A pharmaceutically acceptable carrier includes, but is not limited to, buffers, stabilizers, or preservatives. A pharmaceutically acceptable carrier includes, but is not limited to, diluents, disintegrants, or flow aids; or diluents, disintegrants, wetting agents, flow aids, or lubricants.

[0064] “Prevention” of a disease or condition means prevention of the occurrence of a condition in the subject.

[0065] “Recombinant” refers to a compound formed when fragments from different sources are joined to produce recombinant DNA, antibodies, or proteins.DNA, antibodies, and other proteins prepared, expressed, formed, or isolated by recombinant methods.

[0066] "Refractory" refers to a disease that does not respond to treatment. Refractory diseases may be resistant to treatment before or at the start of treatment, or may become resistant during treatment.

[0067] "Relapse" refers to the recurrence of the disease or signs and symptoms of the disease after a period of improvement following previous treatment with a therapeutic agent.

[0068] "Response," "responsiveness," or "possible response" refers to any type of improvement or positive response, such as the reduction or improvement of one or more symptoms, a decrease in the severity of the disease, stabilization of the disease state (i.e., no worsening), prevention of the spread of the disease, delay or slowing of disease progression, improvement or mitigation of the disease state, and remission (whether partial or complete), whether detectable or undetectable.

[0069] "Solvate" and "hydrate" are solvation addition forms that the compounds of the present invention can form, whereby the multicomponent compound contains 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).

[0070] "Specific binding" or "specifically binding" or "binding" means that an antibody binds to an antigen or an epitope within an antigen with a higher affinity than against other antigens. Typically, when an antibody binds to an antigen or an epitope within an antigen, the equilibrium dissociation constant (KD) is about 5 x 10⁻⁸ M or less, for example, about 1 x 10⁻⁹ M or less, about 1 x 10⁻¹⁰ M or less, about 1 x 10⁻¹¹ M or less, or about 1 x 10⁻¹² M or less, typically at least one hundred times lower than the KD when it binds to nonspecific antigens (e.g., BSA, casein). The dissociation constant can be measured using known protocols. However, antibodies that bind to an antigen or an epitope within an antigen may be cross-reactive to other related antigens, for example, to the same antigen from other species (homologous) (such as humans or monkeys, such as the cynomolgus macaque or the chimpanzee). Monospecific antibodies bind to one antigen or one epitope, while bispecific antibodies bind to two different antigens or two different epitopes.

[0071] In the context of EGFR tyrosine kinase inhibitors (TKIs), “untreated” means a subject who has not yet received EGFR TKI treatment.

[0072] “Humanized antibody” means an antibody in which at least one CDR is derived from a non-human species and at least one frame is derived from a human immunoglobulin sequence. Humanized antibodies may contain substitutions in the frame such that the frame may not be an expressed human immunoglobulin.An exact copy of the germline gene sequence of a globulin or human immunoglobulin.

[0073] "First-generation EGFR tyrosine kinase inhibitors" (first-generation TKIs) refer to reversible EGFR inhibitors (such as gefitinib and erlotinib) that are effective in first-line treatment of NSCLC carrying EGFR activating mutations (such as deletions of exon 19 and exon 21 L858R mutations).

[0074] "Second-generation EGFR tyrosine kinase inhibitors" (second-generation TKIs) refer to covalently irreversible EGFR inhibitors (such as afatinib and dacomitib) that are effective in first-line treatment of NSCLC carrying EGFR activating mutations (such as deletions of exon 19 and exon 21 L858R mutations).

[0075] “Third-generation EGFR tyrosine kinase inhibitors” (third-generation TKIs) refer to covalently irreversible EGFR inhibitors (such as osimertinib and lazertinib) that are selective for EGFR activating mutations (such as exon 19 and exon 21 L858R deletions, alone or in combination with T790M mutations) and have low inhibitory activity against wild-type EGFR.

[0076] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly known to one of ordinary skill in the art. Although methods and materials similar to or equivalent to those described herein may be used in the operation or testing of the present invention, the following describes suitable methods and materials. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety. In case of any conflict, this specification (including definitions) shall prevail. In addition, materials, methods and examples are exemplary only and are not intended to be limiting.

[0077] Other objects, features, aspects and advantages of the invention will become apparent from the following detailed description, drawings and claims.

[0078] Treatment Method 1. Bispecific Anti-EGFR / c-Met Antibody A bispecific anti-EGFR / c-Met antibody inhibits both EGFR and c-Met signaling by blocking ligand-induced activation and by inducing receptor degradation, as described in US Patent No. 9,593,164, which is incorporated herein by reference. Additionally, the presence of high levels of EGFR and c-Met on the surface of tumor cells allows immune effector cells to target and destroy these cells through Fc-mediated effector mechanisms such as antibody-dependent cell cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP). In some embodiments, the bispecific anti-EGFR / c-Met is ervastatin.The monoclonal antibody, also referred to herein as “JNJ-61186372”, is defined by the following amino acid sequence: the EGFR-binding domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, 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 (VH) of SEQ ID NO: 13 and the light chain variable domain (VL) of SEQ ID NO: 14; the c-Met-binding domain comprises SEQ ID NO: VH of SEQ ID NO: 15 and VL of SEQ ID NO: 16; the antibody contains the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19 and the second light chain (LC2) of SEQ ID NO: 20.

[0079] >SEQ ID NO: 1 (HCDR1, EGFR binding arm) TYGMH >SEQ ID NO: 2 (HCDR2, EGFR binding arm) VIWDDGSYKYYGDSVKG >SEQ ID NO: 3 (HCDR3, EGFR binding arm) DGITMVRGVMKDYFDY >SEQ ID NO: 4 (LCDR1, EGFR binding arm) RASQDISSALV >SEQ ID NO: 5 (LCDR2, EGFR binding arm) DASSLES >SEQ ID NO: 6 (LCDR3, EGFR binding arm) QQFNSYPLT >SEQ ID NO: 7 (HCDR1, c-Met binding arm) SYGIS >SEQ ID NO: 8 (HCDR2, c-Met binding arm) WISAYNGYTNYAQKLQG >SEQ ID NO: 9 (HCDR3, c-Met binding arm) DLRGTNYFDY >SEQ ID NO: 10 (LCDR1, c-Met bonding arm) RASQGISNWLA >SEQ ID NO: 11 (LCDR2, c-Met bonding arm) AASSLLS >SEQ ID NO:12 (LCDR3, c‑Met binding arm) QQANSFPIT >SEQ ID NO: 13 (VH, EGFR binding arm) QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFT DESCRIPTION Page 9 of 51 Page 12 CN 121843963 A ISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSS >SEQ ID NO: 14 (VL, EGFR binding arm) AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGT DFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIK >SEQ ID NO:15 (VH, c‑Met binding arm) QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVT MTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSS >SEQ ID NO:16 (VL, c‑Met binding arm) DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQANSFPITFGQGTRLEIK >SEQ ID NO: 17 HC1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSTYGMHWVRQAPGKGLEWVAVIWDDGSYKYYGDSVKGRFT ISRDNSKNTLYLQMNSLRAEDTAVYYCARDGITMVRGVMKDYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGG TAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRV EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K >SEQ ID NO: 18 LC1 AIQLTQSPSSLSASVGDRVTITCRASQDISSALVWYQQKPGKAPKLLIYDASSLESGVPSRFSGSESGT DFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC >SEQ ID NO: 19 HC2 QVQLVQSGAEVKKPGASVKVSCETSGYTFTSYGISWVRQAPGHGLEWMGWISAYNGYTNYAQKLQGRVT MTTDTSTSTAYMELRSLRSDDTAVYYCARDLRGTNYFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGC LVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK >SEQ ID NO: 20 LC2 DIQMTQSPSSVSASVGDRVTITCRASQGISNWLAWFQHKPGKAPKLLIYAASSLLSGVPSRFSGSGSGTIn 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 number according to EU designation) (see, for example, IMGT Web Resources; IMGT Library (IG and TR); Proteins and Alleles; Allotypes). Bispecific anti-EGFR / c-Met antibodies can be any IgG1 allotype, such as G1m17, G1m3, G1m1, G1m2, G1m27, or G1m28. An exemplary amino acid sequence of the constant domain of IgG1 is shown in SEQ ID NO: 21. IgG1 constant domain (SEQ ID NO: 21) Instructions 10 / 51 Page 13 CN 121843963 A ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 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.

[0081] In some embodiments, the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0082] In some embodiments, the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15%, for example, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.

[0083] The relative amount of fucose is the percentage of the fucose-containing structure relative to all sugar structures. These can be characterized and quantified by various methods, such as: 1) using MALDI-TOF with samples treated with N-glycosidase F (e.g., complex structures, mixed structures, oligomannose structures, and high-mannose structures), as described in International Patent Publication No. WO2008 / 077546 2; 2) enzymatic release of Asn297 glycans, followed by derivatization and detection / quantification by HPLC (UPLC) and / or HPLC-MS (UPLC-MS) with fluorescence detection; 3) complete protein analysis of native or reduced mAb with or without treatment of Asn297 glycans with Endo S or other enzymes, which cleave between the first GlcNAc monosaccharide and the second GlcNAc monosaccharide, leaving fucose linked to the first GlcNAc; 4) digestion of mAb 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) using PNGase F on Asn297 glycans. Specific enzymatic deglycosylation at Asn297 separates mAb oligosaccharides from mAb proteins. The released oligosaccharides can be fluorophoretically labeled, separated, and identified using various complementary techniques. These techniques allow for: fine characterization of the glycan structure by comparing experimental and theoretical mass using matrix-assisted laser desorption / ionization (MALDI) mass spectrometry; determination of sialylation levels using ion-exchange HPLC (GlycoSep C); separation and quantification of oligosaccharide forms based on hydrophilicity standards using normal-phase HPLC (GlycoSep N); and separation and quantification of oligosaccharides using high-performance capillary electrophoresis-laser-induced fluorescence (HPCE-LIF).

[0084] The antibody-induced ADCC ability can be enhanced by engineering its oligosaccharide components. Most glycans of human IgG1 or IgG3 are N-glycosylated at Asn297 in the well-known bibranched GO, GOF, G1, G1F, G2, or G2F forms. Antibodies produced by unengineered CHO cells typically contain at least 85% fucose, a polysaccharide. Removing the core fucose from bibranched complex oligosaccharides enhances antibody-dependent cell-mediated cytotoxicity (ADCC) via improved FcγRIIIa binding without altering antigen-binding or complement-dependent cytotoxicity (CDC) activity. Reduced fucose content in antibodies…The antibodies can be prepared using different methods reported for the successful expression of relatively high defucosylation antibodies against Fc oligosaccharides with a biantennary complex, such as controlling culture osmotic pressure (Konno et al., Cytotechnology 64:249-65, 2012), using the variant CHO cell line Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-26740, 2002), using the variant CHO cell line EB66 as the host cell line (Olivier et al., MAbs; 2(4), 2010; pre-print electronic version; PMID:20562582), using the rat hybridoma cell line YB2 / 0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introducing specific antibodies against α1 Small interfering RNA of the 6-fucosyltransferase (FUT8) gene (Mori et al., Biotechnol Bioeng 88:901-908, 2004), or co-expression of β-1,4-N-acetylglucosyltransferase III and Golgi α-mannosidase II or effective α-mannosidase I inhibitors, chitosans (Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Xhou et al., Biotechnol Bioeng 99:652-65, 2008).

[0085] 2. Third-generation EGFR tyrosine kinase inhibitor (TKI) Lazatinib is a third-generation EGFR tyrosine kinase inhibitor (TKI); the structure and synthesis of lazatinib are described in U.S. Patent No. 9,593,098, which is incorporated herein by reference. The chemical name of the free base of lazatinib 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 lazatinib). The mesylate of lazatinib may be represented by formula II: Formula (II).

[0086] Embodiments of lazatinib (e.g., salt and crystalline forms) are described in PCT / KR2018 / 004473, which is also incorporated herein by reference.

[0087] According to a specific embodiment, the free base form of lazatinib has almost no 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, itsTargeting activated EGFR mutations del19 and L858R, as well as the T790M mutation. In one aspect of the invention, the mutation may be delE746-A750, L858R, or T790M, and may be a double mutation selected from delE746-A750 / T790M or L858R / T790M.

[0088] This disclosure provides a method of treating a subject with cancer expressing EGFR or c-Met, the method comprising administering a combination therapy to the subject, wherein the combination therapy comprises a bispecific antibody, a third-generation EGFR TKI of formula (I) or a solvation thereof, a hydrate, a tautomer or a pharmaceutically acceptable salt, and one or more chemotherapeutic agents.

[0089] Formula (I).

[0090] In each embodiment, the bispecific anti-EGFR / c-Met antibody and the lazatinib compound, or their solvates, hydrates, tautomers, or pharmaceutically acceptable salts, may be administered simultaneously (e.g., as part of the same pharmaceutical composition, or in separate pharmaceutical compositions) or at different times, as described herein.

[0091] Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Pharmaceutically acceptable acidic / anionic salts include acetates, benzenesulfonates, benzoates, bicarbonates, tartaric acid salts, bromides, calcium edetate, camphor sulfonates, carbonates, chlorides, citrates, dihydrochlorides, edetates, ethanedisulfonates, etopoates, ethanesulfonates, fumarates, gluconate, gluconate, glutamate, p-hydroxyacetaminophenarsine, hexylresorcinol salts, hydrobromide, hydrochloride, hydroxynaphthyl salt, iodides, hydroxyethylsulfonates, lactates. Lactobionates, malates, maleates, malonates, mandelates, mesylates, methyl sulfates, mucilages, naphthalene sulfonates, nitrates, dihydroxynaphthalate, pantothenates, phosphates / bisphosphonates, polygalacturonic acids, salicylates, stearates, hypoacetates, succinates, sulfates, hydrogen sulfates, tannates, tartrates, theochlorophosphates, toluenesulfonates, and triethyliodide salts. Pharmaceutically acceptable basic / cationic salts include sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucosamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine, and triethanolamine.

[0092] Pharmaceutically acceptable acid salts are formed by reacting the free base form of a 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, and para-amino acids.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, for example, hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), or hexanoate.

[0093] The free acid or free base form of compounds of formula (I) may be prepared from the corresponding base addition salt or acid addition salt form, respectively. For example, the acid addition salt form of the present invention may be converted to the corresponding free base form by treatment with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). The base addition salt form of the present invention may be converted to the corresponding free acid by treatment with a suitable acid (e.g., hydrochloric acid, etc.).

[0094] 3. The methods disclosed for the chemotherapeutic agents include combination therapy, which includes administering one or more chemotherapeutic agents as part of a combination therapy. The chemotherapeutic agents comprise platinum-based chemotherapeutic agents. These methods may include administering platinum-based double chemotherapy. For example, platinum-based double chemotherapy may include intravenous administration of pemetrexed (500 mg / m² body surface area) plus carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg / m²). Administration of one or more chemotherapeutic agents may include administering pemetrexed and carboplatin once every 21 cycles for up to four cycles, followed by maintenance pemetrexed once every 21 cycles thereafter.

[0095] 4. Dosage and 21-day cycle: A method for treating a subject in need of cancer expressing EGFR or expressing hepatocyte growth factor receptor (c-Met). In some embodiments, the method includes administering an isolated bispecific anti-EGFR / c-Met antibody to the subject, wherein the method includes administering the antibody once every 21-day cycle for one or more cycles. In some embodiments, the method includes administering a combination therapy to a subject comprising 1) a bispecific antibody comprising an isolated bispecific anti-EGFR / c-Met antibody, optionally 2) a third-generation EGFR tyrosine kinase inhibitor (TKI), and optionally 3) one or more chemotherapeutic agents. In some embodiments, the combination therapy is administered in 21-day cycles.

[0096] In some embodiments, the bispecific antibody is administered in three or more 21-day cycles at an initial dose of about 1400 mg to a subject weighing less than 80 kg, or at an initial dose of about 1750 mg to a subject weighing 80 kg or more. In some embodiments, the initial dose is a divided dose given over two consecutive days. For example, if the subject's weight...For subjects weighing less than 80 kg, the antibody is administered at a dose of approximately 350 mg on day 1 (D1) of the first cycle and at a dose of approximately 1050 mg on day 2 (D2) of the first cycle, reaching a full starting dose of 1400 mg. Alternatively, if the subject weighs 80 kg or more, the antibody is administered at a dose of approximately 350 mg on day 1 of the first cycle and at a dose of approximately 1400 mg on day 2 of the first cycle, reaching a full starting dose of 1750 mg.

[0097] In the first cycle (cycle 1) of three or more cycles, the method may include administering the bispecific antibody once weekly at a dose of approximately 1400 mg if the subject weighs less than 80 kg, or at a dose of approximately 1750 mg if the subject weighs 80 kg or more.

[0098] In a second cycle (cycle 2) of three or more cycles, the method may include administering the bispecific antibody once at a dose of about 1400 mg if the subject weighs less than 80 kg, or at a dose of about 1750 mg if the subject weighs 80 kg or more.

[0099] In a third cycle (cycle 3) of three or more cycles, the method may include administering the bispecific antibody once at a dose of about 1750 mg if the subject weighs less than 80 kg, or at a dose of about 2100 mg if the subject weighs 80 kg or more.

[0100] In cycles following cycle 3, the method may include administering the bispecific antibody once at a dose of about 1750 mg if the subject weighs less than 80 kg, or at a dose of about 2100 mg if the subject weighs 80 kg or more.

[0101] In some embodiments, the bispecific antibody is administered intravenously. In some embodiments, the bispecific antibody is administered subcutaneously.

[0102] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1400 mg to about 2240 mg. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered at doses of about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg, about 1510 mg, about 1520 mg, about 1530 mg, about 1540 mg, about 1550 mg, about 1560 mg, about 1570 mg, about 1575 ...575 mg, about 1570 mg, about 1575 mg, about 1570 mg, about 1575 mg, about 1570 mg, about 1575 mg, about 1570 mg, about 1575 mg, about 1570 mg, about 1575 mg, about 1570 mg, about 1570 mg, about 1575 mg, about 1570 mg1580mg, approximately 1590mg, approximately 1600mg, approximately 1610mg, 1620mg, approximately 1630mg, approximately 1640mg, approximately 1650mg, approximately 1660mg, approximately 1670mg, approximately 1680mg, approximately 1690mg, approximately 1700mg, approximately 1710mg, approximately 1720mg, approximately 1730mg, approximately 1740mg, approximately 1750mg, approximately 1760mg, approximately 1770mg, approximately 1780mg, approximately 1790mg, approximately 1800mg, approximately 1810mg, approximately 1820mg, approximately 1830mg, approximately 1840mg, approximately 1850mg, approximately 1860mg, approximately 1870mg, approximately 1880mg, 1890mg, approximately 1900mg, approximately 1910mg Approximately 1920 mg, 1930 mg, 1940 mg, 1950 mg, 1960 mg, 1970 mg, 1980 mg, 1990 mg, 2000 mg, 2010 mg, 2020 mg, 2030 mg, 2040 mg, 2050 mg, 2060 mg, 2070 mg, 2080 mg, 2090 mg, 2100 mg, 2110 mg, 2120 mg, 2150 mg, 2200 mg, 2210 mg, 2220 mg, 2230 mg, 2240 mg, 2250 mg, 2260 mg, 2270 mg, 2280 mg, 2290 mg, or 2300 mg can be administered subcutaneously.

[0103] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1400 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1575 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1600 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 2100 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 2240 mg, including administration every 21 days.

[0104] In some embodiments, a third-generation EGFR TKI is administered to the subject daily during each of three or more cycles.

[0105] In some embodiments, a third-generation EGFR TKI is administered to the subject daily at a dose of about 80 mg to about 240 mg during each of three or more cycles. In some embodiments, a third-generation EGFR TKI is administered to the subject daily at a dose of about 80 mg.TKI. In some embodiments, a third-generation EGFR TKI is administered to the subject daily at a dose of about 160 mg (see page 14 / 51 of CN 121843963 A). In some embodiments, a third-generation EGFR TKI is administered to the subject daily at a dose of about 240 mg.

[0106] One or more chemotherapeutic agents comprise platinum, optionally wherein the chemotherapeutic agent comprises carboplatin, preferably wherein the chemotherapeutic agent comprises pemetrexed and carboplatin.

[0107] In some embodiments, one or more chemotherapeutic agents are pemetrexed and carboplatin administered on day 1 of each cycle up to and including the fourth cycle (cycle 4).

[0108] In some embodiments, one or more chemotherapeutic agents are pemetrexed administered at a dose of about 500 mg / m2 and carboplatin administered to achieve an area under the curve (AUC) of 5.

[0109] In some embodiments, one or more chemotherapeutic agents are pemetrexed administered at a dose of about 500 mg / m2 and carboplatin AUC 5 administered on day 1 of each cycle up to and including the fourth cycle (cycle 4), wherein pemetrexed is administered on day 1 of each subsequent cycle at a dose of about 500 mg / m2.

[0110] Methods for treating cancers expressing EGFR or c-Met The disclosed methods may be used to treat a subject with cancers expressing EGFR or c-Met. Cancers expressing EGFR or c-Met may include those associated with wild-type EGFR, EGFR mutations, EGFR gene amplification, elevated levels of circulating HGF, wild-type c-Met, c-Met mutations, c-Met gene amplification, or mutant KRAS.

[0111] In some embodiments, the EGFR mutations are E709K, L718Q, L718V, G719A, G719X, G724X, G724S, I744T, E746K, L747S, E749Q, A750P, A755V, V765M, C775Y, T790M, L792H, L792V, G796S, G796R, G796C, C797S, T854I, L858P, L858R, L861X, delE746-A750, delE746-T751InsKV, delE746_A750InsHS, delE746_T751InsFPT, delE746_T751InsL, delE746_S752InsIP, delE746_P753InsMS, delE746_T751InsA, delE746_T751InsAPT, delE746_T751InsVA,delE746_S752InsV, delE746_P753InsVS, delE746_K754InsGG, delE746_E749, delE746_ E749InsP、delL747_E749、delL747_A750InsP、delL747_T751InsP、delL747_T751InsN、 delL747_S752InsPT, delL747_P753InsNS, delL747_S752InsPI, delL747_S752, delL747_ P753InsS, delL747_K754, 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 InsX1-7, one or more deletions in EGFR exon 20, or one or more insertions in EGFR exon 20, one or more deletions in EGFR exon 19, or one or more insertions in EGFR exon 19, or any combination thereof, wherein X is any amino acid.

[0112] In some embodiments, the EGFR mutation is one or more deletions in exon 19 or L858R, or any combination thereof.

[0113] In some embodiments, the c-Met mutation is a c-Met exon 14 skipping mutation.

[0114] In some embodiments, the mutant KRAS has a G12V, G12C, or G12A substitution.

[0115] In some embodiments, the subject has been diagnosed with an EGFR mutation prior to administration of the combination therapy.

[0116] In some embodiments, the subject has a newly diagnosed cancer expressing EGFR or c-Met.

[0117] In some embodiments, the subject has not been treated with an EGFR tyrosine kinase inhibitor (TKI).

[0118] In some embodiments, the subject is resistant to treatment with erlotinib or gefitinib or has relapsed after treatment with erlotinib (page 15 / 51, CN 121843963 A) or gefitinib.

[0119] In some embodiments, the subject is resistant to treatment with afatinib or has relapsed after treatment with afatinib.

[0120] In some embodiments, the subject is resistant to treatment with osimertinib or has relapsed after treatment with osimertinib.

[0121] In some embodiments, the cancer expressing EGFR or c-Met is non-small cell lung cancer (NSCLC), epithelial cell carcinoma, 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, pharyngeal cancer, nasal cancer, pancreatic cancer, skin cancer, oral cancer, tongue cancer, esophageal cancer, vaginal cancer, cervical cancer, spleen cancer, testicular cancer, gastric cancer, thymic cancer, colon cancer, thyroid cancer, liver cancer, hepatocellular carcinoma (HCC), or sporadic or hereditary papillary renal cell carcinoma (PRCC).

[0122] In some embodiments, the cancer is NSCLC.

[0123] 1. Treatment of EGFR- or c-Met-expressing cancers in subjects weighing less than 80 kg. A method of treating EGFR- or c-Met-expressing cancers in subjects weighing less than 80 kg may include administering a combination therapy to the subject over three or more 21-day cycles, the combination therapy comprising: (a) pemetrexed and carboplatin, (b) a bispecific antibody comprising an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, the first domain comprising the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, the second domain comprising the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, and the HCDR1 of SEQ ID NO: 6. LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12, and a third-generation EGFR tyrosine kinase inhibitor (TKI) of formula (c) (I), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof,Three or more 21-day cycles include cycle 1, cycle 2, and cycle 3, wherein the administration includes: On day 1 of cycle 1, approximately 350 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5; On day 2 of cycle 1, approximately 1050 mg of bispecific antibody; On day 8 of cycle 1, approximately 1400 mg of bispecific antibody; On day 15 of cycle 1, approximately 1400 mg of bispecific antibody; On day 1 of cycle 2, approximately 1400 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5; On day 1 of cycle 3, approximately 1750 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5. 5% carboplatin; and wherein a third-generation EGFR tyrosine kinase inhibitor (TKI) is administered daily at a dose between about 80 mg and about 240 mg.

[0124] In some embodiments, the bispecific antibody is administered intravenously. In some embodiments, the bispecific antibody is administered subcutaneously.

[0125] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose between about 1400 mg and about 2240 mg. In some implementations, the bispecific anti-EGFR / c-Met antibody is administered at doses of approximately 1400 mg, 1410 mg, 1420 mg, 1430 mg, 1440 mg, 1450 mg, 1460 mg, 1470 mg, 1480 mg, 1490 mg, 1500 mg, 1510 mg, 1520 mg, 1530 mg, 1540 mg, 1550 mg, 1560 mg, 1570 mg, 1575 mg, 1580 mg, 1590 mg, 1600 mg, 1610 mg, 1620 mg, 1630 mg, 1640 mg, 1650 mg, and 1660 mg. Approximately 1670mg, approximately 1680mg, approximately 1690mg, approximately 1700mg, approximately 1710mg, approximately 1720mg, approximately 1730mg, approximately 1740mg, approximately 1750mg, approximately 1760mg, approximately 1770mg, approximately 1780mg, approximately 1790mg, approximately 1800mg, approximately 1810mg, approximately 1820mg, approximately 1830mg, approximately 1840mg, approximately 1850mg, approximately 1860mg, approximately 1870mg, approximately 1880mg, 1890mg, approximately 1900mg, approximately 1910mgApproximately 1920 mg, 1930 mg, 1940 mg, 1950 mg, 1960 mg, 1970 mg, 1980 mg, 1990 mg, 2000 mg, 2010 mg, 2020 mg, 2030 mg, 2040 mg, 2050 mg, 2060 mg, 2070 mg, 2080 mg, 2090 mg, 2100 mg, 2110 mg, 2120 mg, 2150 mg, 2200 mg, 2210 mg, 2220 mg, 2230 mg, 2240 mg, 2250 mg, 2260 mg, 2270 mg, 2280 mg, 2290 mg, or 2300 mg can be administered subcutaneously.

[0126] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1400 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1575 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1600 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 2100 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 2240 mg, including administration every 21 days.

[0127] In some embodiments, carboplatin is administered for no more than four cycles.

[0128] In some embodiments, the third-generation EGFR TKI is administered at a dose of about 80 mg, about 160 mg, or about 240 mg.

[0129] In some embodiments, the third-generation EGFR TKI is administered no more than about 2 hours before the administration of the bispecific antibody.

[0130] 2. Treatment of EGFR- or c-Met-expressing cancers in subjects weighing 80 kg or more. Methods of treating EGFR- or c-Met-expressing cancers in subjects weighing 80 kg or more may include administering a combination therapy to the subject in three or more 21-day cycles, the combination therapy comprising: (a) pemetrexed and carboplatin, (b) a bispecific antibody comprising an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, the first domain comprising the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the SEQ ID NO: 6.LCDR3 of formula (6), 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 a third-generation EGFR tyrosine kinase inhibitor (TKI) of formula (c) (I), or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein three or more 21-day cycles include cycle 1, cycle 2 and cycle 3, and wherein administration comprises: administering approximately 350 mg of bispecific antibody, 500 mg / m2 of pemetrexed and carboplatin to achieve AUC 5 on day 1 of cycle 1; administering approximately 1400 mg of bispecific antibody on day 2 of cycle 1; On day 8 of cycle 1, approximately 1750 mg of bispecific antibody was administered; on day 15 of cycle 1, approximately 1750 mg of bispecific antibody was administered; on day 1 of cycle 2, approximately 1750 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5 were administered; on day 1 of cycle 3, approximately 2100 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5 were administered; and wherein a third-generation EGFR tyrosine kinase inhibitor (TKI) was administered daily at a dose between approximately 80 mg and approximately 240 mg.

[0131] In some embodiments, the bispecific antibody was administered intravenously. In some embodiments, the bispecific antibody was administered subcutaneously.

[0132] In some embodiments, the bispecific anti-EGFR / c-Met antibody was administered subcutaneously at a dose between approximately 1400 mg and approximately 2240 mg. In some implementations, the bispecific anti-EGFR / c-Met antibody is administered at doses of approximately 1400 mg, 1410 mg, 1420 mg, 1430 mg, 1440 mg, 1450 mg, 1460 mg, 1470 mg, 1480 mg, 1490 mg, 1500 mg, 1510 mg, 1520 mg, 1530 mg, 1540 mg, 1550 mg, 1560 mg, 1570 mg, 1575 mg, 1580 mg, 1590 mg, 1600 mg, 1610 mg, 1620 mg, 1630 mg, 1640 mg, 1650 mg, and 1660 mg. Approximately 1670mg, approximately 1680mg, approximately 1690mg, approximately 1700mg, approximately 1710mg, approximately 1720mg, approximately 1730mg, approximately 1740mg, approximately1750mg, approximately 1760mg, approximately 1770mg, approximately 1780mg, approximately 1790mg, approximately 1800mg, approximately 1810mg, approximately 1820mg, approximately 1830mg, approximately 1840mg, approximately 1850mg, approximately 1860mg, approximately 1870mg, approximately 1880mg, 1890mg, approximately 1900mg, approximately 1910mg Approximately 1920 mg, 1930 mg, 1940 mg, 1950 mg, 1960 mg, 1970 mg, 1980 mg, 1990 mg, 2000 mg, 2010 mg, 2020 mg, 2030 mg, 2040 mg, 2050 mg, 2060 mg, 2070 mg, 2080 mg, 2090 mg, 2100 mg, 2110 mg, 2120 mg, 2150 mg, 2200 mg, 2210 mg, 2220 mg, 2230 mg, 2240 mg, 2250 mg, 2260 mg, 2270 mg, 2280 mg, 2290 mg, or 2300 mg can be administered subcutaneously. Instructions for Use, Page 18 / 51, CN 121843963 A

[0133] In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1400 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1575 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 1600 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 2100 mg, including administration every 21 days. In some embodiments, the bispecific anti-EGFR / c-Met antibody is administered subcutaneously at a dose of about 2240 mg, including administration every 21 days.

[0134] In some embodiments, carboplatin is administered for no more than four cycles.

[0135] In some embodiments, the third-generation EGFR TKI is administered at a dose of about 80 mg, about 160 mg, or about 240 mg.

[0136] In some embodiments, the third-generation EGFR TKI is administered no more than about 2 hours before the administration of the bispecific antibody.

[0137] Embodiment 1. A method of treating a subject in need of cancer expressing epidermal growth factor receptor (EGFR) or expressing hepatocyte growth factor receptor (c-Met), the method comprising administering to the subject an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, the first domain comprising the heavy chain intercalation of SEQ ID NO: 1.The complementary determinant region 1 (HCDR1), HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, LCDR1 of the light chain of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, wherein the second 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, at a dose of about 1400 mg to 2100 mg, administered once every 21 days.

[0138] 2. The method according to embodiment 1, wherein the method further comprises administering a third-generation EGFR tyrosine kinase inhibitor (TKI).

[0139] 3. The method according to embodiment 2, wherein the third-generation EGFR TKI has formula (I): (I).

[0140] 4. The method according to embodiment 3, wherein the third-generation EGFR TKI is administered at a dose of 240 mg per day.

[0141] 5. The method according to embodiment 1, wherein the starting dose is a divided dose administered over two consecutive days, wherein if the subject weighs less than 80 kg, the antibody is administered at a dose of approximately 350 mg on day 1 (D1) of the first cycle and at a dose of approximately 1050 mg on day 2 (D2) of the first cycle; or if the subject weighs 80 kg or more, the antibody is administered at a dose of approximately 350 mg on day 1 of the first cycle and at a dose of approximately 1400 mg on day 2 of the first cycle.

[0142] 6. The method according to embodiment 1, wherein the method further comprises an initial cycle (cycle 1), the initial cycle comprising administering the bispecific antibody once weekly for three weeks at a dose of about 1400 mg if the subject's weight is less than 80 kg, or at a dose of about 1750 mg if the subject's weight is 80 kg or more. Specification 19 / 51 pages 22 CN 121843963 A

[0143] 7. The method according to embodiment 6, wherein the method further comprises a second cycle (cycle 2), the second cycle comprising administering the bispecific antibody once every three weeks at a dose of about 1400 mg if the subject's weight is less than 80 kg, or at a dose of about 1750 mg if the subject's weight is 80 kg or more.

[0144] 8. The method according to embodiment 1, wherein the method comprises administering the bispecific antibody once weekly for three weeks at a dose of about 1400 mg if the subject's weight is less than 80 kg, or at a dose of about 1750 mg if the subject's weight is 80 kg or more.The bispecific antibody is administered every 3 weeks at a dose of approximately 1750 mg, or at a dose of approximately 2100 mg if the subject weighs 80 kg or more.

[0145] 9. The method according to embodiment 1, wherein the method further comprises one or more platinum-containing chemotherapeutic agents.

[0146] 10. The method according to embodiment 9, wherein the one or more chemotherapeutic agents comprise pemetrexed and / or carboplatin.

[0147] 11. The method according to embodiment 9, wherein the one or more chemotherapeutic agents are pemetrexed and carboplatin administered on day 1 of each 21-day cycle.

[0148] 12. The method according to embodiment 9, wherein the one or more chemotherapeutic agents are pemetrexed at a dose of approximately 500 mg / m² and carboplatin administered to achieve an area under the curve (AUC) of 5.

[0149] 13. The method according to embodiment 9, wherein the one or more chemotherapeutic agents are pemetrexed administered at a dose of about 500 mg / m2 and carboplatin AUC 5 administered on day 1 of each cycle up to and including the fourth cycle (cycle 4), and wherein pemetrexed is administered on day 1 of each subsequent cycle at a dose of about 500 mg / m2.

[0150] 14. A method of treating a subject weighing less than 80 kg with cancer expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), the method comprising administering a combination therapy to the subject in three or more 21-day cycles, the combination therapy comprising: (a) pemetrexed and carboplatin, (b) a bispecific antibody comprising an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, the first domain comprising the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, the second domain comprising the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, and the HCDR1 of SEQ ID NO: 6. LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12, and a third-generation EGFR tyrosine kinase inhibitor (TKI) of formula (I) (c), or a solvate, hydrate, tautomer, or pharmaceutically acceptable salt thereof, wherein the three or more 21-day cycles comprise a first cycle, a second cycle, and a third cycle, and wherein the administration comprises:On day 1 of cycle 1, administer approximately 350 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5; on day 2 of cycle 1, administer approximately 1050 mg of bispecific antibody; on day 8 of cycle 1, administer approximately 1400 mg of bispecific antibody; on day 15 of cycle 1, administer approximately 1400 mg of bispecific antibody; on day 1 of cycle 2, administer approximately 1400 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5; on day 1 of cycle 3, administer approximately 1750 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5; and wherein the third-generation EGFR tyrosine kinase inhibitor (TKI) is administered daily at a dose between approximately 80 mg and approximately 240 mg.

[0151] 15. The method according to embodiment 14, wherein the bispecific antibody is administered by (a) intravenous administration or (b) subcutaneous administration.

[0152] 16. The method according to embodiment 14 or 15, wherein carboplatin is administered for no more than four cycles.

[0153] 17. The method according to any one of embodiments 14 to 16, wherein the third-generation EGFR tyrosine kinase inhibitor (TKI) is administered at a dose of about 240 mg.

[0154] 18. The method according to any one of embodiments 14 to 17, wherein the third-generation EGFR tyrosine kinase inhibitor (TKI) is administered no more than about 2 hours before the bispecific antibody is administered.

[0155] 19. A method of treating a subject weighing 80 kg or more with cancer expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), the method comprising administering a combination therapy to the subject in three or more 21-day cycles, the combination therapy comprising: (a) pemetrexed and carboplatin, (b) a bispecific antibody comprising an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, the first domain comprising the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and the second domain comprising the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, and the HCDR1 of SEQ ID NO: 6. 10 LCDR1, SEQ ID NO:LCDR2 of SEQ ID NO: 11 and LCDR3 of SEQ ID NO: 12, and a third-generation EGFR tyrosine kinase inhibitor (TKI) of formula (I) (I), or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof, wherein the three or more 21-day cycles comprise cycle 1, cycle 2 and cycle 3, and wherein the administration comprises: administering approximately 350 mg of bispecific antibody, 500 mg / m² of pemetrexed and carboplatin to achieve AUC 5 on day 1 of cycle 1; administering approximately 1400 mg of bispecific antibody on day 2 of cycle 1; administering approximately 1750 mg of bispecific antibody on day 8 of cycle 1; administering approximately 1750 mg of bispecific antibody on day 15 of cycle 1; administering approximately 1750 mg of bispecific antibody and 500 mg / m² of carboplatin on day 1 of cycle 2. The method of embodiment 19, wherein the bispecific antibody is administered at a dose of (a) intravenous administration or (b) subcutaneous administration.

[0157] 21. The method of embodiment 19 or 20, wherein the carboplatin is administered for no more than four cycles.

[0158] 22. The method of any one of embodiments 19 to 21, wherein the third-generation EGFR tyrosine kinase inhibitor (TKI) is administered at a dose of about 240 mg.

[0159] 23. The method of any one of embodiments 19 to 22, wherein the third-generation EGFR tyrosine kinase inhibitor (TKI) is administered no more than about 2 hours before the administration of the bispecific antibody.

[0160] 24. The method according to any one of embodiments 1 to 23, wherein the first domain of the bispecific anti-EGFR / c-Met antibody binds EGFR, and the second domain binds c-Met.

[0161] 25. The method according to embodiment 24, wherein the first domain binding 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 binding c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO: 16.

[0162] 26. The method according to any one of embodiments 1 to 25, wherein the bispecific anti-EGFR / c-Met antibody...The antibody is an IgG1 isotype.

[0163] 27. The method according to any one of embodiments 1 to 26, wherein the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO: 20.

[0164] 28. The method according to any one of embodiments 1 to 27, wherein the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15%.

[0165] 29. The method according to any one of embodiments 1 to 28, wherein the compound of formula (I) or its solvate, hydrate, tautomer or pharmaceutically acceptable salt is lazazetinib mesylate.

[0166] 30. The method according to embodiments 2 to 29, wherein the compound of formula (I) or its solvates, hydrates, tautomers or pharmaceutically acceptable salts are lazazetinib mesylate represented by the compound of formula (II): Specification 22 / 51 pages 25 CN 121843963 A 31. (II).

[0167] 32. The method according to any one of embodiments 1 to 30, wherein the cancer expressing EGFR or c-Met 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.

[0168] 33. The method according to embodiment 31, wherein the EGFR mutation is E709K, L718Q, L718V, G719A, G719X, G724X, G724S, I744T, E746K, L747S, E749Q, A750P, A755V, V765M, C775Y, T790M, L792H, L792V, G796S, G796R, G796C, C797S, T854I, L858P, L858R, L861X, delE746- A750, delE746_T751InsKV, delE746_A750InsHS, delE746_T751InsFPT, delE746_T751InsL, delE746_S752InsIP、delE746_P753InsMS、delE746_T751InsA、delE746_T751InsAPT、 delE746_T751InsVA、delE746_S752InsV、delE746_P753InsVS、delE746_K754InsGG、delE746_E749, delE746_E749InsP, delL747_E749, delL747_A750InsP, delL747_T751InsP, delL747_T751InsN, delL747_S752InsPT, delL747_P753InsNS, delL747_S752InsPI, delL747_S752, delL747_P753InsS, delL747_K754, 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 InsX1-7, one or more deletions in EGFR exon 20, or one or more insertions in EGFR exon 20, one or more deletions in EGFR exon 19, or one or more insertions in EGFR exon 19, or any combination thereof, wherein X is any amino acid.

[0169] 34. The method according to embodiment 31 or 32, wherein the EGFR mutation is one or more deletions in exon 19 or L858R, or any combination thereof.

[0170] 35. The method according to embodiment 31, wherein the c-Met mutation is a c-Met exon 14 skipping mutation.

[0171] 36. The method according to embodiment 31, wherein the mutant KRAS has a G12V, G12C, or G12A substitution.

[0172] 37. The method according to any one of embodiments 1 to 35, wherein the subject has been diagnosed with the EGFR mutation prior to administration of the bispecific antibody.

[0173] 38. The method according to any one of embodiments 1 to 36, wherein the subject has a newly diagnosed cancer expressing EGFR or c-Met.

[0174] 39. The method according to any one of embodiments 1 to 37, wherein the subject has not been treated with an EGFR tyrosine kinase inhibitor (TKI). Specification 23 / 51 pages 26 CN 121843963 A

[0175] 40. The method according to any one of embodiments 1 to 37, wherein the subject has progressed during or after EGFR-TKI treatment.

[0176] 41. The method according to embodiment 39, wherein the subject is resistant to or has relapsed after treatment with: erlotinib, gefitinib, lapatinib, vandetanib, afatinib, osimertinib, poziotinib, critinib, cabozantinib, carmatinib, axitinib, lenvatinib, nintedanib, regorafenib, pazopanib, sorafenib, or sunitinib.

[0177] 42. The method according to embodiment 39, wherein the subject is resistant to osimertinib treatment or has relapsed after treatment with osimertinib.

[0178] 43. The method according to embodiment 1 of any one of 41, wherein the cancer expressing EGFR or c-Met is lung cancer.

[0179] 44. The method according to embodiment 42, wherein the cancer is NSCLC.

[0180] 45. A method of treating a subject weighing less than 80 kg with cancer expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), the method comprising administering a combination therapy to the subject in three or more 21-day cycles, the combination therapy comprising: (a) pemetrexed and carboplatin, (b) a bispecific antibody comprising an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, the first domain comprising the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, the second domain comprising the HCDR1 of SEQ ID NO: 7, the HCDR2 of SEQ ID NO: 8, the HCDR3 of SEQ ID NO: 9, and the HCDR1 of SEQ ID NO: 6. LCDR1 of SEQ ID NO: 10, LCDR2 of SEQ ID NO: 11, and LCDR3 of SEQ ID NO: 12, wherein the three or more 21-day cycles include a first cycle, a second cycle, and a third cycle, and wherein the application comprises:On day 1 of cycle 1, approximately 350 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5 were administered; on day 2 of cycle 1, approximately 1050 mg of bispecific antibody was administered; on day 8 of cycle 1, approximately 1400 mg of bispecific antibody was administered; on day 15 of cycle 1, approximately 1400 mg of bispecific antibody was administered; on day 1 of cycle 2, approximately 1400 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5 were administered; on day 1 of cycle 3, approximately 1750 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5 were administered.

[0181] 46. The method according to embodiment 43, wherein the bispecific antibody was administered intravenously.

[0182] 47. The method according to embodiment 43, wherein the bispecific antibody was administered subcutaneously.

[0183] 48. The method according to embodiment 43, wherein carboplatin is administered for no more than four cycles.

[0184] 49. A method of treating a subject weighing 80 kg or more with cancer expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), the method comprising administering a combination therapy to the subject in three or more 21-day cycles, the combination therapy comprising: (a) pemetrexed and carboplatin, (b) a bispecific antibody comprising an isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, the first domain comprising the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and the second domain comprising the HCDR1 of SEQ ID NO: 7, the heavy chain complementarity-determining region 1 of SEQ ID NO: 4, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and the second domain comprising the HCDR1 of SEQ ID NO: 7, the light chain complementarity-determining region 1 of SEQ ID NO: 4, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, the light chain complementarity-determining region 1 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6, and the light chain complementarity-determining region 1 of SEQ ID NO: 4, the light chain complementarity-determining region 1 of SEQ ID NO: 5, and the light chain complementarity-determining region 1 of SEQ ID NO: 6, and the light chain complementarity-determin The three or more 21-day cycles include cycle 1, cycle 2, and cycle 3, and the administration includes: administering approximately 350 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5 on day 1 of cycle 1; and administering approximately 1400 mg of bispecific antibody on day 2 of cycle 1.On day 8 of cycle 1, approximately 1750 mg of bispecific antibody was administered; on day 15 of cycle 1, approximately 1750 mg of bispecific antibody was administered; on day 1 of cycle 2, approximately 1750 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5 were administered; on day 1 of cycle 3, approximately 2100 mg of bispecific antibody, 500 mg / m² of pemetrexed, and carboplatin to achieve AUC 5 were administered.

[0185] 50. The method according to embodiment 47, wherein the bispecific antibody was administered intravenously.

[0186] 51. The method according to embodiment 47, wherein the bispecific antibody was administered subcutaneously.

[0187] 52. The method according to embodiment 47, wherein carboplatin was administered for no more than four cycles.

[0188] 53. Examples Example 1. Safety and efficacy of combination therapy for treating subjects with cancers expressing EGFR or c-Met.

[0189] This study is the first open-label, multicenter phase I trial conducted in humans to evaluate the safety, pharmacokinetic (PK) and efficacy of combination therapy (bispecific antibody ervantumab, third-generation EGFR TKI (lazaitinib), and chemotherapy agents carboplatin and pemetrexed administered in 21-day cycles) in subjects with advanced NSCLC.

[0190] 1. Study Overview: The phase 1b LACP combination cohort of lazaitinib, ervantumab, and chemotherapy (LACP) began with a starting dose of 240 mg of lazaitinib administered orally once daily (QD) in combination with ervantumab and standard-dose platinum-based chemotherapy (carboplatin and pemetrexed) for 4 cycles, followed by maintenance with lazaitinib, ervantumab, and pemetrexed until disease progression or unacceptable toxicity. Participants initially received ervantumab via once-weekly IV infusion at a dose of 1400 mg for participants weighing less than 80 kg and 1750 mg for participants weighing 80 kg or more (the first dose was divided into two doses: 350 mg on day 1 of cycle 1 and 1050 mg on day 2 of cycle 1 for participants weighing less than 80 kg and 1400 mg for participants weighing 80 kg or more), until day 1 of cycle 2. Starting on day 1 of cycle 3, participants received ervantumab on day 1 of each 21-day cycle at a dose of 1750 mg for participants weighing less than 80 kg and 2100 mg for participants weighing 80 kg or more.

[0191] If no dose-limiting toxicities (DLTs) are observed, the study can be based on available pharmacokinetics.(PK) and tolerability data determined the recommended 2-phase chemotherapy dose (RP2ChD) for the LACP combination. After identifying the RP2ChD, the study may recruit additional participants, up to a total of up to 20 participants at this dose. If DLT is observed at 240 mg latezatitinib, the study may recommend sequentially reducing the dose of latezatitinib to 160 mg or 80 mg according to a dose reduction schedule. Study objectives and endpoints are shown in Table 1.

[0192] Table 1. Study objectives and endpoints.

[0193] Overall Design This is a phase 1b open-label, multicenter study in participants with advanced EGFR-mutant NSCLC to evaluate safety, tolerability, PK, and to establish the RP2ChD regimen (phase 1b LACP combination cohort) of latezatitinib in combination with ervantumab and platinum-based standard-of-care chemotherapy (carboplatin and pemetrexed).

[0194] The Phase 1b LACP combination cohort begins with a starting dose of 240 mg lazatinib orally once daily (QD) in combination with ervantumab and platinum-based standard-of-care chemotherapy (carboplatin and pemetrexed) for four cycles over 21 days, followed by maintenance with lazatinib, ervantumab, and pemetrexed until disease progression or unacceptable toxicity.

[0195] If no DLT is observed, the study will determine the RP2ChD of the LACP combination based on available PK and tolerability data. After identifying the RP2ChD of the LACP combination, the study will recruit up to approximately 20 evaluable participants at this dose. If dose-limiting toxicity (DLT) is observed at 240 mg lazatinib, the study may recommend sequentially reducing the dose of lazatinib to 160 mg or 80 mg according to a dose-reduction schedule. Up to six participants may initially be recruited for three DLT-evaluable participants. The DLT period will be either 21 days or the first cycle of the combination therapy. The study will review the DLT cohort to assess tolerability and determine the recommended dose of lazatinib in combination with ervantumab and chemotherapy.

[0196] The Phase 1b LACP combination cohort recruited up to 6 participants in a conventional 3+3 design to ensure at least 3 DLT-evaluable participants. Dose tapering may be performed if the initial dose of lazatinib is deemed intolerable to ervantumab and chemotherapy (carboplatin-pemetrexed).

[0197] Dosage and administration in the LACP combination cohort (Phase 1b) Lazatinib was administered orally QD in a 21-day cycle. During Cycle 1, ervantumab was administered once weekly via IV infusion (the first dose was split into two doses and given on Day 1 and Day 2 of Cycle 1) until Day 1 of Cycle 2. In subsequent cycles, ervantumab was administered every 3 weeks.

[0198] On day 1 of each cycle, chemotherapy (pemetrexed and carboplatin) and ervantomab should be administered in the following order: (Instructions for Use, page 26 / 51, 29 CN 121843963)A. Perform: 1) Pemetrexed, 2) Carboplatin, and 3) Evantumab.

[0199] The duration of carboplatin and pemetrexed infusions should follow local guidelines and regulatory labels (e.g., pemetrexed may be administered over approximately 10 to 15 minutes, and carboplatin may be administered over approximately 30 to 60 minutes).

[0200] Pharmacokinetic Evaluation of Lazazetinib: Plasma samples were collected at specified time points to evaluate the PK of lazazetinib. Individual PK parameters were estimated, and descriptive statistics were calculated for each dose level.

[0201] Evantumab: Serum samples were collected at specified time points to evaluate the PK of vantumab. Individual PK parameters were estimated, and descriptive statistics were calculated.

[0202] Immunogenicity Evaluation: Antibodies binding to anti-vantumab were screened in serum samples, and titers of confirmed positive samples were reported. Further analyses may be performed to further characterize the immunogenicity of vantumab.

[0203] Pharmacokinetics and Biomarker Evaluation: Blood samples were collected for circulating tumor deoxyribonucleic acid (ctDNA) analysis.

[0204] Collected and archived tumor tissue samples may be evaluated for cancer-related biomarkers and / or analyzed to confirm ctDNA results. EGFR and cMet protein levels may also be assessed in tissue samples.

[0205] Safety Evaluation: The safety of lazazetinib and ervantumab was assessed through physical examination, Eastern Oncology Cooperative Group performance status criteria, laboratory tests, vital signs, electrocardiogram, baseline ophthalmological examination, echocardiography, or multi-gated collection and concomitant drug use. AEs occurring between informed consent and 30 days after the last dose of study intervention will be recorded. The severity of AEs will be assessed using NCI-CTCAE version 5.0.

[0206] Statistical methods employed a conventional 3+3 design for the phase 1b LACP combination cohort, in which up to 6 participants were recruited to achieve at least 3 DLT-evaluable participants at the first dose level of latezitinib (240 mg). Additional dose cohorts could be evaluated at 160 mg, and if necessary, then 80 mg of latezitinib (modified with 80 mg reductions, where the minimum dose is 80 mg) in a dose-reduction schedule. Once tolerability was demonstrated and RP2ChD was identified, additional participants (up to approximately 20 participants) could be recruited to further characterize the safety, tolerability, and pharmacokinetics of the combination of latezitinib at the recommended dose within the 21-day dosing regimen with ervantumab and chemotherapy (RP2ChD).

[0207] A schematic overview of the study is provided in Figure 1.

[0208] The activity schedule for the phase 1b latezitinib, ervantumab, and chemotherapy combination (LACP) cohort is detailed in Table 2.

[0209] Table 3 details the pharmacokinetics and immunogenicity activity schedule for the Phase 1b LACP combination cohort.

[0210] Table 2.1b Activity Schedule for the Lazazinib, Evantuzamab, and Chemotherapy Combination (LACP) Cohort Instructions for Use 27 / 51 pages 30 CN 121843963 A Instructions for Use 28 / 51 pages 31 CN 121843963 AC = Cycle; ctDNA = Circulating Tumor DNA; D = Day; ECOG = Eastern Cooperative Oncology Group; EGFR = Epidermal Growth Factor Receptor; HGF = Hepatocyte Growth Factor; min = Minute.

[0211] a. Unless otherwise stated, the dosing date should be assessed prior to administration of the study intervention. Investigators may confirm that participants meet the retreatment criteria (except for administration of Evantuzamab on day 2 of cycle 1) prior to administration of the study intervention.

[0212] b. Participants who fail to meet inclusion and / or exclusion criteria and whose conditions change but who can sign a new informed consent form may be rescreened. Rescreening may be discussed with and approved by the sponsor on a case-by-case basis.

[0213] c. Informed consent may be obtained before any study-related procedures are performed. If the assessment is performed as part of a participant’s routine clinical evaluation and not specifically for the study, it does not need to be repeated after obtaining signed informed consent, provided the assessment meets the study requirements.

[0214] d. Include age (or year of birth), sex, race, and ethnicity.

[0215] e. Include tumor type and date of initial diagnosis and metastatic disease, tumor stage at initial diagnosis, histological and EGFR mutation status, previous anticancer therapies (number and type of previous regimens, best response and duration of therapy), and date of most recent disease progression.

[0216] f. Include relevant past medical diagnoses, surgeries / procedures, and current medical conditions with toxicity levels (including current cancer-related symptoms).

[0217] g. If the assessment is performed within 3 days prior to the administration of the first study intervention, it does not need to be repeated on day 1 of cycle 1. Instructions for Use, Pages 29 / 51, 32, CN 121843963 A

[0218] h. CT scans of the chest (including the supraclavicular region), abdomen, pelvis, and any other disease sites using IV contrast agents. Participants who cannot undergo CT scans with IV contrast agents (e.g., due to allergy or renal insufficiency) may undergo non-contrast CT scans of the chest and MRI of the abdomen and pelvis with IV contrast agents at baseline and during the study, provided the sponsor approves. Contraindications to CT scans with IV contrast agents that occur after baseline should be discussed with the sponsor's medical monitor. MRI should be used to evaluate sites of disease that cannot be adequately imaged using CT (e.g., the brain). Other types of imaging, such as bone scintigraphy, may also be performed based on the investigator's clinical judgment and local standards of care. The guidelines for the use of imaging techniques to determine the appropriate level of contrast agent should also be followed.RECIST v1.1 guidelines for determining disease progression. At screening, all participants are required to undergo a brain MRI. The scan will serve as a baseline for disease assessment / tumor response.

[0219] i. When chemotherapy and ervantumab are administered on the same day, pemetrexed (and carboplatin, up to cycle 4) should be administered before ervantumab.

[0220] j. Any missed planned doses in cycle 1 should be discussed with the medical supervisor before re-administration. For other cycles, refer to specific toxicity management guidelines. Safety assessments should be consistent with the dosing visit, regardless of the planned visit window. See Figure 2 for options for synchronizing ervantumab and chemotherapy doses.

[0221] k. The results of the screening assessment can be reviewed by the investigator prior to recruitment; on the dosing day, the investigator can review the laboratory assessment before administering any study intervention. From C2D1, laboratory assessments can be performed the day before administering the study intervention.

[0222] l. If abnormal, a urine microscopy is performed. m. Only for women of childbearing potential. Serum or urine tests required at screening and within 24 hours prior to the first study intervention administration. Serum or urine pregnancy tests may be performed at other times during the study period as indicated.

[0223] n. A single assessment is performed after the participant has rested in a supine position for at least 5 minutes. Clinically significant abnormal results should be confirmed by a triplicate assessment in which repeated ECGs are obtained as closely as possible consecutively. Results will be recorded.

[0224] o. A 12-lead ECG (triplicate, approximately 2 minutes apart) should be performed at C1D1 prior to lavatinib administration and at C3D1 after the EOI of elevantumab (within 30 minutes) (between 2 and 3 hours after lavatinib administration).

[0225] p. An ophthalmological assessment, including slit-lamp examination, fundus examination, and eye examination (including visual acuity and intraocular pressure measurements), is performed at screening. Baseline examination results are collected, and photographs are taken to record baseline status.

[0226] q. Including heart rate, blood pressure, body temperature, respiratory rate, and oxygen saturation. Vital signs should be measured within 15 minutes before lazazetinib administration (pre-administration), within 30 minutes before each epantuma infusion, at approximately 30-minute intervals (+5 minutes) during each epantuma infusion, and at EOI (+5 minutes, end of infusion). If pre-laczazetinib vital signs are collected ≤30 minutes before epantuma infusion, no repeat assessment is required before epantuma infusion. If lazazetinib is not administered, pre-administration vital signs should be measured within 30 minutes before epantuma infusion.

[0227] r. At all visits following administration of the first dose of the study intervention, participants should be asked about skin and eye symptoms, a physical examination should be performed where appropriate, and a specialist referral should be made as directed. On day 1 of each cycle, weight should be obtained, and a medical history should be recorded.Perform targeted physical examinations of the organs and other body systems involved, as indicated.

[0228] s. If applicable, at screening, CT, MRI and other imaging / examinations of all active disease sites shall be performed at 6 (+1) weeks (i.e., no earlier than day 42), and then every 6 (±1) weeks relative to day 1 of cycle 1; repeat CNS imaging may be performed during treatment as clinically indicated. Results shall be recorded. The same methodology shall be used throughout the study. Researchers shall assess tumor response according to RECIST v1.1. Assessment results shall be available prior to the next planned dose. For participants who interrupt treatment before disease progression, radiological assessments shall continue according to the protocol schedule until disease progression is recorded. Instructions 30 / 51 pages 33 CN 121843963 A If a participant who interrupted treatment begins a new cancer therapy before progression, disease assessment shall be performed prior to the start of the new therapy.

[0229] t. Single sample collection for exploratory ctDNA assessment at screening, before administration and 2 hours before administration on day 1 of cycle 3 and day 1 of cycle 5, and at the end-of-treatment visit 30 (+7) days after the last dose. Additional ctDNA samples will be collected at PD and before any systemic anticancer therapy if the participant is receiving treatment beyond disease progression.

[0230] u. Archived samples from the most recent biopsy should be submitted if available (preferably after EGFR-TKI, e.g., osimertinib). If not available, previous tumor tissue may be submitted.

[0231] v. End-of-treatment visit is conducted when all study drugs are permanently discontinued.

[0232] Table 3: Activity schedule for pharmacokinetics and immunogenicity (for phase 1b LACP combination cohort) EOI = end of infusion; hr = hour; min = minute; PK = pharmacokinetics.

[0233] w. Lazazetinib is administered before the start of chemotherapy infusion.

[0234] x. Evaluation should be performed on the actual day of administration of the study intervention, not on the originally planned day of administration.

[0235] y. Pre-dosing / pre-infusion samples will be collected relative to the administration of its corresponding study intervention. Furthermore, all pre-dosing instructions (pages 31 / 51, CN 121843963 A) should be completed before the start of any study intervention administration.

[0236] z. Within 15 minutes of the completion of the elevantumab infusion, EOI samples will be collected relative to the elevantumab infusion.

[0237] aa. Samples will be collected after cycle 4, and then every 13 cycles at cycles 6, 8, 10, 12, 18, 24, and thereafter until the end of treatment.

[0238] bb. When elevantumab is administered as a fractionated dose, samples should be collected based on the schedule for days 1 and 2 of cycle 1.

[0239] 2. Study: Lazazinib, Evantumab and Platinum-based Double Chemotherapy (LACP) Combination Phase 1b LACP Combination Cohort To achieve at least 3 DLT-evaluable participants, 3 to 6 participants received 240 mg of lazazinib orally as a starting dose in combination with ervantumab and standard-dose platinum-based chemotherapy (carboplatin and pemetrexed) in 21-day cycles for 4 cycles, followed by maintenance with lazazinib, ervantumab and pemetrexed until disease progression or unacceptable toxicity. Participants initially received etanerpab via once-weekly IV infusion at a dose of 1400 mg for participants weighing less than 80 kg and 1750 mg for participants weighing 80 kg or more (the first dose was divided into two administrations: 350 mg on day 1 of cycle 1 and 1050 mg on day 2 of cycle 1 for participants weighing less than 80 kg and 1400 mg for participants weighing 80 kg or more), until day 1 of cycle 2. Starting on day 1 of cycle 3, participants received etanerpab on day 1 of each 21-day cycle at a dose of 1750 mg for participants weighing less than 80 kg and 2100 mg for participants weighing 80 kg or more. If none of the first three participants with evaluable DLT had experienced DLT, this dose could be considered as LACP combined with RP2ChD in this study. If one of the first three participants with evaluable DLT had experienced DLT, at least three additional participants were recruited and treated at this dose level for safety reasons. In these cases, if no DLT occurs in any additional DLT-evaluable participants (i.e., <33% of participants experienced DLT at the current dose level), all additional participants in the cohort can complete cycle 1 of treatment. If the initial 240 mg dose of latezitinib is found to be intolerable (i.e., DLT is observed in ≥33% of participants), the study may recommend exploring a cohort of 3 to 6 participants in each cohort with a reduced dose of latezitinib of 160 mg followed by 80 mg according to a dose reduction schedule. The LACP combination RP2ChD will not exceed the dose level where <33% of participants experienced DLT. After identifying the latezitinib RP2ChD, the study may recommend additional recruitment of up to approximately 20 participants at that dose.

[0240] The Phase 1b LACP combination cohort was divided into two periods: 1) a screening period, in which eligibility for participants was reviewed prior to administration of the first dose of the study intervention; and 2) a treatment period, which began with the first dose and continued until the end of treatment visits.

[0241] The definition of dose-limiting toxicity is based on NCI-CTCAE version 5.0, which classifies toxicity as an adverse event related to the study intervention into severity categories.Grade. Toxicity occurring during Cycle 1, covering the period from the first administration of lasazolidinib to day 21 (Phase 1), will only be used to define DLT and for dose escalation decisions. For participants in the Phase 1b LACP combination cohort, the DLT period begins on day 1 of Cycle 1 with the onset of lasazolidinib and ends on day 21 of Cycle 1 (21-day DLT period). Dose-limiting toxicity is defined as any of the following: ≥ Grade 3 non-hematologic toxicity.

[0242] - Exceptions are as follows: ○ Grade 3 nausea, vomiting, or diarrhea responding to symptomatic treatment ○ Grade 3 fatigue in participants who had Grade 1 or 2 fatigue at baseline ○ Clinically significant transient Grade 3 laboratory abnormalities not perceived by the investigator ○ Rash improved to <Grade 3 within 5 days with standard management (Instructions for Use 32 / 51, page 35, CN 121843963 A) Elevated liver enzymes meeting these criteria: Alanine aminotransferase (ALT) ≥3 × Upper Limit of Normal (ULN) (if baseline is normal; if baseline is abnormal for the LACP cohort, then ≥3.0 × baseline) and total bilirubin ≥2 × ULN (if baseline is normal; if baseline is abnormal for the LACP cohort) (>35% direct bilirubin), no evidence of elevated alkaline phosphatase (ALP) or ALT ≥3 × ULN (if baseline is normal; if baseline is abnormal for the LACP cohort, then ≥3.0 × baseline) and International Normalized Ratio (INR) >1 5. No ALP elevation. Bilirubin elevation is an exception if the participant has Gilbert's disease and the bilirubin elevation is primarily unconjugated.

[0243] - If confirmed by repeated laboratory evaluation, the event should also be reported as a serious adverse event (SAE).

[0244] For the LACP combination cohort, participants received <80% of the planned total dose of latezitinib during cycle 1 due to toxicity (i.e., <4,032 mg over 21 days).

[0245] Dose reduction in the LACP combination cohort: In the phase 1b LACP combination cohort, up to 6 participants were recruited to achieve at least 3 DLT-evaluable participants. In cases where the initial dose of latezitinib was deemed intolerable to ervantumab and chemotherapy (carboplatin-pemetrexed), dose reduction could be carried out after study review and agreement, based on the planning strategy outlined in Table 4 and Figure 1 and the safety profile in already-administered participants. The study will review the PK profile when it becomes available.

[0246] Table 4: Lazazinib Dosage Escalation Plan Table 1b LACP Combination Cohort Starting Dose This study included ervastatinib starting doses of 1400 mg for participants <80 kg and 1750 mg for participants ≥80 kg on days 1 / 2, 8, and 15 of cycle 1 and day 1 of cycle 2, as well as ervastatinib starting doses of 1400 mg for participants <80 kg and 1750 mg for participants ≥80 kg.A dose-reduction regimen of 240 mg lazatinib was used in combination with standard chemotherapy. In cases where the starting dose of lazatinib was deemed intolerable to ervatumab and chemotherapy, dose reduction was performed based on safety in the dosing participants, following the planning strategy outlined in Table 4.

[0247] The study population in the Phase 1b LACP combination cohort consisted of patients with advanced or metastatic EGFR-mutant NSCLC who progressed while or after EGFR-TKIs were the most recent line of treatment, with up to three prior lines of treatment in the metastatic setting.

[0248] PK and Immunogenicity Assessment Plasma samples were collected to evaluate the PK of lazatinib. PK for the Phase 1b LACP combination cohort (Table 3) is shown in Table 3.

[0249] Serum samples were collected to evaluate the PK and immunogenicity of ervatumab. PK for the Phase 1b LACP combination cohort (Table 3) is shown in Table 3.

[0250] Definition of Study Completion: Study completion is considered to be the last planned study evaluation shown in the activity schedule of the last participant in the study (Error! Citation source not found. and Table 3), or termination of the study by the sponsor, whichever occurs first. Within the time frame specified in the clinical trial agreement, final data from the research center will be sent to the sponsor (or designated party) after the final participant evaluation at that research site is completed.

[0251] Definition of Study Completion: A participant is considered to have completed the study if they die before the end of the study, or have not lost follow-up or withdrawn their consent by the end of the study. Specification 33 / 51 pages 36 CN 121843963 A

[0252] 3. Study Population: Screening of eligible participants is conducted within 28 days prior to administration of the study intervention.

[0253] Inclusion Criteria: Each participant meets all of the following study recruitment criteria: Participants will be ≥18 years of age, or of legal consent age in the jurisdiction where the study is conducted. For the stage 1b LACP combined cohort: Histologically or cytologically confirmed advanced or metastatic EGFR-mutant NSCLC that progressed while or after EGFR-TKI as the most recent line of treatment, where up to 3 prior lines of treatment are permitted in a metastatic setting. Evaluable disease: Participants will have measurable disease according to RECIST v1.1. Biopsies of measurable lesions should not be performed during screening, but if only one radiotherapy-naïve measurable lesion is present, it is acceptable for diagnostic biopsy and as a target lesion, provided that a baseline tumor assessment scan is performed at least 7 days after the biopsy. Participants will have an ECOG performance status grade of 0 or 1 for organ and bone marrow function as shown in Table 5: Table 5.a Creatinine clearance will be calculated using the Cockroft-Gault formula and should be >50 mL / min. Estimated creatinine clearance for adultsThe Cockcroft-Gault formula for creatinine clearance was calculated according to Equation 1: eCrCl = (140 - age) × mass (kg) × [0.85, for females]72 × serum creatinine (mg / dL) or according to Equation 2: eCrCl = (140 - age) × mass (kg) × constant serum creatinine (µmol / L) Where the constant = 1.23 for males and 1.04 for females. Participants met the above laboratory criteria and had no history of red blood cell transfusion, platelet transfusion, or granulocyte colony-stimulating factor support within 7 days prior to the test. Instructions for Use, Pages 34 / 51, No. 37, CN 121843963 A. Prior to recruitment, women of reproductive potential must be either not of childbearing potential or of childbearing potential, and must be using a highly effective, user-independent method of contraception and another method, and agree to maintain the use of the highly effective method until 6 months after the last dose. Women of reproductive potential must: - Have negative serum or urine β-human chorionic gonadotropin at screening. - Agree not to breastfeed during the study and for 6 months after the last dose of the study intervention. (Recruitment is not permitted even if a breastfeeding woman has stopped breastfeeding). - Agree not to donate eggs (ovaries, oocytes) for assisted reproductive purposes during the study and for 6 months after the last dose of the study intervention. Men who have sexual intercourse with women of reproductive potential agree to continue using contraception throughout the study, including for up to 6 months after the last dose of the study intervention. Willing and able to comply with the prohibitions and restrictions set forth in this protocol (prohibited lazatinib drugs and therapies). Each participant signed an informed consent form (ICF) indicating that he or she understands the purpose and required procedures of the study and is willing to participate in the study. Exclusion Criteria Any potential participant meeting any of the following criteria was excluded from participation in the study: 1. The participant has an uncontrolled illness, including but not limited to: • Uncontrolled diabetes • Persistent or active infection (including infection requiring treatment with antimicrobial therapy [participants will need to complete antibiotics 1 week prior to starting study treatment] or diagnosed or suspected viral infection). • Active bleeding • Impaired oxygenation requiring continuous oxygen supplementation • Intractable nausea and vomiting, chronic gastrointestinal disease, inability to swallow prepared products, or previous significant bowel resection that would impair adequate absorption of study treatment • Mental illness or any other condition that would limit adherence to study requirements (including social circumstances) • Clinical instability or any ophthalmic condition requiring treatment 2. Prior treatment with anti-PD-1 or anti-PD-L1 antibodies within 6 weeks of the planned first dose of the study intervention. 3. Prior treatment within 2 weeks or 4 half-lives (whichever is longer) prior to the first administration of the study intervention.Chemotherapy, targeted cancer therapy, immunotherapy (see Exclusion Criteria #2 for Anti-PD-1 or Anti-PD-L1 Therapies), or treatment with an investigational anticancer agent. For agents with long half-lives, the maximum required time from the last dose is 4 weeks. Note: Local radiotherapy for palliative purposes should be completed at least 7 days before the first administration of the study intervention. 4. Untreated brain or other CNS metastases, whether symptomatic or asymptomatic. Participants who have completed definitive therapy, are not taking steroids, and have a stable clinical status for at least 2 weeks prior to study treatment may be eligible. If brain metastases are diagnosed on screening imaging, participants may be recruited or re-evaluated after definitive therapy if they meet the above criteria. 5. Any toxicities from previous anticancer therapies should have regressed to CTCAE version 5.0 grade 1 or baseline levels (except for alopecia [any grade], ≤ grade 2 peripheral neuropathy, and ≤ grade 2 hypothyroidism stabilized on hormone replacement therapy). Instructions for Use, Page 35 / 51, No. 38, CN 121843963, A 6. A history of clinically significant cardiovascular disease, including but not limited to: Newly diagnosed deep vein thrombosis or pulmonary embolism within 4 weeks prior to the first dose of study intervention. Clinically insignificant thrombosis (such as non-obstructive catheter-related clots) is not excluded. Participants with a history of deep vein thrombosis or pulmonary embolism should be clinically stable for at least 4 weeks prior to the first dose of study intervention during anticoagulation therapy. Any of the following within 24 weeks prior to the first dose of study intervention: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary / peripheral artery bypass grafting, or any acute coronary syndrome. Prolonged corrected QT interval caused by a Fredericia (QTcF) interval >480 ms, or clinically significant arrhythmias or electrophysiological disorders (e.g., implantation of an implantable cardioverter-defibrillator or atrial fibrillation with an uncontrolled rate or abnormal conduction or morphology of the ECG [e.g., complete left bundle branch block, third- or second-degree heart block, PR interval >250 ms]). Note: Clinically stable participants with a pacemaker are eligible. Any factor that increases the risk of corrected QT interval (QTc) prolongation or arrhythmic events (such as hypokalemia, congenital long QT syndrome, a family history of hereditary long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative) or any concomitant medications known to prolong the QT interval or induce torsades de pointes ventricular tachycardia. Uncontrolled (persistent) hypertension: systolic blood pressure >180 mmHg; diastolic blood pressure >100 mmHg. Congestive heart failure, defined as New York Heart Association class III-IV or hospitalization for congestive heart failure (any New York Heart Association class) within 6 months prior to the first dose of study intervention. Pericarditis / clinically significant pericardial effusion. Myocarditis.Phase 1b Lazatinib + JNJ-327 Extended and LACP Combination Cohort: Baseline LVEF below the lower limit of normal (LLN), as assessed by screening echocardiography or multi-gated acquisition (MUGA) scan. 7. Any disallowed therapy or concomitant therapy prior to the planned first dose of study intervention. 8. Hypersensitivity, allergy, or intolerance to latzatinib or ervantumab or their excipients. For the LACP Combination Cohort: Participants had contraindications to carboplatin or pemetrexed. Participants had a history of hypersensitivity to or inability to take vitamin B12 or folic acid. 9. Received a study intervention (including study vaccines, but excluding anticancer therapies [see Exclusion Criterion #2]) or used an invasive study medical device within 6 weeks prior to the planned first dose of study intervention. 10. Have or plan to have any of the following: Invasive surgical procedures involving the body cavity or major surgery (e.g., requiring general anesthesia) without full recovery within 4 weeks or before Day 1 of Cycle 1, excluding placement of vascular access or percutaneous tumor biopsy. Thoracentesis (if needed and / or clinically indicated) and percutaneous biopsy of tumor tissue samples (if needed) may be performed less than 4 weeks before Day 1 of Cycle 1, provided that the participant has adequately recovered from surgery prior to the first dose of the study intervention, based on the investigator's clinical judgment. Significant traumatic injury within 3 weeks prior to the start of Day 1 of Cycle 1 (all wounds should be fully healed before Day 1). Any medical condition requiring full wound healing capacity, and where a severe reduction in wound healing capacity during study intervention administration is expected to jeopardize participant safety. Major surgery is expected during administration of the study agent or within 6 months after the last dose of the study intervention. 11. Research site personnel directly associated with this study. Instructions for Use, Page 36 / 51, No. 39, CN 121843963 A 12. Participants must have the following at screening: Positive Hepatitis B (Hepatitis B virus [HBV]) surface antigen (HBsAg) Note: Participants with a history of HBV proven by a positive Hepatitis B core antibody are eligible at screening if they have 1) negative HBsAg and 2) HBV DNA (viral load) below the lower limit of quantitation. Participants with positive HBsAg due to recent vaccination are eligible if HBV DNA (viral load) is below the lower limit of quantitation, depending on local testing. Positive Hepatitis C (Hepatitis C virus [HCV]) antibody (anti-HCV) Note: Participants who are positive for HCV antibodies are eligible only if the polymerase chain reaction is negative for HCV ribonucleic acid (RNA). Other clinically active infectious liver diseases. 13. Positive human immunodeficiency virus antibody, or a positive human immunodeficiency virus test at screening. 14.15. A participant has an active or past history of ILD / pneumonia, including drug-induced or radiation-induced ILD / pneumonia. 16. Any condition that the investigator believes will impair the participant's ability to receive or tolerate the planned treatment at the study site, their ability to understand informed consent, or that the researcher believes will hinder the participant's participation in the study or obscure the study's outcomes. 17. The participant has a serious underlying medical or psychiatric condition (e.g., alcohol or drug abuse), including drug-induced or radiation-induced ILD / pneumonia. 18. The researcher believes that participation in this study is not in the participant's best interest (e.g., will impair their health) or may prevent, limit, or obscure the assessment specified in the protocol. 19. The participant has leptomeningeal metastatic disease, whether currently active or a prior history. 10. The participant has uncontrolled tumor-related pain (symptomatic lesions suitable for palliative radiation therapy [e.g., bone metastases or metastases causing nerve impact] should be treated prior to screening). All study recruitment criteria should be met at the time of screening. If a participant’s clinical status changes after screening but before the first dose of the study intervention (including any available laboratory results or receipt of additional medical records) such that the participant no longer meets all eligibility criteria, supportive care may be administered, if necessary, to make the eligibility criteria compliant and to allow for a repeat laboratory test to determine the participant’s eligibility for the study. If the recruitment criteria are not met after further evaluation, the participant should be excluded from the study.

[0254] Contraindicated Drugs and Therapies for Lazazinib Lazazinib is an investigational drug. Lazazinib is considered unlikely to cause clinically significant drug interactions by inducing or inhibiting cytochrome P450 (CYP) enzyme activity. Strong inducers of CYP3A4 can reduce lazazinib exposure when administered concomitantly.

[0255] All patients receiving lazazinib should avoid drugs and herbal supplements known to have strong inducer effects on CYP3A4. Strong inducers of CYP3A4 (including those listed below (Table 6)) should be identified during screening and interrupted for an appropriate period before initiating a study treatment regimen that includes lazazinib.

[0256] The inhibitory potential of CYP3A4 / 5 on lazatinib exposure is considered low at clinically relevant concentrations. To ensure patient safety, the use of drugs known to be strong inhibitors of CYP3A4 and substrates of CYP3A4 / 5 is restricted, and they should be avoided or used with caution where possible (Table 7).

[0257] Table 6. List of prohibited drugs and therapies for lazatinib as a strong inducer of CYP3A4 / 5 (Prescription 37 / 51 pages 40 CN 121843963 A) Table 7. List of restricted drugs and therapies as strong inhibitors and substrates of CYP3A4 / 5 This list is not intended to be exhaustive, and similar restrictions will apply to drugs known to induce or inhibit CYP3A4 / 5 activity.Other agents, or other agents that serve as substrates for CYP3A4 / 5.

[0258] 4.1b Phase LACP Combination Cohort Dosing and Administration Participants received a combination of lazazetinib with ervantumab, carboplatin, and pemetrexed chemotherapy in 21-day cycles. Treatment with the study drug continued until disease progression, unacceptable toxicity, or withdrawal of consent. In this cohort: Lazazetinib was administered orally on a QD basis and was the first therapy administered on day 1 of each cycle in the combination regimen. Product Information 38 / 51 pages 41 CN 121843963 A

[0259] For the first 4 cycles, carboplatin and pemetrexed were administered on day 1 of each cycle according to standards of care, in accordance with local guidelines and regulatory labels, followed by maintenance pemetrexed starting from cycle 5.

[0260] Evantumab was administered weekly during cycle 1, with the first dose administered separately (day 1 / day 2, day 8, and day 15), followed by day 1 of each subsequent cycle. After chemotherapy is completed on day 1 of each cycle, elevantumab is infused (Table 8).

[0261] The order of administration of lazatinib, pemetrexed, carboplatin, and elevantumab is summarized in Table 9.

[0262] Table 8: Schedule and order of administration of lazatinib, elevantumab, and combination chemotherapy a. Agents / drugs arranged in the desired order of administration b. Carboplatin is discontinued after 4 cycles c. If a delay in pemetrexed and carboplatin infusion results in a delay in the start of elevantumab, the elevantumab infusion may be delayed until day 2 and day 3 of cycle 1.

[0263] Table 9: Initial administration of lazatinib with elevantumab and combination chemotherapy elevantumab elevantumab is administered by intravenous infusion, and details of each administration are recorded (including the date, start and stop times of the intravenous infusion, and the volume of infusion). Instructions for Use, Pages 39 / 51, 42 CN 121843963 A

[0264] Chemotherapy (Carboplatin and Pemetrexed) Carboplatin and pemetrexed are administered via IV infusion according to local guidelines and / or product label, and details of each administration are recorded (including the date, start and stop times of the IV infusion, and the volume of infusion).

[0265] Contraindicated Drugs and Therapies The following concomitant drugs and therapies are contraindicated during the study: Any chemotherapy, anticancer therapy, or experimental therapy other than the study intervention.

[0266] Radiotherapy to tumor lesions for which tumor response is being evaluated prior to radiological progression.

[0267] Concomitant use of drugs, herbal supplements, and / or intake of foods known to have a potent (strong) inducer or effect on CYP3A4 / 5 activity. Drugs that inhibit CYP3A4 / 5 activity should be avoided where possible, or should be used with caution. The section titled "Contraindicated Drugs and Therapies for Lazatinib" provides guidance on contraindicated drugs requiring close monitoring and clearance periods; see also Tables 6 and 7.

[0268] Live or attenuated vaccines are prohibited.

[0269] Concomitant administration of aminoglycosides with carboplatin should be avoided.

[0270] Caution should be exercised when pemetrexed and nonsteroidal anti-inflammatory drugs are administered concurrently to participants with creatinine clearance <80 mL / min (exception: low-dose aspirin once daily is permitted during the study).

[0271] Ibuprofen should be avoided for 2 days before, on, and 2 days after pemetrexed administration, as ibuprofen increases pemetrexed exposure in patients with creatinine clearance between 45 mL / min and 79 mL / min.

[0272] Restricted Drugs and Therapies The following concomitant drugs and therapies are restricted during the study and should be avoided or used with caution where possible.

[0273] Lazazinib is an inhibitor of P-glycoprotein (P-gp), multidrug resistance protein 4 (MRP4), breast cancer resistance protein (BCRP), and organic cation transporter 1 (OCT1). Therefore, caution should be exercised when using concomitant medications, herbal supplements, and / or foods that serve as substrates for P-gp, MRP4, BCRP, or OCT1. A list of substrates for P-gp, MRP4, and BCRP is provided in Table 10.

[0274] Table 10. Substrates for P-glycoprotein (P-gp), multidrug resistance protein 4 (MRP4), and breast cancer resistance protein (BCRP). Concomitant medications that may lower serum magnesium should be avoided whenever possible due to the potential presence of hypomagnesemia associated with EGFR inhibitors.

[0275] The use of concomitant medications with dual chemotherapy should follow the locally approved product label and clinical practice guidelines. Instructions for use 40 / 51 pages 43 CN 121843963 A

[0276] Consistent with the Phase 1b LACP Combination Cohort – Standard of Care Guidelines for Chemotherapy Prophylaxis, all participants receiving pemetrexed may receive concomitant therapy with corticosteroids, folic acid, and vitamin B12, in accordance with local regulations and consistent with the pemetrexed product label.

[0277] Dosage Modification and Toxicity Management: When applicable, symptomatic treatment should be provided to participants with any grade of drug-related toxicity. If, for any grade of drug-related toxicity, symptoms are intolerable based on the investigator's clinical assessment, the study intervention will be retained until the experienced toxicity recovers to grade ≤1 or baseline (excluding EGFR-TKI-related rashes). The resolution of toxicity in participants who skipped dosing should be assessed.

[0278] Unless an immediate safety risk is identified, any dose / dosage adjustment should be supervised by a medically qualified research site staff member (preferably a principal or associate investigator). However, if the experienced toxicity is considered attributable to ervantumab or lazatinib, the dose of the responsible agent should be reduced first.

[0279] Dosage Modification Guidelines: For participants receiving ervantumab and lazatinib in combination with chemotherapy, regarding the dosage modification of these agents...The decision to modify the dosage should be guided by the observed toxicities, the safety profile of each drug, and the likelihood of causation for each agent. For EGFR inhibition-related toxicities requiring treatment modification, and which are attributable to either drug, latezitinib should be modified prior to modifying the ervantumab dosing. Dosage modifications of latezitinib administered in the LACP combination are shown in Error! Reference source not found.

[0280] Table 11. Guidelines for stepwise dose reduction of latezitinib.

[0281] Dosage modifications of ervantumab are shown in Error! Reference source not found.

[0282] Table 12. Guidelines for stepwise dose reduction of ervantumab.

[0283] For chemotherapy dose modifications, the final treatment decision should be based on clinical judgment, based on local regulations and labels. For participants receiving a combination of ervantumab and latezitinib with chemotherapy, decisions regarding study drug dose modifications should be guided by the safety profile of each drug and the likelihood of causation.

[0284] Chemotherapy dose modifications will be based on the maximum toxicity experienced during the cycle. Treatment should be delayed until toxicity resolves to ≤ grade 1 or the participant’s baseline status.

[0285] During the toxicity study, participants may have up to two dose modifications for each treatment, after which the medication should be discontinued. If multiple toxicities are experienced simultaneously, dose reduction should be based on the most severe toxicity.

[0286] Treatment Delay and Dosing Concurrent with Evantuumab and Chemotherapy (Phase 1b LACP Combination Cohort) Participants receiving combination chemotherapy met the criteria for re-treatment according to local regulations and guidelines and chemotherapy with ervantuumab before being re-administered the corresponding medication. Prescription 41 / 51 pages 44 CN 121843963 A

[0287] 6. Study Evaluation and Procedure Overview The activity plan table (Error! Reference source not found. and Table 3) summarizes the frequency and timing of screening, efficacy, PK, immunogenicity, PD, biomarkers, safety, and other measures applicable to this study.

[0288] Screening Period The screening period begins upon signing the ICF and ends upon initiation of the first study intervention. The screening period included the items listed in the activity plan (Error! Citation source not found.), including review of medical history to determine eligibility for the study, signing of informed consent forms, and completion of all assessments required to verify eligibility before initiating treatment.

[0289] The eligibility criteria were reviewed, and a full clinical evaluation was performed.

[0290] The treatment period began on Day 1 of Cycle 1 with the administration of the study intervention and continued until the end-of-treatment visit was completed. Details of the frequency of study site visits and the procedures performed are outlined in the activity plan (Error! Citation source not found. and Table 3). The most recent measurement taken before the administration of the study intervention on Day 1 of Cycle 1 or at screening was defined as the baseline value. For all participants, an end-of-treatment visit was planned up to 30 days (+7) after the last dose of the study intervention, including thoseParticipants who discontinue the study intervention for any reason other than loss to follow-up, death, or withdrawal of study participation consent.

[0291] Participants will be evaluated for possible toxicities and adverse events throughout the treatment period. Adverse event information will be graded using NCI-CTCAE version 5.0. All grade 3 or 4 adverse events considered relevant to the study intervention and adverse events leading to discontinuation may be tracked until recovery to baseline or ≤ grade 1 or until deemed irreversible. Unresolved events will be tracked for up to 6 months from the start of the last dose of the study intervention.

[0292] End-of-treatment visits will be conducted up to 30 days (+7) after the last dose of the study intervention and should be completed before initiating any subsequent anticancer therapy.

[0293] Efficacy assessments will be performed according to the activity schedule (Error! Reference source not found.) as planned, regardless of any dose modifications. Response assessments will be performed according to RECIST, version 1.1 criteria. The RECIST assessment at baseline should represent all areas involved in metastasis. Tumor assessments should be performed at any point where clinical progression of disease is suspected. Lesions that have been irradiated or partially resected are generally considered unmeasurable at baseline and are tracked as non-target lesions, except for lesions that have progressed after local irradiation or surgery, provided that the investigator and the sponsor’s medical supervisor agree that it is measurable and will not obscure efficacy evaluation. Additionally, lesions biopsied during screening should only be evaluated as target lesions if post-biopsy CT confirms that they still meet the measurability criteria and are suitable for accurate and reproducible measurement. Tumor response will be reported. The following response criteria (according to RECIST, version 1.1) are acceptable: complete response, partial response, stable disease, disease progression, and unmeasurable.

[0294] Partial or complete response acceptance is confirmed by repeated assessments at least 4 weeks from initial observation. For responses eligible as stable disease, follow-up measurements should meet the stable disease criteria at least once within a minimum interval of at least 6 weeks following the first dose of study intervention.

[0295] If symptom worsening (based on overall deterioration of health status) is documented as the basis for determining disease progression, the decision and date should be documented, along with the clinical findings used to make the decision. If possible, every effort should be made to document radiographic progression, even after treatment is interrupted due to symptom worsening, but before subsequent therapy.

[0296] Treatment after initial disease progression: Due to the potential heterogeneity of the disease, the study intervention may continue beyond the tumor progression determined based on RECIST version 1.1 criteria.

[0297] Safety assessment: Adverse events will be reported and followed up by the investigator.

[0298] Any clinically relevant changes occurring during the study will be documented.

[0299] Any clinically significant abnormalities persisting at the end of the study / early withdrawal will be followed up by the investigator until they subside or until clinically stable endpoint conditions are met.

[0300] The study includes the following evaluations of safety and tolerability based on the time points provided in the activity schedule (Error! Reference source not found.).

[0301] Physical Examination Screening Physical examinations include at least the following: height, weight, general appearance, skin, ears, nose, throat, lungs, heart, abdomen, limbs, musculoskeletal system, lymphatic system, and nervous system examinations of participants. At all visits, participants are asked about skin and eye symptoms, and physical examinations are performed where appropriate, and specialist referrals are made as instructed. On day 1 of each cycle, targeted physical examinations of the organs and other body systems involved are performed as instructed, and the participant's weight is obtained.

[0302] Vital Signs Vital sign measurements are obtained as indicated in the activity schedule (Error! Reference source not found.), and include assessments of the following: body temperature, pulse / heart rate, respiratory rate, SpO2 (using a pulse oximeter), and blood pressure.

[0303] Blood pressure and pulse / heart rate measurements were assessed in a seated position using a fully automated device. Manual techniques were used only when the automated device was unavailable.

[0304] Blood pressure and pulse / heart rate measurements should be taken only after the participants have rested in a quiet, undisturbed environment (e.g., television, mobile phone).

[0305] Electrocardiograms (ECGs) were performed locally on all participants according to the activity schedule (Error! Reference source not found). After the participants had rested in a supine position for at least 5 minutes, a single ECG assessment was performed, including measurements of heart rate, QRS axis and PR interval, uncorrected QT interval (QT), QRS, RR, and QTcF.

[0306] QTcF was calculated using the Friedrichshafen formula: QTcF = QT / (RR)^0.33.

[0307] During ECG collection, participants should be in a quiet, undisturbed environment (e.g., television, mobile phone). Participants should rest in a supine position for at least 5 minutes prior to ECG collection and should avoid talking or moving their arms or legs. If the timing of blood sampling or vital sign measurement coincides with the ECG recording time point, the procedure is recommended to proceed in the following order: ECG, vital signs, and blood draw.

[0308] The investigator reviews the printed results, including the ECG morphology, for immediate administration. Clinically significant abnormal results are confirmed by triplicate evaluation, where repeated ECGs are obtained as closely as possible consecutively. Results are recorded. Abnormalities noted during screening are included in the medical history.

[0309] At each time point where triplicate ECGs are required, three separate ECG lines should be obtained as closely as possible consecutively (approximately 2 minutes apart).

[0310] Clinical safety laboratory assessments are performed at the time points indicated in the activity schedule (Error! Reference source not found.) for serum chemistry, blood...Blood samples for hematology and coagulation and urine samples for urinalysis.

[0311] Blood samples for serological and hematological analysis were collected at each visit prior to administration of the study intervention. Screening laboratory results were evaluated prior to participant recruitment in the study. Laboratory values ​​were reviewed prior to administration of each study intervention. Instructions 43 / 51 pages 46 CN 121843963 A

[0312] ECOG performance status was determined at pre-specified time points listed in the activity schedule (Error! Reference source not found.).

[0313] Ophthalmological examination was performed at screening, including slit-lamp examination, fundus examination, and eye examination (including visual acuity and intraocular pressure measurements). If clinically indicated, an appropriate post-baseline ophthalmological assessment should be repeated, in which any clinically significant findings (including those confirmed by an ophthalmologist) are reported as AEs. Post-baseline examination photographs should be taken (if possible) to document any clinically significant findings.

[0314] Echocardiography or multigated acquisition echocardiography or MUGA scan (if echocardiography is unavailable) should be performed as provided in the activity schedule (Error! Reference source not found.).

[0315] Adverse events and serious adverse events should be reported by the participant (or, where appropriate, by a caregiver, surrogate, or legally acceptable representative of the participant) during the study.

[0316] Adverse events should be documented from the date of obtaining signed and dated informed consent until 30 days after the last dose of the study intervention or until the start of subsequent anticancer therapy (if earlier). Adverse events occurring more than 30 days after the last dose of the study intervention should also be reported if they are considered to be related to the study intervention. The investigator will follow up on adverse events and classify them according to NCI-CTCAE version 5.0.

[0317] Any clinically relevant changes that occur during the study, including abnormal laboratory data, will be documented.

[0318] All disease-related events that do not meet the criteria for adverse events or serious adverse events, and all disease-related outcomes that meet the definition of an SAE, will be reported as SAEs, regardless of whether they are part of the protocol-specified assessment.

[0319] Disease progression should not be recorded as an adverse event or serious adverse event; instead, signs and symptoms of clinical sequelae resulting from disease progression / lack of efficacy will be reported if they meet the definition of a serious adverse event (see Adverse Event Definitions and Classifications below).

[0320] Definitions and Classifications of Adverse Events Adverse Events An adverse event is any adverse medical event that occurs in a clinical study participant administering a drug (investigational or non-investigational) product. Adverse events are not necessarily causally related to the intervention. Therefore, an adverse event can be any unfavorable and unexpected sign (including abnormal findings), symptom, or [other unspecified] temporarily associated with the use of a drug (investigational or non-investigational) product.Disease, whether or not related to the drug (investigational or non-investigational) product. (As defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH]).

[0321] This includes any new or worsening event in severity or frequency compared to baseline, or abnormal results of diagnostic procedures, including abnormal laboratory tests.

[0322] Serious adverse events are defined in the ICH and EU guidelines on pharmaceutical warnings for human use as any adverse medical event at any dose that: • results in death • is life-threatening (the participant was at risk of death at the time of the event. It does not refer to events that hypothetically could lead to death if more severe, as stated on page 44 / 51 of the product information sheet, CN 121843963 A.) • requires hospitalization or prolongs an existing hospital stay • results in persistent or severe disability / incapacity • congenital abnormalities / birth defects • is medically significant due to suspected transmission of any infectious agent via the pharmaceutical product.

[0323] If a serious and unexpected adverse event occurs and there is evidence of a causal relationship between the study intervention and the event (e.g., death due to an allergic reaction), the event is reported as a serious and unexpected suspected adverse event, even if it is a component of the study endpoint (e.g., all-cause mortality).

[0324] Unlisted (unexpected) adverse events / reference safety information are considered unlisted if their nature or severity is inconsistent with the applicable product reference safety information. For latezatitinib and ervantuzumab, the predictability of an adverse event will be determined by whether it is listed in the investigator's brochure.

[0325] Adverse events associated with the use of the intervention are considered associated with the use of the intervention if, according to the definition listed below (see the attribute definition below), the attribute is probable, likely, or highly probable.

[0326] Adverse events whose attribute definition is irrelevant are not related to the use of the intervention.

[0327] Adverse events that are suspected to have alternative explanations, such as concomitant treatment, concomitant disease, or temporal relationship, suggest that a causal relationship is unlikely.

[0328] Adverse events may be due to the use of the intervention. Alternative explanations (e.g., concomitant treatment, concomitant disease) are indeterminate. The temporal relationship is plausible; therefore, causation cannot be ruled out.

[0329] Adverse events are very likely due to the use of the intervention. The temporal relationship is suggestive (e.g., confirmed by de-stimulation). Alternative explanations, such as concomitant treatment, concomitant disease, are unlikely.

[0330] Adverse events are very likely to be listed as possible adverse reactions and cannot be reasonably explained by alternative explanations (e.g., concomitant treatment, concomitant disease). The temporal relationship is highly suggestive (e.g., confirmed by de-stimulation and re-stimulation).

[0331] Severity criteriaResearchers will assess the severity level using the following classification descriptors according to the American Cancer Institute – Common Terminology for Adverse Events, version 5.0: • Level 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observation only; no intervention indicated.

[0332] • Level 2: Moderate; indicates minimal, local or non-invasive intervention; restricts age-appropriate instrumental activities of daily living.

[0333] • Level 3: Serious or medically significant, but not immediately life-threatening; indicates hospitalization or prolonged hospitalization; discontinuation; restricts activities of daily living.

[0334] • Level 4: Life-threatening consequences; indicates urgent intervention.

[0335] • Level 5: Death related to the adverse event.

[0336] Pharmacokinetic plasma samples are used to evaluate the pharmacokinetics (PK) of latezatitinib, and serum samples are used to evaluate the PK of ervantuzumab. Samples collected for PK may also be used to evaluate the safety or efficacy in addressing problems that arise during or after the study period. Participant confidentiality will be maintained.

[0337] Evaluation of latezatitinib: Plasma samples were collected at designated time points according to the activity schedule (Table 3) for evaluation of the PK of latezatitinib. Potential metabolites, including M7, may be evaluated. Individual PK parameters were estimated, and descriptive statistics for each dose level were calculated. Based on individual plasma concentration-time data, using the actual sampling time, the following PK parameters of latezatitinib were derived by non-compartmental analysis: • Cmax: Maximum plasma concentration • Cvalence: Plasma concentration prior to the next intervention administration • tmax: Time to reach maximum plasma concentration • AUC(0-t): Area under the plasma concentration-time curve from time zero to time t • AUCτ: Area under the plasma concentration-time curve during the dose interval (τ) at steady state • CLss / F: Total apparent clearance of the study intervention at steady state • Vss / F: Apparent volume of distribution at steady state • R: Cumulative ratio Additional plasma PK parameters may be determined as appropriate. Furthermore, population pharmacokinetic modeling methods may also be applied to PK analysis.

[0338] Serum samples were collected at specified time points according to the activity schedule (Table 3) for evaluating the PK and immunogenicity of ervantumab. Individual PK parameters were estimated, and descriptive statistics were calculated. Based on individual serum concentration-time data, using the actual sampling time, the following PK parameters of ervantumab were obtained through non-compartmental analysis: • Cmax: maximum serum concentration • Cvalence: serum concentration prior to the next intervention administration. Additional serum PK parameters can be appropriately determined. Furthermore, population pharmacokinetic modeling methods can also be applied to PK analysis.

[0339] Additional information on the collection, handling, and transport of biological samples is available in the laboratory manual.

[0340] The analytical procedures were performed by the sponsor or under the sponsor's supervision using validated, specific, and sensitive methods (e.g., liquid chromatography-tandem mass spectrometry [LC-MS / MS], liquid chromatography-mass spectrometry [LC-MS], immunoassay) to analyze plasma and serum samples to determine the concentrations of lazatinib and ervantumab, respectively.

[0341] If desired, some plasma and serum samples may be analyzed using qualified research methods to record the presence of circulating metabolites. Furthermore, plasma and serum PK samples may be stored for future analysis of other co-administered treatments and protein binding and metabolite profiles.

[0342] Pharmacokinetics and Biomarkers Specification 46 / 51 pages 49 CN 121843963 A ctDNA analysis was performed on screening blood samples from all participants to evaluate the pre-treatment mutational status of EGFR, cMet, and other key oncogenes, thereby characterizing the tumor. Additional blood samples were collected during the study, and ctDNA evaluation could be performed on them to assess changes in the level or type of gene alterations observed over time and to monitor the emergence of potential biomarkers of resistance to the study therapy.

[0343] Blood samples were collected at the time points specified in the activity schedule (Error! Reference source not found.). Changes in circulating biomarkers can be assessed in samples before and after treatment, and levels are correlated with response to the study intervention. PBMCs can be used to determine the relationship between ervantumab activity and Fc-γ receptor IIIa polymorphism, a receptor expressed on certain immune cells that interacts with ervantumab.

[0344] Collected tumor tissue samples can be evaluated for cancer-related biomarkers and / or analyzed to confirm ctDNA results. Levels of EGFR and cMet proteins can also be assessed in tissue samples.

[0345] Immunogenicity assessment screens serum samples for antibodies binding to anti-ervantumab, and titers of confirmed positive samples are reported. Further analyses can be performed to further characterize the immunogenicity of ervantumab.

[0346] Anti-ervantumab antibodies were evaluated in serum samples collected from all participants according to the activity schedule (Table 3). In addition, serum samples will be collected from participants who interrupted the study intervention or withdrew from the study during the final visit.

[0347] Serum samples will be used to evaluate the immunogenicity of ervantumab.

[0348] Analytical procedures will be performed by the sponsor or under the sponsor's supervision using validated assays to detect and characterize the anti-ervantumab antibody. All samples used to detect the anti-ervantumab antibody will be collected for evaluation of ervantumab serum concentrations to enable the interpretation of immunogenicity data. The ability of the antibody to neutralize the study intervention may be further characterized and / or evaluated.

[0349] 7. Statistical Considerations The following is a general description of the statistical methods used to analyze efficacy and safety data.

[0350] Descriptive statistics will be used to summarize the data. Continuous variables will be summarized as needed using the number of observations, mean, SD, coefficient of variation, median, and range. Categorical values ​​will be summarized as needed using the number of observations and percentage.

[0351] Statistical hypothesis The hypothesis in the Phase 1b LACP combination cohort is that lazazetinib can be safely administered in combination with ervantumab and standard-of-care chemotherapy in participants with advanced or metastatic EGFR-mutant NSCLC who have failed EGFR TKIs and have a probability of DLT < 33.3%.

[0352] Sample size determination In the Phase 1b LACP combination cohort, up to 6 participants were recruited to achieve at least 3 DLT evaluable participants at the first dose level of lazazetinib (240 mg). Additional participants may be administered in subsequent cohorts where lazazetinib is started at 160 mg, and then reduced to 80 mg if necessary. Once tolerability has been demonstrated, up to 20 participants in total may be recruited after study review and consent to further characterize the safety, tolerability, and pharmacokinetics of lazazetinib in combination with ervantumab and chemotherapy (RP2ChD) at the recommended dose.

[0353] For the purposes of the analysis, the following analysis sets are defined: The “Complete” analysis set consists of participants who received at least one dose of any study intervention. Unless otherwise stated, this population is considered to be the primary efficacy analysis and is used for all analyses.

[0354] The “DLT-evaluable” analysis set consists of participants who received any amount of the study intervention during the first 21 days (Phase 1) prior to the first study intervention infusion.

[0355] The “Response-evaluable” analysis set consists of all participants who received at least one dose of the study intervention and had at least one post-baseline disease assessment, clinical progression, or died due to disease progression prior to the first post-baseline disease assessment.

[0356] The “PK” analysis set consists of participants who received at least one dose of the study intervention and had at least one evaluable concentration measurement of latezatitinib or ervantumab.

[0357] - Participants will be removed from the estimation of certain PK parameters on a separate basis due to, for example, the absence of PK samples, making it impossible to properly derive PK parameters. These participants will be identified along with the reason for their removal at the time of analysis.

[0358] The “Immunogenicity” analysis set consists of all participants who received at least one dose of ervantumab and had at least one post-infusion immunogenicity sample.

[0359] Statistical Analysis Primary Endpoints Through the study phase, the primary endpoint of the study was: • Frequency of DLT • Adverse events as defined by the NCI-CTCAE criteria, version 5.0 (LACP combination cohort only) Secondary Endpoints The secondary endpoints of this study were: • Plasma latezatitinib PK parameters • Serum ervantumab PK parameters• Incidence of anti-Evantuza antibody.

[0360] Safety Analysis All participants assigned to the study intervention and receiving at least one dose of the study intervention will be included in the safety and tolerability analysis.

[0361] Baselines for all laboratory evaluations, vital signs, and ECG measurements will be defined as the final evaluation performed prior to the first administration of the study intervention.

[0362] Any adverse event occurring at or after the initial administration of the study intervention up to the day of the last dose plus 30 days will be considered a treatment-induced (TE) event. All reported TEAEs will be included in the analysis. For each adverse event, the percentage of participants experiencing at least one occurrence of a given event will be summarized by systemic organ class, preferred terminology, and worst-case grade experienced by the participant.

[0363] Parameters with predefined NCI-CTCAE version 5.0 toxicity grades will be summarized. Changes in the worst-case grade experienced by participants during the study period from baseline will be provided as a change table.

[0364] Clinical Laboratory Tests Laboratory data will be summarized by type of laboratory test. Descriptive statistics for each laboratory analyte will be calculated at baseline, and the values ​​observed at each planned time point and the changes relative to baseline will be calculated. Pre- and post-intervention cross-tabulation (with categories of below-normal, within-normal, and above-normal) will present changes relative to baseline results.

[0365] A frequency list of abnormalities will be created. A list of participants whose laboratory results were outside the reference range will be provided. A list of participants with any significantly abnormal laboratory results will also be provided.

[0366] Parameters with predefined NCI-CTCAE, version 5.0 toxicity levels will be summarized. Changes in the worst adverse event level experienced by participants during the study period, as per CN 121843963 A (pages 48 / 51 of the instruction manual), will be provided as a variation table.

[0367] Electrocardiograms will be evaluated for their impact on cardiovascular variables using descriptive statistics and frequency lists. These tables will include observations and changes relative to baseline values ​​for each planned time point in the ECG parameters (the pre-drug ECG will be used as the baseline), including heart rate, QRS axis and PR interval, QT interval, QRS interval, RR interval, and QTcF interval. A list of abnormal frequencies will be created.

[0368] At each planned time point, descriptive statistics on the QTc interval and changes relative to baseline will be summarized. The percentage of participants with QTc intervals >450 ms, >480 ms, or >500 ms, and the percentage of participants whose QTc intervals increased from baseline by >30 ms or >60 ms will be summarized.

[0369] Vital signs will be measured at each planned time point for body temperature, pulse / heart rate, respiratory rate, SpO2 (pulse oximetry), and...Descriptive statistics of blood pressure (systolic and diastolic) values ​​and changes relative to baseline are summarized. The percentage of participants whose summarized values ​​exceed clinically important limits is presented.

[0370] The efficacy analysis ORR is defined as the proportion of participants achieving a complete response (CR) or partial response (PR) in the complete analysis set (or the response evaluable analysis set for interim monitoring), as defined by investigator assessment using RECIST v1.1. Observed ORRs and their two-sided 95% exact confidence intervals will be presented. Confirmation of investigator-assessed ORRs may be performed via IRC if indicated.

[0371] The clinical benefit rate (CBR) is defined as the percentage of participants achieving a complete or partial response or durable stable disease (duration of at least 11 weeks) as defined by RECIST v1.1. Observed ORRs and CBRs, along with their two-sided 95% confidence intervals, will be presented as appropriate for each cohort and dose level.

[0372] The event endpoint times, including PFS, duration of response (DOR), time to treatment failure (TTF), and overall survival (OS), will be estimated using the Kaplan-Meier method. DOR will be calculated as the time from an initial response of CR or PR to progressive disease (PD) or death from any cause, prioritizing those who achieved CR or PR. PFS is defined as the time from the first infusion of the study intervention to PD or death from any cause. TTF is defined as the time from the first administration of the study intervention to discontinuation of treatment for any cause (including disease progression, treatment toxicity, and death) and will be used to capture the clinical benefit of continued treatment beyond disease progression as defined in RECIST v1.1. OS is defined as the time from the first infusion of the study intervention to death from any cause. For the endpoint times, the Kaplan-Meier estimates will be presented graphically, and the median time of the event along with the corresponding 95% CI will be obtained from the Kaplan-Meier estimates. If indicated, confirmation of investigator-assessed DOR, PFS, and CBR can be performed via IRC.

[0373] Pharmacokinetic Analysis Pharmacokinetic Analysis Procedure (Lazettinib and Evantuzumab) All plasma and serum concentrations below the minimum quantifiable concentration or missing data will be marked as such in the concentration data display or statistical analysis system dataset. In the summary statistics, concentrations below the minimum quantifiable concentration will be treated as zero.

[0374] For each compound, plasma or serum concentration data for participants will be listed, and descriptive statistics for each nominal time point will be summarized by cohort in tables of mean, SD, median, and range over time, as appropriate. PK parameters for participants will be estimated, and descriptive statistics will be calculated by cohort.

[0375] Mean or median concentration-time curves will be plotted, and individual concentration-time curves may also be plotted. If appropriate, nonlinear mixed-effects modeling may be used for population PK modeling of plasma or serum concentration-time data. Data may be combined with data from other selected studies (pages 49 / 51, CN 121843963 A). Results of any population PK analysis will be presented in a separate report.

[0376] Immunogenicity analysis will summarize the incidence and titer of anti-ervant antibodies in all participants who received at least one dose of ervantumab and had an appropriate sample for detecting anti-ervantumab antibodies (i.e., participants with at least one sample obtained after their first dose of ervantumab).

[0377] A list of participants who were positive for anti-ervantumab antibodies will be provided. For participants who were positive for anti-ervantumab antibodies, the maximum titer of anti-ervantumab antibodies will also be summarized.

[0378] Further immunogenicity analyses may be performed to further characterize the resulting immune response.

[0379] Example 2. The LACP (lazatinib, ervatinib, carboplatin, pemetrexed) cohort of the CHRYSALIS-2 study (Clinicaltrials_gov identifier NCT04077463) recruited patients with EGFR-mutant NSCLC whose disease progressed during or after treatment with EGFR TKIs as the last line of therapy (up to 3 previous lines). Patients received 1400 mg (1750 mg for patients weighing ≥80 kg) of ervant intravenously weekly for the first four doses (the first dose was divided into two doses: 350 mg on day 1 of cycle 1 and 1050 mg on day 2 of cycle 1 (1400 mg for patients weighing ≥80 kg)) until day 1 of cycle 2, followed by 1750 mg (2100 mg for patients weighing ≥80 kg) every 3 weeks (21-day cycle), in combination with 240 mg of lazatinib orally daily and 500 mg / m² pemetrexed in carboplatin (AUC5). Carboplatin therapy was discontinued after 4 cycles. Adverse events were graded using CTCAE, v.5. Responses in patients with at least one post-baseline disease assessment were assessed by the investigator according to RECIST v1.1.

[0380] The recruited patients had received a median line of prior therapy of 2 (range, 1–3), including osimertinib (n=14), gefitinib (n=3), and afatinib (n=3). To date, during at least 3 months of follow-up, the best response included 10 patients with confirmed partial response, 7 patients with stable disease, and 3 patients with progressive disease. The most common adverse events occurring during treatment were infusion-related reactions (73.3%), neutropenia (66.7%), rash (46.7%), and blood...Thrombocytopenia (40.0%), fatigue, and nausea (33.3% each). Of the 5 participants who discontinued treatment, 2 were due to chemotherapy-related serious adverse events and 3 were due to disease progression.

[0381] The combination of ervantumab with lazatinib and chemotherapy produced a high overall response rate in patients who progressed with EGFR TKIs as prior therapy. The safety profile of the LACP regimen was consistent with that of the single agent, with no new safety signals or evidence of additive toxicity.

[0382] Example 3. Combination of ervantumab with chemotherapy in patients with advanced NSCLC The combination of ervantumab with chemotherapy in combination with the chemotherapy agents carboplatin and pemetrexed in a 21-day cycle was investigated in the CHRYSALIS study (Clinicaltrials_gov identifier NCT02609776) in subjects with advanced non-small cell lung cancer (NSCLC).

[0383] Methods Patients had advanced NSCLC and were receiving platinum-based chemotherapy that met the criteria for care. In a 21-day cycle, for the first four doses, ervantumab was administered weekly at 1400 mg (1750 mg for patients ≥80 kg), followed by 1750 mg (2100 mg for patients ≥80 kg) every 3 weeks (Q3W), in combination with pemetrexed (500 mg / m2) and carboplatin (AUC 5; until cycle 4). The first dose of ervantumab was divided into 350 mg on day 1 of cycle 1 and 1050 mg on day 2 (1400 mg for patients ≥80 kg). Response was assessed by the investigator according to RECIST v1.1. Tolerability was assessed using a 3+3 dose-decrease design.

[0384] Results: Of the initial 5 patients, 3 were evaluable for dose-limiting toxicities (DLTs); no DLTs were observed, and dose scaling up to 20 patients was initiated. Twenty patients (5 weighing ≥80 kg) received the combination therapy; 16 patients completed 4 cycles and continued maintenance; 15 patients exceeded 6 cycles, and 1 patient exceeded 13 cycles. The median age was 62 years (range, 36–83 years). Nineteen patients had EGFR mutations, including exon 19 deletion (9 patients), L858R (2 patients), exon 20 insertion (7 patients), and exon 20 S768I (1 patient). One patient had a KRAS mutation (G13R). Four patients had a history of brain metastases, and 15 patients had ≥1 prior line of therapy (LOT), of whom 9 had been heavily pretreated (2–7 prior LOTs). The median treatment duration was 5.6 months (range: 0.1–9.2 months). The most common treatment-emergent adverse events (TEAEs) were infusion-related reactions (65%) and rash (60% dermatitis-acne-like + 30% rash). Twelve patients(44%) had ≥ grade 3 TEAEs; the most common events reflected the expected cytopenia (45% neutropenia, 6% anemia, 6% thrombocytopenia) – one patient discontinued carboplatin due to anemia. Preliminary cycle 1 pharmacokinetic (PK) data (n=9) indicated that chemotherapy had no effect on ervatumab exposure (Figures 3A to 3C). Preliminary trough concentration comparisons indicated that the higher dose of ervantumab administered in Q3W (21-day cycle) was similar to the recommended dose of monotherapy administered every 2 weeks (1050 mg (weight <80 kg) / 1400 mg (weight >80 kg) in QW during cycle 1 (C1) (28-day cycle), followed by 1050 mg / 1400 mg in Q2W in C2 and thereafter (Figures 4A to 4B).

[0385] Eighteen patients were evaluable for response (Figure 5). One patient discontinued prior to the first disease assessment, and another patient had unmeasurable disease; neither is included in the figure (Figure 5). Antitumor activity was observed in a heterogeneous population. Of the 18 evaluable patients, 8 reported best PR response (partial response). Of the 5 patients with untreated EGFR exon 20 insertion-positive disease, 4 had best PR response (Figure 5).

[0386] In summary, no dose-limiting toxicities were observed, and the RP2DQ3W of ervantumab was determined (1750 mg for <80 kg, 2100 mg for ≥80 kg). The combination of ervantumab with chemotherapy was well-tolerated, and its toxicity profile was consistent with that observed with each therapy alone. Antitumor activity was observed in various NSCLC populations, including in treatment-naïve patients with EGFR exon 20 insertion NSCLC. Evantumab exposure was not affected by chemotherapy. Similar ervantumab exposure was achieved with 28-day Q2W and 21-day Q3W dosing. (See product information page 51 / 51, page 54, CN 121843963 A, Figure 1, Figure 2; Product information page 55, page 55, CN 121843963 A, Figure 3A, Figure 3B; Product information page 56, page 56, CN 121843963 A, Figure 3C, Figure 4A; Product information page 57, page 57, CN 121843963 A, Figure 4B, Figure 5) Instruction manual, Figure 4 / 4, page 58, CN 121843963 A

Claims

1. A method of treating a subject with cancer expressing epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met), the method comprising administering to the subject... An isolated bispecific anti-EGFR / c-Met antibody comprising a first domain and a second domain, wherein the first domain comprises the heavy chain complementarity-determining region 1 (HCDR1) of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, HCDR3 of SEQ ID NO: 3, the light chain complementarity-determining region 1 (LCDR1) of SEQ ID NO: 4, LCDR2 of SEQ ID NO: 5, and LCDR3 of SEQ ID NO: 6, and the second 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, administered at a dose of approximately 1400 mg to 2100 mg every 21 days.

2. The method of claim 1, wherein the method further comprises administering a third-generation EGFR tyrosine kinase inhibitor (TKI).

3. The method according to claim 2, wherein the third-generation EGFR TKI has formula (I): (I)。 4. The method of claim 3, wherein the third-generation EGFR TKI is administered at a dose of 240 mg per day.

5. The method of claim 1, wherein the initial dose of the bispecific anti-EGFR / c-Met antibody is administered in divided doses over two consecutive days, wherein... If the subject's weight is less than 80 kg, the antibody is administered at a dose of approximately 350 mg on day 1 (D1) of the first cycle and at a dose of approximately 1050 mg on day 2 (D2) of the first cycle, or If the subject weighs 80 kg or more, the antibody is administered at a dose of approximately 350 mg on day 1 of the first cycle and at a dose of approximately 1400 mg on day 2 of the first cycle.

6. The method of claim 1, wherein the method further comprises an initial cycle (cycle 1), the initial cycle comprising administering the bispecific antibody once weekly for three weeks at a dose of about 1400 mg if the subject weighs less than 80 kg, or at a dose of about 1750 mg if the subject weighs 80 kg or more.

7. The method of claim 6, wherein the method further comprises a second cycle (second cycle) comprising administering the bispecific antibody once every three weeks at a dose of about 1400 mg if the subject weighs less than 80 kg, or at a dose of about 1750 mg if the subject weighs 80 kg or more.

8. The method of claim 1, wherein the method comprises administering the bispecific antibody once every 3 weeks at a dose of about 1750 mg if the subject weighs less than 80 kg, or at a dose of about 2100 mg if the subject weighs 80 kg or more.

9. The method of claim 1, wherein the method further comprises one or more platinum-containing chemotherapeutic agents.

10. The method of claim 9, wherein the one or more chemotherapeutic agents comprise pemetrexed and / or carboplatin.

11. The method of claim 9, wherein the one or more chemotherapeutic agents are pemetrexed and carboplatin administered on day 1 of each 21-day cycle.

12. The method of claim 9, wherein the one or more chemotherapeutic agents are administered at about 500 mg / m². 2 The dosage of pemetrexed and carboplatin was administered to achieve an area under the curve (AUC) of 5.

13. The method of claim 9, wherein the one or more chemotherapeutic agents are administered at about 500 mg / m². 2 The dosage of pemetrexed administered and carboplatin AUC 5 administered on day 1 of each cycle up to and including the fourth cycle (cycle 4), wherein pemetrexed is administered on day 1 of each subsequent cycle at approximately 500 mg / m². 2 Dosage administration.

14. The method of claim 1, wherein the first domain of the bispecific anti-EGFR / c-Met antibody binds to EGFR, and the second domain binds to c-Met.

15. The method of claim 14, wherein the first domain of 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 of c-Met comprises the VH of SEQ ID NO: 15 and the VL of SEQ ID NO:

16.

16. The method of claim 15, wherein the bispecific anti-EGFR / c-Met antibody is an IgG1 isotype.

17. The method of claim 15, wherein the bispecific anti-EGFR / c-Met antibody comprises the first heavy chain (HC1) of SEQ ID NO: 17, the first light chain (LC1) of SEQ ID NO: 18, the second heavy chain (HC2) of SEQ ID NO: 19, and the second light chain (LC2) of SEQ ID NO:

20.

18. The method of claim 15, wherein the bispecific anti-EGFR / c-Met antibody has a bibranched glycan structure with a fucose content between about 1% and about 15%.

19. The method according to claim 3, wherein the compound of formula (I) or its solvate, hydrate, tautomer or pharmaceutically acceptable salt is lazazetinib mesylate represented by the compound of formula (II): (II).

20. The method according to claim 19, wherein the compound of formula (I) or its solvate, hydrate, tautomer or pharmaceutically acceptable salt is N-(5-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide.

21. The method of claim 1, wherein the cancer expressing EGFR or c-Met is lung cancer.

22. The method of claim 21, wherein the cancer is non-small cell lung cancer (NSCLC).

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