Combination of Anti-her2 antibody-drug conjugate and VEGF inhibitor

Abstract

A pharmaceutical product, wherein an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula (I) (wherein A represents a connecting position to an antibody) is conjugated to the antibody via a thioether bond, and a VEGF inhibitor are administered in combination, and / or a method of treatment, wherein the antibody-drug conjugate and the inhibitor are administrated in combination to a subject.

Description

[Document Name] Description[Title of Invention]COMBINATION OF ANTI-HER2 ANTIBODY-DRUG CONJUGATE AND VEGF INHIBITOR[Technical Field]The present disclosure relates to a pharmaceutical product wherein a specific anti-HER2 antibody-drug conjugate and a VEGF inhibitor are administered in combination, and / or a method of treatment comprising administering a specific anti-HER2 antibody-drug conjugate and a VEGF inhibitor in combination to a sub j ect .[Background Art]Angiogenesis which contributes to the supply of nutrients or oxygen and the excretion of metabolic wastes is important for solid tumor growth. Vascular endothelial growth factor (VEGF) , particularly, VEGF-A, has been identified as an important factor for inducing tumor angiogenesis . VEGF can activate the VEGF signal transduction of endothelial cells through its interaction with a VEGF receptor, thereby stimulating the growth and survival of the endothelial cells, increasing vascular permeability, and supporting metabolic needs of growing tumor . VEGF inhibitors are known as drugs that inhibit15324259-1angiogenesis by inhibiting the interaction between VEGF and a VEGF receptor, and exhibit an antitumor effect . Examples of such VEGF inhibitors can include anti-VEGF antibodies, anti-VEGF receptor antibodies, fusion proteins comprising a VEGF receptor extracellular domain, and bispecific antibodies comprising an anti-VEGF binding domain (Non Patent Literatures 1 to 4 ) .An antibody-drug conjugate (ADC) in which an antibody that binds to an antigen expressed on the surface of cancer cells and can internalize the antigen into the cell is conjugated to a drug having cytotoxic activity can selectively deliver the drug to cancer cells, and can thereby kill the cancer cells by accumulating the drug in the cancer cells . An antibodydrug conjugate comprising an anti-HER2 antibody and a topoisomerase I inhibitor exatecan derivative as components is known as an anti-HER2 antibody-drug conjugate (Patent Literature 1 ) .However, neither test results exhibiting an excellent combinatorial effect nor scientific basis suggesting such test results has been published when the anti-HER2 antibody-drug conjugate described above and a VEGF inhibitor are used in combination.[Citation List][Patent Literature]15324259-1[ Patent Literature 1 ] International Publication No .W02015 / 115091[Non Patent Literature ][Non Patent Literature 1 ] Garcia et al . , Cancer Treat . Rev . ( 2020 ) 86 : 102017[Non Patent Literature 2 ] Geindreau et al . Int . J . Mol . Sci . ( 2021 ) 22 ( 9 ) : 4871 .[Non Patent Literature 3 ] Es fandiari et al . , Nat . Rev . Drug Discov . ( 2022 ) 21 ( 6 ) : 411-412 .[Non Patent Literature 4 ] Xu et al . , Cancer Lett . ( 2022 ) 538 : 215699 .[ Summary of disclosure ][ Technical Problem]The anti-HER2 antibody-drug conj ugate ( anti-HER2 antibody-drug conj ugate comprising an exatecan derivative as a component ) used in the present disclosure has been confirmed to exhibit an excellent antitumor ef fect even when used alone . However, use of the anti-HER2 antibodydrug conj ugate in combination with an additional anticancer agent that di f fers in mechanism of action therefrom compositely inhibits the growth of cancer cells , and it is thus expected to acquire a treatment method capable of exerting a much better antitumor ef fect .An obj ect of the present disclosure is to provide a pharmaceutical product wherein a speci fic anti-HER215324259-1antibody-drug conjugate and a VEGF inhibitor are administered in combination, and / or a method of treatment comprising administering a specific anti-HER2 antibodydrug conjugate and a VEGF inhibitor in combination to a sub j ect .[Solution to Problem]The present inventors have conducted intensive studies directed towards achieving the above-described obj ect, and consequently completed the present disclosure by finding that a specific anti-HER2 antibody-drug conjugate and a VEGF inhibitor administered in combination exhibit an excellent combinatorial effect (highly safe and marked antitumor effect) .Specifically, the present disclosure provides the following [Al ] to [E48 ] .[Al ]A pharmaceutical product comprising an anti-HER2 antibody-drug conjugate and a VEGF inhibitor for administration in combination, whereinthe anti-HER2 antibody-drug conjugate is an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula :15324259-1[Formula 1 ]wherein A represents a connecting position to an antibody,is conjugated to the antibody via a thioether bond .[A2 ]The pharmaceutical product according to [Al ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 comprising an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 comprising an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 comprising an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 comprising an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 comprising an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 comprising an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.15324259-1[A3]The pharmaceutical product according to [Al ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1 and a light chain comprising a light chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2 .[A4 ]The pharmaceutical product according to [Al ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 1 and a light chain comprising an amino acid sequence represented by SEQ ID NO: 2.[A5]The pharmaceutical product according to [Al ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain comprising an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.[A6]The pharmaceutical product according to any one of [Al ] to [A5] , wherein the anti-HER2 antibody-drug conjugate is represented by the following formula :15324259-1[Formula 2 ]wherein 'Antibody' indicates the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n indicates an average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate, wherein n is in the range of from 7 to 8 .[A7 ]The pharmaceutical product according to any one of [Al ] to [A6] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.[A8 ]The pharmaceutical product according to [A7 ] , wherein the VEGF inhibitor is an anti-VEGF antibody.[A9]The pharmaceutical product according to [A8 ] , wherein the anti-VEGF antibody is bevacizumab .[A10]15324259-1The pharmaceutical product according to [A7 ] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.[All ]The pharmaceutical product according to [A10] , wherein the anti-VEGF receptor antibody is ramucirumab .[A12 ]The pharmaceutical product according to [A7 ] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.[A13]The pharmaceutical product according to [A12 ] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept .[A14 ]The pharmaceutical product according to [A7 ] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.[A15]The pharmaceutical product according to [A14 ] , wherein the multispecific antibody is a bispecific antibody.[Al 6]The pharmaceutical product according to any one of [Al ] to [A15] , wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are separately contained as active components in different formulations, and are administered at the same time or at different times .[A17 ]15324259-1The pharmaceutical product according to any one of [Al ] to [A15] , wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are contained as active components in a single formulation for administration.[Al 8 ]The pharmaceutical product according to any one of [Al ] to [A17 ] , wherein the pharmaceutical product is for use in treating cancer .[Al 9]The pharmaceutical product according to any one of [Al ] to [A17 ] , wherein the pharmaceutical product is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget ' s disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, hepatocellular carcinoma, gastrointestinal stromal tumor, kidney cancer, cervical cancer, and sarcoma .[A20]The pharmaceutical product according to [A19] , wherein the pharmaceutical product is for use in treating breast cancer .[A21 ]15324259-1The pharmaceutical product according to [A19] , wherein the pharmaceutical product is for use in treating triplenegative breast cancer .[A22 ]The pharmaceutical product according to [A19] , wherein the pharmaceutical product is for use in treating gastric cancer .[A23]The pharmaceutical product according to [A19] , wherein the pharmaceutical product is for use in treating ovarian cancer .[A24 ]The pharmaceutical product according to [A19] , wherein the pharmaceutical product is for use in treating lung cancer .[A25]The pharmaceutical product according to [A19] , wherein the pharmaceutical product is for use in treating pancreatic cancer .[A26]The pharmaceutical product according to any one of [A18 ] to [A25] , wherein the cancer is metastatic .[A27 ]The pharmaceutical product according to any one of [Al ] to [A26] , wherein the anti-HER2 antibody is trastuzumab deruxtecan .[A28 ]15324259-1The pharmaceutical product according to any one of [Al ] to [A26 ] , wherein the pharmaceutical product is pharmaceutical composition . In another embodiment , the pharmaceutical product according to any one of [Al ] to [A27 ] , wherein the pharmaceutical product is pharmaceutical composition .[A29 ]The pharmaceutical product according to any one of [Al ] to [A28 ] , wherein the anti-HER2 antibody-drug conj ugate is administered at a dose of 0 . 8 to 12 . 4 mg / kg .[A30 ]The pharmaceutical product according to [A27 ] or [A28 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg or 6 . 4 mg / kg .[A31 ]The pharmaceutical product according to [A27 ] or [A28 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg .[A32 ]The pharmaceutical product according to [A27 ] or [A28 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg per administration at intervals of 3 weeks .[A33 ]The pharmaceutical product according to any one of [Al ] to [A32 ] , wherein the VEGF inhibitor is administered at a dose of 1 to 20 mg / kg .[A34 ]15324259-1The pharmaceutical product according to [A33] , wherein the VEGF inhibitor is administered at a dose of 5 to 15 mg / kg .[A35]The pharmaceutical product according to any one of [Al ] to [A32 ] , wherein the VEGF inhibitor is administered at a dose of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, or 15 mg / kg .[A36]The pharmaceutical product according to any one of [Al ] to [A32 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg.[A37 ]The pharmaceutical product according to any one of [Al ] to [A32 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[A38 ]The pharmaceutical product according to any one of [A33] to [A37 ] , wherein the VEGF inhibitor is bevacizumab .[A39]The pharmaceutical product according to [A38 ] , wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks, and bevacizumab is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[A40]15324259-1The pharmaceutical product according to [A39] , wherein trastuzumab deruxtecan and bevacizumab are administered on the same day.[A41 ]The pharmaceutical product according to [A39] or [A40] , wherein trastuzumab deruxtecan is administered up to 34 cycles, and bevacizumab is administered up to 16 cycles .[A42 ]The pharmaceutical product according to [A41 ] , wherein bevacizumab is administered up to 6 cycles before the 16 cycles of bevacizumab administration as a front-line chemotherapy .[A43]The pharmaceutical product according to any one of [A38 ] to [A42 ] , wherein the pharmaceutical product is for use in treating HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer .[A44 ]The pharmaceutical product according to [A43] , wherein the pharmaceutical product is for use in treating HER2 expressing ( IHC 3+ / 2+ / 1+) epithelial ovarian cancer .[A45]The pharmaceutical product according to [A43] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced epithelial ovarian cancer .[A46]15324259-1The pharmaceutical product according to [A43] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer .[A47 ]The pharmaceutical product according to [A43] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer as maintenance therapy.[A48 ]The pharmaceutical product according to [A46] or [A47 ] , wherein the pharmaceutical product is for use in treating HER2 expressing ( IHC 3+ / 2+) advanced high-grade epithelial ovarian cancer .[A49]The pharmaceutical product according to [A46] or [A47 ] , wherein the pharmaceutical product is for use in treating HER2 expressing ( IHC 1+) advanced high-grade epithelial ovarian cancer .[Bl ]A method of treatment, comprising administering an anti-HER2 antibody-drug conjugate and a VEGF inhibitor for administration in combination, whereinthe anti-HER2 antibody-drug conjugate is an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula :15324259-1[Formula 3]wherein A represents a connecting position to an antibody,is conjugated to the antibody via a thioether bond.[B2 ]The method of treatment according to [Bl ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 comprising an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 comprising an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 comprising an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 comprising an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 comprising an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 comprising an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.15324259-1[B3]The method of treatment according to [Bl ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1 and a light chain comprising a light chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2 .[B4 ]The method of treatment according to [Bl ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 1 and a light chain comprising an amino acid sequence represented by SEQ ID NO: 2.[B5]The method of treatment according to [Bl ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain comprising an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.[B6]The method of treatment according to any one of [Bl ] to [B5] , wherein the anti-HER2 antibody-drug conjugate is represented by the following formula :15324259-1[Formula 4 ]wherein 'Antibody' indicates the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n indicates an average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate, wherein n is in the range of from 7 to 8 .[B7 ]The method of treatment according to any one of [Bl ] to [B6] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.[B8 ]The method of treatment according to [B7 ] , wherein the VEGF inhibitor is an anti-VEGF antibody.[B9]The method of treatment according to [B8 ] , wherein the anti-VEGF antibody is bevacizumab .[BIO]15324259-1The method of treatment according to [B7 ] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.[Bll ]The method of treatment according to [BIO] , wherein the anti-VEGF receptor antibody is ramucirumab .[B12 ]The method of treatment according to [B7 ] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.[B13]The method of treatment according to [B12 ] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept .[B14 ]The method of treatment according to [B7 ] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.[B15]The method of treatment according to [B14 ] , wherein the multispecific antibody is a bispecific antibody.[B16]The method of treatment according to any one of [Bl ] to [B15] , wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are separately contained as active components in different formulations, and are administered at the same time or at different times . [B17 ]15324259-1The method of treatment according to any one of [Bl ] to [B15] , wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are contained as active components in a single formulation for administration.[B18 ]The method of treatment according to any one of [Bl ] to [B17 ] , wherein the method of treatment is for use in treating cancer .[B19]The method of treatment according to any one of [Bl ] to [B17 ] , wherein the method of treatment is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget ' s disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, hepatocellular carcinoma, gastrointestinal stromal tumor, kidney cancer, cervical cancer, and sarcoma .[B20]The method of treatment according to [B19] , wherein the method of treatment is for use in treating breast cancer .[B21 ]The method of treatment according to [B19] , wherein the method of treatment is for use in treating triplenegative breast cancer .15324259-1[B22 ]The method of treatment according to [B19] , wherein the method of treatment is for use in treating gastric cancer .[B23]The method of treatment according to [B19] , wherein the method of treatment is for use in treating ovarian cancer .[B24 ]The method of treatment according to [B19] , wherein the method of treatment is for use in treating lung cancer .[B25]The method of treatment according to [B19] , wherein the method of treatment is for use in treating pancreatic cancer .[B26]The method of treatment according to any one of [B18 ] to [B25] , wherein the cancer is metastatic .[B27 ]The method of treatment according to any one of [Bl ] to [B26] , wherein the anti-HER2 antibody is trastuzumab deruxtecan .[B28 ]The method of treatment according to any one of [Bl ] to [B27 ] , wherein the anti-HER2 antibody-drug conjugate is administered at a dose of 0.8 to 12.4 mg / kg.[B29]15324259-1The method of treatment according to [B27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg or 6 . 4 mg / kg .[B30 ]The method of treatment according to [B27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg .[B31 ]The method of treatment according to [B27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg per administration at intervals of 3 weeks .[B32 ]The method of treatment according to any one of [Bl ] to [B31 ] , wherein the VEGF inhibitor is administered at a dose of 1 to 20 mg / kg .[B33 ]The method of treatment according to any one of [Bl ] to [B31 ] , wherein the VEGF inhibitor is administered at a dose of 5 to 15 mg / kg .[B34 ]The method of treatment according to any one of [Bl ] to [B31 ] , wherein the VEGF inhibitor is administered at a dose of 5 mg / kg, 7 . 5 mg / kg, 10 mg / kg, 12 . 5 mg / kg, or 15 mg / kg .[B35 ]15324259-1The method of treatment according to any one of [Bl ] to [B31 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg.[B36]The method of treatment according to any one of [Bl ] to [B31 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[B37 ]The method of treatment according to any one of [B32 ] to [B36] , wherein the VEGF inhibitor is bevacizumab .[B38 ]The method of treatment according to [B37 ] , wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks, and bevacizumab is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[B39]The method of treatment according to [B38 ] , wherein trastuzumab deruxtecan and bevacizumab are administered on the same day.[B40]The method of treatment according to [B38 ] or [B39] , wherein trastuzumab deruxtecan is administered up to 34 cycles, and bevacizumab is administered up to 16 cycles .[B41 ]The method of treatment according to [B40] , wherein15324259-1bevaci zumab is administered up to 6 cycles before the 16 cycles of bevaci zumab administration as a front-line chemotherapy .[B42 ]The method of treatment according to any one of [B37 ] to [B41 ] , wherein the method of treatment is for use in treating HER2 expressing ( IHC 3+ / 2+ / 1+ ) ovarian cancer .[B43 ]The method of treatment according to [B42 ] , wherein the method of treatment is for use in treating HER2 expressing ( IHC 3+ / 2+ / 1+ ) epithelial ovarian cancer . [B44 ]The method of treatment according to [B42 ] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+ ) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+ ) advanced epithelial ovarian cancer .[B45 ]The method of treatment according to [B42 ] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+ ) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+ ) advanced high-grade epithelial ovarian cancer .[B46 ]The method of treatment according to [B42 ] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+ ) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+ ) advanced high-grade epithelial ovarian cancer as maintenance therapy .[B47 ]15324259-1The method of treatment according to [B45] or [B46] , wherein the method of treatment is for use in treating HER2 expressing ( IHC 3+ / 2+) advanced high-grade epithelial ovarian cancer .[B48 ]The method of treatment according to [B45] or [B46] , wherein the method of treatment is for use in treating HER2 expressing ( IHC 1+) advanced high-grade epithelial ovarian cancer .[Cl ]An anti-HER2 antibody-drug conjugate for use in a method of treating a disease, wherein the method comprises administering the antibody-drug conjugate in combination with a VEGF inhibitor, whereinthe anti-HER2 antibody-drug conjugate is an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula :[Formula 5]15324259-1wherein A represents a connecting position to an antibody,is conjugated to the antibody via a thioether bond.[C2 ]The anti-HER2 antibody-drug conjugate for use according to [Cl ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 comprising an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 comprising an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 comprising an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 comprising an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 comprising an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 comprising an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

[0003] The anti-HER2 antibody-drug conjugate for use according to

[0001] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1 and a light chain comprising a light chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2.15324259-1

[0004] The anti-HER2 antibody-drug conjugate for use according to [Cl ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 1 and a light chain comprising an amino acid sequence represented by SEQ ID NO: 2 .

[0005] The anti-HER2 antibody-drug conjugate for use according to

[0001] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain comprising an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2 .

[0006] The anti-HER2 antibody-drug conjugate for use according to any one of

[0001] to

[0005] , wherein the anti-HER2 antibody-drug conjugate is represented by the following formula :15324259-1[Formula 6]wherein 'Antibody' indicates the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n indicates an average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate, wherein n is in the range of from 7 to 8 .[C7 ]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C6] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.[C8 ]The anti-HER2 antibody-drug conjugate for use according to [C7 ] , wherein the VEGF inhibitor is an anti-VEGF antibody .[C9]The anti-HER2 antibody-drug conjugate for use according to [C8 ] , wherein the anti-VEGF antibody is bevacizumab .15324259-1[CIO]The anti-HER2 antibody-drug conjugate for use according to [C7 ] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.[Cl 1 ]The anti-HER2 antibody-drug conjugate for use according to [CIO] , wherein the anti-VEGF receptor antibody is ramucirumab .[C12 ]The anti-HER2 antibody-drug conjugate for use according to [C7 ] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.[C13]The anti-HER2 antibody-drug conjugate for use according to [C12 ] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept .[C14 ]The anti-HER2 antibody-drug conjugate for use according to [C7 ] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.[C15]The anti-HER2 antibody-drug conjugate for use according to [C14 ] , wherein the multispecific antibody is a bispecific antibody.[C16]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C15] , wherein the anti-HER215324259-1antibody-drug conjugate and the VEGF inhibitor are separately contained as active components in different formulations, and are administered at the same time or at different times .[C17 ]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C15] , wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are contained as active components in a single formulation for administration.[C18 ]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C17 ] , wherein the disease is for use in treating cancer .[C19]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C17 ] , wherein the disease is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget ' s disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, hepatocellular carcinoma, gastrointestinal stromal tumor, kidney cancer, cervical cancer, and sarcoma .[C20]15324259-1The anti-HER2 antibody-drug conjugate for use according to [C19] , wherein the disease is breast cancer .[C21 ]The anti-HER2 antibody-drug conjugate for use according to [C19] , wherein the disease is triple-negative breast cancer .[C22 ]The anti-HER2 antibody-drug conjugate for use according to [C19] , wherein the disease is gastric cancer .[C23]The anti-HER2 antibody-drug conjugate for use according to [C19] , wherein the disease is ovarian cancer .[C24 ]The anti-HER2 antibody-drug conjugate for use according to [C19] , wherein the disease is lung cancer .[C25]The anti-HER2 antibody-drug conjugate for use according to [C19] , wherein the disease is pancreatic cancer . [C26]The anti-HER2 antibody-drug conjugate for use according to any one of [C18 ] to [C25] , wherein the cancer is metastatic .[C27 ]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C26] , wherein the anti-HER2 antibody is trastuzumab deruxtecan.[C28 ]15324259-1The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C27 ] , wherein the anti-HER2 antibody-drug conjugate is administered at a dose of 0.8 to 12.4 mg / kg .[C29]The anti-HER2 antibody-drug conjugate for use according to [C27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg or 6.4 mg / kg.[C30]The anti-HER2 antibody-drug conjugate for use according to [C27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg.[C31 ]The anti-HER2 antibody-drug conjugate for use according to [C27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks .[C32 ]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C31 ] , wherein the VEGF inhibitor is administered at a dose of 1 to 20 mg / kg.[C33]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C31 ] , wherein the VEGF inhibitor is administered at a dose of 5 to 15 mg / kg.[C34 ]15324259-1The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C31 ] , wherein the VEGF inhibitor is administered at a dose of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, or 15 mg / kg.[C35]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C31 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg.[C36]The anti-HER2 antibody-drug conjugate for use according to any one of [Cl ] to [C31 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[C37 ]The anti-HER2 antibody-drug conjugate for use according to any one of [C32 ] to [C36] , wherein the VEGF inhibitor is bevacizumab .[C38 ]The anti-HER2 antibody-drug conjugate for use according to [C37 ] , wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks, and bevacizumab is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[C39]The anti-HER2 antibody-drug conjugate for use according to [C38 ] , wherein15324259-1trastuzumab deruxtecan and bevacizumab are administered on the same day.[C40]The anti-HER2 antibody-drug conjugate for use according to [C38 ] or [C39] , wherein trastuzumab deruxtecan is administered up to 34 cycles, and bevacizumab is administered up to 16 cycles .[C41 ]The anti-HER2 antibody-drug conjugate for use according to [C40] , whereinbevacizumab is administered up to 6 cycles before the 16 cycles of bevacizumab administration as a front-line chemotherapy .[C42 ]The anti-HER2 antibody-drug conjugate for use according to any one of [C37 ] to [C41 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer .[C43]The anti-HER2 antibody-drug conjugate for use according to [C42 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ / 1+) epithelial ovarian cancer .[C44 ]The anti-HER2 antibody-drug conjugate for use according to [C42 ] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced epithelial ovarian cancer .[C45]15324259-1The anti-HER2 antibody-drug conjugate for use according to [C42 ] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer .[C46]The anti-HER2 antibody-drug conjugate for use according to [C42 ] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer as maintenance therapy .[C47 ]The anti-HER2 antibody-drug conjugate for use according to [C45] or [C46] , wherein the disease is HER2 expressing ( IHC 3+ / 2+) advanced high-grade epithelial ovarian cancer .[C48 ]The anti-HER2 antibody-drug conjugate for use according to [C45] or [C46] , wherein the disease is HER2 expressing ( IHC 1+) advanced high-grade epithelial ovarian cancer .[DI ]Use of an anti-HER2 antibody-drug conjugate or a VEGF inhibitor for the manufacture of a medicament for treating a disease by administration of the anti-HER2 antibody-drug conjugate and the inhibitor in combination, wherein15324259-1the anti-HER2 antibody-drug conjugate is an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula :[Formula 7 ]wherein A represents a connecting position to an antibody,is conjugated to the antibody via a thioether bond.[D2 ]The use according to [DI ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 comprising an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 comprising an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 comprising an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 comprising an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 comprising an amino acid sequence consisting of amino acid residues15324259-150 to 52 of SEQ ID NO: 2, and CDRL3 comprising an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2 .[D3]The use according to [DI ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1 and a light chain comprising a light chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2 .[D4 ]The use according to [DI ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 1 and a light chain comprising an amino acid sequence represented by SEQ ID NO: 2 .[D5]The use according to [DI ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain comprising an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2 .[D6]15324259-1The use according to any one of [DI ] to [D5] , wherein the anti-HER2 antibody-drug conjugate is represented by the following formula :[Formula 8 ]wherein 'Antibody' indicates the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n indicates an average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate, wherein n is in the range of from 7 to 8 .[D7 ]The use according to any one of [DI ] to [D6] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.[D8 ]The use according to [D7 ] , wherein the VEGF inhibitor is an anti-VEGF antibody.[D9]15324259-1The use according to [D8 ] , wherein the anti-VEGF antibody is bevacizumab .[DIO]The use according to [D7 ] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.[Dll ]The use according to [DIO] , wherein the anti-VEGF receptor antibody is ramucirumab.[D12 ]The use according to [D7 ] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain .[D13]The use according to [D12 ] , wherein the fusion protein comprising a VEGF receptor extracellular domain is af libercept .[D14 ]The use according to [D7 ] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain .[D15]The use according to [D14 ] , wherein the multispecific antibody is a bispecific antibody.[D16]The use according to any one of [DI ] to [D15] , wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are separately contained as active components15324259-1in different formulations, and are administered at the same time or at different times .[D17 ]The use according to any one of [DI ] to [D15] , wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are contained as active components in a single formulation for administration.[D18 ]The use according to any one of [DI ] to [D17 ] , wherein the disease is for use in treating cancer .[D19]The use according to any one of [DI ] to [D17 ] , wherein the disease is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget ' s disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, hepatocellular carcinoma, gastrointestinal stromal tumor, kidney cancer, cervical cancer, and sarcoma .[D20]The use according to [D19] , wherein the disease is breast cancer .[D21 ]The use according to [D19] , wherein the disease is triple-negative breast cancer .15324259-1[ D22 ]The use according to [D19] , wherein the disease is gastric cancer .[D23]The use according to [D19] , wherein the disease is ovarian cancer .[D24 ]The use according to [D19] , wherein the disease is lung cancer .[D25]The use according to [D19] , wherein the disease is pancreatic cancer .[D26]The use according to any one of [D18 ] to [D25] , wherein the cancer is metastatic .[D27 ]The use according to any one of [DI ] to [D26] , wherein the anti-HER2 antibody is trastuzumab deruxtecan.[D28 ]The use according to any one of [DI ] to [D27 ] , wherein the anti-HER2 antibody-drug conjugate is administered at a dose of 0.8 to 12.4 mg / kg.[D29]The use according to [D27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg or 6.4 mg / kg .[D30]15324259-1The use according to [ D27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg .[ D31 ]The use according to [ D27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg per administration at intervals of 3 weeks .[ D32 ]The use according to any one of [ DI ] to [ D31 ] , wherein the VEGF inhibitor is administered at a dose of 1 to 20 mg / kg .[ D33 ]The use according to any one of [ DI ] to [ D31 ] , wherein the VEGF inhibitor is administered at a dose of 5 to 15 mg / kg .[ D34 ]The use according to any one of [ DI ] to [ D31 ] , wherein the VEGF inhibitor is administered at a dose of 5 mg / kg, 7 . 5 mg / kg, 10 mg / kg, 12 . 5 mg / kg, or 15 mg / kg .[ D35 ]The use according to any one of [ DI ] to [ D31 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg .[ D36 ]The use according to any one of [ DI ] to [ D31 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[ D37 ]15324259-1The use according to any one of [D32 ] to [D36] , wherein the VEGF inhibitor is bevacizumab .[D38 ]The use according to [D37 ] , wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks, and bevacizumab is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[D39]The use according to [D38 ] , whereintrastuzumab deruxtecan and bevacizumab are administered on the same day.[D40]The use according to [D38 ] or [D39] , wherein trastuzumab deruxtecan is administered up to 34 cycles, and bevacizumab is administered up to 16 cycles .[D41 ]The use according to [D40] , whereinbevacizumab is administered up to 6 cycles before the 16 cycles of bevacizumab administration as a front-line chemotherapy .[D42 ]The use according to any one of [D37 ] to [D41 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer .[D43]15324259-1The use according to [ D42 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ / 1+ ) epithelial ovarian cancer . [ D44 ]The use according to [ D42 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ / 1+ ) advanced epithelial ovarian cancer .[ D45 ]The use according to [ D42 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ / 1+ ) advanced high-grade epithelial ovarian cancer .[ D46 ]The use according to [ D42 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ / 1+ ) advanced high-grade epithelial ovarian cancer as maintenance therapy .[ D47 ]The use according to [ D45 ] or [ D46 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ ) advanced high-grade epithelial ovarian cancer .[ D48 ]The use according to [ D45 ] or [ D46 ] , wherein the disease is HER2 expressing ( IHC 1+ ) advanced high-grade epithelial ovarian cancer .[El ]A VEGF inhibitor for use in a method of treating a disease , wherein the method comprises administering the inhibitor in combination with an anti-HER2 antibody-drug conj ugate , wherein15324259-1the anti-HER2 antibody-drug conjugate is an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula :[Formula 9]wherein A represents a connecting position to an antibody,is conjugated to the antibody via a thioether bond.[E2 ]The inhibitor for use according to [El ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 comprising an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 comprising an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 comprising an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 comprising an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 comprising an amino acid sequence consisting of15324259-1amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 comprising an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.[E3]The inhibitor for use according to [El ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1 and a light chain comprising a light chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2 .[E4 ]The inhibitor for use according to [El ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 1 and a light chain comprising an amino acid sequence represented by SEQ ID NO: 2.[E5]The inhibitor for use according to [El ] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence comprising amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain comprising an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.[E6]15324259-1The inhibitor for use according to any one of [El ] to [E5] , wherein the anti-HER2 antibody-drug conjugate is represented by the following formula :[Formula 10]wherein 'Antibody' indicates the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n indicates an average number of units of the drug-linker conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate, wherein n is in the range of from 7 to 8 .[E7 ]The inhibitor for use according to any one of [El ] to [E6] , wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.[E8 ]The inhibitor for use according to [E7 ] , wherein the VEGF inhibitor is an anti-VEGF antibody.15324259-1[E9]The inhibitor for use according to [ E 8 ] , wherein the anti-VEGF antibody is bevacizumab .[E10]The inhibitor for use according to [E7 ] , wherein the VEGF inhibitor is an anti-VEGF receptor antibody.[Ell ]The inhibitor for use according to [E10] , wherein the anti-VEGF receptor antibody is ramucirumab.[E12 ]The inhibitor for use according to [E7 ] , wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.[E13]The inhibitor for use according to [E12 ] , wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept .[E14 ]The inhibitor for use according to [E7 ] , wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.[E15]The inhibitor for use according to [E14 ] , wherein the multispecific antibody is a bispecific antibody.[E16]The inhibitor for use according to any one of [El ] to [E15] , wherein the anti-HER2 antibody-drug conjugate and15324259-1the VEGF inhibitor are separately contained as active components in different formulations, and are administered at the same time or at different times .[E17 ]The inhibitor for use according to any one of [El ] to [E15] , wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are contained as active components in a single formulation for administration.[E18 ]The inhibitor for use according to any one of [El ] to [E17 ] , wherein the disease is for use in treating cancer .[E19]The inhibitor for use according to any one of [El ] to [E17 ] , wherein the disease is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget ' s disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, hepatocellular carcinoma, gastrointestinal stromal tumor, kidney cancer, cervical cancer, and sarcoma .[E20]The inhibitor for use according to [E19] , wherein the disease is breast cancer .[E21 ]15324259-1The inhibitor for use according to [E19] , wherein the disease is triple-negative breast cancer .[E22 ]The inhibitor for use according to [E19] , wherein the disease is gastric cancer .[E23]The inhibitor for use according to [E19] , wherein the disease is ovarian cancer .[E24 ]The inhibitor for use according to [E19] , wherein the disease is lung cancer .[E25]The inhibitor for use according to [E19] , wherein the disease is pancreatic cancer .[E26]The inhibitor conjugate for use according to any one of [E18 ] to [E25] , wherein the cancer is metastatic .[E27 ]The inhibitor for use according to any one of [El ] to [E26] , wherein the anti-HER2 antibody is trastuzumab deruxtecan .[E28 ]The inhibitor for use according to any one of [El ] to [E27 ] , wherein the anti-HER2 antibody-drug conjugate is administered at a dose of 0.8 to 12.4 mg / kg.[E29]15324259-1The inhibitor for use according to [E27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg or 6 . 4 mg / kg .[E30 ]The inhibitor for use according to [E27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg .[E31 ]The inhibitor for use according to [E27 ] , wherein trastuzumab deruxtecan is administered at a dose of 5 . 4 mg / kg per administration at intervals of 3 weeks .[E32 ]The inhibitor for use according to any one of [El ] to [E31 ] , wherein the VEGF inhibitor is administered at a dose of 1 to 20 mg / kg .[E33 ]The inhibitor for use according to any one of [El ] to [E31 ] , wherein the VEGF inhibitor is administered at a dose of 5 to 15 mg / kg .[E34 ]The inhibitor for use according to any one of [El ] to [E31 ] , wherein the VEGF inhibitor is administered at a dose of 5 mg / kg, 7 . 5 mg / kg, 10 mg / kg, 12 . 5 mg / kg, or 15 mg / kg .[E35 ]15324259-1The inhibitor for use according to any one of [El ] to [E31 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg.[E36]The inhibitor for use according to any one of [El ] to [E31 ] , wherein the VEGF inhibitor is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[E37 ]The inhibitor for use according to any one of [E32 ] to [E36] , wherein the VEGF inhibitor is bevacizumab .[E38 ]The inhibitor for use according to [E37 ] , wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks, and bevacizumab is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .[E39]The inhibitor for use according to [E38 ] , wherein trastuzumab deruxtecan and bevacizumab are administered on the same day.[E40]The inhibitor for use according to [E38 ] or [E39] , wherein trastuzumab deruxtecan is administered up to 34 cycles, and bevacizumab is administered up to 16 cycles .[E41 ]The inhibitor for use according to [E40] , wherein15324259-1bevaci zumab is administered up to 6 cycles before the 16 cycles of bevaci zumab administration as a front-line chemotherapy .[E42 ]The inhibitor for use according to any one of [E37 ] to [E41 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ / 1+ ) ovarian cancer .[E43 ]The inhibitor for use according to [E42 ] , wherein the disease is HER2 expressing ( IHC 3+ / 2+ / 1+ ) epithelial ovarian cancer .[E44 ]The inhibitor for use according to [E42 ] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+ ) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+ ) advanced epithelial ovarian cancer .[E45 ]The inhibitor for use according to [E42 ] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+ ) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+ ) advanced high-grade epithelial ovarian cancer .[E46 ]The inhibitor for use according to [E42 ] , wherein the HER2 expressing ( IHC 3+ / 2+ / 1+ ) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+ ) advanced high-grade epithelial ovarian cancer as maintenance therapy .[E47 ]15324259-1The inhibitor for use according to [E45] or [E46] , wherein the disease is HER2 expressing ( IHC 3+ / 2+) advanced high-grade epithelial ovarian cancer .[E48 ]The inhibitor for use according to [E45] or [E46] , wherein the disease is HER2 expressing ( IHC 1+) advanced high-grade epithelial ovarian cancer .[Advantageous Effects of disclosure]The present disclosure can provide a pharmaceutical product wherein a specific anti-HER2 antibody-drug conjugate and a VEGF inhibitor are administered in combination, and / or a method of treatment comprising administering a specific anti-HER2 antibody-drug conjugate and a VEGF inhibitor in combination to a sub j ect .[Brief Description of Drawings][Figure 1 ] Figure 1 is a diagram showing the amino acid sequence (SEQ ID NO: 1 ) of human HER2 EC3 .[Figure 2 ] Figure 2 is a diagram showing the amino acid sequence (SEQ ID NO: 2 ) of anti-HER2 antibody heavy chain CDRH1 .[Figure 3] Figure 3 is a diagram showing the tumor growth suppressing effects in human colon cancer cell line COLO201 .15324259-1[Figure 4 ] Figure 4 is a diagram showing the tumor growth suppressing effects in human ovarian cancer cell line 0V-90 .[Figure 5] Figure 5 is a diagram showing the tumor growth suppressing effects in human ovarian cancer cell line SK-OV-3 .[Figure 6] Figure 6 shows Safety run-in Study design. [Figure 7 ] Figure 7 shows Randomize phase study design.Description of Embodiments

[0001] Hereinafter, preferred modes for carrying out the present disclosure are described. The embodiments described below are given merely for illustrating one example of a typical embodiment of the present disclosure and are not intended to limit the scope of the present disclosure .1. Antibody-drug conjugate

[0002] The anti-HER2 antibody-drug conjugate used in the present disclosure is an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula :15324259-1[Formula 11 ]wherein A represents a connecting position to an antibody,is conjugated to the antibody via a thioether bond.

[0003] In the present disclosure, the partial structure consisting of a linker and a drug in the anti-HER2 antibody-drug conjugate is referred to as a "druglinker" . The drug-linker is connected to a thiol group (in other words, the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody.

[0004] The drug-linker of the present disclosure includes exatecan ( IUPAC name : (IS, 9S) -l-amino-9-ethyl-5-fluoro-1, 2, 3, 9, 12, 15-hexahydro-9-hydroxy-4-methyl-10H, 13H-benzo [de ] pyrano [ 3 ' , 4 ' : 6, 7 ] indolizino [ 1 , 2-b] quinol in-10, 13-dione, (also expressed as chemical name : ( 1S, 9S) -1-15324259-1amino-9-ethyl-5-f luoro-2 , 3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de ] pyrano [ 3 ' , 4 ' : 6, 7 ] indolizino [ 1, 2-b] quinolin-10, 13 ( 9H, 15H) -dione) ) , which is a topoisomerase I inhibitor, as a component . Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula :[Formula 12 ]

[0005] The anti-HER2 antibody-drug conjugate used in the present disclosure can also be represented by the following formula :[Formula 13]wherein, the drug-linker is conjugated to an antibody via a thioether bond. The meaning of n is the same as that of what is called the average number of conjugated drug15324259-1molecules (DAR; Drug-to-Antibody Ratio) , and indicates the average number of units of the drug-linker conjugated per antibody molecule .

[0006] After migrating into cancer cells, the anti-HER2 antibody-drug conjugate used in the present disclosure is cleaved at the linker portion to release the compound represented by the following formula :[Formula 14 ]

[0007] The aforementioned compound is inferred to be the original source of the antitumor activity of the anti-HER2 antibody-drug conjugate used in the present disclosure, and has been confirmed to have a topoisomerase I inhibitory effect (Ogitani Y. et al . , Clinical Cancer Research, 2016, Oct 15; 22 (20) : 5097-5108, Epub 2016 Mar 29. )

[0008] The anti-HER2 antibody-drug conjugate used in the present disclosure is also known to have a bystander15324259-1effect (Ogitani Y. et al . , Cancer Science (2016) 107, 1039-1046) .

[0009] The bystander effect is exerted through a process such that the anti-HER2 antibody-drug conjugate used in the present disclosure is internalized in cancer cells expressing the target, and the aforementioned compound is released and then exerts an antitumor effect also on cancer cells which are present therearound and not expressing the target .

[0010] The bystander effect is also exerted as an excellent antitumor effect when the anti-HER2 antibody-drug conjugate according to the present disclosure is used in combination with a VEGF inhibitor .2. Antibody in the anti-HER2 antibody-drug conjugate

[0011] The antibody in the anti-HER2 antibody-drug conjugate used in the present disclosure may be derived from any species and is in some instances an antibody derived from a human, a rat, a mouse, or a rabbit . In cases when the antibody is derived from species other than human species, it is in some instances chimerized or humanized using a well-known technique . The antibody of the present disclosure may be a polyclonal antibody or a15324259-1monoclonal antibody and is in some instances a monoclonal antibody .

[0012] The antibody in the anti-HER2 antibody-drug conjugate used in the present disclosure is an antibody in some instances having the characteristic of being able to target cancer cells, and is in some instances an antibody possessing, for example, the property of being able to recognize a cancer cell, the property of being able to bind to a cancer cell, the property of being internalized in a cancer cell, and / or cytocidal activity against cancer cells .

[0013] The binding activity of the antibody against cancer cells can be confirmed using flow cytometry. The internalization of the antibody into tumor cells can be confirmed using ( 1 ) an assay of visualizing an antibody incorporated in cells under a fluorescence microscope using a secondary antibody ( fluorescently labeled) binding to the therapeutic antibody (Cell Death and Differentiation (2008 ) 15, 751-761 ) , (2 ) an assay of measuring a fluorescence intensity incorporated in cells using a secondary antibody ( fluorescently labeled) binding to the therapeutic antibody (Molecular Biology of the Cell, Vol . 15, 5268-5282, December 2004 ) , or (3) a Mab-ZAP assay using an immunotoxin binding to the therapeutic antibody wherein the toxin is released upon15324259-1incorporation into cells to inhibit cell growth (Bio Techniques 28 : 162-165, January 2000) . As the immunotoxin, a recombinant complex protein of a diphtheria toxin catalytic domain and protein G may be used .

[0014] The antitumor activity of the antibody can be confirmed in vitro by determining inhibitory activity against cell growth. For example, a cancer cell line overexpressing a target protein for the antibody is cultured, and the antibody is added at varying concentrations into the culture system to determine inhibitory activity against focus formation, colony formation, and spheroid growth. The antitumor activity can be confirmed in vivo, for example, by administering the antibody to a nude mouse with a transplanted cancer cell line highly expressing the target protein, and determining changes in the cancer cells .

[0015] Since the compound conjugated in the anti-HER2 antibody-drug conjugate exerts an antitumor effect, it is preferred but not essential that the antibody itself should have an antitumor effect . For the purpose of specifically and selectively exerting the cytotoxic activity of the antitumor compound against cancer cells, it is important and also preferred that the antibody15324259-1should have the property of being internalized to migrate into cancer cells .

[0016] The antibody in the anti-HER2 antibody-drug conjugate used in the present disclosure can be obtained by a procedure known in the art . For example, the antibody of the present disclosure can be obtained using a method usually carried out in the art, which involves immunizing animals with an antigenic polypeptide and collecting and purifying antibodies produced in vivo . The origin of the antigen is not limited to humans, and the animals may be immunized with an antigen derived from a non-human animal such as a mouse, a rat and the like . In this case, the cross-reactivity of antibodies binding to the obtained heterologous antigen with human antigens can be tested to screen for an antibody applicable to a human disease .

[0017] Alternatively, antibody-producing cells which produce antibodies against the antigen can be fused with myeloma cells according to a method known in the art ( for example, Kohler and Milstein, Nature ( 1975) 256, p .495-497 ; Kennet, R. ed. , Monoclonal Antibodies, p . 365-367, Plenum Press, N.Y. ( 1980) ) , to establish hybridomas, from which monoclonal antibodies can in turn be obtained.

[0018] 15324259-1The antigen can be obtained by genetically engineering host cells to produce a gene encoding the antigenic protein. Specifically, vectors that permit expression of the antigen gene are prepared and transferred to host cells so that the gene is expressed. The antigen thus expressed can be purified. The antibody can also be obtained by a method of immunizing animals with the above-described genetically engineered antigenexpressing cells or a cell line expressing the antigen.

[0019] The antibody in the anti-HER2 antibody-drug conjugate used in the present disclosure is in some instances a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans such as a chimeric antibody or a humanized antibody, or is in some instances an antibody having only the gene sequence of an antibody derived from a human, that is, a human antibody. These antibodies can be produced using a known method.

[0020] As the chimeric antibody, an antibody in which antibody variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse- or rat-derived antibody variable region is connected to a human-derived antibody constant region can be exemplified (Proc. Natl . Acad. Sci . USA, 81, 6851-6855, ( 1984 ) ) .15324259-1

[0021] As the humani zed antibody, an antibody obtained by integrating only the complementarity determining region ( CDR) of a heterologous antibody into a human-derived antibody (Nature ( 1986 ) 321 , pp . 522-525 ) , an antibody obtained by grafting a part of the amino acid residues of the framework of a heterologous antibody as well as the CDR sequence of the heterologous antibody to a human antibody by a CDR-grafting method (WO 90 / 07861 ) , and an antibody humani zed using a gene conversion mutagenesis strategy (U . S . Patent No . 5821337 ) can be exempli fied .

[0022] As the human antibody, an antibody generated by using a human antibody-producing mouse having a human chromosome fragment including genes of a heavy chain and light chain of a human antibody ( see Tomi zuka, K . et al . , Nature Genetics ( 1997 ) 16 , p . 133- 143 ; Kuroiwa, Y . et . al . , Nucl . Acids Res . ( 1998 ) 26 , p . 3447-3448 ; Yoshida, H . et . al . , Animal Cell Technology : Basic and Applied Aspects vol . 10 , p . 69-73 (Kitagawa, Y . , Matsuda, T . and l ij ima, S . eds . ) , Kluwer Academic Publishers , 1999 ;Tomi zuka, K . et . al . , Proc . Natl . Acad . Sci . USA ( 2000 ) 97 , p . 722-727 , etc . ) can be exempli fied . As an alternative , an antibody obtained by phage display, the antibody being selected from a human antibody library ( see Wormstone , I . M . et . al , Investigative Ophthalmology & Visual Science . ( 2002 ) 43 ( 7 ) , p . 2301-2308 ; Carmen, S .15324259-1et . al . , Briefings in Functional Genomics and Proteomics (2002 ) , 1 (2 ) , p . 189-203; Siriwardena, D. et . al . , Ophthalmology (2002 ) 109 (3) , p . 427-431, etc . ) can be exemplified.

[0023] In the antibody in the anti-HER2 antibody-drug conjugate used in present disclosure, modified variants of the antibody are also included. The modified variant refers to a variant obtained by subj ecting the antibody according to the present disclosure to chemical or biological modification. Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N-linked or O-linked carbohydrate chain, etc . Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine) , and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell . Further, an antibody labeled so as to enable the detection or isolation of the antibody or an antigen according to the present disclosure, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the15324259-1meaning of the modified variant . Such a modified variant of the antibody according to the present disclosure is useful for improving the stability and blood retention of the antibody, reducing the antigenicity thereof, detecting or isolating an antibody or an antigen, and so on .

[0024] Further, by regulating the modification of a glycan which is linked to the antibody according to the present disclosure (glycosylation, defucosylation, etc . ) , it is possible to enhance antibody-dependent cellular cytotoxic activity. As the technique for regulating the modification of a glycan of antibodies, International Publication No . WO 99 / 54342, International Publication No . WO 00 / 61739, International Publication No . WO 02 / 31140, International Publication No . WO 2007 / 133855, International Publication No . WO 2013 / 120066, etc . are known. However, the technique is not limited thereto . In the antibody according to the present disclosure, antibodies in which the modification of a glycan is regulated are also included.

[0025] It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell is deleted (Journal of Chromatography A, 705 : 129-134 ( 1995) ) , and it is also known that two amino acid residues (glycine and lysine)15324259-1at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell are deleted and a proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360 : 75-83 (2007 ) ) . However, such deletion and modification of the heavy chain sequence do not affect the antigen-binding affinity and the effector function (complement activation, antibody-dependent cellular cytotoxicity, etc . ) of the antibody. Therefore, in the antibody according to the present disclosure, antibodies subj ected to such modification and functional fragments of the antibody are also included, and deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of the deletion variants ( for example, a heavy chain in which the carboxyl terminal proline residue has been amidated) , and the like are also included. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present disclosure is not limited to the above variants as long as the antigenbinding affinity and the effector function are conserved. The two heavy chains constituting the antibody according to the present disclosure may be of one type selected from the group consisting of a full-length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom. The ratio15324259-1of the amount of each deletion variant can be affected by the type of cultured mammalian cells which produce the antibody according to the present disclosure and the culture conditions; however, an antibody in which one amino acid residue at the carboxyl terminus has been deleted in both of the two heavy chains in the antibody according to the present disclosure can be in some instances exemplified.

[0026] As isotypes of the antibody according to the present disclosure, for example, IgG ( IgGl, IgG2, IgG3, IgG4 ) can be exemplified. In some instances, IgGl or IgG2 can be exemplified.

[0027] Furthermore, while specific amino acid sequences are provided herein for certain antibodies, antibodies with a small number of mutations, truncations, or additions to those sequences should also be considered within the scope of the disclosure . So, in certain embodiments, an antibody includes a number of mutations, truncations, or additions to the specific amino acid sequences provided herein. For example, 1 to 20, 1 to 10, 1 to 5, 1 to 4, 1 to 3, 1 to 2, or 1 amino acid residues may be substituted, deleted, inserted, and / or added in relation to the reference amino acid sequence . In other embodiments, the antibody comprises at15324259-1least a certain % sequence homology to the specific amino acid sequences provided herein, for example, at least 80%, at least 90%, at least 95%, at least 99%, at least 99.5%, or at least 99.9% sequence homology to the reference amino acid sequence . A suitable algorithm such as BLAST may be used to ascertain sequence homology.

[0028] In the present disclosure, the term "anti-HER2 antibody" refers to an antibody which binds specifically to HER2 (Human Epidermal Growth Factor Receptor Type 2 ; ErbB-2 ) , and in some instances has an activity of internalization in HER2-expressing cells by binding to HER2 .

[0029] Examples of the anti-HER2 antibody include trastuzumab (U. S . Patent No . 5821337 ) and pertuzumab ( International Publication No . WO 01 / 00245) . In some instances, trastuzumab can be exemplified.3. Production of the anti-HER2 antibody-drug conjugate

[0030] A drug-linker intermediate for use in the production of the anti-HER2 antibody-drug conjugate according to the present disclosure is represented by the following formula .15324259-1[Formula 15]

[0031] The drug-linker intermediate can be expressed as the chemical name N- [ 6- (2, 5-dioxo-2, 5-dihydro-lH-pyrrol-l-yl ) hexanoyl ] glycylglycyl-L-phenylalanyl-N- [ (2- { [ ( IS , 9S ) -9-ethyl-5-f luoro-9-hydroxy- 4 -methyl- 10 , 13-dioxo-2, 3, 9, 10, 13, 15-hexahydro-lH, 12H-benzo [de ] pyrano [ 3 ' , 4 ' : 6, 7 ] indolizino [ 1 , 2-b] quinolin- 1-yl ] amino } -2-oxoethoxy) methyl ] glycinamide, and can be produced with reference to descriptions in International Publication No . WO 2014 / 057687, International Publication No . WO 2015 / 098099, International Publication No . WO 2015 / 115091, International Publication No . WO 2015 / 155998, International Publication No . WO 2019 / 044947, and so on.

[0032] The anti-HER2 antibody-drug conjugate used in the present disclosure can be produced by reacting the abovedescribed drug-linker intermediate and an antibody having15324259-1a thiol group (alternatively referred to as a sulfhydryl group) .

[0033] The antibody having a sulfhydryl group can be obtained by a method well known in the art (Hermanson, G. T, Bioconjugate Techniques, pp . 56-136, pp . 456-493, Academic Press ( 1996) ) . For example, by using 0.3 to 3 molar equivalents of a reducing agent such as tris (2-carboxyethyl ) phosphine hydrochloride (TCEP) per interchain disulfide within the antibody and reacting with the antibody in a buffer solution containing a chelating agent such as ethylenediamine tetraacetic acid (EDTA) , an antibody having a sulfhydryl group with partially or completely reduced interchain disulfides within the antibody can be obtained.

[0034] Further, by using 2 to 20 molar equivalents of the drug-linker intermediate per the antibody having a sulfhydryl group, an anti-HER2 antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced.

[0035] The average number of conjugated drug molecules per antibody molecule of the anti-HER2 antibody-drug conjugate produced can be determined, for example, by a method of calculation based on measurement of UV absorbance for the anti-HER2 antibody-drug conjugate and15324259-1the conjugation precursor thereof at two wavelengths of 280 nm and 370 nm (UV method) , or a method of calculation based on quantification through HPLC measurement for fragments obtained by treating the anti-HER2 antibodydrug conjugate with a reducing agent (HPLC method) .

[0036] Conjugation between the antibody and the drug-linker intermediate and calculation of the average number of conjugated drug molecules per antibody molecule of the anti-HER2 antibody-drug conjugate can be performed with reference to descriptions in International Publication No . WO 2014 / 057687, International Publication No . WO 2015 / 098099, International Publication No . WO 2015 / 115091, International Publication No . WO 2015 / 155998, International Publication No . WO 2018 / 135501, and International Publication No . WO 2018 / 212136, and so on.

[0037] In the present disclosure, the term "anti-HER2 antibody-drug conjugate" refers to an antibody-drug conjugate such that the antibody in the antibody-drug conjugate according to the disclosure is an anti-HER2 antibody .

[0038] The anti-HER2 antibody is in some instances an antibody comprising a heavy chain comprising CDRH1 consisting of an amino acid sequence consisting of amino15324259-1acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2, in some instances an antibody comprising a heavy chain comprising a heavy chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1 and a light chain comprising a light chain variable region consisting of an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2, and in some instances an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2 .

[0039] 15324259-1The average number of units of the drug-linker conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in some instances 2 to 8, in some instances 3 to 8, in some instances 7 to 8, in some instances 7.5 to 8, and in some instances about 8.

[0040] The anti-HER2 antibody-drug conjugate can be produced with reference to descriptions in International Publication No . WO 2015 / 115091 and so on.

[0041] One such antibody-drug conjugate is trastuzumab deruxtecan (DS-8201a) , which is composed of a HER2-targeting antibody and a derivative of exatecan. In particular, WO 2015 / 115091 provides a detailed description of exemplary HER2-targeting antibody-drug conjugates, including trastuzumab deruxtecan (DS-8201a) .4 . VEGF inhibitor

[0042] In the present disclosure, the term "VEGF inhibitor" refers to an agent that inhibits an interaction between VEGF and a VEGF receptor .

[0043] The VEGF inhibitor according to the present disclosure is not particularly limited as long as the agent has the above-described properties . The VEGF inhibitor may be an antibody, a functional fragment of15324259-1the antibody, a fusion protein, an immunoadhesin, a nucleic acid, an oligonucleotide, an aptamer, a polypeptide, or a low-molecular-weight compound. The VEGF inhibitor according to the present disclosure is in some instances an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.

[0044] In the present disclosure, the term "anti-VEGF antibody" refers to an antibody that specifically binds to VEGF, or a functional fragment of the antibody.

[0045] In the present disclosure, the term "anti-VEGF receptor antibody" refers to an antibody that specifically binds to a VEGF receptor, or a functional fragment of the antibody.

[0046] In the present disclosure, the term "fusion protein comprising a VEGF receptor extracellular domain" refers to a fusion protein having a VEGF binding domain (also including a mutant of the VEGF binding domain) derived from a VEGF receptor extracellular domain.

[0047] In the present disclosure, the term "multispecific antibody comprising an anti-VEGF binding domain" refers to an antibody having binding specificities for at least15324259-1two different sites, or a functional fragment of the antibody, wherein at least one of the binding specificities is for VEGF.

[0048] In the present disclosure, the term "bispecific antibody comprising an anti-VEGF binding domain" refers to an antibody having binding specificities for two different sites, or a functional fragment of the antibody, wherein one of the binding specificities is for VEGF.

[0049] The VEGF inhibitor according to the present disclosure is in some instances an anti-VEGF antibody. The anti-VEGF antibody according to the present disclosure is in some instances bevacizumab or sevacizumab, and in some instances bevacizumab .

[0050] The VEGF inhibitor according to the present disclosure is in some instances an anti-VEGF receptor antibody. The anti-VEGF receptor antibody according to the present disclosure is in some instances ramucirumab .

[0051] The VEGF inhibitor according to the present disclosure is in some instances a fusion protein comprising a VEGF receptor extracellular domain. The fusion protein comprising a VEGF receptor extracellular15324259-1domain according to the present disclosure is in some instances aflibercept .

[0052] The VEGF inhibitor according to the present disclosure is in some instances a multispecific antibody comprising an anti-VEGF binding domain, and still in some instances a bispecific antibody comprising an anti-VEGF binding domain. The bispecific antibody comprising an anti-VEGF binding domain according to the present disclosure is in some instances ivonescimab (Non Patent Literature 3) , CTX-009 (also referred to as ABL-001 ; Non Patent Literature 4 ) , BI836880 (Clin. Exp . Metastasis (2020) 37 ( 6) : 637-648 ) , navicixi zumab (Non Patent Literature 3) , vanucizumab (Non Patent Literature 4 ) , or PM8002 (Journal of Clinical Oncology 41, no . 16_suppl (June 01, 2023) 2536-2536) .5. Medicament

[0053] Described in the following are a pharmaceutical product and a method of treatment according to the present disclosure, wherein an anti-HER2 antibody-drug conjugate and a VEGF inhibitor are administered in combination .

[0054] The pharmaceutical product and method of treatment of the present disclosure may be those in which the anti-15324259-1HER2 antibody-drug conjugate and a VEGF inhibitor are separately contained as active components in different formulations and are administered simultaneously or at different times, or may be those in which the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are contained as active components in a single formulation and administered. The anti-HER2 antibody-drug conjugate and the VEGF inhibitor may be administered at different intervals when the anti-HER2 antibody-drug conjugate and VEGF inhibitor are separately contained as active components in different formulations .

[0055] The term "pharmaceutical product" refers to a preparation which is in such form as to permit the biological activity of the active ingredients, either as a composition containing all the active ingredients ( for simultaneous administration) , or as a combination of separate compositions (a combined preparation) each containing at least one but not all of the active ingredients ( for administration sequentially or simultaneously) , and which contains no additional components which are unacceptably toxic to a subj ect to which the product would be administered. Such product can be sterile .

[0056] The pharmaceutical product and method of treatment of the present disclosure can be used for treating15324259-1cancer, and can be in some instances used for treating at least one disease selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget ' s disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, hepatocellular carcinoma, gastrointestinal stromal tumor, kidney cancer, cervical cancer, and sarcoma .

[0057] The pharmaceutical product and method of treatment of the present disclosure can be used for treating ovarian cancer, and can be in some instances used for treating HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer, and can be in some instances used for treating HER2 expressing ( IHC 3+ / 2+ / 1+) epithelial ovarian cancer, and can be in some instances used for treating HER2 expressing ( IHC 3+ / 2+ / 1+) advanced epithelial ovarian cancer, and can be in some instances used for treating HER2 expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer, and can be in some instances used for treating HER2 expressing ( IHC 3+ / 2+) advanced high-grade epithelial ovarian cancer, and can be in some instances used for treating HER2 expressing ( IHC 1+) advanced high-grade epithelial ovarian cancer .

[0058] 15324259-1Ovarian cancer is staged surgically, radiologically and pathologically, and its development stage can be diagnosed with FIGO staging classification ( International Journal of Gynecologic Oncology, 124 (2014 ) 1-5) .Advanced ovarian cancer is categorized in FIGO Stage III or IV. Diagnosis of epithelial ovarian cancer and determination of grade (e . g. , high-grade or low-grade) can be made, referring to "Annals of Oncology. , Volume 34, Issue 10, October 2023, 833-848."

[0059] In one embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating breast cancer . In another embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating triplenegative breast cancer . In another embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating HER2 low-expressing breast cancer .

[0060] In one embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating lung cancer . In another embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating non-small cell lung cancer .

[0061] 15324259-1In one embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating colorectal cancer .

[0062] In one embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating cervical cancer .

[0063] In one embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating kidney cancer .

[0064] In one embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating hepatocellular carcinoma .

[0065] In one embodiment, the pharmaceutical product and method of treatment of the present disclosure can be used for treating ovarian cancer .

[0066] The pharmaceutical product and method of treatment of the present disclosure can be in some instances used not only for HER2-overexpressing cancer but also for HER2 low-expressing cancer and HER2 -mutated cancer .

[0067] In the present disclosure, the term "HER2-overexpressing cancer" is not particularly limited as15324259-1long as it is recognized as HER2-overexpressing cancer by those skilled in the art . Preferred examples of the HER2-overexpressing cancer can include cancer given a score of 3+ for the expression of HER2 in an immunohistochemical method, and cancer given a score of 2+ for the expression of HER2 in an immunohistochemical method and determined as positive for the expression of HER2 in an in situ hybridization method. The in situ hybridization method of the present disclosure includes a fluorescence in situ hybridization method (FISH) and a dual color in situ hybridization method (DISH) .

[0068] In the present disclosure, the term "HER2 low-expressing cancer" is not particularly limited as long as it is recognized as HER2 low-expressing cancer by those skilled in the art . Preferred examples of the HER2 low-expressing cancer can include cancer given a score of 2+ for the expression of HER2 in an immunohistochemical method and determined as negative for the expression of HER2 in an in situ hybridization method, and cancer given a score of 1+ for the expression of HER2 in an immunohistochemical method. Another example of the HER2 low-expressing cancer can include, but is not particularly limited to, cancer given a score of >0 and <1+ for the expression of HER2 in an immunohistochemical method .

[0069] 15324259-1The method for scoring the degree of HER2 expression by the immunohistochemical ( IHC) method, or the method for determining positivity or negativity to HER2 expression by the in situ hybridization method is not particularly limited as long as it is recognized by those skilled in the art . Examples of the method can include a method described in the 4th edition of the guidelines for HER2 testing, breast cancer (developed by the Japanese Pathology Board for Optimal Use of HER2 for Breast Cancer) .

[0070] The HER2 low-expressing cancer for which the pharmaceutical product and method of treatment of the present disclosure can be used is in some instances HER2 low-expressing breast cancer, HER2 low-expressing gastric cancer, HER2 low-expressing colorectal cancer, or HER2 low-expressing non-small cell lung cancer, and is in some instances HER2 low-expressing breast cancer .

[0071] The pharmaceutical product and method of treatment of the present disclosure can be in some instances used for mammals, and can be in some instances used for humans .

[0072] The pharmaceutical product and method of treatment of the present disclosure can be in some instances used for a maintenance therapy. The pharmaceutical product and15324259-1method of treatment of the present disclosure may be used for the purpose of preventing the recurrence of a tumor after initial chemotherapy.

[0073] In the present disclosure, the term "maintenance therapy" is used to mean treatment that is given to help prevent cancer from coming back after it has disappeared following an initial therapy. The term is defined on the basis of "maintenance therapy" in the following reference .

[0074] NCI Dictionaries, "maintenance therapy", NCI Dictionary of Cancer Terms [online] . National Cancer Institute [retrieved on 2023-04-10] . Retrieved from < cancer . gov / publications / dictionaries / cancerterms / def / maintenance -therapy > .

[0075] The antitumor effect of the pharmaceutical product and method of treatment of the present disclosure can be confirmed by, for example, generating a model in which cancer cells are transplanted to a test animal, and measuring reduction in tumor volume, life-prolonging effects due to applying the pharmaceutical product and method of treatment of the present disclosure .Furthermore, comparison with the antitumor effect of single administration of each of the anti-HER2 antibodydrug conjugate and the VEGF inhibitor used in the present15324259-1disclosure can provide confirmation of the combined effect of the anti-HER2 antibody-drug conjugate and the VEGF inhibitorused in the present disclosure .

[0076] In addition, the antitumor effect of the pharmaceutical product and method of treatment of the present disclosure can be confirmed, in a clinical study, with the Response Evaluation Criteria in Solid Tumors (RECIST) evaluation method, WHO' s evaluation method, Macdonald' s evaluation method, measurement of body weight, and other methods; and can be determined by indicators such as Complete response (CR) , Partial response (PR) , Progressive disease (PD) , Obj ective response rate (ORR) , Duration of response (DoR) , Progression-free survival (PFS) , and Overall survival (OS) .

[0077] The foregoing methods can provide confirmation of superiority in terms of the antitumor effect of the pharmaceutical product and method of treatment of the present disclosure compared to existing pharmaceutical products and methods of treatment for cancer therapy.

[0078] The pharmaceutical product and method of treatment of the present disclosure can retard growth of cancer cells, suppress their proliferation, and further can kill cancer cells . These effects can allow cancer patients to15324259-1be free from symptoms caused by cancer or can achieve an improvement in the QOL of cancer patients and attain a therapeutic effect by sustaining the lives of the cancer patients . Even if the pharmaceutical product and method of treatment do not accomplish the killing of cancer cells, they can achieve higher QOL of cancer patients while achieving longer-term survival, by inhibiting or controlling the growth of cancer cells . Furthermore, the pharmaceutical product and method of treatment of the present disclosure can show a sustained antitumor effect .

[0079] The pharmaceutical product of the present disclosure can be expected to exert a therapeutic effect by application as systemic therapy to patients, and additionally, by local application to cancer tissues .

[0080] The pharmaceutical product of the present disclosure includes a pharmaceutical composition containing at least one pharmaceutically suitable ingredient . The pharmaceutically suitable ingredient can be suitably selected and applied from formulation additives or the like that are generally used in the art, in accordance with the dosage, administration concentration or the like of the anti-HER2 antibody-drug conjugate used in the present disclosure and the VEGF inhibitor . For example, the anti-HER2 antibody-drug conjugate used in the present disclosure can be administered as a pharmaceutical15324259-1product containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as Polysorbate 80 or 20. The pharmaceutical product containing the anti-HER2 antibodydrug conjugate used in the present disclosure can be in some instances used as an inj ection, can be in some instances used as an aqueous inj ection or a lyophilized inj ection, and can be in some instances used as a lyophilized inj ection.

[0081] In the case that the pharmaceutical product containing the anti-HER2 antibody-drug conjugate used in the present disclosure is an aqueous inj ection, it can be in some instances diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be in some instances exemplified, and a 5% dextrose solution can be in some instances exemplified.

[0082] In the case that the pharmaceutical product containing the anti-HER2 antibody-drug conjugate used in the present disclosure is a lyophilized inj ection, it can be in some instances dissolved in water for inj ection, subsequently a required amount can be diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, a dextrose solution,15324259-1physiological saline, and the like, can be exemplified, and a dextrose solution can be in some instances exemplified, and a 5% dextrose solution can be in some instances exemplified.

[0083] Examples of the administration route which may be used to administer the pharmaceutical product of the present disclosure include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes; and in some instances include an intravenous route .

[0084] The anti-HER2 antibody-drug conjugate used in the present disclosure can be administered to a human once at intervals of 1 to 180 days, and can be in some instances administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks, and can be in some instances administered once every 3 weeks . Also, the anti-HER2 antibody-drug conjugate used in the present disclosure can be administered at a dose of about 0.001 to 100 mg / kg, and can be in some instances administered at a dose of 0.8 to 12.4 mg / kg. In another embodiment, it can be in some instances administered once every 3 weeks at a dose of 0.8 mg / kg, 1. 6 mg / kg, 3.2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg.

[0085] The VEGF inhibitor used in the present disclosure can be administered to a human once at intervals of 1 to15324259-1180 days, and can be in some instances administered once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks, or more and can be in some instances administered once every 3 weeks . Also, the VEGF inhibitor used in the present disclosure can be administered at a dose of about 0.001 to 100 mg / kg, and can be in some instances administered at a dose of 1 to 20 mg / kg. In another embodiment, it can be in some instances administered at a dose of 5 to 15 mg / kg. In another embodiment, it can be in some instances administered at a dose of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, or 15 mg / kg and can be in some instances administered at a dose of 15 mg / kg.

[0086] When the VEGF inhibitor used in the present disclosure is bevacizumab, examples of the administration method include, but are not limited to, the following dosages and administrations . For example, bevacizumab is inj ected by intravenous drips at 5 mg / kg (body weight) or 10 mg / kg (body weight) per administration.Administration intervals are set to 2 weeks or more .

[0087] As another dosage and administration, bevacizumab is inj ected by intravenous drips at 7.5 mg / kg (body weight) per administration. Administration intervals are set to 3 weeks or more .

[0088] 15324259-1As another dosage and administration, bevacizumab is inj ected by intravenous drips at 15 mg / kg (body weight) per administration. Administration intervals are set to 3 weeks or more .

[0089] As another dosage and administration, bevacizumab is inj ected by intravenous drips at 10 mg / kg (body weight) per administration. Administration intervals are set to 2 weeks or more .

[0090] As another dosage and administration, bevacizumab is inj ected by intravenous drips at 10 mg / kg (body weight) per administration at intervals of 2 weeks or at 15 mg / kg (body weight) per administration at intervals of 3 weeks .

[0091] As another dosage and administration, bevacizumab is inj ected by intravenous drips at 5 mg / kg or 10 mg / kg per administration at intervals of 2 weeks .

[0092] As another dosage and administration, bevacizumab is inj ected by intravenous drips at 15 mg / kg per administration at intervals of 3 weeks .

[0093] As another dosage and administration, trastuzumab deruxtecan (DS-8201a) is administered intravenously at 5.4 mg / kg per administration at intervals of 3 weeks, and15324259-1bevacizumab is inj ected by intravenous drips at 15 mg / kg per administration at intervals of 3 weeks .

[0094] As another dosage and administration, bevacizumab is inj ected by intravenous drips at 10 mg / kg per administration at intervals of 2 weeks .

[0095] When the VEGF inhibitor used in the present disclosure is ramucirumab, examples of the administration method include, but are not limited to, the following dosages and administrations . For example, ramucirumab is inj ected by intravenous drips at 8 mg / kg (body weight) per administration over approximately 60 minutes every 2 weeks . The length of time of administration at the second administration or later can be shortened up to 30 minutes .

[0096] As another dosage and administration, ramucirumab is inj ected by intravenous drips at 10 mg / kg (body weight) per administration over approximately 60 minutes every 3 weeks . The length of time of administration at the second administration or later can be shortened up to 30 minutes .

[0097] As another dosage and administration, ramucirumab is inj ected by intravenous drips at 10 mg / kg (body weight) per administration over approximately 60 minutes every 215324259-1weeks . The length of time of administration at the second administration or later can be shortened up to 30 minutes .

[0098] When the VEGF inhibitor used in the present disclosure is aflibercept, examples of the administration method include, but are not limited to, the following dosages and administrations . For example, aflibercept is inj ected by intravenous drips at 4 mg / kg (body weight) per administration over approximately 60 minutes every 2 weeks .

[0099] The pharmaceutical product and method of treatment of the present disclosure may further contain a cancer therapeutic agent other than the anti-HER2 antibody-drug conjugate and the VEGF inhibitor according to the present disclosure . The pharmaceutical product and method of treatment of the present disclosure can also be administered in combination with another cancer therapeutic agent, thereby enhancing the antitumor effect . Other cancer therapeutic agents to be used for such purpose may be administered to a subj ect simultaneously, separately, or sequentially with the pharmaceutical composition of the present disclosure, or may be administered with varying each dosage interval . Such cancer therapeutic agents are not limited as long as they are agents having antitumor activity, and can be15324259-1exemplified by at least one selected from the group consisting of irinotecan (CPT-11 ) , cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU) , gemcitabine, capecitabine, paclitaxel, docetaxel, doxorubicin, epirubicin, cyclophosphamide, mitomycin C, tegafur-gimeracil-oteracil combination, cetuximab, panitumumab, bevacizumab, ramucirumab, regorafenib, trif luridine-tipiracil combination, gefitinib, erlotinib, afatinib, methotrexate, pemetrexed, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, progesterone formulation, trastuzumab, pertuzumab, and lapatinib .

[0100] The pharmaceutical product and method of treatment of the present disclosure can also be used in combination with radiotherapy. For example, a cancer patient may receive radiotherapy before and / or after or simultaneously with receiving therapy with the pharmaceutical product of the present disclosure .

[0101] The pharmaceutical product and method of treatment of the present disclosure can also be used as an adjuvant chemotherapy in combination with a surgical procedure . The pharmaceutical product of the present disclosure may be administered for the purpose of diminishing the size of a tumor before a surgical procedure (referred to as pre-operative adjuvant chemotherapy or neoadjuvant15324259-1therapy) , or may be administered after a surgical procedure for the purpose of preventing the recurrence of a tumor (referred to as post-operative adjuvant chemotherapy or adjuvant therapy) .[Examples ]

[0102] The present disclosure is specifically described in view of the examples shown below. However, the present disclosure is not limited to these . Further, it is by no means to be interpreted in a limited way.

[0103] Example 1 : Production of the anti-HER2 antibody-drug conjugate ( 1 )In accordance with a production method described in International Publication No . WO 2015 / 115091 with use of an anti-HER2 antibody (an antibody comprising a heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2 ) , an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula :15324259-1[ Formula 16 ]wherein A represents a connecting position to an antibody,is conj ugated to the anti-HER2 antibody via a thioether bond (hereinafter referred to as the "HER2-ADC ( 1 ) " ( trastuzumab deruxtecan / DS- 8201a ) ) was produced . The DAR of the HER2-ADC ( 1 ) is 7 . 7 or 7 . 8 .

[0104] Example 2 : Antitumor study ( 1 )Mouse : female 5- to 6-week-old BALB / c nude mice ( Charles River Laboratories Japan, Inc . or Jackson laboratory Japan, Inc . ) were subj ected to the experiments .Measurement and calculation formula : the maj or axis and minor axis of tumors were measured twice a week with an electronic digital caliper, and the tumor volume (mm3) was calculated . The calculation formula is as shown below .15324259-1Tumor volume (mm3) = 1 / 2 x Major axis (mm) x [Minor axis (mm) ]2Tumor growth inhibition (TGI ) was calculated in accordance with the following calculation formula .TGI (%) = 100 x ( 1-T / C)T : average tumor volume of mice of test substance administration groupC : average tumor volume of mice of control group HER2-ADC ( 1 ) was diluted with ABS buffer ( 10 mM acetate buffer [pH 5.5] , 5% sorbitol) , and intravenously administered in a fluid volume of 10 mL / kg to the tail vein. Bevacizumab was diluted with physiological saline, and intraperitoneally administered in a fluid volume of 10 mL / kg. In the Figure of result, the abscissa axis represents days after first administration, and the longitudinal axis represents tumor volume . These methods are common to Examples 2 to 4 .Human colon cancer cell line COLO201, which was purchased from American Type Culture Collection (ATCC) , was suspended into 50% Matrigel Matrix, subcutaneously transplanted at 5.0xl06cells into right side of mice . The mice were randomly grouped 10 days after the transplantation (Day 0) , and HER2-ADC ( 1 ) was administered at a dose of 3 mg / kg on Day 0. Bevacizumab was administered at a dose of 5 mg / kg on Days 0, 7, and 14. Single administration groups of each drug, a combined administration group, and a solvent of HER2-ADC15324259-1( 1 ) group as a control group were set up (N=6 for each group) .

[0105] Result of a combination of HER2-ADC ( 1 ) and bevacizumab is shown in Figure 3. On the date of evaluation (Day 21 ) , single administration of HER2-ADC ( 1 ) showed a TGI of 54%, and single administration of bevacizumab showed a TGI of 59% . On the other hand, combined administration of HER2-ADC ( 1 ) and bevacizumab showed a TGI of 86% and exhibited a significantly superior tumor suppression effect compared with single administration of HER2-ADC ( 1 ) (P < 0.0001 [calculated by Dunnett' s test; the same applies hereinafter] ) and single administration of bevacizumab (P < 0.0001 ) . In addition, treatment of the test drugs did not cause obvious adverse effect on body weight change .

[0106] Example 3 : Antitumor study (2 )Human ovarian cancer cell line OV90, which was purchased from ATCC, was suspended into Matrigel Matrix, subcutaneously transplanted at 3.0xl06cells into right side of mice . The mice were randomly grouped 10 days after the transplantation (Day 0) , and HER2-ADC ( 1 ) was administered at a dose of 10 mg / kg on Day 0. Bevacizumab was administered at a dose of 5 mg / kg on Days 0, 7, and 14. Single administration groups of each drug, a15324259-1combined administration group, and an untreated group as a control group were set up (N=6 for each group) .Result of a combination of HER2-ADC ( 1 ) and bevacizumab is shown in Figure 4. On the date of evaluation (Day 21 ) , single administration of HER2-ADC ( 1 ) showed a TGI of 74%, and single administration of bevacizumab showed a TGI of 68% . On the other hand, combined administration of HER2-ADC ( 1 ) and bevacizumab showed a TGI of 89% and exhibited a significantly superior tumor suppression effect compared with single administration of HER2-ADC ( 1 ) (P = 0.0026) and single administration of bevacizumab (P = 0.0001 ) . In addition, treatment of the test drugs did not cause obvious adverse effect on body weight change .

[0107] Example 4 : Antitumor study (3)Human ovarian cancer cell line SK-OV-3, which was purchased from ATCC, was suspended into Matrigel Matrix, subcutaneously transplanted at 5.0xl06cells into right side of mice . The mice were randomly grouped 17 days after the transplantation (Day 0) , and HER2-ADC ( 1 ) was administered at a dose of 5 mg / kg on Day 0. Bevacizumab was administered at a dose of 5 mg / kg on Days 0, 7, and 14. Single administration groups of each drug, a combined administration group, and an untreated group as a control group were set up (N=6 for each group) .15324259-1Result of a combination of HER2-ADC ( 1 ) and bevacizumab is shown in Figure 5. On the date of evaluation (Day 21 ) , single administration of HER2-ADC ( 1 ) showed a TGI of 58%, and single administration of bevacizumab showed a TGI of 55% . On the other hand, combined administration of HER2-ADC ( 1 ) and bevacizumab showed a TGI of 79% and exhibited a significantly superior tumor suppression effect compared with single administration of HER2-ADC ( 1 ) (P < 0.0001 ) and single administration of bevacizumab (P < 0.0001 ) . In addition, treatment of the test drugs did not cause obvious adverse effect on body weight change .

[0108] Example 5 : Clinical trial protocol to evaluate the efficacy and safety of T-DXd in combination with bevacizumab versus bevacizumab monotherapy as first-line maintenance therapyThis is a global, multicenter, open-label, Phase 3 trial to evaluate the efficacy and safety of T-DXd in combination with bevacizumab versus bevacizumab monotherapy as first-line maintenance therapy, in participants with HER2-expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer .A non-randomized safety run-in phase will be established to assess the safety of T-DXd in combination with bevacizumab . Analysis of safety run-in will be conducted after approximately 2015324259-1participants have completed at least 2 cycles of trial intervention. All participants will receive T-DXd ( 5.4 mg / kg IV) Q3W up to a maximum of 34 cycles in combination with bevacizumab ( 15 mg / kg Q3W up to 16 cycles in the maintenance setting is allowed) .Enrollment of the randomization phase will start when a decision has been made to proceed with the randomization phase based on the safety run-in assessment, approximately 562 eligible participants (which will include a minimum of 168 [30%] participants who are HER2 IHC 3+ and a maximum of 82 [15%] participants who are HER2 IHC 1+) will be randomized in a 1 : 1 ratio to T-DXd in combination with bevacizumab or bevacizumab monotherapy as first-line maintenance therapy after first-line platinum-based chemotherapy. No crossover between treatment arms within trial will be allowed.• Treatment Arm A (experimental arm) : T-DXd ( 5.4 mg / kg IV Q3W up to a maximum of 34 cycles) in combination with bevacizumab ( 15 mg / kg Q3W up to 16 cycles in the maintenance setting is allowed; NOTE : a maximum of 22 cycles for bevacizumab is allowed including the doses given in combination with front-line chemotherapy) .• Treatment Arm B (control arm) : Bevacizumab monotherapy as first-line maintenance therapy15324259-1( 15 mg / kg IV Q3W up to 16 cycles; a maximum of 22 cycles for bevacizumab is allowed including the doses given in combination with front-line chemotherapy) .In the randomized phase, participants will be stratified by:• HER2 status : IHC 3+ versus 2+ versus 1+ .• Outcome of surgery: No residual disease after PDS versus otherNote : "Other" will include participants with either residual disease after PDS or IDS or no surgery .• Histology: high-grade serous versus non-serous histology.Study schema is depicted in Figure 6 (Safety run-in Study design) and Figure 7 (Randomize phase study design)The tables below list primary and secondary trial obj ectives and endpoints which have outcome measures .15324259-1Table 1-1 : Safety run inTable 1-2 : Randomization phase15324259-1Table 1-2 : Randomization phase (Continued)15324259-1Table 1-2 : Randomization phase (Continued)15324259-1Table 1-2 : Randomization phase (Continued)15324259-1Table 1-2 : Randomization phase (Continued)15324259-1Table 1-2 : Randomization phase (Continued)Eligibili ty cri teria :Participants must meet all of the following criteria to be eligible for enrollment / randomization into the trial :Inclusion Criteria :1. Sign and date the tissue prescreening ICF, prior to HER2 central testing. Sign and date the Main ICF, prior to the start of any trial- specific qualification procedures .Consent to optional PGx prior to any PGx procedures .15324259-1• For participants in the safety run-in phase, a safety run-in ICF needs to be signed and dated prior to the start of any trial-specific qualification procedures .2. Adults >18 years of age on the day of signing the ICF. Follow local regulatory requirements if the legal age of consent for trial participation is >18 years old.3. Has histologically confirmed diagnosis of epithelial high-grade ovarian, fallopian tube or primary peritoneal carcinoma per local assessment (including but not limiting to serous, endometrioid, clear cell, carcinosarcoma, mucinous) .4. Is newly diagnosed FIGO Stage III or IV.5. Has HER2 expression per 2016 ASCO-CAP gastric cancer IHC scoring (3 + / 2 + / 1+)found, by prospective central testing.• For participants in the safety run-in phase, HER2 expression assessed by either local (require using ASCO-CAP gastric cancer IHC scoring [ IHC 3+ / 2+ / 1+] guidelines) or central assessment (if available) is acceptable . Submission of the pathology report is required for participants enrolled based on local HER2 IHC results .6. Has adequate tumor tissue sample available for assessment of HER2 by central laboratory. Tumor tissue block or sufficient tissue slides are15324259-1required for HER2 testing and retrospective HRD status determination.• Participants in the safety run-in phase who are enrolled based on local HER2 IHC results are recommended to provide tumor tissue sample from the same specimen for central assessment .7. Has a local HRD or BRCA test result available .Participants with BRCA-wildtype will have a local HRD test results, as applicable .8. Has received up to 6 cycles of standard of care bevacizumab in combination with front-line platinumbased chemotherapy as per approved indication and clinical guidelines and is eligible to continue single agent bevacizumab maintenance per standard of care and investigator discretion.9. Has non-PD after completion of at least 6 cycles and maximum of 8 cycles of front-line platinum-taxane (intravenous or intraperitoneal orneoadj uvant / adj uvant chemotherapy or Hyperthermic Intraperitoneal Chemotherapy [HIPEC] is allowed) . • Participants with less than 6 cycles of frontline chemotherapy are eligible, only if they had experienced toxicity that precludes additional chemotherapy. In this case, patients must have received a minimum of 4 cycles of platinum-based chemotherapy and the reason for receiving less than 6 cycles will be recorded in the eCRF.15324259-1• Taxanes including but not limited to paclitaxel, albumin-bound paclitaxel, paclitaxel liposome, and docetaxel are acceptable if it is recommended by local guidelines .• Platinum including but not limited to carboplatin, cisplatin and nedaplatin are acceptable if it is recommended by local guidelines .• Non-PD is defined as no evidence of disease (defined as no residual after PDS) or complete response / partial response / stable disease as per RECIST vl . 1 assessed by the investigator at the end of front-line chemotherapy. There should be no clinical evidence (physical examination, imagery, or CA 125) of disease progression throughout the participant' s front-line treatment and prior to trial randomization.10. Trial intervention to start within 3 to 12 weeks of the last dose of front-line chemotherapy.Participants who started bevacizumab maintenance monotherapy before randomization are not eligible .Exclusion CriteriaParticipants who meet any of the following criteria will be disqualified from entering the trial :1. Has ovarian, fallopian tube, or peritoneal cancer of non-epithelial origin.15324259-12. Has a known or suspected deleterious BRCA alteration as per local test that makes the patient eligible for PARP inhibitor .3. Participant to receive PARP inhibitor as maintenance per standard of care and investigator discretion. Reasons for which the participant is not eligible for PARP inhibitor will be recorded in the eCRF as follows :• HRD negative• HRD positive with SD as best response after platinum• HRD positive non-serous histology• HRD tested, but inconclusive• HRD positive but safety concern (safety concern to be specified) .4. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug products and other monoclonal antibodies .5. Previous Cerebral-Vascular Accident, Transient Ischemic Attack or Sub- Arachnoids Hemorrhage within 6 months prior to randomization.6. Has evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation therapy) .15324259-1Ill7. Has a history of hemorrhagic disorders, abdominal fistula, gastrointestinal perforation, or active gastrointestinal bleeding within 6 months before randomization .8. Evidence of active or ongoing bowel obstruction. 9. Has a history of (non-inf ectious ) ILD / pneumonitis that required steroids, has current ILD / pneumonitis, or where suspected ILD / pneumonitis cannot be ruled out by imaging at Screening.10. Has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, pneumonectomy, etc . ) .11. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie pulmonary emboli within 3 months of the trial enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc . ) , and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (ie Rheumatoid arthritis, Sjogren' s, sarcoidosis etc . ) , or prior pneumonectomy.15324259-1Investigational Medicinal Product, Dosing and. Mode of AdministrationStudy drug formulation, dose, regimen and duration of the trial intervention is depicted in the Table 2 .Table 2 Study Drug Dosing Inf ormationError ! No document variable supplied.Participants in the T-DXD + bevacizumab group (experimental arm) will receive 5.4 mg / kg of T-DXd as IV infusion Q3W (±3 days) , along with 15 mg / kg of15324259-1bevacizumab intravenously on Day 1 of each cycle . T-DXd will be given first, followed by bevacizumab, with approximately 30 minutes between infusions . Bevacizumab will be administered in accordance with the locally approved label . Participants who discontinue either of the trial intervention due to toxicity are allowed to continue the other per investigator decision.For T-DXd, the first dose of trial intervention will be administered over approximately 90 minutes (±10 minutes) . If there is no IRR after the initial dose, subsequent doses of the trial intervention will be administered over approximately 30 minutes (±10 minutes) . If a participant experiences IRR, management guidelines for AEs in should be followed.The participant' s weight at baseline (Screening) will be used to calculate the initial dose for T-DXd. If, during the course of treatment, the participant' s weight change by >10% of the baseline weight, the participant' s dose must be recalculated based on the participant' s updated weight . For weight changes <10%, dose-calculation adjustments should follow local guidelines .15324259-1[ Industrial Applicability]From the above-described experimental results, the anti-HER2 antibody-drug conjugate according to the present disclosure has been found to exhibit an excellent antitumor effect by administering the anti-HER2 antibodydrug conjugate and a VEGF inhibitor in combination.15324259-1[Free Text of Sequence Listing]SEQ ID NO: 1 - Amino acid sequence of the heavy chain of an anti-HER2 antibodySEQ ID NO: 2 - Amino acid sequence of the light chain of an anti-HER2 antibody15324259-1

Claims

Claims

1. A pharmaceutical product comprising an anti-HER2 antibody-drug conjugate and a VEGF inhibitor for administration in combination, whereinthe anti-HER2 antibody-drug conjugate is an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula :[Formula 17 ]wherein A represents a connecting position to an antibody,is conjugated to the antibody via a thioether bond.

2. The pharmaceutical product according to Claim 1, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 comprising an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 comprising an amino acid sequence consisting of15324259-1amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 comprising an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 comprising an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 comprising an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 comprising an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

3. The pharmaceutical product according to Claim 1, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1 and a light chain comprising a light chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2 .

4. The pharmaceutical product according to Claim 1, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 1 and a light chain comprising an amino acid sequence represented by SEQ ID NO: 2.

5. The pharmaceutical product according to Claim 1, wherein the anti-HER2 antibody is an antibody comprising a heavy15324259-1chain comprising an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain comprising an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

6. The pharmaceutical product according to any one of Claims 1 to 5, wherein the anti-HER2 antibody-drug conjugate is represented by the following formula :[Formula 18 ]wherein 'Antibody' indicates the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n indicates an average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate, wherein n is in the range of from 7 to 8 .

7. The pharmaceutical product according to any one of Claims 1 to 6, wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain,15324259-1or a multispecific antibody comprising an anti-VEGF binding domain.

8. The pharmaceutical product according to Claims 7, wherein the VEGF inhibitor is an anti-VEGF antibody.

9. The pharmaceutical product according to Claims 8, wherein the anti-VEGF antibody is bevacizumab .

10. The pharmaceutical product according to Claims 7, wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

11. The pharmaceutical product according to Claims 10, wherein the anti-VEGF receptor antibody is ramucirumab .

12. The pharmaceutical product according to Claims 7, wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.

13. The pharmaceutical product according to Claims 12, wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept .

14. The pharmaceutical product according to Claims 7, wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

15. 15324259-1The pharmaceutical product according to Claims 14, wherein the multispecific antibody is a bispecific antibody .

16. The pharmaceutical product according to any one of Claims 1 to 15, wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are separately contained as active components in different formulations, and are administered at the same time or at different times .

17. The pharmaceutical product according to any one of Claims 1 to 15, wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are contained as active components in a single formulation for administration.

18. The pharmaceutical product according to any one of Claims 1 to 17, wherein the pharmaceutical product is for use in treating cancer .

19. The pharmaceutical product according to any one of Claims 1 to 17, wherein the pharmaceutical product is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget ' s disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine15324259-1carcinosarcoma, hepatocellular carcinoma, gastrointestinal stromal tumor, kidney cancer, cervical cancer, and sarcoma .

20. The pharmaceutical product according to Claim 19, wherein the pharmaceutical product is for use in treating breast cancer .

21. The pharmaceutical product according to Claim 19, wherein the pharmaceutical product is for use in treating triplenegative breast cancer .

22. The pharmaceutical product according to Claim 19, wherein the pharmaceutical product is for use in treating gastric cancer .

23. The pharmaceutical product according to Claim 19, wherein the pharmaceutical product is for use in treating ovarian cancer .

24. The pharmaceutical product according to Claim 19, wherein the pharmaceutical product is for use in treating lung cancer .

25. The pharmaceutical product according to Claim 19, wherein the pharmaceutical product is for use in treating pancreatic cancer .15324259-1

26. The pharmaceutical product according to any one of Claims 18 to 25, wherein the cancer is metastatic .

27. The pharmaceutical product according to any one of Claims 1 to 26, wherein the anti-HER2 antibody is trastuzumab deruxtecan (DS-8201a) .

28. The pharmaceutical product according to any one of Claims 1 to 27, wherein the pharmaceutical product is pharmaceutical composition.

29. The pharmaceutical product according to any one of Claims 1 to 28, wherein the anti-HER2 antibody-drug conjugate is administered at a dose of 0.8 to 12.4 mg / kg.

30. The pharmaceutical product according to Claims 27 or 28, wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg or 6.4 mg / kg.

31. The pharmaceutical product according to Claims 27 or 28, wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg.

32. The pharmaceutical product according to Claims 27 or 28, wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks .15324259-1

33. The pharmaceutical product according to any one of Claims 1 to 32, wherein the VEGF inhibitor is administered at a dose of 1 to 20 mg / kg.

34. The pharmaceutical product according to Claim 33, wherein the VEGF inhibitor is administered at a dose of 5 to 15 mg / kg .

35. The pharmaceutical product according to any one of Claims 1 to 32, wherein the VEGF inhibitor is administered at a dose of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, or 15 mg / kg .

36. The pharmaceutical product according to any one of Claims 1 to 32, wherein the VEGF inhibitor is administered at a dose of 15 mg / kg.

37. The pharmaceutical product according to any one of Claims 1 to 32, wherein the VEGF inhibitor is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .

38. The pharmaceutical product according to any one of Claims 33 to 37, wherein the VEGF inhibitor is bevacizumab .

39. 15324259-1The pharmaceutical product according to Claim 38, wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks, and bevacizumab is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .

40. The pharmaceutical product according to Claim 39, wherein trastuzumab deruxtecan and bevacizumab are administered on the same day.

41. The pharmaceutical product according to Claims 39 or 40, wherein trastuzumab deruxtecan is administered up to 34 cycles, and bevacizumab is administered up to 16 cycles .

42. The pharmaceutical product according to Claim 41, wherein bevacizumab is administered up to 6 cycles before the 16 cycles of bevacizumab administration as a front-line chemotherapy .

43. The pharmaceutical product according to any one of Claims 38 to 42, wherein the pharmaceutical product is for use in treating HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer .

44. The pharmaceutical product according to Claim 43, wherein the pharmaceutical product is for use in treating HER2 expressing ( IHC 3+ / 2+ / 1+) epithelial ovarian cancer .15324259-1

45. The pharmaceutical product according to Claim 43, wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced epithelial ovarian cancer .

46. The pharmaceutical product according to Claim 43, wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer .

47. The pharmaceutical product according to Claim 43, wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer as maintenance therapy.

48. The pharmaceutical product according to Claims 46 or 47, wherein the pharmaceutical product is for use in treating HER2 expressing ( IHC 3+ / 2+) advanced high-grade epithelial ovarian cancer .

49. The pharmaceutical product according to Claims 46 or 47, wherein the pharmaceutical product is for use in treating HER2 expressing ( IHC 1+) advanced high-grade epithelial ovarian cancer .

50. 15324259-1A method of treatment, comprising administering an anti-HER2 antibody-drug conjugate and a VEGF inhibitor for administration in combination, whereinthe anti-HER2 antibody-drug conjugate is an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula :[Formula 19]wherein A represents a connecting position to an antibody,is conjugated to the antibody via a thioether bond.

51. The method of treatment according to Claim 50, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 comprising an amino acid sequence consisting of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 comprising an amino acid sequence consisting of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 comprising an amino acid sequence consisting of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light15324259-1chain comprising CDRL1 comprising an amino acid sequence consisting of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 comprising an amino acid sequence consisting of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 comprising an amino acid sequence consisting of amino acid residues 89 to 97 of SEQ ID NO: 2.

52. The method of treatment according to Claim 50, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 120 of SEQ ID NO: 1 and a light chain comprising a light chain variable region comprising an amino acid sequence consisting of amino acid residues 1 to 107 of SEQ ID NO: 2 .

53. The method of treatment according to Claim 50, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 1 and a light chain comprising an amino acid sequence represented by SEQ ID NO: 2.

54. The method of treatment according to Claim 50, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light15324259-1chain comprising an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2.

55. The method of treatment according to any one of Claims 50 to 54, wherein the anti-HER2 antibody-drug conjugate is represented by the following formula :[Formula 20]wherein 'Antibody' indicates the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n indicates an average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate, wherein n is in the range of from 7 to 8 .

56. The method of treatment according to any one of Claims 1 to 55, wherein the VEGF inhibitor is an anti-VEGF antibody, an anti-VEGF receptor antibody, a fusion protein comprising a VEGF receptor extracellular domain, or a multispecific antibody comprising an anti-VEGF binding domain.

57. 15324259-1The method of treatment according to Claim 56, wherein the VEGF inhibitor is an anti-VEGF antibody.

58. The method of treatment according to Claim 57, wherein the anti-VEGF antibody is bevacizumab .

59. The method of treatment according to Claim 56, wherein the VEGF inhibitor is an anti-VEGF receptor antibody.

60. The method of treatment according to Claim 59, wherein the anti-VEGF receptor antibody is ramucirumab .

61. The method of treatment according to Claim 57, wherein the VEGF inhibitor is a fusion protein comprising a VEGF receptor extracellular domain.

62. The method of treatment according to Claim 61, wherein the fusion protein comprising a VEGF receptor extracellular domain is aflibercept .

63. The method of treatment according to Claim 56, wherein the VEGF inhibitor is a multispecific antibody comprising an anti-VEGF binding domain.

64. The method of treatment according to Claim 63, wherein the multispecific antibody is a bispecific antibody.

65. 15324259-1The method of treatment according to any one of Claims 50 to 64, wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are separately contained as active components in different formulations, and are administered at the same time or at different times .

66. The method of treatment according to any one of Claims 50 to 64, wherein the anti-HER2 antibody-drug conjugate and the VEGF inhibitor are contained as active components in a single formulation for administration.

67. The method of treatment according to any one of Claims 50 to 66, wherein the method of treatment is for use in treating cancer .

68. The method of treatment according to any one of Claims 50 to 66, wherein the method of treatment is for use in treating at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head-and-neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget ' s disease, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, uterine carcinosarcoma, hepatocellular carcinoma, gastrointestinal stromal tumor, kidney cancer, cervical cancer, and sarcoma .

69. 15324259-1The method of treatment according to Claim 68, wherein the method of treatment is for use in treating breast cancer .

70. The method of treatment according to Claim 68, wherein the method of treatment is for use in treating triplenegative breast cancer .

71. The method of treatment according to Claim 68, wherein the method of treatment is for use in treating gastric cancer .

72. The method of treatment according to Claim 68, wherein the method of treatment is for use in treating ovarian cancer .

73. The method of treatment according to Claim 68, wherein the method of treatment is for use in treating lung cancer .

74. The method of treatment according to Claim 68, wherein the method of treatment is for use in treating pancreatic cancer .

75. The method of treatment according to any one of Claims 67 to 74, wherein the cancer is metastatic .

76. 15324259-1The method of treatment according to any one of Claims 50 to 75, wherein the anti-HER2 antibody is trastuzumab deruxtecan .

77. The method of treatment according to any one of Claims 50 to 76, wherein the anti-HER2 antibody-drug conjugate is administered at a dose of 0.8 to 12.4 mg / kg.

78. The method of treatment according to Claim 76, wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg or 6.4 mg / kg.

79. The method of treatment according to Claim 76, wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg .

80. The method of treatment according to Claim 76, wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks .

81. The method of treatment according to any one of Claims 50 to 80, wherein the VEGF inhibitor is administered at a dose of 1 to 20 mg / kg.

82. The method of treatment according to any one of Claims 50 to 80, wherein the VEGF inhibitor is administered at a dose of 5 to 15 mg / kg.15324259-1

83. The method of treatment according to any one of Claims 50 to 80, wherein the VEGF inhibitor is administered at a dose of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg, or 15 mg / kg .

84. The method of treatment according to any one of Claims 50 to 80, wherein the VEGF inhibitor is administered at a dose of 15 mg / kg.

85. The method of treatment according to any one of Claims 50 to 80, wherein the VEGF inhibitor is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .

86. The method of treatment according to any one of Claims 81 to 85, wherein the VEGF inhibitor is bevacizumab .

87. The method of treatment according to Claim 86, wherein trastuzumab deruxtecan is administered at a dose of 5.4 mg / kg per administration at intervals of 3 weeks, and bevacizumab is administered at a dose of 15 mg / kg per administration at intervals of 3 weeks .

88. The method of treatment according to Claim 87, wherein trastuzumab deruxtecan and bevacizumab are administered on the same day.15324259-1

89. The method of treatment according to Claims 87 or 88, wherein trastuzumab deruxtecan is administered up to 34 cycles, and bevacizumab is administered up to 16 cycles .

90. The method of treatment according to Claim 89, wherein bevacizumab is administered up to 6 cycles before the 16 cycles of bevacizumab administration as a front-line chemotherapy .

91. The method of treatment according to any one of Claims 85 to 90, wherein the method of treatment is for use in treating HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer .

92. The method of treatment according to Claim 91, wherein the method of treatment is for use in treating HER2 expressing ( IHC 3+ / 2+ / 1+) epithelial ovarian cancer .

93. The method of treatment according to Claim 91, wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced epithelial ovarian cancer .

94. The method of treatment according to Claim 91, wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer .15324259-1

95. The method of treatment according to Claim 91, wherein the HER2 expressing ( IHC 3+ / 2+ / 1+) ovarian cancer is HER2 expressing ( IHC 3+ / 2+ / 1+) advanced high-grade epithelial ovarian cancer as maintenance therapy.

96. The method of treatment according to Claims 94 or 95, wherein the method of treatment is for use in treating HER2 expressing ( IHC 3+ / 2+) advanced high-grade epithelial ovarian cancer .

97. The method of treatment according to Claims 94 or 95, wherein the method of treatment is for use in treating HER2 expressing ( IHC 1+) advanced high-grade epithelial ovarian cancer .15324259-1

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