Treatment of HER2 mutated cancer by administration of anti-HER2 antibody-drug conjugates

Abstract

The present invention relates to the treatment of HER2 mutated cancers by administering an anti-HER2 antibody-drug conjugate. The present invention relates to a therapeutic agent for HER2 mutated cancer, and more specifically, to a therapeutic agent for HER2 mutated cancer comprising, as an active ingredient, an anti-HER2 antibody-drug conjugate in which a drug-linker represented by the following formula (wherein A represents a connection position to an anti-HER2 antibody) is conjugated to an antibody through a thioether bond, and / or to a method for treating cancer, the present invention also relates to a method for preparing the anti-HER2 antibody-drug conjugate, which comprises administering the anti-HER2 antibody-drug conjugate to a subject having a cancer determined to have an HER2 mutation. # imgabs0 #

Description

This application is a divisional application of Chinese patent application No. 201980035852.5, filed on May 27, 2019, “Treatment of HER2-mutated cancer by administering anti-HER2 antibody-drug conjugates.” Technical Field

[0001] The present invention relates to a therapeutic agent for HER2-mutated cancer, comprising a specific anti-HER2 antibody-drug conjugate, and / or a method for treating cancer, comprising administering a specific anti-HER2 antibody-drug conjugate to a subject determined to have HER2-mutated cancer. Background Art

[0002] Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor belonging to the epidermal growth factor receptor subfamily of receptor protein tyrosine kinases (Non-patent References 1 to 6).

[0003] HER2 is overexpressed in various cancer types such as breast cancer and gastric cancer (Non-patent References 7 to 12), and has been reported to be a negative prognostic factor in breast cancer (Non-patent References 13 and 14). As anti-HER2 drugs effective for cancers that overexpress HER2, trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib, etc. are known.

[0004] Meanwhile, HER2 has a mutant, which is known to be one of the cancer-driving mutations. Such HER2-mutated cancers have been reported to exist in a percentage of about 2% to 3% in, for example, non-small cell lung cancer (non-patent references 15 to 20). Studies have been conducted to verify the effects of anti-HER2 drugs on HER2-mutated cancers (non-patent references 21 and 22).

[0005] Therefore, antibody-drug conjugates (ADCs) having a cytotoxic drug conjugated to an antibody whose antigen is expressed on the surface of cancer cells and which also binds to an antigen capable of cell internalization and thus can selectively deliver the drug to cancer cells are expected to cause the drug to accumulate inside cancer cells and kill the cancer cells (Non-patent References 23 to 27).

[0006] As one such antibody-drug conjugate, an antibody-drug conjugate comprising an anti-HER2 antibody and a derivative of exatecan, which is a topoisomerase I inhibitor, as its components is known (Patent References 1 to 3 and Non-Patent References 28 to 31).

[0007] Citation List Patent Literature Patent Reference 1 International Publication No. WO 2015 / 115091 Patent Reference 2 International Publication No. WO 2015 / 155976 Patent Reference 3 International Publication No. WO 2018 / 066626 Non-patent literature Non-patent reference 1: Coussens L, et al., Science. 1985; 230(4730): 1132-1139. Non-patent reference 2: Graus-Porta G, et al., EMBO J. 1997; 16: 1647-1655. Non-patent reference 3: Karnagaran D, et al., EMBO J. 1996; 15: 254-264. Non-patent reference 4: Sliwkowski MX, et al., J Biom Chem. 1994; 269: 14661-14665. Non-patent reference 5: Di Fore PP, et al., Science. 1987; 237: 178-182. Non-patent reference 6: Hudziak RM, et al., Proc Natl Acad Sci US A. 1987; 84: 7159-7163. Non-patent reference 7: Hardwick R, et al., Eur. J Surg Oncol. 1997(23):30-35. Non-patent reference 8: Korkaya H, et al., Oncogene. 2008; 27(47): 6120-6130. Non-patent reference 9: Yano T, et al., Oncol Rep. 2006; 15(1): 65-71. Non-patent reference 10: Slamon DJ, et al., Science. 1987; 235: 177-182. Non-patent reference 11: Gravalos C, et al., Ann Oncol 19:1523-1529, 2008. Non-patent reference 12: Fukushige S et al., Mol Cell Biol 6:955-958, 1986. Non-patent reference 13: Slamon DJ, et al., Science. 1989; 244: 707-712. Non-patent reference 14: Kaptain S, et al., Diagn Mol Pathol 10:139-152, 2001. Non-patent reference 15: Mazieres J, et al., J Clin Oncol 2013;31:1997-2003. Non-patent reference 16: Arcila ME, et al., Clin Cancer Res 2012;18:4910-8. Non-patent reference 17: Li C, et al., J Thorac Oncol 2012;7:85-9. Non-patent reference 18: Tomizaka K, et al., Lung Cancer 2011; 74: 139-44. Non-patent reference 19: Shigematsu H, et al., Cancer Res 2005; 65: 1642-6. Non-patent reference 20: Yokoyama T, et al., Cancer Sci 2006; 97: 753-9. Non-patent reference 21: Connell CM, et al., ESMO Open 2017;2:e000279. Non-patent reference 22: MG Kris, et al., Annals of Oncology 26:1421-1427, 2015. Non-patent reference 23: Ducry, L., et al., Bioconjugate Chem. (2010) 21, 5-13. Non-patent reference 24: Alley, SC, et al., Current Opinion in Chemical Biology (2010) 14, 529-537. Non-patent reference 25: Damle NK Expert Opin. Biol. Ther. (2004) 4, 1445-1452. Non-patent reference 26: Senter PD, et al., Nature Biotechnology (2012) 30, 631-637. Non-patent reference 27: Howard A. et al., J Clin Oncol 29:398-405. Non-patent reference 28: Ogitani Y. et al., Clinical Cancer Research (2016) 22(20), 5097-5108. Non-patent reference 29: Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046. Non-patent reference 30: Doi T, et al., Lancet Oncol 2017;18:1512-22. Non-patent reference 31: Takegawa N, et al., Int. J. Cancer: 141, 1682-1689 (2017). Summary of the Invention Technical issues It is known that anti-HER2 antibody-drug conjugates comprising an anti-HER2 antibody and a derivative of exatecan (which is a topoisomerase I inhibitor) as active ingredients exert anti-tumor effects on cancers determined to have overexpression of HER2. However, it has not yet been demonstrated that anti-HER2 antibody-drug conjugates can exert anti-tumor effects on cancers with HER2 mutations. The present invention aims to provide a therapeutic agent for cancers with HER2 mutations, comprising a specific anti-HER2 antibody-drug conjugate, and / or a method for treating cancer comprising administering a specific anti-HER2 antibody-drug conjugate to a subject determined to have a cancer with a HER2 mutation.

[0008] Problem Solving As a result of intensive studies to solve the above-mentioned problems, the present inventors have discovered that specific anti-HER2 antibody-drug conjugates exhibit excellent anti-tumor effects on HER2-mutated cancers, thereby completing the present invention.

[0009] Therefore, the present invention provides the following [1] to

[176] . [1] A therapeutic agent for HER2-mutated cancer, comprising an anti-HER2 antibody-drug conjugate as an active ingredient, wherein the drug-linker represented by the following formula is conjugated to the anti-HER2 antibody via a thioether bond: [Formula 1] Where A represents the connection position with the anti-HER2 antibody. [2] The therapeutic agent according to [1], wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insA YVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delins AVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G7 78insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L. [3] The therapeutic agent according to [2], wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F. [4] The therapeutic agent according to [1], wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation. [5] The therapeutic agent according to [4], wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP. [6] The therapeutic agent according to [5], wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, and G776delinsVC. [7] The therapeutic agent according to [1], wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein. [8] The therapeutic agent according to [7], wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V. [9] The therapeutic agent according to [8], wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[10] The therapeutic agent according to [1], wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[11] The therapeutic agent according to

[10] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

[12] The therapeutic agent according to

[11] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[13] The therapeutic agent according to any one of [1] to

[12] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, and uterine carcinosarcoma.

[14] The therapeutic agent according to any one of [1] to

[12] , wherein the cancer is non-small cell lung cancer.

[15] The therapeutic agent according to

[14] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[16] The therapeutic agent according to any one of [1] to

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

[17] The therapeutic agent according to any one of [1] to

[15] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[18] The therapeutic agent according to any one of [1] to

[17] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[19] The therapeutic agent according to any one of [1] to

[17] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[20] The therapeutic agent according to any one of [1] to

[19] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg. [twenty one] The therapeutic agent according to any one of [1] to

[19] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg. [twenty two] The therapeutic agent according to any one of [1] to

[21] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks. [twenty three] A therapeutic agent for HER2-mutated cancer, comprising an anti-HER2 antibody-drug conjugate represented by the following formula as an active ingredient: [Formula 2] wherein the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond, and n is the average number of drug-linker units conjugated per antibody molecule. [twenty four] The therapeutic agent according to

[23] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insA YVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delins AVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G7 78insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L.

[25] The therapeutic agent according to

[24] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[26] The therapeutic agent according to

[23] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[27] The therapeutic agent according to

[26] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP.

[28] The therapeutic agent according to

[27] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup and G776delinsVC.

[29] The therapeutic agent according to

[23] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[30] The therapeutic agent according to

[29] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V.

[31] The therapeutic agent according to

[30] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[32] The therapeutic agent according to

[23] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[33] The therapeutic agent according to

[32] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

[34] The therapeutic agent according to

[33] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[35] The therapeutic agent according to any one of

[23] to

[34] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma.

[36] The therapeutic agent according to any one of

[23] to

[34] , wherein the cancer is non-small cell lung cancer.

[37] The therapeutic agent according to

[36] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[38] The therapeutic agent according to any one of

[23] to

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

[39] The therapeutic agent according to any one of

[23] to

[37] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[40] The therapeutic agent according to any one of

[23] to

[39] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[41] The therapeutic agent according to any one of

[23] to

[39] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[42] The therapeutic agent according to any one of

[23] to

[41] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[43] The therapeutic agent according to any one of

[23] to

[41] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg.

[44] The therapeutic agent according to any one of

[23] to

[43] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[45] A method for treating cancer, comprising administering an anti-HER2 antibody-drug conjugate to a subject determined to have cancer with a HER2 mutation, wherein the anti-HER2 antibody-drug conjugate is conjugated to the anti-HER2 antibody via a thioether bond: [Formula 3] Where A represents the connection position with the anti-HER2 antibody.

[46] The method of treatment according to

[45] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C , R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R , Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771ins AYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delin sAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G 778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L.

[47] The method of treatment according to

[46] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[48] The method of treatment according to

[45] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[49] The method of treatment according to

[48] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP.

[50] The method of treatment according to

[49] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup and G776delinsVC.

[51] The method of treatment according to

[45] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[52] The method of treatment according to

[51] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V.

[53] The method of treatment according to

[52] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[54] The method of treatment according to

[45] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[55] The method of treatment according to

[54] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

[56] The method of treatment according to

[55] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[57] The method of any one of

[45] to

[56] , wherein the cancer in the HER2 mutated cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma.

[58] The method of any one of

[45] to

[56] , wherein the cancer is non-small cell lung cancer.

[59] The method of treatment according to

[58] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[60] The method of treatment according to any one of

[45] to

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

[61] The method of any one of

[45] to

[59] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[62] The method of any one of

[45] to

[61] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[63] The method of any one of

[45] to

[61] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[64] The method of any one of

[45] to

[63] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[65] The method of any one of

[45] to

[63] , wherein the dose of the anti-HER2 antibody-drug conjugate is 6.4 mg / kg per administration.

[66] The method of any one of

[45] to

[65] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[67] A method for treating cancer, comprising administering an anti-HER2 antibody-drug conjugate represented by the following formula to a subject with cancer confirmed to have a HER2 mutation: [Formula 4] wherein the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond, and n is the average number of drug-linker units conjugated per antibody molecule.

[68] The method of treatment according to

[67] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C , R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R , Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771ins AYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delin sAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G 778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L.

[69] The method of treatment according to

[68] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[70] The method of treatment according to

[67] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[71] The method of treatment according to

[70] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP.

[72] The method of treatment according to

[71] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup and G776delinsVC.

[73] The method of treatment according to

[67] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[74] The method of treatment according to

[73] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V.

[75] The method of treatment according to

[74] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[76] The method of treatment according to

[67] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[77] The method of

[76] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

[78] The method of treatment according to

[77] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[79] The method of any one of

[67] to

[78] , wherein the cancer in the HER2 mutated cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma.

[80] The method of any one of

[67] to

[78] , wherein the cancer is non-small cell lung cancer.

[81] The method of treatment according to

[80] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[82] The method of treatment according to any one of

[67] to

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

[83] The method of any one of

[67] to

[81] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[84] The method of any one of

[67] to

[83] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[85] The method of any one of

[67] to

[83] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[86] The method of any one of

[67] to

[85] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[87] The method of any one of

[67] to

[85] , wherein the dose of the anti-HER2 antibody-drug conjugate is 6.4 mg / kg per administration.

[88] The method of any one of

[67] to

[87] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[89] An anti-HER2 antibody-drug conjugate for treating HER2-mutated cancer, wherein the drug-linker represented by the following formula is conjugated to the anti-HER antibody via a thioether bond: [Formula 5] Where A represents the connection position with the anti-HER2 antibody.

[90] The anti-HER2 antibody-drug conjugate according to

[89] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319 Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A77 1insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776de linsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777 _G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L.

[91] The anti-HER2 antibody-drug conjugate according to

[90] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[92] The anti-HER2 antibody-drug conjugate according to

[89] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[93] The anti-HER2 antibody-drug conjugate according to

[92] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP.

[94] The anti-HER2 antibody-drug conjugate according to

[93] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup and G776delinsVC.

[95] The anti-HER2 antibody-drug conjugate according to

[89] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[96] The anti-HER2 antibody-drug conjugate according to

[95] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V.

[97] The anti-HER2 antibody-drug conjugate according to

[96] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[98] The anti-HER2 antibody-drug conjugate according to

[89] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[99] The anti-HER2 antibody-drug conjugate according to

[98] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

[100] The anti-HER2 antibody-drug conjugate according to

[99] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[101] The anti-HER2 antibody-drug conjugate according to any one of

[89] to

[100] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma.

[102] The anti-HER2 antibody-drug conjugate according to any one of

[89] to

[100] , wherein the cancer is non-small cell lung cancer.

[103] The anti-HER2 antibody-drug conjugate according to

[102] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[104] An anti-HER2 antibody-drug conjugate according to any one of

[89] to

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

[105] The anti-HER2 antibody-drug conjugate according to any one of

[89] to

[103] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[106] The anti-HER2 antibody-drug conjugate according to any one of

[89] to

[105] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[107] The anti-HER2 antibody-drug conjugate according to any one of

[89] to

[105] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[108] The anti-HER2 antibody-drug conjugate according to any one of

[89] to

[107] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[109] The anti-HER2 antibody-drug conjugate according to any one of

[89] to

[107] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg.

[110] The anti-HER2 antibody-drug conjugate according to any one of

[89] to

[109] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[111] An anti-HER2 antibody-drug conjugate for treating HER2-mutated cancer is represented by the following formula: [Formula 6] wherein the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond, and n is the average number of drug-linker units conjugated per antibody molecule.

[112] The anti-HER2 antibody-drug conjugate according to

[111] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N31 9Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L , G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A7 71insAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776de linsAVGC、G776delinsVV、G776_V777insL、G776L、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777 _G778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L.

[113] The anti-HER2 antibody-drug conjugate according to

[112] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[114] The anti-HER2 antibody-drug conjugate according to

[111] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[115] The anti-HER2 antibody-drug conjugate according to

[114] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP.

[116] The anti-HER2 antibody-drug conjugate according to

[115] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup and G776delinsVC.

[117] The anti-HER2 antibody-drug conjugate according to

[111] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[118] The anti-HER2 antibody-drug conjugate according to

[117] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V.

[119] The anti-HER2 antibody-drug conjugate according to

[118] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[120] The anti-HER2 antibody-drug conjugate according to

[111] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[121] The anti-HER2 antibody-drug conjugate according to

[120] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

[122] The anti-HER2 antibody-drug conjugate according to

[121] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[123] The anti-HER2 antibody-drug conjugate according to any one of

[111] to

[122] , wherein the cancer in the HER2-mutated cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma.

[124] The anti-HER2 antibody-drug conjugate according to any one of

[111] to

[122] , wherein the cancer is non-small cell lung cancer.

[125] The anti-HER2 antibody-drug conjugate according to

[124] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[126] An anti-HER2 antibody-drug conjugate according to any one of

[111] to

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

[127] The anti-HER2 antibody-drug conjugate according to any one of

[111] to

[125] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[128] The anti-HER2 antibody-drug conjugate according to any one of

[111] to

[127] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[129] The anti-HER2 antibody-drug conjugate according to any one of

[111] to

[127] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[130] The anti-HER2 antibody-drug conjugate according to any one of

[111] to

[129] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[131] The anti-HER2 antibody-drug conjugate according to any one of

[111] to

[129] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg.

[132] The anti-HER2 antibody-drug conjugate according to any one of

[111] to

[131] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[133] Use of an anti-HER2 antibody-drug conjugate for preparing a drug for treating HER2-mutated cancer, wherein the drug-linker represented by the following formula is conjugated to the anti-HER2 antibody via a thioether bond: [Formula 7] Where A represents the connection position with the anti-HER2 antibody.

[134] The method according to

[133] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insA YVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delins AVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G7 78insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L.

[135] The use according to

[134] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[136] The use according to

[133] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[137] The use according to

[136] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP.

[138] The use according to

[137] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup and G776delinsVC.

[139] The use according to

[133] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[140] The use according to

[139] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V.

[141] The use according to

[140] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[142] The use according to

[133] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[143] The use according to

[142] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

[144] The use according to

[143] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[145] The use according to any one of

[133] to

[144] , wherein the cancer in the HER2 mutated cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma.

[146] The use according to any one of

[133] to

[144] , wherein the cancer is non-small cell lung cancer.

[147] The use according to

[146] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[148] The use according to any one of

[133] to

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

[149] The use according to any one of

[133] to

[147] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[150] The use according to any one of

[133] to

[149] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[151] The use according to any one of

[133] to

[149] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[152] The use according to any one of

[133] to

[151] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[153] The use according to any one of

[133] to

[151] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg.

[154] The use according to any one of

[133] to

[153] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[155] Use of an anti-HER2 antibody-drug conjugate for preparing a drug for treating HER2-mutated cancer, wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: [Formula 8] wherein the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond, and n is the average number of drug-linker units conjugated per antibody molecule.

[156] The method according to

[155] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771insA YVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delins AVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G7 78insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L.

[157] The use according to

[156] , wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[158] The use according to

[155] , wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

[159] The use according to

[158] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP.

[160] The use according to

[159] , wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup and G776delinsVC.

[161] The use according to

[155] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

[162] The use according to

[161] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V.

[163] The use according to

[162] , wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

[164] The use according to

[155] , wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

[165] The use according to

[164] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

[166] The use according to

[165] , wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

[167] The use according to any one of

[155] to

[166] , wherein the cancer in the HER2 mutated cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma.

[168] The use according to any one of

[155] to

[166] , wherein the cancer is non-small cell lung cancer.

[169] The use according to

[168] , wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

[170] The use according to any one of

[155] to

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

[171] The use according to any one of

[155] to

[169] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[172] The use according to any one of

[155] to

[171] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[173] The use according to any one of

[155] to

[171] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[174] The use according to any one of

[155] to

[173] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[175] The use according to any one of

[155] to

[173] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg.

[176] The use according to any one of

[155] to

[175] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[0186] Furthermore, the present invention can also be expressed as follows: [1] A therapeutic agent for cancer with a HER2 gene mutation, comprising an anti-HER2 antibody-drug conjugate as an active ingredient, wherein the drug-linker represented by the following formula is conjugated to the anti-HER2 antibody via a thioether bond: [Formula 9] Where A represents the connection position with the anti-HER2 antibody. [2] The therapeutic agent according to [1], wherein the cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma. [3] The therapeutic agent according to [1], wherein the cancer is non-small cell lung cancer. [4] The therapeutic agent according to any one of [1] to [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain and a light chain, the heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and the light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2. [5] The therapeutic agent according to any one of [1] to [3], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2. [6] The therapeutic agent according to any one of [1] to [5], wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8. [7] The therapeutic agent according to any one of [1] to [5], wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8. [8] The therapeutic agent according to any one of [1] to [7], wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg. [9] The therapeutic agent according to any one of [1] to [7], wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg.

[10] The therapeutic agent according to any one of [1] to [9], wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[11] A method for treating cancer, comprising administering an anti-HER2 antibody-drug conjugate to a subject confirmed to have cancer with a HER2 gene mutation, wherein the anti-HER2 antibody-drug conjugate is conjugated to the anti-HER2 antibody via a thioether bond: [Equation 10] Where A represents the connection position with the anti-HER2 antibody.

[12] The method of treatment according to

[11] , wherein the cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma.

[13] The method of treatment according to

[11] , wherein the cancer is non-small cell lung cancer.

[14] The method of treatment according to any one of

[11] to

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

[15] The method of any one of

[11] to

[13] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[16] The method of any one of

[11] to

[15] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[17] The method of any one of

[11] to

[15] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[18] The method of any one of

[11] to

[17] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[19] The method of any one of

[11] to

[17] , wherein the dose of the anti-HER2 antibody-drug conjugate is 6.4 mg / kg per administration.

[20] The method of any one of

[11] to

[19] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks. [twenty one] An anti-HER2 antibody-drug conjugate for treating cancer with HER2 gene mutation, wherein the drug-linker represented by the following formula is conjugated to the anti-HER antibody through a thioether bond: [Equation 11] Where A represents the connection position with the anti-HER2 antibody. [twenty two] The anti-HER2 antibody-drug conjugate according to

[21] , wherein the cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma. [twenty three] The anti-HER2 antibody-drug conjugate according to

[21] , wherein the cancer is non-small cell lung cancer. [twenty four] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

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

[25] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

[23] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[26] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

[25] , wherein the average number of drug-linker units conjugated per antibody molecule is in the range of 7 to 8.

[27] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

[25] , wherein the average number of drug-linker units conjugated per antibody molecule is in the range of 7.5 to 8.

[28] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

[27] , wherein the dose per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[29] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

[27] , wherein the dose per administration is 6.4 mg / kg.

[30] The anti-HER2 antibody-drug conjugate according to any one of

[21] to

[29] , which is administered once every three weeks.

[31] Use of an anti-HER2 antibody-drug conjugate for preparing a drug for treating cancer with a HER2 gene mutation, wherein the drug-linker represented by the following formula is conjugated to the anti-HER2 antibody via a thioether bond: [Formula 7] Where A represents the connection position with the anti-HER2 antibody.

[32] The use according to

[31] , wherein the cancer is at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma.

[33] The use according to

[31] , wherein the cancer is non-small cell lung cancer.

[34] The use according to any one of

[31] to

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

[35] The use according to any one of

[31] to

[33] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence shown in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence shown in SEQ ID NO: 2.

[36] The use according to any one of

[31] to

[35] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

[37] The use according to any one of

[31] to

[35] , wherein the average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

[38] The use according to any one of

[31] to

[37] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

[39] The use according to any one of

[31] to

[37] , wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg.

[40] The use according to any one of

[31] to

[39] , wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

[0226] Advantageous Effects of the Invention The present invention can provide a therapeutic agent for HER2-mutated cancer, comprising a specific anti-HER2 antibody-drug conjugate, and / or a method for treating HER2-mutated cancer, comprising administering a specific anti-HER2 antibody-drug conjugate to a subject determined to have HER2-mutated cancer. BRIEF DESCRIPTION OF THE DRAWINGS [ Figure 1 ] Figure 1 The amino acid sequence of the heavy chain of the humanized anti-HER2 antibody is shown (SEQ ID No: 1).

[0227] [ Figure 2 ] Figure 2The amino acid sequence of the light chain of the humanized anti-HER2 antibody is shown (SEQ ID No: 2).

[0228] [ Figure 3 ] Figure 3 The maximum tumor reduction as a function of the effectiveness of HER2-ADC (1) for subjects with non-small cell lung cancer determined to have HER2 expression or HER2 mutations is shown. In the figure, "NE" represents subjects with no or unmeasurable HER2 mutations, "E20" represents subjects determined to have exon 20 insertion mutations in the HER2 protein, "TM" represents subjects determined to have single base pair substitution mutations in the transmembrane domain of the HER2 protein, and "EC" represents subjects determined to have single base pair substitution mutations in the extracellular domain of the HER2 protein.

[0229] [ Figure 4 ] Figure 4 Shown is the time course of tumor shrinkage as a function of the effectiveness of HER2-ADC (1) in subjects with non-small cell lung cancer identified as having HER2 expression or HER2 mutation.

[0230] [ Figure 5 ] Figure 5 The amino acid sequence of the HER2 protein is shown (SEQ ID No: 3). DETAILED DESCRIPTION Hereinafter, preferred modes for implementing the present invention are described. The embodiment described below is given only as an example for illustrating a typical embodiment of the present invention and is not intended to limit the scope of the present invention.

[0231] [definition] In the present invention, "HER2" is synonymous with human epidermal growth factor receptor 2 (which may also be referred to as neu or ErbB-2), and is a transmembrane receptor that belongs to the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases along with HER1 (EGFR or ErbB-1), HER3 (ErbB-3), and HER4 (ErbB-4). HER2 is known to play an important role in cell proliferation, differentiation, and survival in normal and tumor cells by forming heterodimers with HER1, HER3, or HER4 and being activated by autophosphorylation of intercellular tyrosine residues.

[0232] In the present invention, the term "HER2 protein" is used with the same meaning as HER2. The expression of HER2 protein can be detected using methods well known to those skilled in the art, such as immunohistochemistry (IHC).

[0233] SEQ ID No: 3( Figure 5 ) shows the amino acid sequence of the HER2 protein. In SEQ ID No: 3, the amino acid sequence consisting of amino acid residues 1 to 652 is referred to as the "extracellular domain of the HER2 protein," the amino acid sequence consisting of amino acid residues 653 to 675 is referred to as the "transmembrane domain of the HER2 protein," and the amino acid sequence consisting of amino acid residues 676 to 1255 is referred to as the "intercellular domain of the HER2 protein."

[0234] In the present invention, "HER2 gene" is synonymous with human epidermal growth factor receptor type 2-related oncogene. HER2 protein is one of the gene products of HER2 gene.

[0235] SEQ ID No: 4 shows the nucleotide sequence of HER2 gene (cDNA).

[0236] In the present invention, "HER2 mutation" refers to a mutation in the amino acid sequence of the HER2 protein.

[0237] In the present invention, "HER2-mutated cancer" refers to a cancer that has a mutation in the amino acid sequence of the HER2 protein. Furthermore, cancers that include cancer cells with HER2 mutations are also included in the term "HER2-mutated cancer," even if the HER2 mutation is not present in all tumor tissues.

[0238] In the present invention, "HER2 gene mutation" refers to a mutation in the HER2 gene.

[0239] In the present invention, "HER2 gene mutation cancer" refers to a cancer that has a mutation in the HER2 gene. In addition, cancers containing cancer cells that have a HER2 gene mutation are also included in the term "HER2 gene mutation cancer" even if the HER2 gene mutation is not present in all tumor tissues.

[0240] HER2 gene mutations cause mutations in the amino acid sequence of the HER2 protein as the gene product, thereby causing HER2 mutations.

[0241] Specific examples of HER2 mutations may include mutations that repeat the amino acid sequence YVMA (tyrosine, valine, methionine, and alanine) at positions 772 to 775 of the HER2 protein (which may also be referred to as "Y772_A775dup" or "A775_G776insYVMA") (see, for example, Nature. 2004 Sep 30; 431(7008): 525-6, Cancer Res. 2005 Mar 1; 65(5): 1642-6, Cancer Res. 2005 Sep 1; 65(17): 7591-5, Int J Cancer. 2006 Dec 1; 119(11): 2586-91, Mol Cancer Res. 2008 Nov; 6(11): 1678-90, Nat Med. 2017 Jun; 23(6): 703-713, and Nature. 2018 Feb 8; 554(7691): 189-194), a mutation that repeats the amino acid sequence GSP (glycine, serine and proline) at positions 778 to 780 of the HER2 protein (which may also be referred to as "G778_P780dup" or "P780_Y781insGSP") (see, for example, Cancer Res. 2005 Mar 1; 65(5): 1642-6, Pathobiology. 2008; 75(1): 2-8, Nature. 2012 May 16; 486(7403): 400-4, Clin Cancer Res. 2013 May 15; 19(10): 2668-76, Nature. 2016 Jun 2; 534(7605): 47-54, Cancer. 2016 Sep 1; 122(17): 2654-62, PLoS Med. 2016 Dec 27; 13(12): e1002201, and Nat Med. 2017 Jun; 23(6): 703-713), a mutation that replaces G (glycine) at amino acid position 776 of the HER2 protein with VC (valine and cysteine) (which may also be referred to as "G776delinsVC" or "G776>VC") (see, for example, Cancer Res. 2005 Mar 1; 65(5): 1642-6, Cancer Sci. 2006 Aug; 97(8): 753-9, Cancer Genet Cytogenet. 2007 Mar; 173(2): 107-13, Clin Cancer Res. 2012 Sep 15; 18(18): 4910-8, and Nature.2018 Feb 8;554(7691):189-194), a mutation that replaces L (leucine) at amino acid position 775 of the HER2 protein with S (serine) (which may also be referred to as "L755S") (see, for example, Clin Cancer Res. 2006 Jan 1;12(1):57-61, Hum Mutat. 2008 Mar;29(3):441-50, Nature. 2012 Apr 4;486(7403):395-9, Breast Cancer Res Treat. 2012 Jul;134(2):561-7, Clin Cancer Res. 2012 Sep 15;18(18):4910-8, and Cancer Lett. 2013 Mar 1;330(1):33-40), a mutation that replaces V (valine) at amino acid position 777 of the HER2 protein with L (leucine) (which may also be referred to as "V777L") (see, for example, Clin Cancer Res. 2006 Jan 1;12(1):57-61, Int J Cancer. 2006 Dec 1;119(11):2586-91, Nature. 2010 Aug 12;466(7308):869-73, Nature. 2012 Jun 10;486(7403):353-60, Cancer Cell. 2016 Feb 8;29(2):229-40, and Cancer. 2016 Sep 1;122(17):2654-62), a mutation in which V (valine) at amino acid position 659 of the HER2 protein is replaced by E (glutamic acid) (which may also be referred to as "V659E") (see, for example, Cancer Discov. 2013 Nov;3(11):1238-44, J Natl Cancer Inst. 2014 Jan;106(1):djt338, Nat Med. 2017 Jun;23(6):703-713, and Nature. 2018 Feb 8;554(7691):189-194), a mutation in which G (glycine) at amino acid position 660 of the HER2 protein is replaced by D (aspartic acid) (which may also be referred to as "G660D"), (see, for example, Nat Genet. 2014 Dec;46(12):1264-6, Cancer Cell. 2016 Feb 8;29(2):229-40, and Cell Rep.2016 Apr 26; 15(4): 857-865), and a mutation that replaces S (serine) at amino acid position 310 of the HER2 protein with F (phenylalanine) (which may also be referred to as "S310F") (see, for example, Nature. 2008 Oct 23; 455(7216): 1069-75, Nature. 2011 Jun 29; 474(7353): 609-15, Nat Genet. 2011 Oct 30; 43(12): 1219-23, Nature. 2012 Apr 4; 486(7403): 395-9, Genome Res. 2012 Nov; 22(11): 2109-19, and Clin Cancer Res. 2013 May 15; 19(10): 2668-76).

[0242] Further, other specific examples of HER2 mutations may also include a mutation in which A (alanine) at amino acid position 20 of the HER2 protein is replaced by T (threonine) (which may also be referred to as "A20T") (see, for example, Nature 2010; 466(7308):869-73), a mutation in which A (alanine) at amino acid position 21 of the HER2 protein is replaced by S (serine) (which may also be referred to as "A21S") (see, for example, Nature medicine 2017; 23(6):703-713), a mutation in which R (arginine) at amino acid position 143 of the HER2 protein is replaced by Q (glutamine) (which may also be referred to as "R143Q") (see, for example, Nature communications 2015; 6:10131, and Cancer biology & therapy 2014; 15(9): 1239-47), a mutation that replaces K (lysine) at amino acid position 200 of the HER2 protein with N (asparagine) (which may also be referred to as "K200N") (e.g., see Nature medicine 2017; 23(6): 703-713), a mutation that replaces A (alanine) at amino acid position 242 of the HER2 protein with V (valine) (which may also be referred to as "A242V") (e.g., see Nature medicine 2017; 23(6): 703-713), a mutation that replaces D (aspartic acid) at amino acid position 277 of the HER2 protein with Y (tyrosine) (which may also be referred to as "D277Y") (e.g., see Nature medicine 2017; 23(6): 703-713, and Nature genetics 2013; 45(12): 1459-63), a mutation in which A (alanine) at amino acid position 293 of HER2 protein is replaced by P (proline) (which may also be referred to as "A293P") (for example, see Nature medicine 2017; 23(6): 703-713), a mutation in which N (asparagine) at amino acid position 302 of HER2 protein is replaced by K (lysine) (which may also be referred to as "N302K") (for example, see Nature medicine 2017; 23(6): 703-713), a mutation in which V (valine) at amino acid position 308 of HER2 protein is replaced by M (methionine) (which may also be referred to as "V308M") (for example, see Cell Rep. 2016Apr 26; 15(4): 857-865), a mutation that replaces S (serine) at amino acid position 310 of the HER2 protein with Y (tyrosine) (which may also be referred to as "S310Y") (e.g., see Nature genetics 2014;46(8):872-6, Nature 2016; 534(7605):47-54, and Nature medicine 2017; 23(6):703-713), a mutation that replaces N (asparagine) at amino acid position 319 of the HER2 protein with Y (tyrosine) (which may also be referred to as "N319Y") (see, for example, Cell. 2018 May 3; 173(4):864-878.e29), a mutation that replaces S (serine) at amino acid position 335 of the HER2 protein with C (cysteine) (which may also be referred to as "S335C") (see, for example, Nature medicine 2017; 23(6):703-713), a mutation that replaces R (arginine) at amino acid position 340 of the HER2 protein with P (proline) (which may also be referred to as "R340P") (see, for example, Nature medicine 2017; 23(6): 703-713), a mutation that replaces S (serine) at amino acid position 418 of HER2 protein with T (threonine) (which may also be referred to as "S418T") (see, for example, Cell 2012; 150(6): 1107-20), a mutation that replaces W (tryptophan) at amino acid position 452 of HER2 protein with C (cysteine) (which may also be referred to as "W452C") (see, for example, Cell. 2018 May 3; 173(4): 864-878.e29), a mutation that replaces V (valine) at amino acid position 541 of HER2 protein with M (methionine) (which may also be referred to as "V541M") (see, for example, Cell. 2018 May 3;173(4):864-878.e29), a mutation that replaces I (isoleucine) at amino acid position 613 of HER2 protein with V (valine) (which may also be referred to as "I613V") (see, for example, Scientific reports 2016;6:31628), a mutation that replaces P (proline) at amino acid position 627 of HER2 protein with H (histidine) (which may also be referred to as "P627H") (see, for example, PloS one 2016;11(4):e0154133), a mutation that replaces A (alanine) at amino acid position 644 of HER2 protein with V (valine) (which may also be referred to as "A644V") (see, for example, Nat Genet. 2012 Oct;44(10):1104-10, and Nature 2015;524(7563):47-53), a mutation that replaces R (arginine) at amino acid position 647 of the HER2 protein with G (glycine) (which may also be referred to as "R647G") (e.g., see Cell. 2018 May 3;173(4):864-878.e29), a mutation that replaces I (isoleucine) at amino acid position 654 of the HER2 protein with V (valine) (which may also be referred to as "I654V") (see, for example, Br J Cancer. 2017 Jun 27; 117(1):136-143, and Cell. 2018 May 3; 173(4):864-878.e29), a mutation that replaces I (isoleucine) at amino acid position 655 of the HER2 protein with V (valine) (which may also be referred to as "I655V") (see, for example, Oncotarget 2017; 8(40):68026-68037, Nature communications 2015; 6:10131, and Nature genetics 2014; 46(6): 595-600), a mutation that replaces I (isoleucine) at amino acid position 661 of the HER2 protein with V (valine) (which may also be referred to as "I661V") (for example, see Nature medicine 2017; 23(6): 703-713), a mutation that replaces R (arginine) at amino acid position 678 of the HER2 protein with Q (glutamine) (which may also be referred to as "R678Q") (for example, see Nature 2018; 554(7691): 189-194), a mutation that replaces Q (glutamine) at amino acid position 680 of the HER2 protein with H (histidine) (which may also be referred to as "Q680H") (for example, see Nature medicine 2017;23(6):703-713), a mutation that replaces V (valine) at amino acid position 697 of the HER2 protein with L (leucine) (which may also be referred to as "V697L") (e.g., see Nature 2018;554(7691):189-194, Nature medicine 2017;23(6):703-713, and PLoS medicine 2016;13(12):e1002162), a mutation that replaces G (glycine) at amino acid position 704 of the HER2 protein with R (arginine) (which may also be referred to as "G704R") (e.g., see Lung 2016;194(1):125-35), a mutation that replaces Q (glutamine) at amino acid position 709 of the HER2 protein with L (leucine) (which may also be referred to as "Q709L") (e.g., see Nature medicine 2017; 23(6): 703-713), a mutation that replaces Q (glutamine) at amino acid position 711 of the HER2 protein with H (histidine) (which may also be referred to as "Q711H") (e.g., see Nature medicine 2017;23(6):703-713), a mutation that replaces G (glycine) at amino acid position 727 of HER2 protein with A (alanine) (which may also be referred to as "G727A") (for example, see Nature medicine 2017; 23(6):703-713), a mutation that replaces T (threonine) at amino acid position 733 of HER2 protein with I (isoleucine) (which may also be referred to as "T733I") (for example, see Nature 2018; 554(7691):189-194), a mutation that replaces E (glutamic acid) at amino acid position 744 of HER2 protein with G (glycine) (which may also be referred to as "E744G") (for example, see Cancer research 2007;67(12):5667-72), a mutation that replaces N (asparagine) at amino acid position 745 of the HER2 protein with D (aspartic acid) (which may also be referred to as "N745D") (e.g., see Cancer research 2007;67(12):5667-72), a mutation that replaces L (leucine) at amino acid position 755 of the HER2 protein with P (proline) (which may also be referred to as "L755P") (e.g., see Oncotarget 2016;7(28):44322-44329, Nature 2004;431(7008):525-6, and Nature medicine 2006;432(7008):525-6 2017;23(6):703-713), a mutation that replaces L (leucine) at amino acid position 755 of HER2 protein with A (alanine) (which may also be referred to as "L755A") (for example, see Nature 2018;554(7691):189-194, and Nature medicine 2017;23(6):703-713), a mutation that replaces L (leucine) at amino acid position 755 of HER2 protein with F (phenylalanine) (which may also be referred to as "L755F") (for example, see Clin Cancer Res. 2015 Aug 15;21(16):3631-9), a mutation that replaces S (serine) at amino acid position 760 of HER2 protein with F (phenylalanine) (which may also be referred to as "S760F") (for example, see Clin Cancer Res. 2006 Apr 15; 12(8): 2538-44), a mutation that replaces D (aspartic acid) at amino acid position 769 of the HER2 protein with H (histidine) (which may also be referred to as "D769H") (see, for example, Cancer 2016; 122(17): 2654-62, Nature medicine 2017; 23(6): 703-713, and Nature 2018;554(7691):189-194), a mutation that replaces D (aspartic acid) at amino acid position 769 of the HER2 protein with N (asparagine) (which may also be referred to as "D769N") (see, for example, Nature 2018; 554(7691):189-194), and a mutation that replaces D (aspartic acid) at amino acid position 769 of the HER2 protein with Y (tyrosine) (which may also be referred to as "D769Y") (see, for example, Nature 2018; 554(7691):189-194). ;

[0243] Further, other specific examples of HER2 mutations may also include a mutation in which AYVM (alanine, tyrosine, valine, and methionine) is inserted between E (glutamic acid) at amino acid position 770 and A (alanine) at amino acid position 771 of the HER2 protein (which may also be referred to as "E770_A771insAYVM") (see, for example, Nature medicine 2017; 23(6):703-713, and Nature 2018;554(7691):189-194), a mutation in which YVMA (tyrosine, valine, methionine, and alanine) is inserted between A (alanine) at amino acid position 771 and Y (tyrosine) at amino acid position 772 of the HER2 protein (which may also be referred to as "A771_Y772insYVMA") (e.g., see Nature 2018;554(7691):189-194), a mutation in which AYVM (alanine, tyrosine, valine, and methionine) is inserted between M (methionine) at amino acid position 774 and A (alanine) at amino acid position 775 of the HER2 protein (which may also be referred to as "M774_A775insAYVM") (e.g., see J Thorac Oncol. 2013 Feb;8(2):e19-20, and The American journal of surgical pathology 2006;30(10):1309-15), a mutation that inserts YVMA (tyrosine, valine, methionine, and alanine) between A (alanine) at amino acid position 775 and G (glycine) at amino acid position 776 of the HER2 protein (which may also be referred to as "A775_G776insYVMA") (see, for example, Clin Cancer Res.2013May 15;19(10):2668-76, Cancer 2016;122(17):2654-62, and European urology 2016;70(2):348-57), a mutation that replaces A (alanine) at amino acid position 775 of the HER2 protein with G (glycine) (which may also be referred to as "A775G") (see, for example, Anticancer research 2013;33(11):5127-33), a mutation that replaces G (glycine) at amino acid position 776 of the HER2 protein with LC (leucine and cysteine) (which may also be referred to as "G776delinsLC" or "G776>LC") (see, for example, Cancer research 2005; 65(5): 1642-6), a mutation that replaces G (glycine) at amino acid position 776 of the HER2 protein with C (cysteine) (which may also be referred to as "G776C") (see, for example, Clin Cancer Res. 2012 Sep 15; 18(18): 4910-8), a mutation that replaces G (glycine) at amino acid position 776 of the HER2 protein with AVGC (alanine, valine, glycine and cysteine) (which may also be referred to as "G776delinsAVGC" or "G776>AVGC") (see, for example, Nature 2018; 554(7691): 189-194, and Nature medicine 2017;23(6):703-713), a mutation in which G (glycine) at amino acid position 776 of the HER2 protein is replaced by VV (valine and valine) (which may also be referred to as "G776delinsVV" or "G776>VV") (e.g., see Nature medicine 2017;23(6):703-713), a mutation in which L (leucine) is inserted between G (glycine) at amino acid position 776 and V (valine) at amino acid position 777 of the HER2 protein (which may also be referred to as "G776_V777insL") (e.g., see Oncotarget 2016;7(20):29761-9), a mutation in which G (glycine) at amino acid position 776 of the HER2 protein is replaced by L (leucine) (which may also be referred to as "G776L") (e.g., see Lung Cancer. 2012 Apr; 76 (1): 123-7), a mutation that inserts VC (valine and cysteine) between G (glycine) at amino acid position 776 and V (valine) at amino acid position 777 of the HER2 protein (which may also be referred to as "G776_V777insVC") (see, for example, J Clin Oncol.2013Jun 1; 31(16): 1997-2003), a mutation in which VGC (valine, glycine and cysteine) is inserted between G (glycine) at amino acid position 776 and V (valine) at amino acid position 777 of the HER2 protein (which may also be referred to as "G776_V777insVGC") (e.g., see Nature 2018; 554(7691): 189-194), a mutation in which CG (cysteine and glycine) is inserted between V (valine) at amino acid position 777 and G (glycine) at amino acid position 778 of the HER2 protein (which may also be referred to as "V777_G778insCG") (e.g., see Clin Cancer Res.2012Sep15;18(18):4910-8), a mutation in which G (glycine) is inserted between V (valine) at amino acid position 777 and G (glycine) at amino acid position 778 of the HER2 protein (which may also be referred to as "V777_G778insG") (see, for example, Nature 2018;554(7691):189-194), a mutation in which G (glycine) is inserted between G (glycine) at amino acid position 778 and S (serine) at amino acid position 779 of the HER2 protein (which may also be referred to as "G778_S779insG") (see, for example, Nature 2018;554(7691):189-194), a mutation in which S (serine) at amino acid position 779 of the HER2 protein is replaced by P (proline) (which may also be referred to as "S779P") (see, for example, Virchows Arch. 2016 Jun; 468(6): 651-62), a mutation in which VGS (valine, glycine and serine) is inserted between S (serine) at amino acid position 779 and P (proline) at amino acid position 780 of the HER2 protein (which may also be referred to as "S779_P780insVGS") (see, for example, Nature 2004; 431(7008): 525-6, and J Thorac Oncol. 2009 Jan; 4(1): 5-11), a mutation in which GSP (glycine, serine and proline) is inserted between P (proline) at amino acid position 780 and Y (tyrosine) at amino acid position 781 of the HER2 protein (which may also be referred to as "P780_Y781insGSP") (see, for example, Nature Medicine 2017; 23(6): 703-713), a mutation that replaces R (arginine) at amino acid position 784 of the HER2 protein with C (cysteine) (which may also be referred to as "R784C") (for example, see Gynecol Oncol.2018 Feb; 148(2): 311-316, Nature genetics 2014; 46(12): 1264-6, and Cell Rep. 2016 Apr 26; 15(4): 857-865), a mutation in which R (arginine) at amino acid position 784 of the HER2 protein is replaced by H (histidine) (which may also be referred to as "R784H") (see, for example, Cell Rep. 2016 Apr 26; 15(4): 857-865, Virchows Arch. 2016 Jun; 468(6): 651-62, and Eur J Cancer. 2014 Jul; 50(10): 1740-1746), a mutation in which L (leucine) at amino acid position 785 of the HER2 protein is replaced by R (arginine) (which may also be referred to as "L785R") (see, for example, Br J Cancer.2015Dec 22;113(12):1704-11), a mutation in which L (leucine) at amino acid position 786 of the HER2 protein is replaced by V (valine) (which may also be referred to as "L786V") (see, for example, Nature 2018;554(7691):189-194), a mutation in which T (threonine) at amino acid position 791 of the HER2 protein is replaced by I (isoleucine) (which may also be referred to as "T791I") (see, for example, Cancerresearch 2007;67(12):5667-72), a mutation in which G (glycine) at amino acid position 804 of the HER2 protein is replaced by S (serine) (which may also be referred to as "G804S") (see, for example, Clin Cancer Res.2006 Apr 15;12(8):2538-44), a mutation that replaces L (leucine) at amino acid position 807 of HER2 protein with F (phenylalanine) (which may also be referred to as "L807F") (see, for example, Eur J Cancer. 2015 Sep;51(13):1803-11), a mutation that replaces S (serine) at amino acid position 819 of HER2 protein with F (phenylalanine) (which may also be referred to as "S819F") (see, for example, PLoS medicine 2016;13(12):e1002162, and Cancer cell 2015;27(3):327-41), a mutation that replaces I (isoleucine) at amino acid position 829 of HER2 protein with T (threonine) (which may also be referred to as "I829T") (see, for example, Clin Cancer Res.2006 Apr 15; 12(8): 2538-44), a mutation that replaces V (valine) at amino acid position 842 of the HER2 protein with I (isoleucine) (which may also be referred to as "V842I") (see, for example, Nature 2018; 554(7691): 189-194), a mutation that replaces L (leucine) at amino acid position 846 of the HER2 protein with F (phenylalanine) (which may also be referred to as "L846F") (see, for example, Oncotarget. 2016 Sep 20; 7(38): 61755-61763), a mutation that replaces T (threonine) at amino acid position 862 of the HER2 protein with I (isoleucine) (which may also be referred to as "T862I") (see, for example, Nature 2018;554(7691):189-194), a mutation in which R (arginine) at amino acid position 868 of the HER2 protein is replaced by W (tryptophan) (which may also be referred to as "R868W") (see, for example, Nature 2012;487(7407):330-7, and Br J Cancer. 2015 Dec 22;113(12):1704-11), a mutation in which L (leucine) at amino acid position 869 of the HER2 protein is replaced by R (arginine) (which may also be referred to as "L869R") (see, for example, Nature medicine 2017;23(6):703-713, Nature 2018;554(7691):189-194, and PLoS medicine 2016; 13 (12): e1002201), a mutation that replaces T (threonine) at amino acid position 875 of the HER2 protein with I (isoleucine) (which may also be referred to as "T875I") (see, for example, Br J Cancer. 2015 Dec 22; 113 (12): 1704-11), a mutation that removes W (tryptophan) at amino acid position 906 of the HER2 protein (which may also be referred to as "W906*") (see, for example, Nature 2008; 455 (7216): 1069-75), a mutation that replaces T (threonine) at amino acid position 917 of the HER2 protein with S (serine) (which may also be referred to as "T917S") (see, for example, Carcinogenesis. 2012 Jul; 33(7): 1270-6), a mutation that removes the Q (glutamine) at amino acid position 943 of the HER2 protein (which may also be referred to as "Q943*") (see, for example, Cell 2012; 150(6): 1107-20), a mutation that removes the S (serine) at amino acid position 1007 of the HER2 protein (which may also be referred to as "S1007*") (see, for example, Cell.2018 May 3; 173(4): 864-878.e29), and a mutation that replaces S (serine) at amino acid position 1151 of the HER2 protein with L (leucine) (which may also be referred to as "S1151L") (for example, see Nature medicine 2017; 23(6): 703-713). .

[0244] The HER2 mutation in the present invention is not particularly limited as long as the amino acid sequence of the HER2 protein has a mutation, but specific examples thereof may include at least one selected from the above-mentioned HER2 mutations, and preferably, at least one selected from Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

[0245] In the present invention, an "exon 20 insertion mutation" refers to a HER2 mutation caused by a base pair insertion into exon 20 of the HER2 gene. Exon 20 of the HER2 gene is represented by the nucleotide sequence of nucleotides 2308 to 2493 of SEQ ID No: 4, and the HER2 protein encoded thereby is represented by the amino acid sequence consisting of amino acid residues 770 to 831 of SEQ ID No: 3.

[0246] The exon 20 insertion mutation in the present invention is not particularly limited as long as it is a HER2 mutation caused by the insertion of a base pair into exon 20 of the HER2 gene, but examples thereof may include those selected from Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsVC, At least one of sAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP, and preferably, at least one selected from Y772_A775dup, G778_P780dup and G776delinsVC.

[0247] In the present invention, a "single base pair substitution mutation" refers to a HER2 mutation caused by substitution of one base pair in the HER2 gene by another base pair.

[0248] The single base pair substitution mutation in the present invention is not particularly limited as long as it is a HER2 mutation caused by substitution of one base pair of the HER2 gene by another base pair, but examples thereof may include those selected from L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709 L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D76 9N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S, L80 7F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L, and preferably, at least one selected from L755S, V777L, V659E, G660D and S310F.

[0249] In the present invention, "a single base pair substitution mutation in the transmembrane domain of the HER2 protein" refers to a HER2 mutation caused in the transmembrane domain of the HER2 protein by substituting one base pair of the HER2 gene for another base pair.

[0250] The single base pair substitution mutation in the transmembrane domain of the HER2 protein in the present invention is not particularly limited as long as it is a HER2 mutation caused in the transmembrane domain of the HER2 protein by substituting one base pair of the HER2 gene for another base pair, but examples thereof may include at least one selected from V659E, G660D, I654V, I655V and I661V, and preferably G660D.

[0251] In the present invention, "a single base pair substitution mutation in the extracellular domain of the HER2 protein" refers to a HER2 mutation caused in the extracellular domain of the HER2 protein by substituting one base pair of the HER2 gene for another base pair.

[0252] The single base pair substitution mutation in the extracellular domain of the HER2 protein in the present invention is not particularly limited as long as it is a HER2 mutation caused in the extracellular domain of the HER2 protein by substituting one base pair of the HER2 gene for another base pair, but examples thereof may include at least one selected from S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G, and preferably S310F.

[0253] The therapeutic agent and / or treatment method of the present invention can be preferably used to identify cancers having a HER2 mutation of at least one of the above mutations, but there is no limitation on these mutations as long as the cancer has a mutation in HER2.

[0254] For example, the presence or absence of HER2 mutations can be determined by collecting tumor tissue from a subject with cancer and performing real-time quantitative PCR (qRT-PCR) or microarray analysis on formalin-fixed paraffin-embedded specimens (FFPE).

[0255] In addition, the presence or absence of HER2 mutations can also be determined by collecting cell-free circulating tumor DNA (ctDNA) from subjects with cancer and performing next-generation sequencing (NGS) thereof, etc. (see, for example, J Clin Oncol 2013; 31: 1997-2003, Clin Cancer Res 2012; 18: 4910-8, J Thorac Oncol 2012; 7: 85-9, Lung Cancer 2011; 74: 139-44, Cancer Res 2005; 65: 1642-6, Cancer Sci 2006; 97: 753-9, ESMO Open 2017; 2: e000279 and Annals of Oncology 26: 1421-1427, 2015).

[0256] In the present invention, the term "HER2 mutation" is used with the same meaning as HER2 gene mutation.

[0257] In the present invention, an "anti-HER2 antibody" refers to an antibody that specifically binds to HER2, preferably has an activity of binding to HER2, and is thereby internalized into cells expressing HER2. In other words, it refers to an antibody that has an activity of binding to HER2 and thereafter moves into cells expressing HER2.

[0258] [Anti-HER2 antibody-drug conjugate] The anti-HER2 antibody-drug conjugate used in the present invention is an anti-HER2 antibody-drug conjugate in which the drug-linker represented by the following formula is conjugated to the antibody via a thioether bond: [Equation 13] Where A represents the linking site to the antibody.

[0259] In the present invention, the partial structure consisting of a linker and a drug of an anti-HER2 antibody-drug conjugate is referred to as a "drug-linker." The drug-linker is linked to a thiol group (in other words, a sulfur atom of a cysteine residue) formed at the interchain disulfide bond sites of the antibody (two sites between heavy chains and two sites between heavy and light chains).

[0260] The drug-linker of the present invention includes exatecan (IUPAC name: (1S,9S)-1-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]quinoline-10,13-dione (also expressed as chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione)) as a component. Exatecan is a camptothecin derivative represented by the following formula and having antitumor effects: [Equation 14]

[0261] The anti-HER2 antibody-drug conjugate used in the present invention can also be represented by the following formula: [Equation 15] The drug-linker is conjugated to the anti-HER2 antibody via a thioether bond. n has the same meaning as the average number of conjugated drug molecules (DAR; drug-to-antibody ratio) and represents the average number of drug-linker units conjugated per antibody molecule.

[0262] The average number of drug linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugates used in the present invention is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, even more preferably about 8.

[0263] After migrating into cancer cells, the anti-HER2 antibody-drug conjugate used in the present invention is cleaved at the linker portion, and the compound represented by the following formula is released: [Equation 16]

[0264] The above compounds are inferred to be the original source of the anti-tumor activity of the anti-HER2 antibody-drug conjugates used in the present invention, and have been confirmed to have topoisomerase I inhibitory effects (Ogitani Y. et al., Clinical Cancer Research, 2016, Oct 15; 22(20): 5097-5108, Epub 2016 Mar 29).

[0265] It is also known that the anti-HER2 antibody-drug conjugates used in the present invention have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046). The bystander effect is exerted by a process in which the anti-HER2 antibody-drug conjugates used in the present invention are internalized into cancer cells that express the target, and the above-mentioned compound then also exerts an anti-tumor effect on cancer cells that are present nearby and do not express the target.

[0266] The anti-HER2 antibody-drug conjugate used in the present invention can be produced with reference to the description in International Publication No. WO 2015 / 115091 and the like.

[0267] [Production of anti-HER2 antibodies] The HER2 protein used in the present invention can be directly purified from cells expressing HER2 of humans or non-human mammals (e.g., rats and mice), or prepared using the cell membrane fraction of such cells, or can be obtained by synthesizing HER2 in vitro or producing HER2 in host cells by genetic engineering. In genetic engineering, HER2 cDNA can be incorporated into an expressible vector, and then HER2 can be synthesized in a solution containing the enzymes, substrates, and energy substances required for transcription and translation, or other prokaryotic or eukaryotic host cells can be transformed to express HER2 to specifically obtain the protein. Further, cells expressing HER2 or cell lines expressing HER2 as HER2 protein can also be used by genetic engineering.

[0268] The HER2 protein used in the present invention can be directly purified from cells expressing human HER2, the cell membrane fraction of such cells as HER2 protein can be used to prepare (when used as an antigen), or can be obtained by synthesizing HER2 in vitro or producing HER2 in host cells by genetic engineering. In genetic engineering, HER2 cDNA can be incorporated into an expressible vector, and then the vector can be hatched in a solution containing the enzyme, substrate and energy substances required for transcription and translation to specifically synthesize HER2. Alternatively, protein can be obtained by using a vector to transform other prokaryotic or eukaryotic host cells to express HER2. Further, the cell expressing HER2 or the cell line expressing HER2 as a HER2 protein antigen can also be used by genetic engineering.

[0269] The DNA sequence and amino acid sequence of HER2 are published in public databases and can be accessed, for example, by accession numbers such as M11730 (Genbank) and NP_004439.2 (NCBI).

[0270] Furthermore, HER2 also includes proteins consisting of an amino acid sequence having one or more substituted, deleted and / or added amino acids in the amino acid sequence of HER2 and having biological activities equivalent to those of the protein.

[0271] The human HER2 protein consists of a signal sequence consisting of 22 amino acid residues at the N-terminus, an extracellular domain consisting of 630 amino acid residues, a transmembrane domain consisting of 23 amino acid residues, and an intercellular domain consisting of 580 amino acid residues.

[0272] The anti-HER2 antibodies used in the present invention can be obtained by known methods. For example, antibodies can be obtained using the method routinely performed in this area, which involves immunizing an animal with any polypeptide selected from the amino acid sequence of HER2 or HER2 used as an antigen, collecting the antibodies produced in the body, and purifying the antibodies. The source of the antigen is not limited to humans, and can be immunized with an antigen derived from a non-human animal such as a mouse, rat, etc. In this case, the cross-reactivity of the antibody bound to the obtained heterologous antigen with the human antigen can be tested to screen for anti-HER2 antibodies applicable to human diseases.

[0273] Alternatively, antibody-producing cells that produce antibodies to the antigen are fused with myeloma cells according to methods known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495-497; Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, NY (1980)) to establish hybridomas, from which monoclonal antibodies can be obtained.

[0274] Antigens can be obtained by genetically engineering host cells to produce genes encoding antigenic proteins. Specifically, a vector that allows the expression of the antigen gene is prepared and transferred to the host cell to express the gene. The antigen expressed in this way can be purified. Antibodies can also be obtained by immunizing animals with cells expressing the antigen or cell lines expressing the antigen that are genetically engineered to express the antigen.

[0275] The anti-HER2 antibodies used in the present invention are preferably recombinant antibodies obtained by artificial modification for the purpose of reducing heterologous antigenicity to humans, such as chimeric antibodies or humanized antibodies, or preferably antibodies having only human-derived antibodies, i.e., human antibody gene sequences. These antibodies can be produced using known methods.

[0276] As chimeric antibodies, there can be exemplified antibodies in which the antibody variable region and constant region are derived from different species, for example, a chimeric antibody in which an antibody variable region derived from a mouse or rat is linked to an antibody constant region derived from a human (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0277] Examples of humanized antibodies include antibodies obtained by integrating only the complementarity determining region (CDR) of a heterologous antibody into an antibody derived from a human (Nature (1986) 321, pp. 522-525), antibodies obtained by transplanting a portion of the amino acid residues of the heterologous antibody framework and the CDR sequence of the heterologous antibody into a human antibody by a CDR grafting method (WO90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Patent No. 5,821,337).

[0278] As human antibodies, antibodies produced by using human antibody-producing mice having human chromosome segments including genes for heavy and light chains of human antibodies can be exemplified (see Tomizuka, 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 Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et al., Proc. Natl. Acad. Sci. USA (2000) 97, p. 722-727, etc.). Alternatively, antibodies obtained by phage display, which are selected from a human antibody library (see Wormstone, IM et.al, Investigative Ophthalmology & Visual Science. (2002) 43(7), p.2301-2308; Carmen, S. et.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.

[0279] In the present invention, also included are variants of modifications for the anti-HER2 antibodies of the present invention. Modified variants refer to variants obtained by chemical or biological modification of the antibody according to the present invention. Examples of chemically modified variants include: variants comprising the connection of a chemical moiety to an amino acid backbone; variants comprising the connection of a chemical moiety to an N-connected or O-connected carbohydrate chain, etc. Examples of biologically modified variants include variants obtained by post-translational modification (e.g., N-connected or O-connected glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine), and variants in which methionine residues have been added to the N-terminus by expression in prokaryotic host cells. Further, labels have been carried out to enable detection or separation of antibodies for the anti-HER2 antibodies of the present invention or antigens, such as enzyme-labeled antibodies, fluorescently labeled antibodies, and affinity-labeled antibodies, which are also included in the meaning of modified variants. Such modified variants for the anti-HER2 antibodies of the present invention can be used to improve antibody stability and blood retention, reduce their antigenicity, detect or separate antibodies or antigens, etc.

[0280] Further, by regulating the modification (glycosylation, defucosylation, etc.) of the glycans connected to the anti-HER2 antibodies used in the present invention, the cytotoxic activity of antibody-dependent cells can be enhanced. As a technology for regulating the modification of the glycans of antibodies, WO 99 / 54342, WO 00 / 61739 and WO 02 / 31140, etc. are known. However, this technology is not limited thereto. Among the anti-HER2 antibodies used in the present invention, antibodies in which the modification of glycans is regulated are also included.

[0281] It is known that the lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in cultured mammalian cells is deleted (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that the two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in cultured mammalian cells are deleted, and the proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletions and modifications of the heavy chain sequence do not affect the antigen binding affinity and effector function (complement activation, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, the anti-HER2 antibodies used in the present invention also include antibodies and functional fragments of such modifications, and also include deletion variants in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of deletion variants (e.g., heavy chains in which the carboxyl terminal proline residue has been amidated), and the like. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the anti-HER2 antibody of the present invention is not limited to the above-mentioned variant, as long as the antigen binding affinity and effector function are retained. The two heavy chains constituting the anti-HER2 antibody of the present invention can be a type selected from the full-length heavy chain and the above-mentioned deletion variant, or can be two types selected from a combination thereof. The ratio of the amount of each deletion variant can be affected by the type and culture conditions of the cultured mammalian cells produced for the anti-HER2 antibody of the present invention. However, it is preferred that an antibody is exemplified in which an amino acid residue at the carboxyl terminus has been deleted in all two heavy chains of the anti-HER2 antibody of the present invention.

[0282] As the isotype of the anti-HER2 antibody used in the present invention, for example, IgG (IgG1, IgG2, IgG3, IgG4) can be exemplified, and preferably IgG1 or IgG2 can be exemplified.

[0283] Examples of the anti-HER2 antibody used in the present invention include trastuzumab (US Pat. No. 5,821,337) and pertuzumab (International Publication No. WO 01 / 00245), and preferably trastuzumab can be exemplified.

[0284] In the present invention, "trastuzumab" is a humanized anti-HER2 antibody comprising a heavy chain and a light chain, wherein the heavy chain consists of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 ( Figure 1 ), wherein the light chain consists of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2 ( Figure 2 ).

[0285] Preferred anti-HER2 antibodies for use in producing the anti-HER2 antibody-drug conjugates according to the present invention are: (1) an antibody comprising a heavy chain and a light chain, wherein the heavy chain consists of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and the light chain consists of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2; or (2) An antibody comprising a heavy chain and a light chain, wherein the heavy chain consists of the amino acid sequence shown in SEQ ID No: 1, and the light chain consists of the amino acid sequence shown in SEQ ID No: 2.

[0286] [Production of anti-HER2 antibody-drug conjugates] The drug-linker intermediate used to produce the anti-HER2 antibody-drug conjugate according to the present invention is represented by the following formula.

[0287] [Equation 17]

[0288] The drug-linker intermediate can be represented by the chemical name N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]glycylglycyl-L-phenylalanyl-N-[(2-{[(1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycine amide and can be produced with reference to the description of International Publication No. WO 2015 / 115091.

[0289] The anti-HER2 antibody-drug conjugate used in the present invention can be produced by reacting the above-mentioned drug-linker intermediate with an anti-HER2 antibody having a thiol group (alternatively referred to as a sulfhydryl group).

[0290] Anti-HER2 antibodies having sulfhydryl groups can be obtained by methods well known to those skilled in the art (Hermanson, GT, 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 in the antibody and reacting with the anti-HER2 antibody in a buffer solution containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA), an anti-HER2 antibody having sulfhydryl groups can be obtained, which has partially or completely reduced interchain disulfides in the antibody.

[0291] Furthermore, by using 2 to 20 molar equivalents of the drug-linker intermediate per anti-HER2 antibody having a thiol group, an anti-HER2 antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody molecule can be produced.

[0292] The average number of drug molecules conjugated per antibody molecule of the produced anti-HER2 antibody-drug conjugate can be determined, for example, by a calculation method based on measurement of UV absorbance at two wavelengths of 280 nm and 370 nm of the anti-HER2 antibody-drug conjugate and its conjugation precursor (UV method), or by a quantitative calculation method based on HPLC measurement of fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[0293] The conjugation of the anti-HER2 antibody to the drug-linker intermediate and the calculation of the average number of drug molecules conjugated per antibody molecule of the anti-HER2 antibody-drug conjugate can be performed with reference to the description in International Publication No. WO 592015 / 115091, etc.

[0294] [Therapeutic agents and / or treatment methods] The therapeutic agents and / or treatment methods of the present invention comprise administering specific anti-HER2 antibody-drug conjugates and can be used to treat HER2-mutated cancers.

[0295] The HER2-mutated cancer for which the therapeutic agent and / or treatment method of the present invention can be used is preferably at least one selected from the group consisting of lung cancer (including non-small cell lung cancer), breast cancer, gastric cancer (also known as gastric adenocarcinoma), colorectal cancer (also known as colon and rectal cancer, and including colon cancer and rectal cancer), esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, Liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasma cell tumor, myeloma, head and neck cancer, pharyngeal cancer, glioblastoma multiforme and melanoma, more preferably at least one selected from the group consisting of non-small cell lung cancer, breast cancer, gastric cancer, colorectal cancer, esophageal cancer, salivary gland cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer and uterine carcinosarcoma, even more preferably non-small cell lung cancer, and even more preferably unresectable and / or metastatic non-small cell lung cancer.

[0296] In the therapeutic agents and treatment methods of the present invention, the dosage of the anti-HER2 antibody-drug conjugate of the present invention per administration is preferably in the range of 5.4 mg / kg (indicating that the dosage per kg of body weight is 5.4 mg, which is applicable to the following instructions) to 8 mg / kg, more preferably 5.4 mg / kg, 6.4 mg kg, 7.4 mg / kg or 8 mg / kg, even more preferably 5.4 mg / kg or 6.4 mg / kg, and even more preferably 6.4 mg / kg.

[0297] The therapeutic agents and treatment methods of the present invention preferably comprise administering the anti-HER2 antibody-drug conjugate of the present invention once every three weeks.

[0298] In addition to the anti-HER2 antibody-drug conjugates for the present invention, the therapeutic agent and therapies of the present invention may include one or more drugs (such as a second drug). Therefore, the therapeutic agent of the present invention or the anti-HER2 antibody-drug conjugates for the present invention may be administered in combination with another drug, and the anti-cancer effect may be enhanced. Another drug for this purpose may be administered to the subject simultaneously, respectively, or sequentially with the anti-HER2 antibody-drug conjugates for the present invention, or may be administered at different dosing intervals. Another drug or the second drug is preferably a cancer therapeutic agent. Such a cancer therapeutic agent is not limited as long as it is a drug having antitumor activity, but examples thereof may include 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, trifluridine-tipiracil combination, gefitinib, erlotinib, afatinib, methotrexate, pemetrexed, trastuzumab-emtansine, trastuzumab, pertuzumab, tamoxifen, toremifene, fulvestrant, leuprorelin, goserelin, letrozole, anastrozole, and progesterone preparations.

[0299] The therapeutic agents and treatment methods of the present invention can be selectively used as drug therapeutic agents, which are the main methods for treating cancer, and as a result, can delay the development of cancer cells, inhibit their growth, and further kill cancer cells. These effects can allow cancer patients to be free from the symptoms caused by cancer, or achieve an improvement in the quality of life of cancer patients, and achieve a therapeutic effect by maintaining the life of cancer patients. Even if the therapeutic agents and treatment methods of the present invention do not kill cancer cells, they can also achieve a higher quality of life for cancer patients by inhibiting or controlling the growth of cancer cells, while achieving longer-term survival.

[0300] In such drug treatment, the therapeutic agents and treatment methods of the present invention can be used alone, and further, they can be used in combination with other treatments in adjuvant therapy, and can be combined with surgery, radiation therapy, hormone therapy, etc. In addition, they can also be used for drug treatment in neoadjuvant therapy.

[0301] In addition to the therapeutic uses described above, for example, the therapeutic agents and treatment methods of the present invention can also be expected to have preventive effects, such as inhibiting the growth of small metastatic cancer cells and further killing them. For example, it can be expected to inhibit and kill cancer cells in body fluids during the metastasis process, or, for example, to inhibit and kill small cancer cells immediately after implantation in any tissue. Thus, it can be expected to inhibit cancer metastasis or preventive effects, especially after surgical resection of cancer.

[0302] The therapeutic agents and treatment methods of the present invention are expected to exert their therapeutic effects by application to the patient as a systemic treatment, and additionally, by local application to cancerous tissue.

[0303] The therapeutic agent and treatment method of the present invention can be preferably used in mammals, and can be more preferably used in humans.

[0304] The therapeutic agent of the present invention can be administered as a pharmaceutical composition comprising at least one pharmaceutically suitable ingredient. Based on the dosage, administration concentration, etc. of the anti-HER2 antibody-drug conjugate used for the present invention, pharmaceutically suitable ingredients can be appropriately selected and applied from the formulation additives commonly used in the art. For example, the therapeutic agent of the present invention can be administered as a pharmaceutical composition containing a buffer, such as a histidine buffer, an excipient, such as sucrose, and a surfactant, such as polysorbate 80 (hereinafter referred to as "pharmaceutical composition for the present invention"). The pharmaceutical composition for the present invention can be preferably used as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection.

[0305] When the pharmaceutical composition used in the present invention is an aqueous injection, it can be preferably diluted with a suitable diluent and then administered in the form of intravenous infusion. As the diluent, glucose solution, physiological saline, etc. can be exemplified, glucose solution can be preferably exemplified, and 5% glucose solution can be more preferably exemplified.

[0306] When the pharmaceutical composition used in the present invention is a lyophilized injection, the composition is preferably dissolved in water for injection, and then the required amount can be diluted with a suitable diluent and then administered as an intravenous infusion. As the diluent, glucose solution, physiological saline, etc. can be exemplified, preferably glucose solution, and more preferably 5% glucose solution can be exemplified.

[0307] Examples of administration routes that can be used to administer the pharmaceutical composition for use in the present invention include intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, and preferably include an intravenous route. Example

[0308] The present invention will be described in detail with reference to the following examples. However, the present invention is not limited to these examples and is not to be construed in a limiting sense.

[0309] Example 1: Production of anti-HER2 antibody-drug conjugates According to the production method described in International Publication No. WO 2015 / 115091, an anti-HER2 antibody-drug conjugate was produced using a humanized anti-HER2 antibody (an antibody comprising a heavy chain and a light chain, the heavy chain consisting of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and the light chain consisting of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2), wherein a drug-linker represented by the following formula is conjugated to the anti-HER2 antibody via a thioether bond (referred to as "HER2-ADC (1)" in the present invention): [Equation 18] Where A represents the attachment position to the antibody. The average number of drug units conjugated per antibody molecule in HER2-ADC (1) ranges from 7 to 8.

[0310] Example 2: Clinical study (Phase I study) A phase I study of a HER2-ADC (1) was conducted in subjects with HER2-positive breast cancer (previously treated with trastuzumab-emtansine), subjects with HER2-positive gastric cancer (previously treated with trastuzumab), subjects with HER2-low expressing breast cancer (with IHC 1+ or IHC 2+ and ISH-), and subjects with other solid cancers that expressed HER2 (with IHC 1+ or higher) or were HER2-mutated (as determined by IHC, FISH, NGS, or other methods). Adverse events (AEs), response rate (ORR: CR (complete response) + PR (partial response)), and disease control rate (DCR: CR + PR + SD (stable disease)) were assessed.

[0311] From September 2015 to April 2018, HER2-ADC (1) (6.4 mg / kg) was administered to 12 subjects with HER2-expressing or HER2-mutated non-small cell lung cancer. The median age of the subjects was 58.5 years, and the median number of previous treatments for the subjects was 3. At the time of data cutoff, 8 / 12 (66.7%) of the subjects were still receiving treatment. The median duration of treatment was 3.663 months. The ORR and DCR in the evaluable subjects were 62.5% (5 / 8) and 75.0% (6 / 8), respectively. Among them, 4 subjects were determined to have HER2 mutations, and the PR was 75.0% (3 / 4). The median duration of response was 11.5 months. Tumor shrinkage was observed in 8 / 10 (80.0%) of the subjects who underwent one or more post-baseline scans (100% of the subjects showed tumor shrinkage at the first post-baseline scan (approximately 6 weeks after administration)). The reasons for treatment discontinuation were PD (3 / 4, 75.0%) and AE (1 / 4, 25.0%). Grade 3 or higher AEs were observed in 3 / 12 subjects (25.0%). As the main AE, alopecia was observed in 41.7% (0.0% for Grade 3 or higher) and fatigue was observed in 41.7% (0.0% for Grade 3 or higher) (data as of April 18, 2018).

[0312] Example 3: Clinical study (Phase I study) According to Example 2, a Phase I study of HER2-ADC (1) was conducted. To date, HER2-ADC (1) has been administered (6.4 mg / kg) to 18 subjects with HER2-expressing or HER2-mutated non-small cell lung cancer. The median age of the subjects was 58.0 years, and the median number of previous treatments for the subjects was 3. Of these 18 subjects, 11 subjects were confirmed to have HER2 mutations (61.1%).

[0313] As for the antitumor effects of HER2-ADC (1), Table 1 shows the objective response rate (ORR), disease control rate (DCR), duration of response (DoR), time to response (TTR), and progression-free survival (PFS).

[0314] [Table 1]

[0315] In a cohort of subjects with HER2-expressing or HER2-mutated non-small cell lung cancer (18 subjects), HER2-ADC (1) showed an ORR of 58.8% (10 / 17) and a DCR of 88.2% (15 / 17). The median DoR was 9.9 months, the median TTR was 1.4 months, and the median PFS was 14.1 months.

[0316] In a cohort of subjects with HER2-mutated non-small cell lung cancer (11 subjects), HER2-ADC (1) showed an ORR of 72.7% (8 / 11) and a DCR of 100% (11 / 11). The median DoR was 11.5 months, the median TTR was 1.4 months, and the median PFS was 14.1 months. Figure 3 showed the greatest tumor shrinkage, and Figure 4 Showing the time course of tumor reduction.

[0317] Table 2 shows the major adverse events (AEs) observed with treatment with HER2-ADC (1). All AEs were generally low grade.

[0318] [Table 2]

[0319] In addition to the above, adverse events of special interest were interstitial lung disease observed in one patient (5.6%) and pneumonitis observed in one patient (5.6%) (data cutoff as of August 10, 2018).

[0320] Example 4: Clinical study (Phase II study) A Phase II study of HER2-ADC(1) was conducted in subjects with unresectable and / or metastatic NSCLC that overexpressed HER2 (with IHC 3+ or 2+) (approximately 40 subjects: Cohort 1) and subjects with unresectable and / or metastatic NSCLC that harbored a HER2 mutation (approximately 40 subjects: Cohort 2). HER2-ADC(1) was administered at a dose of 6.4 mg / kg every three weeks to assess response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

[0321] Free text for sequence listings SEQ ID No: 1 - Amino acid sequence of the heavy chain of a humanized anti-HER2 antibody SEQ ID No: 2 - Amino acid sequence of the light chain of a humanized anti-HER2 antibody SEQ ID No: 3-Amino acid sequence of HER2 protein SEQ ID No: 4—Nucleotide sequence of HER2 gene (cDNA).

Claims

1. Use of an anti-HER2 antibody-drug conjugate for preparing a medicament for treating a HER2-mutated cancer, wherein the anti-HER2 antibody-drug conjugate has a drug-linker represented by the following formula: [Formula 1] Where A represents the linking position to the anti-HER2 antibody; The drug-linker is conjugated to the anti-HER antibody via a thioether bond; wherein the anti-HER2 antibody is an antibody comprising a heavy chain and a light chain, wherein the heavy chain consists of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and the light chain consists of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2; and The HER2-mutated cancer is non-small cell lung cancer.

2. The method according to claim 1, wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335 C. R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R , Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771ins AYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, A775G, G776delinsLC, G776C, G776delin sAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G 778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L.

3. The use according to claim 2, wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

4. The use according to claim 1, wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

5. The use according to claim 4, wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP.

6. The use according to claim 5, wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, and G776delinsVC.

7. The method according to claim 1, wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

8. The use according to claim 7, wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V.

9. The use according to claim 8, wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

10. The use according to claim 1, wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

11. The method according to claim 10, wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

12. The use according to claim 11, wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

13. The use according to claim 1, wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

14. The use according to any one of claims 1 to 13, wherein the average number of drug-linker units conjugated per antibody in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

15. The use according to any one of claims 1 to 13, wherein the average number of drug-linker units conjugated per antibody in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

16. The use according to any one of claims 1 to 13, wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

17. The use according to any one of claims 1 to 13, wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 5.4 mg / kg or 6.4 mg / kg.

18. The use according to any one of claims 1 to 13, wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 5.4 mg / kg.

19. The use according to any one of claims 1 to 13, wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg.

20. The use according to any one of claims 1 to 13, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

21. The use according to claim 15, wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 5.4 mg / kg or 6.4 mg / kg.

22. The use according to claim 15, wherein the dose of the anti-HER2 antibody-drug conjugate administered each time is 5.4 mg / kg.

23. The use according to claim 15, wherein the dose of the anti-HER2 antibody-drug conjugate is 6.4 mg / kg per administration.

24. The use according to claim 21, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

25. The use according to claim 22, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

26. The use according to claim 23, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

27. Use of an anti-HER2 antibody-drug conjugate for preparing a medicament for treating cancer with a HER2 mutation, wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: [Formula 2] wherein the drug-linker is conjugated to the anti-HER2 antibody via a thioether bond, and n is the average number of drug-linker units conjugated per antibody; wherein the anti-HER2 antibody is an antibody comprising a heavy chain and a light chain, wherein the heavy chain consists of an amino acid sequence consisting of amino acid residues 1 to 449 of SEQ ID NO: 1, and the light chain consists of an amino acid sequence consisting of amino acid residues 1 to 214 of SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of the amino acid sequence set forth in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence set forth in SEQ ID NO: 2; and The HER2-mutated cancer is non-small cell lung cancer.

28. The method according to claim 27, wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S33 5C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704 R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, E770_A771in sAYVM、A771_Y772insYVMA、M774_A775insAYVM、A775_G776insYVMA、A775G、G776delinsLC、G776C、G776delin sAVGC, G776delinsVV, G776_V777insL, G776L, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G 778insG, G778_S779insG, S779P, S779_P780insVGS, P780_Y781insGSP, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, and S1151L.

29. The use according to claim 28, wherein the HER2 mutation in the HER2-mutated cancer is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L and S310F.

30. The use according to claim 27, wherein the HER2 mutation in the HER2-mutated cancer is an exon 20 insertion mutation.

31. The use according to claim 30, wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, A775_G776insYVMA, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, S779_P780insVGS and P780_Y781insGSP.

32. The use according to claim 31, wherein the exon 20 insertion mutation is at least one selected from the group consisting of Y772_A775dup, G778_P780dup, and G776delinsVC.

33. The use according to claim 27, wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the transmembrane domain of the HER2 protein.

34. The use according to claim 33, wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is at least one selected from the group consisting of V659E, G660D, I654V, I655V and I661V.

35. The use according to claim 34, wherein the single base pair substitution mutation in the transmembrane domain of the HER2 protein is G660D.

36. The use according to claim 27, wherein the HER2 mutation in the HER2-mutated cancer is a single base pair substitution mutation in the extracellular domain of the HER2 protein.

37. The method according to claim 36, wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is at least one selected from the group consisting of S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V and R647G.

38. The use according to claim 37, wherein the single base pair substitution mutation in the extracellular domain of the HER2 protein is S310F.

39. The use according to claim 27, wherein the non-small cell lung cancer is unresectable and / or metastatic non-small cell lung cancer.

40. The use according to any one of claims 27 to 39, wherein the average number of drug-linker units conjugated per antibody in the anti-HER2 antibody-drug conjugate is in the range of 7 to 8.

41. The use according to any one of claims 27 to 39, wherein the average number of drug-linker units conjugated per antibody in the anti-HER2 antibody-drug conjugate is in the range of 7.5 to 8.

42. The use according to any one of claims 27 to 39, wherein the dose of the anti-HER2 antibody-drug conjugate per administration is in the range of 5.4 mg / kg to 8 mg / kg.

43. The use according to any one of claims 27 to 39, wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 5.4 mg / kg or 6.4 mg / kg.

44. The use according to any one of claims 27 to 39, wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 5.4 mg / kg.

45. The use according to any one of claims 27 to 39, wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 6.4 mg / kg.

46. The use according to any one of claims 27 to 39, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

47. The use according to claim 41, wherein the dose of the anti-HER2 antibody-drug conjugate per administration is 5.4 mg / kg or 6.4 mg / kg.

48. The use according to claim 41, wherein the dose of the anti-HER2 antibody-drug conjugate is 5.4 mg / kg per administration.

49. The use according to claim 41, wherein the dose of the anti-HER2 antibody-drug conjugate is 6.4 mg / kg per administration.

50. The use according to claim 47, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

51. The use according to claim 48, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

52. The use according to claim 49, wherein the anti-HER2 antibody-drug conjugate is administered once every three weeks.

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