Combination of antibody-drug conjugate and RASG12C inhibitor

Abstract

Medicaments are provided for administering an anti-HER2 antibody-drug conjugate in combination with a RASG12C inhibitor.Therapeutic uses and methods are also provided, in which an antibody-drug conjugate and a RASG12C inhibitor are administered in combination to a subject.

Description

[Technical field]

[0001] The present disclosure relates to pharmaceutical agents for administering an antibody-drug conjugate having an anti-tumor drug conjugated via a linker structure to an anti-HER2 antibody in combination with a RASG12C inhibitor, and to therapeutic uses and methods in which a specific antigen-drug conjugate and a RASG12C inhibitor are administered in combination to a subject. [Background technology]

[0002] The KRAS, NRAS and HRAS genes encode a set of closely related small GTPase proteins, KRas, NRas and HRas, which share 82-90% overall sequence identity, collectively referred to herein as Ras proteins or Ras. Ras proteins are key components of signaling pathways that transmit signals from cell surface receptors to control cell proliferation, survival and differentiation.

[0003] Ras proteins are 188-189 amino acids long and function as molecular switches, cycling between an inactive GDP-bound state and an active GTP-bound state. Specifically, Ras proteins have a highly conserved N-terminal G domain that contains a p-loop region that binds nucleotides, and switch I and switch II regions that are important for regulation and effector protein interaction. The best-characterized effector of Ras is the serine / threonine kinase Raf, which controls the activity of the mitogen-activated protein kinase (MAPK) pathway. The PI3K pathway is another important effector pathway downstream of Ras, in which the p110 catalytic subunit of class I phosphoinositide 3-kinase interacts with Ras. Other effectors of Ras have also been described, including RalGDS, Tiam1, PLC-e, and Rassf1 (Cox, et al. Nature Reviews Drug Discovery, 2014, 13:828-851).

[0004] RAS mutations are frequently found in cancer, with approximately 30% of all human cancers harboring mutations in the KRAS, NRAS, or HRAS genes. Oncogenic Ras is typically, but not exclusively, associated with mutations at glycine 12, glycine 13, or glutamine 61 of Ras. These residues are located in the active site of Ras, and mutations impair intrinsic and / or GAP-catalyzed GTPase activity, favoring the formation of GTP-bound Ras and the aberrant activation of downstream effector pathways. KRAS is the most frequently mutated RAS gene in cancer, followed by NRAS, then HRAS. There are several tumor types that display a high frequency of activating mutations in KRAS, including pancreatic (approximately 90% prevalence), colorectal (approximately 40% prevalence), and non-small cell lung cancer (approximately 30% prevalence). KRAS mutations are also found in other cancer types, including multiple myeloma, uterine cancer, cholangiocarcinoma, gastric cancer, bladder cancer, diffuse large B-cell lymphoma, rhabdomyosarcoma, squamous cell carcinoma of the skin, cervical cancer, and testicular germ cell cancer.

[0005] The glycine to cysteine ​​mutation at residue 12 of Ras (G12C mutation), which occurs by a GC to TA transversion at codon 12, is a common mutation in the RAS gene, accounting for 14% of all KRAS mutations, 2% of all NRAS mutations, and 2% of all HRAS mutations across cancer types. G12C mutations are particularly prevalent in KRAS mutant non-small cell lung cancers, about half of which harbor this mutation, and have been linked to DNA adducts formed by cigarette smoke. G12C mutations are not exclusively associated with lung cancer but are found in other RAS mutant cancer types, including 8% of all KRAS mutant colorectal cancers.

[0006] Compounds exhibiting G12C mutant Ras protein inhibitory activity (RASG12C inhibitors) are disclosed, for example, in International Publication Nos. 2019 / 099524, 2019 / 215203, 2020 / 178282, 2021 / 118877, and 2021 / 245051. Known RASG12C inhibitors include compounds designated LY3537982 (Loxo / Lilly), AZD4625 (AstraZeneca), AMG510 (sotorasib: Amgen), MRTX849 (adagrasib: Mirati), JDQ443 (Novartis), GDC-6036 (Genentech), BI 1,823,911 (Boehringer Ingelheim), D1553 (InventisBio), and JNJ-74699157 (Johnson and Johnson).

[0007] Antibody-drug conjugates (ADCs), consisting of a cytotoxic drug conjugated to an antibody, are expected to be able to selectively deliver the drug to cancer cells, thus resulting in accumulation of the drug in the cancer cells and killing the cancer cells (Ducry, L., et al., Bioconjugate Chem. (2010) 21, 5-13; Alley, SC, et al., Current Opinion in Chemical Biology (2010) 14, 529-537; Damle NK Expert Opin. Biol. Ther. (2004) 4, 1445-1452; Senter PD, et al., Nature Biotechnology (2012) 30, 631-637; Burris HA., et al., J. Clin. Oncol. (2011) 29(4):398-405).

[0008] ADCs comprising an anti-HER2 antibody conjugated to a drug via a linker are disclosed, for example, in WO 2015 / 115091. Known ADCs include trastuzumab emtansine (Kadcyla®, T-DM1), which is composed of a HER2-targeting antibody (trastuzumab) covalently linked to a cytotoxic microtubule inhibitor (DM1), and trastuzumab deruxtecan (Enhertu®, DS-8201), which is composed of a derivative of trastuzumab and exatecan (Ogitani Y. et al., Clinical Cancer Research (2016) 22 (20), 5097-5108; Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).

[0009] Trastuzumab deruxtecan (Enhertu®, DS-8201) has shown significant clinical efficacy in HER2-expressing solid tumors, including breast, gastric, colorectal and non-small cell lung cancers. Significantly, DS-8201 has demonstrated promising activity in tumors with low HER2 expression in the above indications. However, combination partners for DS-8201 still need to be identified to enhance its therapeutic potential. Summary of the Invention [Problem to be solved by the invention]

[0010] Despite the therapeutic potential of anti-HER2-ADCs, such as trastuzumab emtansine and trastuzumab deruxtecan, and RASG12C inhibitors, there remains a need for improved therapeutic compositions and methods that may enhance the efficacy of existing cancer treatments, prolong the durability of therapeutic responses, improve patient tolerance, and / or reduce dose-dependent toxicity.

[0011] Various antibody-drug conjugates (e.g., anti-HER2 antibody-drug conjugates containing as components a derivative of a microtubule inhibitor (DM1) or the topoisomerase I inhibitor exatecan) have been shown to exhibit superior antitumor effects when administered alone in the treatment of certain cancers, such as breast and gastric cancer. In addition, RASG12C inhibitors have been confirmed to exhibit antitumor effects in the treatment of certain cancers. However, it is desirable to provide agents and treatments that can provide superior antitumor effects in the treatment of cancer, such as enhanced efficacy, prolonged duration of therapeutic response, and / or reduced dose-dependent toxicity. [Means for solving the problem]

[0012] The present disclosure provides a pharmaceutical agent that can show excellent antitumor effects in the treatment of cancer through the administration of an anti-HER2 antibody-drug conjugate in combination with a RASG12C inhibitor. The present disclosure also provides therapeutic uses and methods of administering an anti-HER2 antibody-drug conjugate and a RASG12C inhibitor in combination to a subject.

[0013] Specifically, the present disclosure relates to the following [1] to

[63] .

[0014] [1] A pharmaceutical product comprising an antibody-drug conjugate, wherein the antibody is an anti-HER2 antibody, and a RASG12C inhibitor, for combined administration.

[0015] [2] The pharmaceutical composition according to [1], wherein the RASG12C inhibitor is a compound represented by the following formula (I): [ka] (In the formula, A is phenyl or a bicyclic heteroaryl group; X and Y are connected by a double bond, and i) X is CR 7 and Y is CR 8 or ii) X is N and Y is CR 8 or iii) X is CR 7 and Y is N, or X and Y are both C(O)NR 9 or X and Y are adjacent ring atoms of an optionally substituted 5- or 6-membered N-heterocycle that is fused to an aromatic ring substituted with Z, and X and Y are both C or C and N; Z is O, NH or NMe; R 1 is independently selected from F, Cl, Br, OH, CHOH, OMe, CHOMe, C1-C3 alkyl, and C1-C3 fluoroalkyl; n is 0, 1, 2 or 3; R 2 is H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe or OEt; R 3a and R 3b are both =O or R 3a and R 3b is H, R 4 is H or Me, R 5 is H or Me, R 6 is H or CH2NMe2, R 7 and R 8 are independently selected from H, F, Cl, CCH, CC(C1-C3 alkyl), CCCH2NMe2, CCCH2O(C1-C3 alkyl), CN, Me, C1-C6 alkyl, OH, OMe, O(C1-C3 alkyl), O(C1-C3 deuteroalkyl), O(C1-C3 fluoroalkyl), O(C3-C6 cycloalkyl), C1-C3 fluoroalkyl, OCH2CH2NMe2, OCH2CH2OMe, CHOMe, OCH2CH2N(CH2CH2)2CH, OCH2CH2N(CH2CH2)2O, OCH2CH2(2-pyridyl) or an optionally substituted 3-, 4-, 5- or 6-membered carbocyclic or heterocyclic ring; R 7 and R 8are joined to form an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring; R 9 is selected from H, Me, Et, C3H7 and C1-C3 fluoroalkyl or a pharma- ceutically acceptable salt thereof.

[0016] [3] The pharmaceutical composition according to [2], wherein in formula (I), i) X is CR 7 and Y is CR 8 or ii) X is N and Y is CR 8 or iii) X is CR 7 and Y is N.

[0017] [4] The pharmaceutical agent according to [2] or [3], wherein in formula (I), Z is O.

[0018] [5] The pharmaceutical composition according to any one of [2] to [4], wherein in formula (I), R 3a and R 3b is H, a pharmaceutical product.

[0019] [6] The pharmaceutical composition according to any one of [2] to [5], wherein in formula (I), R 4 is H, a pharmaceutical product.

[0020] [7] The pharmaceutical agent according to any one of [2] to [6], wherein in formula (I), R 6 is H, a pharmaceutical product.

[0021] [8] The pharmaceutical agent according to any one of [2] to [7], wherein in formula (I), A is phenyl.

[0022] [9][2] The pharmaceutical agent according to the present invention, wherein the RASG12C inhibitor is (12aS)-2-Acryloyl-10-chloro-9-(5-methyl-1H-indazol-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one; 1-((12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-Chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; (12aR)-10-Chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-((12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-Chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-7-carbonitrile; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; (12aR)-10-Chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 8-[(12aR)-10-chloro-8-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-9-yl]-7-methylisoquinolin-1(2H)-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aS)-10-Chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepin-6(2H)-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aS)-10-Chloro-11-methyl-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepin-6(2H)-one; 1-[(12aR)-10-chloro-9-(2,3-difluoro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-Chloro-9-(2-hydroxy-6-methylphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-[2-fluoro-6-(hydroxymethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-[2-hydroxy-6-(trifluoromethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-ethyl-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-[2-(difluoromethyl)-6-hydroxyphenyl]-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; (12aR)-10-Chloro-9-(2-chloro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-10-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-10-ethynyl-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-ethynyl-8-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-1-one; 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-1-one; 1-[(8aR)-6-chloro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydro-14H-pyrazino[2,1-c][1,2,4]triazolo[4',3':1,2]pyrido[3,4-f][1,4]oxazepin-10(8H)-yl]prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazol-9(7H)-yl]prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazol-9(7H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-10-chloro-8-ethynyl-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-chloro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydroimidazo[4,5-g]pyrazino[2,1-c][1,4]benzoxazepin-9(7H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-methyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-7,8-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-7,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropyloxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridin-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(2-methoxyethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidin-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( 2 H3methyloxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(methoxymethyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-7-[2-(dimethylamino)ethoxy]-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(prop-1-yn-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; and 1-((6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl)prop-2-en-1-one; or Pharmaceutically acceptable salts thereof A pharmaceutical agent, which is a compound selected from the group consisting of

[0023]

[10] [2] The pharmaceutical agent according to the present invention, wherein the RASG12C inhibitor is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one.

[0024]

[11] [2] The pharmaceutical agent according to the present invention, wherein the RASG12C inhibitor is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one.

[0025]

[12] The pharmaceutical agent according to [1], wherein the RASG12C inhibitor is selected from LY3537982 (Loxo / Lilly), AZD4625 (AstraZeneca), sotorasib (AMG510), adagrasib (MRTX849), JDQ443 (Novartis), GDC-6036 (Genentech), BI 1,823,911 (Boehringer Ingelheim), D1553 (InventisBio) and JNJ-74699157 (Johnson and Johnson) or a pharma- ceutical acceptable salt thereof.

[0026]

[13] The pharmaceutical composition according to [1], wherein the RASG12C inhibitor is a compound represented by the following formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0027]

[14] The pharmaceutical product according to any one of [1] to

[13] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 [= amino acid residues 26 to 33 of SEQ ID NO: 1] consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 [= amino acid residues 51 to 58 of SEQ ID NO: 1] consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 [= amino acid residues 97 to 109 of SEQ ID NO: 1] consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 [= amino acid residues 27 to 32 of SEQ ID NO: 2] consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 [= amino acid residues 50 to 52 of SEQ ID NO: 2] consisting of the amino acid sequence represented by SEQ ID NO: 7, and CDRL3 [= amino acid residues 89 to 97 of SEQ ID NO: 2] consisting of the amino acid sequence represented by SEQ ID NO: 8.

[0028]

[15] A pharmaceutical product according to any one of [1] to

[13] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9 [= amino acid residues 1 to 120 of SEQ ID NO: 1], and a light chain having a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10 [= amino acid residues 1 to 107 of SEQ ID NO: 2].

[0029]

[16] A pharmaceutical product according to any one of [1] to

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

[0030]

[17] A pharmaceutical product according to any one of [1] to

[13] , wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 [= amino acid residues 1 to 449 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2.

[0031]

[18] The pharmaceutical according to any one of [1] to

[17] , wherein the antibody-drug conjugate has the following formula: [ka] (wherein A represents the attachment position to the antibody). The pharmaceutical agent is an antibody-drug conjugate, in which a drug-linker represented by:

[0032]

[19] The pharmaceutical product according to any one of [1] to

[18] , wherein the anti-HER2 antibody-drug conjugate is represented by the following formula: [ka] (wherein "antibody" refers to an anti-HER2 antibody conjugated to a drug-linker via a thioether bond, and n refers to the average number of drug-linker units conjugated per antibody molecule in the antibody-drug conjugate, where n is in the range of 7 to 8.) Represented by, pharmaceuticals.

[0033]

[20] A pharmaceutical product according to any one of [1] to

[13] , wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) or trastuzumab emtansine (T-DM1).

[0034]

[21] The pharmaceutical according to

[20] , wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201).

[0035]

[22] A pharmaceutical product according to any one of [1] to

[21] , which is a composition comprising an anti-HER2 antibody-drug conjugate and a RASG12C inhibitor for simultaneous administration separately.

[0036]

[23] A pharmaceutical product according to any one of [1] to

[21] , which is a combined preparation comprising an anti-HER2 antibody-drug conjugate and a RASG12C inhibitor for sequential administration.

[0037]

[24] A pharmaceutical agent according to any one of [1] to

[23] , which is used for treating cancer.

[0038]

[25] The pharmaceutical product according to

[24] , wherein the cancer is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, esophagogastric junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

[0039]

[26] A pharmaceutical agent according to

[25] , wherein the cancer is breast cancer.

[0040]

[27] The pharmaceutical agent described in

[26] , wherein the breast cancer has a HER2 status score of IHC 3+.

[0041]

[28] A pharmaceutical agent according to

[26] , wherein the breast cancer is HER2 low-expressing breast cancer.

[0042]

[29] The pharmaceutical agent described in

[26] , wherein the breast cancer has a HER2 status score of IHC 2+.

[0043]

[30] The pharmaceutical agent described in

[26] , wherein the breast cancer has a HER2 status score of IHC 1+.

[0044]

[31] The pharmaceutical agent described in

[26] , wherein the breast cancer has an IHC>0 and a HER2 status score of <1+.

[0045]

[32]

[26] A pharmaceutical agent according to the present invention, wherein the breast cancer is triple-negative breast cancer.

[0046]

[33]

[24] A pharmaceutical agent according to the present invention, wherein the cancer is gastric cancer.

[0047]

[34] The pharmaceutical composition according to

[24] , wherein the cancer is colorectal cancer.

[0048]

[35] A pharmaceutical agent according to

[24] , wherein the cancer is lung cancer.

[0049]

[36] A pharmaceutical agent according to

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

[0050]

[37] A pharmaceutical composition according to

[24] , wherein the cancer is pancreatic cancer.

[0051]

[38] A pharmaceutical agent according to

[24] , wherein the cancer is ovarian cancer.

[0052]

[39] A pharmaceutical agent according to

[24] , wherein the cancer is prostate cancer.

[0053]

[40] A pharmaceutical agent according to

[24] , wherein the cancer is renal cancer.

[0054]

[41] A pharmaceutical product as defined in any one of [1] to

[23] for use in the treatment of cancer.

[0055] A pharmaceutical for use according to

[42]

[41] , wherein the cancer is as defined in any one of

[25] to

[40] .

[0056]

[43] Use of an anti-HER2 antibody-drug conjugate in the manufacture of a medicament for use in combination with a RASG12C inhibitor to treat cancer, wherein the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor are as defined in any one of [1] to

[21] .

[0057]

[44] The use according to

[43] , wherein the medicament is for use in combination with a RASG12C inhibitor by sequential administration.

[0058]

[45] The use according to

[43] , wherein the medicament is for use in combination with a RASG12C inhibitor by separate simultaneous administration.

[0059]

[46] Use of a RASG12C inhibitor in the manufacture of a medicament for use in combination with an anti-HER2 antibody-drug conjugate to treat cancer, wherein the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor are as defined in any one of [1] to

[21] .

[0060]

[47] The use according to

[46] , wherein the agent is for use in combination with an anti-HER2 antibody-drug conjugate by sequential administration.

[0061]

[48] ​​The use according to

[46] , wherein the agent is for use in combination with an anti-HER2 antibody-drug conjugate by separate simultaneous administration.

[0062] The use according to any one of

[49]

[43] to

[48] , wherein the cancer is as defined in any one of

[25] to

[40] .

[0063]

[50] An anti-HER2 antibody-drug conjugate for use in combination with a RASG12C inhibitor in the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor are as defined in any one of [1] to

[21] .

[0064]

[51] An anti-HER2 antibody-drug conjugate for use according to

[50] , wherein the cancer is as defined in any one of

[25] to

[40] .

[0065]

[52] An anti-HER2 antibody-drug conjugate for use according to

[50] or

[51] , wherein the use comprises sequential administration of the anti-HER2 antibody-drug conjugate and a RASG12C inhibitor.

[0066]

[53] An anti-HER2 antibody-drug conjugate for use according to

[50] or

[51] , wherein the use comprises separate and simultaneous administration of the anti-HER2 antibody-drug conjugate and a RASG12C inhibitor.

[0067]

[54] An anti-HER2 antibody-drug conjugate for use in treating cancer in a subject, said treatment comprising sequential or separate simultaneous administration to said subject of i) the anti-HER2 antibody-drug conjugate and ii) a RASG12C inhibitor, wherein the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor are as defined in any one of [1] to

[21] .

[0068]

[55] A RASG12C inhibitor for use in combination with an anti-HER2 antibody-drug conjugate in the treatment of cancer, wherein the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor are as defined in any one of [1] to

[21] .

[0069]

[56] A RASG12C inhibitor for use according to

[55] , wherein the cancer is as defined in any one of

[25] to

[40] .

[0070]

[57] A RASG12C inhibitor for use according to

[55] or

[56] , wherein the use comprises sequential administration of an anti-HER2 antibody-drug conjugate and a RASG12C inhibitor.

[0071]

[58] A RASG12C inhibitor for use according to

[55] or

[56] , wherein the use comprises separate and simultaneous administration of an anti-HER2 antibody-drug conjugate and a RASG12C inhibitor.

[0072]

[59] A RASG12C inhibitor for use in treating cancer in a subject, the treatment comprising sequential or separate simultaneous administration to the subject of i) the RASG12C inhibitor and ii) an anti-HER2 antibody-drug conjugate, wherein the RASG12C inhibitor and the anti-HER2 antibody-drug conjugate are as defined in any one of [1] to

[21] .

[0073]

[60] A method for treating cancer, comprising administering to a subject in need thereof a combination of an anti-HER2 antibody-drug conjugate defined in any one of [1] to

[21] and a RASG12C inhibitor.

[0074] The method according to

[61]

[60] , wherein the cancer is as defined in any one of

[25] to

[40] .

[0075] The method according to

[62] ,

[60] or

[61] , comprising sequentially administering an anti-HER2 antibody-drug conjugate and a RASG12C inhibitor.

[0076] The method according to

[63] ,

[60] or

[61] , comprising administering the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor separately and simultaneously. Effect of the Invention

[0077] The present disclosure provides a pharmaceutical product in which an anti-HER2 antibody-drug conjugate having an antitumor drug conjugated to the anti-HER2 antibody via a linker structure and a RASG12C inhibitor are administered in combination, and a therapeutic use and method, in which a specific antibody-drug conjugate and a RASG12C inhibitor are administered in combination to a subject. Thus, the present disclosure can provide a drug and treatment that can obtain excellent antitumor effects in the treatment of cancer. [Brief description of the drawings]

[0078] [Figure 1] FIG. 1 shows the amino acid sequence of the heavy chain of an anti-HER2 antibody (SEQ ID NO:1). [Diagram 2] FIG. 2 shows the amino acid sequence of the light chain of an anti-HER2 antibody (SEQ ID NO:2). [Diagram 3] FIG. 2 shows the amino acid sequence of heavy chain CDRH1 (SEQ ID NO: 3 [=amino acid residues 26 to 33 of SEQ ID NO: 1]). [Figure 4] FIG. 2 shows the amino acid sequence of heavy chain CDRH2 (SEQ ID NO: 4 [=amino acid residues 51 to 58 of SEQ ID NO: 1]). [Diagram 5] FIG. 1 shows the amino acid sequence of heavy chain CDRH3 (SEQ ID NO:5 [=amino acid residues 97 to 109 of SEQ ID NO:1]). [Figure 6] FIG. 1 shows the amino acid sequence of light chain CDRL1 (SEQ ID NO: 6 [=amino acid residues 27-32 of SEQ ID NO: 2]). [Figure 7] FIG. 1 shows an amino acid sequence including the amino acid sequence (SAS) of light chain CDRL2 (SEQ ID NO: 7 [=amino acid residues 50 to 56 of SEQ ID NO: 2]). [Figure 8] FIG. 1 shows the amino acid sequence of light chain CDRL3 (SEQ ID NO: 8 [=amino acid residues 89-97 of SEQ ID NO: 2]). [Figure 9] FIG. 1 shows the amino acid sequence of the heavy chain variable region (SEQ ID NO: 9 [=amino acid residues 1 to 120 of SEQ ID NO: 1]). [Figure 10] FIG. 1 shows the amino acid sequence of the light chain variable region (SEQ ID NO: 10 [=amino acid residues 1 to 107 of SEQ ID NO: 2]). [Figure 11] FIG. 1 shows the amino acid sequence of the heavy chain (SEQ ID NO: 11 [=amino acid residues 1 to 449 of SEQ ID NO: 1]). [Figure 12] 1 shows a combination matrix for the combination of Compound A with DS-8201 in KRASG12C lung cancer cell lines H358 and H2122 and the KRASG12C esophageal cell line KYSE410. [Figure 13] 1 shows a graph depicting the effect of the combination of Compound A and DS-8201 on tumor growth inhibition and regrowth upon cessation of treatment in eight KRASG12C cancer cell lines in vitro. [Figure 14] 1 shows a graph depicting the effect of the combination of Compound A and DS-8201 on tumor growth inhibition in vivo in the KRASG12C mutant lung cancer xenograft model NCI-H358. [Figure 15] 1 shows a graph depicting the effect of the combination of Compound A and DS-8201 on tumor growth inhibition in vivo in the KRASG12C mutant lung cancer xenograft model NCI-H2122. [Figure 16] 1 shows a graph depicting the effect of the combination of Compound A and DS-8201 on tumor growth inhibition in vivo in the KRASG12C mutant lung cancer xenograft model LU99. [Figure 17] 1 shows a graph depicting the effect of the combination of Compound A and DS-8201 on tumor growth inhibition in vivo in the KRASG12C mutant colorectal cancer patient-derived xenograft model CTG-1489. [Figure 18] 1 shows a graph depicting the effect of the combination of Compound A and DS-8201 on tumor growth inhibition in vivo in the KRASG12C mutant colorectal cancer patient-derived xenograft model CTG-0387. [Figure 19A] 1 shows a combination matrix for the combination of Compound A, AMG510 or MRTX849 with T-DM1 in KRASG12C lung cancer cell line H358. [Figure 19B] 1 shows a combination matrix for the combination of Compound A, AMG510 or MRTX849 with trastuzumab in KRASG12C lung cancer cell line H358. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] In order that this disclosure may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0080] Before describing the present disclosure in detail, it is to be understood that the present disclosure is not limited to specific compositions or method steps, as such may vary. As used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as "one or more" and "at least one" may be used interchangeably herein.

[0081] Furthermore, "and / or" as used herein should be considered as a specific disclosure of each of the two particular features or components, with or without the other features or components. Thus, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (single) and "B" (single). Similarly, the term "and / or" when used in phrases such as "A, B and / or C" is intended to encompass each of the following aspects: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0082] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this disclosure.

[0083] Units, prefixes and symbols are expressed in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers that define the range.

[0084] Whenever an embodiment is described herein with the word "comprising," it is understood that otherwise similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0085] The terms "inhibit," "block," and "suppress" are used interchangeably herein and refer to any statistically significant decrease in biological activity, including complete blocking of activity. For example, "inhibition" may refer to about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease in biological activity. Cell proliferation may be assayed using art-recognized techniques that measure the rate of cell division and / or the proportion of cells in a cell population undergoing cell division and / or the rate of cell loss from a cell population due to terminal differentiation or cell death (e.g., thymidine incorporation).

[0086] The term "subject" refers to any animal (e.g., mammal) that will be the recipient of a particular treatment, including, but not limited to, humans, non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to human subjects.

[0087] The term "pharmaceutical product" refers to a formulation that is in a form that allows the biological activity of the active ingredients, either as a composition containing all the active ingredients (for simultaneous administration) or as a combination of separate compositions (combined preparations) each containing at least one but not all of the active ingredients (for sequential or simultaneous administration), and does not contain additional ingredients that are unacceptably toxic to the subject to whom the product is administered. Such a product may be sterile. "Simultaneous administration" means that the active ingredients are administered at the same time. "Sequential administration" means that the active ingredients are administered one after the other in any order with a time interval between the individual administrations. The time interval may be, for example, less than 24 hours, preferably less than 6 hours, and more preferably less than 2 hours.

[0088] The terms "treating" or "treatment" or "treat" or "alleviating" or "alleviating" refer to both (1) therapeutic measures that cure, slow, reduce, and / or halt the progression of a diagnosed condition or disorder, and (2) prophylactic or preventative measures that prevent and / or slow the onset of the targeted condition or disorder. Thus, those in need of treatment include those who already have the disorder, those prone to have the disorder, and those in whom the disorder should be prevented. In certain embodiments, a subject's cancer is successfully "treated" according to the methods of the present disclosure, for example, when the patient shows a complete, partial, or temporary remission of a particular type of cancer.

[0089] The terms "cancer", "tumor", "cancerous" and "malignant" refer to or describe a physical condition in a mammal that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma and melanoma. Cancers include hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, and solid tumors such as breast cancer, lung cancer, neuroblastoma, and colon cancer.

[0090] The term "cytotoxic agent" as used herein is broadly defined and refers to a substance that inhibits or prevents the function of cells and / or causes destruction of cells (cell death) and / or exerts an anti-neoplastic / anti-proliferative effect. For example, a cytotoxic agent directly or indirectly prevents the development, maturation or spread of neoplastic tumor cells. The term also includes those agents that cause only cytostatic effects and not merely cytotoxic effects. The term includes chemotherapeutic agents as defined below as well as other HER2 antagonists, anti-angiogenic agents, tyrosine kinase inhibitors, protein kinase A inhibitors, members of the cytokine family, radioisotopes and toxins, such as enzymatically active toxins of bacterial, fungal, plant or animal origin.

[0091] The term "chemotherapeutic agent" is a subset of the term "cytotoxic agent" which includes natural or synthetic compounds.

[0092] According to the method or use of the present disclosure, a compound of the present disclosure may be administered to a patient to promote a positive therapeutic response for cancer. The term "positive therapeutic response" for cancer treatment refers to an improvement in symptoms associated with the disease. For example, an improvement in the disease may be characterized as a complete response. The term "complete remission" refers to the absence of clinically detectable disease normalizing any prior test results. Alternatively, an improvement in the disease may be classified as being a partial remission. A "positive therapeutic response" encompasses a reduction in the progression and / or duration of cancer or a reduction or improvement in the severity of cancer and / or an improvement in one or more of its symptoms resulting from administration of a compound of the present disclosure. In a specific embodiment, such a term refers to one, two, or three or more results following administration of a compound of the present disclosure: (1) stabilization, reduction or elimination of cancer cell populations; (2) stabilization or reduction of cancer growth; (3) Reduction of cancer formation (4) eradicating, removing, or controlling primary, regional, and / or metastatic cancer; (5) reducing mortality rates; (6) Increase in duration or rate of disease-free, recurrence-free, progression-free, and / or overall survival; (7) Increase in response rate, durability of response, or number of patients responding or achieving remission, (8) A reduction in hospitalization rates; (9) Reduction in hospital stays, (10) The size of the cancer is maintained and does not increase or increases by less than 10%, preferably less than 5%, preferably less than 4%, preferably less than 2%; and (11) Increase in the number of patients in remission. (12) A reduction in the number of adjuvant therapies (e.g., chemotherapeutic or hormonal therapy agents) that would otherwise be required to treat the cancer.

[0093] Clinical response can be assessed using the following: screening techniques such as PET, magnetic resonance imaging (MRI) scan, X-ray imaging, computed tomography (CT) scan, flow cytometry or fluorescence activated cell sorter (FACS) analysis, histological examination, macroscopic findings, and changes detectable by blood chemistry tests such as, but not limited to, ELISA, RIA, chromatography, and the like. In addition to these positive therapeutic responses, subjects undergoing treatment can experience the beneficial effect of ameliorating symptoms associated with the disease.

[0094] The alkyl groups and moieties may be straight or branched chain, e.g., C 1~8 Alkyl, C 1~6 Alkyl, C 1~4 Alkyl or C 5~6 Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl, e.g. methyl or n-hexyl.

[0095] A fluoroalkyl group is an alkyl group in which one or more H atoms are replaced by one or more fluoro atoms, such as C 1~8 Fluoroalkyl, C 1~6 Fluoroalkyl, C 1~4 Fluoroalkyl or C 5~6 Fluoroalkyl. Examples include fluoromethyl (CH2F-), difluoromethyl (CHF2-), trifluoromethyl (CF3-), 2,2,2-trifluoroethyl (CF3CH2-), 1,1-difluoroethyl (CH3CHF2-), 2,2-difluoroethyl (CHF2CH2-) and 2-fluoroethyl (CH2FCH2-).

[0096] Halo means fluoro, chloro, bromo and iodo, hi one embodiment, halo is fluoro or chloro.

[0097] As used herein, the phrase "effective amount" refers to an amount of a compound or composition that is sufficient to significantly and positively alter (e.g., provide a positive clinical response to) the condition and / or pathology being treated. The effective amount of an active ingredient used in a pharmaceutical preparation will vary within the knowledge and expertise of the attending physician, depending on the particular condition being treated, the severity of the condition, the duration of treatment, the nature of the concurrent therapy, the particular active ingredient being utilized, the particular pharma- ceutically acceptable excipients / carriers being utilized, and similar factors. Specifically, an effective amount of a compound used in the treatment of cancer in combination with an antibody-drug conjugate is an amount such that the combination is sufficient to alleviate symptoms in a warm-blooded animal (e.g., human), alleviate symptoms of cancer, delay the progression of cancer, or reduce the risk of progression in a patient with a cancer condition.

[0098] As used herein, and unless otherwise indicated, the term "pharmacologically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0099] It is understood that the compounds of formula (I) or (II) may form stable pharma- ceutically acceptable acid or base salts, and in such cases administration of the compounds as salts may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexylsulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrochloride, hydroiodide, hydroxymaleate, and the like. Salts include, for example, salts of the formula (I), lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Non-toxic, physiologically acceptable salts are preferred, although other salts may be useful, for example, in isolating or purifying the product.

[0100] The salts may be formed by conventional means, for example, by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble or in a solvent such as water (which is removed by vacuum or lyophilization), or by exchanging the anion of an existing salt for another anion on a suitable ion exchange resin.

[0101] It is to be understood that the compounds of formula (I) or (II) may have multiple chiral centers, and the present application encompasses all individual stereoisomers, enantiomers and diastereoisomers, as well as mixtures thereof. Thus, to the extent that the compounds of formula (I) or (II) may exist in optically active or racemic forms due to one or more asymmetric carbon atoms, it is to be understood that the present application includes, by definition, any such optically active or racemic forms that have the above activity. The present application encompasses all such stereoisomers that have the activity defined herein.

[0102] Therefore, throughout this specification, when referring to a compound of formula (I) or (II), it is to be understood that the term compound includes diastereoisomers, mixtures of diastereoisomers, and enantiomers that are RASG12C inhibitors.

[0103] It is also understood that certain compounds of formula (I) or (II) and pharmaceutical salts thereof can exist in solvated and non-solvated forms, for example, hydrated and anhydrous forms. It is also understood that the compounds herein include all such solvated forms. For clarity, this includes both the solvated (e.g., hydrated) form of the free form of the compound and the solvated (hydrated) form of the salt of the compound.

[0104] Some of the compounds of formula (I) or (II) may be crystalline and may have multiple crystal forms.It should be understood that the present disclosure encompasses any crystalline or amorphous form or mixtures thereof that have RASG12C inhibitory activity.It is generally known that crystalline materials can be analyzed using conventional techniques, such as, for example, X-ray powder diffraction (hereinafter, XRPD) analysis and differential scanning calorimetry (DSC).

[0105] Formula (I) or (II) described herein is intended to include all isotopes of its constituent atoms. For example, H (or hydrogen) is 1 H, 2 H(D) and 3 H(T), and C includes all isotopic forms of hydrogen, such as 12 C. 13 C and14 C includes all isotopic forms of carbon, and O includes 16 O. 17 O and 18 O includes all isotopic forms of oxygen, such as N 13 N, 14 N and 15 N includes all isotopic forms of nitrogen, such as F, 19 F and 18 In one embodiment, the compounds of formula (I) or (II) contain isotopes of the atoms contained therein in amounts corresponding to their natural abundance. However, in certain cases, it may be desirable to enrich one or more atoms with a particular isotope that may normally be present in a lower abundance. For example, 1 H is typically present in greater than 99.98% abundance, however, in one aspect, the compounds of any formula provided herein may have at least one H at one or more positions where H is present. 2 H or 3 H. In another embodiment, the compounds of any of the formulae presented herein can be enriched with radioactive isotopes, e.g. 3 H and 14 When enriched in C, the compounds may be useful in drug and / or substrate tissue distribution assays. It is to be understood that the present application encompasses all such isotopic forms.

[0106] In the following, preferred modes for carrying out the present disclosure will be described. The embodiments described below are merely provided to illustrate examples of typical embodiments of the present disclosure, and are not intended to limit the scope of the present disclosure.

[0107] 1. Antibody-drug conjugates The antibody-drug conjugate used in the present disclosure is an antibody-drug conjugate in which the antibody is an anti-HER2 antibody conjugated to a drug by a linker. The anti-HER2 antibody-drug conjugate used in the present disclosure is not particularly limited and may be selected from the list including, for example, trastuzumab deruxtecan, trastuzumab emtansine, trastuzumab duocarmazine (SYD985), A166, XMT-1522, RC48, ALT-P7, ARX788, PF-06804103, MRG002, ZW49 and BDC-1001. Preferably, the antibody-drug conjugate used in the present disclosure has the following formula: [ka] (wherein A represents the attachment position to the antibody). is conjugated to the anti-HER2 antibody via a thioether bond (e.g., trastuzumab deruxtecan). Alternatively, the antibody-drug conjugate can be trastuzumab emtansine (T-DM1).

[0108] In the present disclosure, the partial structure consisting of a linker and a drug in an antibody-drug conjugate is referred to as a "drug-linker". This drug-linker can be connected to a thiol group (in other words, a sulfur atom of a cysteine ​​residue) formed at an interchain disulfide bond site (two sites between heavy chains and two sites between heavy and light chains) in an antibody.

[0109] For example, the drug-linker 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, (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, which is a topoisomerase I inhibitor. Exatecan is a camptothecin derivative with antitumor activity and has the following formula: [ka] It is represented by:

[0110] A preferred anti-HER2 antibody-drug conjugate for use in the present disclosure has the following formula: [ka] It can also be represented by:

[0111] Here, the drug-linker is conjugated to the anti-HER2 antibody ("antibody-") via a thioether bond. The meaning of n is the same as that of what is referred to as the average number of drug molecules conjugated (DAR; drug-antibody ratio), which indicates the average number of drug-linker units conjugated per antibody molecule.

[0112] After entry into the cancer cell, the preferred anti-HER2 antibody-drug conjugate (e.g., trastuzumab deruxtecan) is cleaved at the linker moiety to yield the following formula: [ka] The compound may be released from the reaction.

[0113] This compound is presumed to be the original source of the antitumor activity of preferred anti-HER2 antibody-drug conjugates (e.g., trastuzumab deruxtecan) and has 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).

[0114] Trastuzumab deruxtecan, a preferred anti-HER2 antibody-drug conjugate, is known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046). This bystander effect is exerted throughout the process whereby the antibody-drug conjugate used in the present disclosure is internalized into cancer cells expressing the target, and the released compound then exerts an anti-tumor effect on cancer cells in the vicinity that do not express the target. This bystander effect can also be exerted as a superior anti-tumor effect when the anti-HER2 antibody-drug conjugate is used in combination with a RASG12C inhibitor according to the present disclosure.

[0115] In alternative embodiments, the antibody-drug conjugate may include as a component a maytansinoid such as mertansine (DM1) or another microtubule inhibitor. In certain embodiments, the maytansinoid may be linked to the antibody via a non-cleavable thioether linker such as succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). In other embodiments, the antibody-drug conjugate may include as a component a DNA alkylating agent (e.g., duocarmycin), an auristatin derivative (e.g., duostatin-5, monomethylauristatin E (MMAE), or AUR-06380101), a tubulin inhibitor (e.g., AS269), or a TLR 7 / 8 agonist.

[0116] 2. Antibodies in antibody-drug conjugates The anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure can be derived from any species, and is preferably an anti-HER2 antibody derived from human, rat, mouse or rabbit.If the antibody is derived from a species other than human, it is preferably chimerized or humanized using well-known techniques.The anti-HER2 antibody can be a polyclonal antibody or a monoclonal antibody, and is preferably a monoclonal antibody.

[0117] The antibody in the antibody-drug conjugate used in the present disclosure is preferably an anti-HER2 antibody having the property of being able to target cancer cells, and is preferably an antibody having, for example, the property of recognizing cancer cells, the property of binding to cancer cells, the property of being internalized into cancer cells, and / or cytocidal activity against cancer cells.

[0118] The binding activity of anti-HER2 antibody to cancer cells can be confirmed using flow cytometry. The internalization of antibody into cancer cells can be confirmed using: (1) visualization assay of antibody incorporated into cells under a fluorescent microscope using a secondary antibody (fluorescently labeled) that binds to therapeutic antibody (Cell Death and Differentiation (2008) 15, 751-761); (2) measurement of fluorescence intensity incorporated into cells using a secondary antibody (fluorescently labeled) that binds to therapeutic antibody (Molecular Biology of the Cell, Vol. 15, 5268-5282, December 2004); or (3) Mab-ZAP assay using an immunotoxin that binds to therapeutic antibody, which is released when incorporated into cells and inhibits cell growth (Bio Techniques 28: 162-165, January 2000). Recombinant complex protein of diphtheria toxin catalytic domain and protein G can be used as immunotoxin.

[0119] The antitumor activity of anti-HER2 antibody can be confirmed in vitro by measuring the inhibitory activity against cell growth.For example, a cancer cell line that overexpresses HER2 as the target protein of the antibody is cultured, and the antibody is added to the culture system at various concentrations to measure the inhibitory activity against foci formation, colony formation and spheroid growth.For example, the antibody can be administered to nude mice transplanted with a cancer cell line that expresses a large amount of the target protein, and the antitumor activity can be confirmed in vivo by measuring the change in the cancer cells.

[0120] Since a compound exerting an antitumor effect is bound to the anti-HER2 antibody-drug conjugate, it is preferable but not essential that the anti-HER2 antibody itself has an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxic activity of the antitumor compound against cancer cells, it is important and preferable that the anti-HER2 antibody has the property of being internalized and transferred into tumor cells.

[0121] The anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure can be obtained by procedures known in the art. For example, the antibody of the present disclosure can be obtained using the method usually performed in the art, which involves immunizing an animal with an antigenic polypeptide, and collecting and purifying the antibody produced in vivo. The origin of the antigen is not limited to human, and animals can be immunized with antigens derived from non-human animals such as mice and rats. In this case, the cross-reactivity of the obtained antibody that binds to the heterologous antigen and human antigen can be tested to screen for antibodies that are applicable to human diseases.

[0122] Alternatively, antibody-producing cells that produce antibodies against an antigen can be fused with myeloma cells according to methods known in the art (e.g., Kohler and Milstein, Nature (1975) 256, p. 495-497; and Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, NY (1980)) to establish hybridomas from which monoclonal antibodies can then be obtained.

[0123] Antigens can be obtained by genetically engineering host cells to produce genes encoding antigenic proteins. Specifically, a vector capable of expressing an antigenic gene is prepared and introduced into a host cell to express the gene. The antigen thus expressed can be purified. Antibodies can also be obtained by immunizing animals with the above genetically engineered antigen-expressing cells or cell lines expressing the antigen.

[0124] The anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure is preferably a recombinant antibody obtained by artificial modification for the purpose of reducing heterologous antigenicity to humans, such as a chimeric antibody or a humanized antibody, or preferably an antibody having only the gene sequence of an antibody derived from a human (i.e., a human antibody). These antibodies can be produced using known methods.

[0125] An example of a chimeric antibody is an antibody whose variable and constant regions are derived from different species, for example, a chimeric antibody in which the variable region of an antibody derived from a mouse or rat is joined to a constant region derived from a human (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0126] Examples of humanized antibodies include antibodies obtained by incorporating only the complementarity determining regions (CDRs) of a heterologous antibody into a human-derived antibody (Nature (1986) 321, pp. 522-525), antibodies obtained by grafting a portion of the amino acid residues of the framework of a heterologous antibody and the CDR sequence of the heterologous antibody into a human antibody by a CDR grafting method (WO 90 / 07861), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Pat. No. 5,821,337).

[0127] An example of a human antibody is an antibody produced by using a human antibody-producing mouse having a human chromosome fragment containing the heavy and light chain genes of a human antibody (see, for example, 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). Alternatively, examples include antibodies obtained by phage display and antibodies selected from human antibody libraries (see Wormstone, I Met. 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.).

[0128] The present disclosure also includes modified variants of the anti-HER2 antibody in the antibody-drug conjugate used in the present disclosure. The modified variant refers to a variant obtained by subjecting the antibody according to the present disclosure to chemical or biological modification. Examples of chemically modified variants include: variants including linking a chemical moiety to an amino acid backbone, variants including linking a chemical moiety to an N-linked or O-linked carbohydrate chain, etc. Examples of biologically modified variants include: variants obtained by post-translational modification (e.g., N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, aspartic acid isomerization, or methionine oxidation) and variants that have been expressed in a prokaryotic host cell to add a methionine residue to the N-terminus. In addition, the modified variant also includes antibodies labeled to allow detection or isolation of the antibody or antigen according to the present disclosure (e.g., enzyme-, fluorescently, and affinity-labeled antibodies). Such engineered variants of the antibodies of the present disclosure are useful for improving the stability and blood retention of the antibody, reducing its antigenicity, detecting or isolating the antibody or antigen, and the like.

[0129] Furthermore, antibody-dependent cellular cytotoxicity activity can be enhanced by regulating the modification (glycosylation, defucosylation, etc.) of the glycan linked to the antibody according to the present disclosure. Techniques for regulating the modification of the glycan of an antibody are known, such as those disclosed in International Publication Nos. 99 / 54342, 00 / 61739, 02 / 31140, 2007 / 133855, and 2013 / 120066. However, this technique is not limited thereto. Anti-HER2 antibodies according to the present disclosure also include antibodies in which the modification of the glycan is regulated.

[0130] It is known that a lysine residue is deleted at the carboxyl terminus of the heavy chain of an antibody produced in cultured mammalian cells (Journal of Chromatography A, 705:129-134 (1995)) and that two amino acid residues (glycine and lysine) are deleted at the carboxyl terminus of the heavy chain of an antibody produced in cultured mammalian cells, and that a proline residue newly positioned at this 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 functions (complement activation, antibody-dependent cellular cytotoxicity, etc.) of the antibody. Therefore, the anti-HER2 antibody according to the present disclosure includes such modified antibodies and functional fragments of the antibodies, including 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 is 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 according to the present disclosure is not limited to the above variants, as long as the antigen-binding affinity and effector function are preserved. The two heavy chains constituting the antibody according to the present disclosure may be one type selected from the group consisting of a full-length heavy chain and the above deletion variants, or two types in a combination selected therefrom. The ratio of the amount of each deletion variant may be influenced by the type of cultured mammalian cells producing the anti-HER2 antibody according to the present disclosure and the culture conditions. However, an antibody according to the present disclosure in which one amino acid residue is deleted at the carboxyl terminus of both of the two heavy chains may be a preferred example.

[0131] Typical examples of the isotype of the anti-HER2 antibody according to the present disclosure include IgG (IgG1, IgG2, IgG3, IgG4), and preferred examples include IgG1 or IgG2.

[0132] In this disclosure, the term "anti-HER2 antibody" refers to an antibody that specifically binds to HER2 (human epidermal growth factor receptor type 2; ErbB-2) and preferably has internalization activity in HER2-expressing cells upon binding to HER2.

[0133] Examples of anti-HER2 antibodies include trastuzumab (US Pat. No. 5,821,337) and pertuzumab (WO 01 / 00245), with trastuzumab being a preferred example. In alternative embodiments, the anti-HER2 antibody may be selected from the list including hertuzumab, HT-19, MAB802 and ZW25.

[0134] 3. Preparation of Antibody-drug Conjugates A preferred drug-linker intermediate for use in the preparation of an anti-HER2 antibody-drug conjugate according to the present disclosure has the following formula: [ka] It is represented by:

[0135] This drug-linker intermediate has 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] glycinamide, and can be produced with reference to the descriptions in International Publication Nos. 2014 / 057687, 2015 / 098099, 2015 / 115091, 2015 / 155998, and 2019 / 044947, etc.

[0136] A preferred anti-HER2 antibody-drug conjugate (e.g., trastuzumab deruxtecan) can be prepared by reacting the drug-linker intermediate described above with an anti-HER2 antibody bearing a thiol group (also called a sulfhydryl group).

[0137] Anti-HER2 antibodies having sulfhydryl groups can be obtained by methods well known in the art (Hermanson, GT, Bioconjugate Techniques, pp.56-136, pp.456-493, Academic Press (1996)). For example, an anti-HER2 antibody having a sulfhydryl group with a partially or completely reduced interchain disulfide in the antibody can be obtained by reacting the antibody with a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in an amount of 0.3 to 3 molar equivalents per interchain disulfide in the antibody in a buffer containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA).

[0138] Furthermore, by using 2-20 molar equivalents of drug-linker intermediate per anti-HER2 antibody bearing a sulfhydryl group, anti-HER2 antibody-drug conjugates in which 2-8 drug molecules are conjugated per antibody molecule can be produced.

[0139] The average number of drug molecules conjugated per anti-HER2 antibody molecule of the produced antibody-drug conjugate can be determined, for example, by a calculation method based on measurement of UV absorption for the antibody-drug conjugate and its conjugation precursor at two wavelengths, 280 nm and 370 nm (UV method), or by a calculation method based on quantification through HPLC measurement of fragments obtained by treating the antibody-drug conjugate with a reducing agent (HPLC method).

[0140] Conjugation of an anti-HER2 antibody with a drug-linker intermediate and calculation of the average number of drug molecules conjugated per antibody molecule of an antibody-drug conjugate may be performed with reference to the descriptions in, for example, WO 2014 / 057687, WO 2015 / 098099, WO 2015 / 115091, WO 2015 / 155998, WO 2017 / 002776, and WO 2018 / 212136.

[0141] In this disclosure, the term "anti-HER2 antibody-drug conjugate" refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present disclosure is an anti-HER2 antibody.

[0142] The anti-HER2 antibody preferably comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence of amino acid residues 26 to 33 of SEQ ID NO: 1, CDRH2 consisting of the amino acid sequence of amino acid residues 51 to 58 of SEQ ID NO: 1, and CDRH3 consisting of the amino acid sequence of amino acid residues 97 to 109 of SEQ ID NO: 1, and a light chain comprising CDRL1 consisting of the amino acid sequence of amino acid residues 27 to 32 of SEQ ID NO: 2, CDRL2 consisting of the amino acid sequence of amino acid residues 50 to 52 of SEQ ID NO: 2, and CDRL3 consisting of the amino acid sequence of amino acid residues 89 to 97 of SEQ ID NO: 2. The antibody is preferably an antibody comprising a heavy chain having a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 1 and a light chain having a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 2, and more preferably an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2, or an antibody comprising a heavy chain consisting of amino acid residues 1 to 449 of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 2.

[0143] The average number of drug-linker units conjugated per antibody molecule in the anti-HER2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, even more preferably 7.5 to 8, and even more preferably about 8.

[0144] A preferred anti-HER2 antibody-drug conjugate for use in the present disclosure can be produced by referring to the descriptions in WO 2015 / 115091, etc.

[0145] In a preferred embodiment, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) or trastuzumab emtansine (T-DM1), preferably trastuzumab deruxtecan.

[0146] 4. RASG12C inhibitors In the present disclosure, the term "RASG12C inhibitor" refers to a compound that inhibits G12C mutant Ras protein (e.g., protein encoded by KRAS, NRAS or HRAS gene, preferably protein encoded by KRAS gene). Preferred examples of RASG12C inhibitors may include those disclosed herein.

[0147] Examples of RASG12C inhibitors that may be used in accordance with the present disclosure include compounds of formula (I) disclosed in WO 2019 / 215203 (e.g., Compound A) and compounds disclosed in WO 2019 / 099524, WO 2020 / 178282, WO 2021 / 118877 and WO 2021 / 245051. Further examples include compounds named LY3537982 (Loxo / Lilly), AZD4625 (AstraZeneca), AMG510 (sotorasib: Amgen), MRTX849 (adagrasib: Mirati), JDQ443 (Novartis), GDC-6036 (Genentech), BI 1,823,911 (Boehringer Ingelheim), D1553 (InventisBio) and JNJ-74699157 (Johnson and Johnson). Preferably, the RASG12C inhibitor used has physicochemical properties that allow it to cross the blood-brain barrier.

[0148] Thus, in a preferred embodiment of the RASG12C inhibitor used in the present disclosure, the RASG12C inhibitor has the following formula (I): [ka] (In the formula, A is phenyl or a bicyclic heteroaryl group; X and Y are connected by a double bond, and i) X is CR 7 and Y is CR 8 or ii) X is N and Y is CR 8 or iii) X is CR 7 and Y is N, or X and Y are both C(O)NR 9 or X and Y are adjacent ring atoms of an optionally substituted 5- or 6-membered N-heterocycle that is fused to an aromatic ring substituted with Z, and X and Y are both C or C and N; Z is O, NH or NMe; R 1 is independently selected from F, Cl, Br, OH, CHOH, OMe, CHOMe, C1-C3 alkyl, and C1-C3 fluoroalkyl, and n is 0, 1, 2, or 3; R 2 is H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe or OEt; R 3a and R 3b are both =O or R 3a and R 3b is H, R 4 is H or Me, R 5 is H or Me, R 6 is H or CH2NMe2, R 7 and R 8 are independently selected from H, F, Cl, CCH, CC(C1-C3 alkyl), CCCH2NMe2, CCCH2O(C1-C3 alkyl), CN, Me, C1-C6 alkyl, OH, OMe, O(C1-C3 alkyl), O(C1-C3 deuteroalkyl), O(C1-C3 fluoroalkyl), O(C3-C6 cycloalkyl), C1-C3 fluoroalkyl, OCH2CH2NMe2, OCH2CH2OMe, CHOMe, OCH2CH2N(CH2CH2)2CH, OCH2CH2N(CH2CH2)2O, OCH2CH2(2-pyridyl) or an optionally substituted 3-, 4-, 5- or 6-membered carbocyclic or heterocyclic ring; R 7 and R 8 are joined to form an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring; R 9 is selected from H, Me, Et, C3H7 and C1-C3 fluoroalkyl or a pharma- ceutically acceptable salt thereof.

[0149] In another embodiment, the RASG12C inhibitor is represented by formula (I), 7 and Y is CR 8 or ii) X is N and Y is CR 8 or iii) X is CR 7 and Y is N. In another embodiment, the RASG12C inhibitor is a compound of formula (I) where Z is O. In another embodiment, the RASG12C inhibitor is a compound of formula (I) where R 3a and R 3b In another embodiment, the RASG12C inhibitor is a compound of formula (I), 4 In another embodiment, the RASG12C inhibitor is a compound of formula (I), 6 is H. In another embodiment, the RASG12C inhibitor is a compound of formula (I) where A is phenyl.

[0150] In another embodiment, the RASG12C inhibitor is (12aS)-2-Acryloyl-10-chloro-9-(5-methyl-1H-indazol-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one; 1-((12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-Chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; (12aR)-10-Chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-((12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-Chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-7-carbonitrile; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; (12aR)-10-Chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 8-[(12aR)-10-chloro-8-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-9-yl]-7-methylisoquinolin-1(2H)-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aS)-10-Chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepin-6(2H)-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aS)-10-Chloro-11-methyl-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepin-6(2H)-one; 1-[(12aR)-10-chloro-9-(2,3-difluoro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-Chloro-9-(2-hydroxy-6-methylphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-[2-fluoro-6-(hydroxymethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-[2-hydroxy-6-(trifluoromethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-ethyl-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-[2-(difluoromethyl)-6-hydroxyphenyl]-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; (12aR)-10-Chloro-9-(2-chloro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-10-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-10-ethynyl-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-ethynyl-8-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-1-one; 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-1-one; 1-[(8aR)-6-chloro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydro-14H-pyrazino[2,1-c][1,2,4]triazolo[4',3':1,2]pyrido[3,4-f][1,4]oxazepin-10(8H)-yl]prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazol-9(7H)-yl]prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazol-9(7H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-10-chloro-8-ethynyl-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-chloro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydroimidazo[4,5-g]pyrazino[2,1-c][1,4]benzoxazepin-9(7H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-methyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-7,8-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-7,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropyloxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridin-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(2-methoxyethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidin-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( 2 H3methyloxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(methoxymethyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-7-[2-(dimethylamino)ethoxy]-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(prop-1-yn-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; and 1-((6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl)prop-2-en-1-one; or Pharmaceutically acceptable salts thereof is a compound of formula (I) selected from:

[0151] In another embodiment, the RASG12C inhibitor is a compound of formula (I) which is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one.

[0152] In another embodiment, the RASG12C inhibitor is a compound of formula (I) which is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one.

[0153] In another preferred embodiment of the RASG12C inhibitor used in the present disclosure, the RASG12C inhibitor is represented by the following formula (II): [ka] (In the formula, Ring A is selected from phenyl and bicyclic heteroaryl; R 1 In each occurrence, C 1~4 Alkyl, halo, hydroxy, C 1~4 Alkoxy, C 1~3 Fluoroalkyl, C 1~3 independently selected from fluoroalkoxy, cyano, and acetylenyl; b is 0, 1, 2 or 3; Y is CH2 or CH2CH2, R 2 Cyano, halo, C 1~4 Alkyl, C 1~4 Alkoxy or C 1~3 is a fluoroalkyl; R 3 is F, Me, Et, MeO or C 1~2 is a fluoroalkyl; R 4 is H or Me, R 5 is H or Me, R 6 is H or CH2NMe2) or a pharma- ceutically acceptable salt thereof, wherein Y is CH2 and R 2 is Cl, and R 3 is F, A is phenyl, b is 2, and R 1When the groups are F and OH and are respectively ortho to the biaryl bond and R 4 and R 6 If both are H, then R 5 is Me.

[0154] In one embodiment, the RASG12C inhibitor has the structure: [ka] The compound of formula (II) has the structure:

[0155] In another embodiment, the RASG12C inhibitor is a compound of formula (II), wherein ring A is: [ka] is a compound of formula (II) selected from the group consisting of:

[0156] In another embodiment, the RASG12C inhibitor is a compound of formula (II) 4 is H. In another embodiment, the RASG12C inhibitor is a compound of formula (II) wherein R 6 In another embodiment, the RASG12C inhibitor is a compound of formula (II) where R is H. In another embodiment, the RASG12C inhibitor is a compound of formula (II) where Y is CH. In another embodiment, the RASG12C inhibitor is a compound of formula (II) where Y is CHCH. In another embodiment, the RASG12C inhibitor is a compound of formula (II) where R is H. 2 In another embodiment, the RASG12C inhibitor is a compound of formula (II) wherein R 3 is F. In another embodiment, the RASG12C inhibitor is a compound of formula (II) wherein R 4 is H and R 5 is Me,

[0157] In another embodiment, the RASG12C inhibitor is 7-[(8aS)-10-Acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methyl-2,3-dihydro-1H-isoindol-1-one; 1-[(8aS,11R)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-[(8aS,11R)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 5-[(8aS)-10-Acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methylquinazolin-4(3H)-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]isoquinolin-1(2H)-one; 1-[(8aS)-6-chloro-4-fluoro-5-(1H-indazol-3-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-[(8aS)-6-chloro-4-fluoro-5-(2-hydroxy-6-methylphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-1(2H)-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl)prop-2-en-1-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1-methyl-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl)prop-2-en-1-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-fluoroisoquinolin-1(2H)-one; (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 8-[3-chloro-1-fluoro-8-(prop-2-enoyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-2-yl]-7-methylisoquinolin-1(2H)-one; 1-[(6aS,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 1-[(6aR,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 1-[(6aS,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 1-[(8aS)-4-chloro-6-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 8-[(8aS,llR)-6-chloro-4-fluoro-ll-methyl-10-(prop-2-enoyl)-8,8a,9,10,ll,12-hexahydropyrazino, [2',l':3,4][l,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-l(2H)-one; (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; and (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; or Pharmaceutically acceptable salts thereof is a compound of formula (II) selected from

[0158] In a particularly preferred embodiment, the RASG12C inhibitor used in the present disclosure has the following formula: [ka] or a pharma- ceutical acceptable salt thereof.

[0159] In another preferred embodiment, the RASG12C inhibitor used in the present disclosure is AMG510 (sotorasib: Amgen).

[0160] In another preferred embodiment, the RASG12C inhibitor used in the present disclosure is MRTX849 (adagrasib: Mirati).

[0161] In another embodiment, the RASG12C inhibitor used in the present disclosure is 4-[(13aS)-10-chloro-8-fluoro-6-oxo-2-prop-2-enoyl-1,3,4,12,13,13a-hexahydropyrazino[2,ld][1,5]benzoxazocin-9-yl]-2-amino-7-fluoro-benzothiophene-3-carbonitrile.

[0162] 5. Combination of Antibody-Drug Conjugate and RASG12C Inhibitor In a first combination embodiment of the present disclosure, the antibody-drug conjugate combined with a RASG12C inhibitor is an antibody-drug conjugate in which the antibody is an anti-HER2 antibody.

[0163] In one embodiment of the first combination embodiment described above, the antibody-drug conjugate combined with the RASG12C inhibitor is an antibody-drug conjugate, in which the anti-HER2 antibody is an antibody comprising a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, CDRL2 consisting of the amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 7, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 8.

[0164] In another embodiment of the first combination embodiment described above, the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9, and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10.

[0165] In another embodiment of the first combination embodiment described above, the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO:1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:2.

[0166] In another embodiment of the first combination embodiment described above, the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO:11 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:2.

[0167] In another embodiment of the first combination embodiment described above, the antibody-drug conjugate has the following formula: [ka] (wherein A represents the attachment position to the antibody). is conjugated to the anti-HER2 antibody via a thioether bond.

[0168] In another combination embodiment of the disclosure, the antibody-drug conjugate combined with the RASG12C inhibitor is trastuzumab deruxtecan (DS-8201) or trastuzumab emtansine (T-DM1).

[0169] In certain embodiments of each of the above combination embodiments, the antibody-drug conjugate defined for the above combination embodiment has the following formula (I): [ka] (In the formula, A is phenyl or a bicyclic heteroaryl group; X and Y are connected by a double bond, and i) X is CR 7 and Y is CR 8 or ii) X is N and Y is CR 8 or iii) X is CR 7 and Y is N, or X and Y are both C(O)NR 9 or X and Y are adjacent ring atoms of an optionally substituted 5- or 6-membered N-heterocycle that is fused to an aromatic ring substituted with Z, and X and Y are both C or C and N; Z is O, NH or NMe; R 1 is independently selected from F, Cl, Br, OH, CHOH, OMe, CHOMe, C1-C3 alkyl, and C1-C3 fluoroalkyl, and n is 0, 1, 2, or 3; R 2 is H, F, Cl, CCH, CCMe, CN, Br, C1-C3 alkyl, C1-C3 fluoroalkyl, OMe or OEt; R 3a and R 3b are both =O or R 3a and R 3b is H, R 4is H or Me, R 5 is H or Me, R 6 is H or CH2NMe2, R 7 and R 8 are independently selected from H, F, Cl, CCH, CC(C1-C3 alkyl), CCCH2NMe2, CCCH2O(C1-C3 alkyl), CN, Me, C1-C6 alkyl, OH, OMe, O(C1-C3 alkyl), O(C1-C3 deuteroalkyl), O(C1-C3 fluoroalkyl), O(C3-C6 cycloalkyl), C1-C3 fluoroalkyl, OCH2CH2NMe2, OCH2CH2OMe, CH2OMe, OCH2CH2N(CH2CH2)2CH, OCH2CH2N(CH2CH2)2O, OCH2CH2(2-pyridyl) or an optionally substituted 3, 4, 5 or 6 carbocyclic or heterocyclic ring; R 7 and R 8 are joined to form an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring; R 9 is selected from H, Me, Et, C3H7 and C1-C3 fluoroalkyl or a pharma- ceutically acceptable salt thereof.

[0170] In another preferred embodiment, the antibody-drug conjugate defined for the above combination embodiment is a RASG12C inhibitor as defined above, wherein in formula (I) i) X is CR 7 and Y is CR 8 or ii) X is N and Y is CR 8 or iii) X is CR 7 and Y is N. In another embodiment, in formula (I), Z is O. In another embodiment, in formula (I), R 3a and R 3b is H. In another embodiment, in formula (I), R 4is H. In another embodiment, in formula (I), R 6 is H. In another embodiment, in Formula (I), A is phenyl.

[0171] In another combination embodiment, an anti-HER2 antibody-drug conjugate as defined for the above combination embodiment is combined with a RASG12C inhibitor, which RASG12C inhibitor is (12aS)-2-Acryloyl-10-chloro-9-(5-methyl-1H-indazol-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one; 1-((12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-Chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; (12aR)-10-Chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-((12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-Chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-7-carbonitrile; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; (12aR)-10-Chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 8-[(12aR)-10-chloro-8-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-9-yl]-7-methylisoquinolin-1(2H)-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aS)-10-Chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepin-6(2H)-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aS)-10-Chloro-11-methyl-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepin-6(2H)-one; 1-[(12aR)-10-chloro-9-(2,3-difluoro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-Chloro-9-(2-hydroxy-6-methylphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-[2-fluoro-6-(hydroxymethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-[2-hydroxy-6-(trifluoromethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-ethyl-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-[2-(difluoromethyl)-6-hydroxyphenyl]-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; (12aR)-10-Chloro-9-(2-chloro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-10-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-10-ethynyl-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-ethynyl-8-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-1-one; 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-1-one; 1-[(8aR)-6-chloro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydro-14H-pyrazino[2,1-c][1,2,4]triazolo[4',3':1,2]pyrido[3,4-f][1,4]oxazepin-10(8H)-yl]prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazol-9(7H)-yl]prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazol-9(7H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-10-chloro-8-ethynyl-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-chloro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydroimidazo[4,5-g]pyrazino[2,1-c][1,4]benzoxazepin-9(7H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-methyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-7,8-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-7,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropyloxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridin-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(2-methoxyethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidin-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( 2 H3methyloxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(methoxymethyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-7-[2-(dimethylamino)ethoxy]-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(prop-1-yn-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; and 1-((6aR)-4-Chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl)prop-2-en-1-one or a pharma- ceutically acceptable salt thereof.

[0172] In another combination embodiment, the RASG12C inhibitor is a compound of formula (I) which is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one.

[0173] In another combination embodiment, the RASG12C inhibitor is a compound of formula (I) which is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one.

[0174] In another embodiment of each of the above combination embodiments, the antibody-drug conjugate defined for the above combination embodiment has the following formula (II): [ka] (In the formula, Ring A is selected from phenyl and bicyclic heteroaryl; R 1 In each occurrence, C 1~4Alkyl, halo, hydroxy, C 1~4 Alkoxy, C 1~3 Fluoroalkyl, C 1~3 independently selected from fluoroalkoxy, cyano, and acetylenyl; b is 0, 1, 2 or 3; Y is CH2 or CH2CH2, R 2 Cyano, halo, C 1~4 Alkyl, C 1~4 Alkoxy or C 1~3 is a fluoroalkyl; R 3 is F, Me, Et, MeO or C 1~2 is a fluoroalkyl; R 4 is H or Me, R 5 is H or Me, R 6 is H or CH2NMe2) or a pharma- ceutically acceptable salt thereof, wherein Y is CH2 and R 2 is Cl, and R 3 is F, A is phenyl, b is 2, and R 1 When the groups are F and OH and are respectively ortho to the biaryl bond and R 4 and R 6 If both are H, then R 5 is combined with a RASG12C inhibitor, which is a compound, or a pharma- ceutically acceptable salt thereof, wherein Me is

[0175] In another combination embodiment, the antibody-drug conjugate defined for the above combination embodiment has the structure: [ka] in combination with a RASG12C inhibitor as defined above,

[0176] In another combination embodiment, the antibody-drug conjugate defined for the above combination embodiment is a RASG12C inhibitor as defined above, wherein in formula (II), ring A is [ka] and in combination with a RASG12C inhibitor selected from the group consisting of:

[0177] In another combination embodiment, the antibody-drug conjugate defined for the above combination embodiment is a RASG12C inhibitor as defined above, wherein R 4 is combined with a RASG12C inhibitor, wherein R is H. In another embodiment, 6 In another embodiment, in formula (II), Y is H. In another embodiment, in formula (II), Y is CH. In another embodiment, in formula (II), R 2 In another embodiment, in formula (II), R 3 is F. In another embodiment, in formula (II), R 4 is H and R 5 is Me.

[0178] In another combination embodiment, the anti-HER2 antibody-drug conjugate defined for the above combination embodiment is a RASG12C inhibitor, 7-[(8aS)-10-Acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methyl-2,3-dihydro-1H-isoindol-1-one; 1-[(8aS,11R)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-[(8aS,11R)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-11-methyl-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 5-[(8aS)-10-Acryloyl-6-chloro-4-fluoro-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-6-methylquinazolin-4(3H)-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]isoquinolin-1(2H)-one; 1-[(8aS)-6-chloro-4-fluoro-5-(1H-indazol-3-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-[(8aS)-6-chloro-4-fluoro-5-(2-hydroxy-6-methylphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-1(2H)-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl)prop-2-en-1-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-((8aS)-6-chloro-4-fluoro-5-(5-fluoro-1-methyl-1H-benzo[d]imidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl)prop-2-en-1-one; 1-[(8aS)-6-chloro-4-fluoro-5-(5-fluoro-1H-benzotriazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 8-[(8aS)-6-chloro-4-fluoro-10-(prop-2-enoyl)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-fluoroisoquinolin-1(2H)-one; (2E)-1-[(8aS)-6-chloro-4-fluoro-5-(5-methyl-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 1-[(6aR,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 8-[3-chloro-1-fluoro-8-(prop-2-enoyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-2-yl]-7-methylisoquinolin-1(2H)-one; 1-[(6aS,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 1-[(6aR,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 1-[(6aS,9S)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one; 1-[(8aS)-4-chloro-6-fluoro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]prop-2-en-1-one; 8-[(8aS,llR)-6-chloro-4-fluoro-ll-methyl-10-(prop-2-enoyl)-8,8a,9,10,ll,12-hexahydropyrazino, [2',l':3,4][l,4]oxazepino[5,6,7-de]quinazolin-5-yl]-7-methylisoquinolin-l(2H)-one; (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-benzimidazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; and (2E)-1-[(8aS,11R)-6-chloro-4-fluoro-11-methyl-5-(5-methyl-1H-indazol-4-yl)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-10(8H)-yl]-4-(dimethylamino)but-2-en-1-one; or Pharmaceutically acceptable salts thereof is combined with a RASG12C inhibitor which is a compound of formula (II) selected from:

[0179] In another combination embodiment, the anti-HER2 antibody-drug conjugate defined for the above combination embodiment is a RASG12C inhibitor having the following formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0180] In another combination embodiment, an anti-HER2 antibody-drug conjugate as defined for the above combination embodiments is combined with a RASG12C inhibitor selected from LY3537982 (Loxo / Lilly), AZD4625 (AstraZeneca), AMG510 (sotorasib: Amgen), MRTX849 (adagrasib: Mirati), JDQ443 (Novartis), GDC-6036 (Genentech), BI 1,823,911 (Boehringer Ingelheim), D1553 (InventisBio) and JNJ-74699157 (Johnson and Johnson).

[0181] In another combination embodiment, an anti-HER2 antibody-drug conjugate as defined for the combination embodiments above is combined with a RASG12C inhibitor, which is AMG510 (sotorasib).

[0182] In another combination embodiment, an anti-HER2 antibody-drug conjugate as defined above is combined with a RASG12C inhibitor, which is MRTX849 (adagrasib).

[0183] In a particularly preferred combination embodiment of the disclosure, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) and the RASG12C inhibitor is of the following formula: [ka] The compound is represented by the formula (also identified as Compound A):

[0184] In another particularly preferred combination embodiment of the present disclosure, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) and the RASG12C inhibitor is AMG510 (sotorasib).

[0185] In another particularly preferred combination embodiment of the present disclosure, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) and the RASG12C inhibitor is MRTX849 (adagrasib).

[0186] 6. Therapeutic combinations and treatment methods Medicaments and therapeutic uses and methods are described below, in which an anti-HER2 antibody-drug conjugate according to the present disclosure and a RASG12C inhibitor are administered in combination.

[0187] The pharmaceutical agents and therapeutic uses and methods of the present disclosure may be characterized in that the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor are contained separately as active ingredients in different formulations and administered at the same time or at different times, or in that the antibody-drug conjugate and the RASG12C inhibitor are contained as active ingredients in a single formulation and administered.

[0188] In the pharmaceutical agents and treatment methods of the present disclosure, a single RASG12C inhibitor used in the present disclosure may be administered in combination with an anti-HER2 antibody-drug conjugate, or two or more different RASG12C inhibitors may be administered in combination with an antibody-drug conjugate.

[0189] The medicaments and therapeutic methods of the present disclosure may be used to treat cancer, preferably breast cancer (including triple negative breast cancer and luminal breast cancer), gastric cancer (also known as gastric adenocarcinoma), colorectal cancer (also known as colon and rectal cancer, including colon and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer), esophagogastric junction adenocarcinoma, biliary tract cancer (including cholangiocarcinoma) Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumors, It may be used to treat at least one cancer selected from the group consisting of cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma and melanoma, and more preferably may be used to treat at least one cancer selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer (preferably non-small cell lung cancer), pancreatic cancer, ovarian cancer, prostate cancer and kidney cancer.

[0190] The presence or absence of the HER2 tumor marker can be determined, for example, by taking tumor tissue from a cancer patient and preparing a formalin-fixed, paraffin-embedded (FFPE) specimen and subjecting the specimen to testing for the gene product (protein) using, for example, immunohistochemistry (IHC), flow cytometry or Western blot techniques, or testing for gene transcription using, for example, in situ hybridization (ISH), quantitative PCR (q-PCR) or microarray analysis, or by taking cell-free circulating tumor DNA (ctDNA) from a cancer patient and subjecting the ctDNA to testing using methods such as next generation sequencing (NGS).

[0191] The medicaments and treatment methods of the disclosure may be used for HER2-expressing cancers, which may be HER2-overexpressing cancers (high or moderate) or HER2-low expressing cancers.

[0192] In the present disclosure, the term "HER2 overexpressing cancer" is not particularly limited, as long as it is recognized by those skilled in the art as a HER2 overexpressing cancer.Preferred examples of HER2 overexpressing cancer may include cancer that has a score of 3+ for HER2 expression by IHC method and cancer that has a score of 2+ for HER2 expression by IHC method and is determined to be positive for HER2 expression by in situ hybridization method (ISH).The in situ hybridization method of the present disclosure includes fluorescent in situ hybridization method (FISH) and dual color in situ hybridization method (DISH).

[0193] In the present disclosure, the term "HER2 low-expressing cancer" is not particularly limited, as long as it is recognized as a HER2 low-expressing cancer by those skilled in the art.Preferred examples of HER2 low-expressing cancer include cancer that is assigned a score of 2+ for HER2 expression by IHC method and determined to be negative for HER2 expression by in situ hybridization method, and cancer that is assigned a score of 1+ for HER2 expression by IHC method.

[0194] The method of scoring the degree of HER2 expression by the IHC method or the method of determining whether HER2 expression is positive or negative by the in situ hybridization method is not particularly limited, as long as it is recognized by those skilled in the art. An example of this method may be the method described in the 4th edition of the guidelines for HER2 testing, breast cancer (edited by the Japanese Pathology Board for Optimal Use of HER2 for Breast Cancer).

[0195] The cancer (particularly with respect to the treatment of breast cancer) may be a HER2 overexpressing (high or moderate) or low expressing breast cancer or a triple negative breast cancer, and / or may have a HER2 status score of IHC 3+, IHC 2+, IHC 1+ or IHC>0 and <1+.

[0196] The pharmaceutical agents and treatment methods of the present disclosure are preferably used in mammals, and more preferably in humans.

[0197] The antitumor effect of the pharmaceutical agent and the treatment method of the present disclosure can be confirmed by preparing a model by transplanting cancer cells into a test animal and measuring the reduction in tumor burden or the life-prolonging effect by applying the pharmaceutical agent and the treatment method of the present disclosure.The effect of the combined use of the antibody-drug conjugate used in the present disclosure and the RASG12C inhibitor can then be confirmed by comparing the antitumor effect with the single administration of the antibody-drug conjugate used in the present disclosure and the single administration of the RASG12C inhibitor.

[0198] The antitumor effects of the pharmaceutical agents and treatment methods disclosed herein may be confirmed in clinical trials using any of the Response Evaluation Criteria in Solid Tumors (RECIST), WHO evaluation method, Macdonald evaluation method, weight measurement, and other approaches, and may be determined based on indicators such as complete response (CR), partial response (PR), progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival (PFS), and overall survival rate (OS).

[0199] By using the above method, the superiority of the antitumor effects of the pharmaceutical agents and therapeutic methods of the present disclosure over existing pharmaceutical agents and therapeutic methods for the treatment of cancer can be confirmed.

[0200] The pharmaceuticals and treatment methods of the present disclosure can delay the development of cancer cells, inhibit their growth, and even kill cancer cells. These effects can eliminate symptoms caused by cancer in cancer patients, or achieve an improvement in the quality of life (QOL) of cancer patients, and achieve a therapeutic effect by preserving the life of cancer patients. Even if the pharmaceuticals and treatment methods of the present disclosure do not complete the death of cancer cells, they can achieve a higher QOL for cancer patients while achieving longer survival by inhibiting or regulating the growth of cancer cells.

[0201] The pharmaceutical agents of the present disclosure are expected to exert a therapeutic effect when administered to patients as systemic therapy, as well as by local application to cancer tissue.

[0202] In another aspect, the pharmaceutical agent and method of treatment of the present disclosure provide for use as an adjunct to cancer treatment using ionizing radiation or other chemotherapeutic agents. For example, in the treatment of cancer, the treatment may include administering to a subject in need of treatment an effective amount of the pharmaceutical agent, either simultaneously or sequentially with ionizing radiation or other chemotherapeutic agents.

[0203] The pharmaceuticals and treatment methods of the present disclosure can be used as adjuvant chemotherapy in combination with surgery. The pharmaceuticals of the present disclosure can be administered before surgery to reduce tumor size (referred to as pre-operative adjuvant chemotherapy or neo-adjuvant therapy), or after surgery to prevent tumor recurrence (referred to as post-operative adjuvant chemotherapy or adjuvant therapy).

[0204] In some embodiments, the cancer cells may have a BRCA1 and / or BRCA2 deficient phenotype, i.e., the cancer cells have reduced or absent BRCA1 and / or BRCA2 activity. Cancer cells with this phenotype may be BRCA1 and / or BRCA2 deficient, i.e., the expression and / or activity of BRCA1 and / or BRCA2 may be reduced or absent in the cancer cells, for example, due to a mutation or polymorphism in the encoding nucleic acid or an amplification, mutation or polymorphism in a gene encoding a regulator (e.g., the EMSY gene encoding the BRCA2 regulator) (Hughes-Davies, et al., Cell, 115, 523-535). BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers (Jasin M., Oncogene, 21(58), 8981-93 (2002); Tutt, et al., Trends Mol Med., 8(12), 571-6, (2002)). The association of mutations in BRCA1 and / or BRCA2 with breast cancer has been well characterized in the art (Radice, PJ, Exp Clin Cancer Res., 21(3 Suppl), 9-12 (2002)). Amplification of the EMSY gene, which encodes a BRCA2 binding factor, is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at increased risk of certain cancers, including breast, ovarian, pancreatic, prostate, hematological, gastrointestinal and lung cancers. In some embodiments, the individual is heterozygous for one or more variations (eg, mutations and polymorphisms) in BRCA1 and / or BRCA2 or regulators thereof.Detection of variations in BRCA1 and BRCA2 is known in the art and is described, for example, in EP 699754, EP 705903, Neuhausen, SL and Ostrander, EA, Genet. Test, 1, 75-83 (1992); Chappnis, PO and Foulkes, WO, Cancer Treat Res, 107, 29-59 (2002); Janatova M., et al., Neoplasma, 50(4), 246-505 (2003); Jancarkova, N., Ceska Gynekol., 68{1), 11-6 (2003)). Determination of amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies, et al., Cell, 115, 523-535).

[0205] Cancer-associated mutations and polymorphisms can be detected at the nucleic acid level, by detecting the presence of a variant nucleic acid sequence, or at the protein level, by detecting the presence of a variant (i.e. mutant or allelic variant) polypeptide.

[0206] The pharmaceutical preparation of the present disclosure may be administered containing at least one pharma- ceutical suitable component. The pharma-ceutical suitable component may be suitably selected from formulation additives generally used in the art according to the dosage, administration concentration, etc. of the antibody-drug conjugate and RASG12C inhibitor used in the present disclosure. The anti-HER2 antibody-drug conjugate used in the present disclosure may be administered as a pharmaceutical preparation containing, for example, a buffer solution, such as a histidine buffer solution, a vehicle, such as sucrose and trehalose, and a surfactant, such as polysorbate 80 and 20. The pharmaceutical preparation containing the antibody-drug conjugate used in the present disclosure may be preferably used as an injection, more preferably as an aqueous injection or a lyophilized injection, and even more preferably as a lyophilized injection. When the pharmaceutical preparation containing the anti-HER2 antibody-drug conjugate used in the present disclosure is an aqueous injection, the aqueous injection may be preferably diluted with a suitable diluent and then given as an intravenous drip. Examples of diluents include dextrose solution, and preferably include saline, dextrose solution, and more preferably include 5% dextrose solution. When the pharmaceutical product of the present disclosure is a lyophilized injection, the required amount of the lyophilized injection, which is pre-dissolved in water for injection, can be preferably diluted with a suitable diluent and then given as an intravenous drip. Examples of the diluent include dextrose solution and saline, and preferably dextrose solution, more preferably 5% dextrose solution.

[0207] Examples of administration routes applicable for administration of the pharmaceutical agents of the present disclosure may include intravenous, intradermal, subcutaneous, intramuscular and intraperitoneal routes, with the intravenous route being preferred.

[0208] The anti-HER2 antibody-drug conjugate used in the present disclosure may be administered to humans at intervals of 1 to 180 days, preferably at intervals of 1 week, 2 weeks, 3 weeks, or 4 weeks, more preferably at intervals of 3 weeks. The anti-HER2 antibody-drug conjugate used in the present disclosure may be administered at a dose of about 0.001 to 100 mg / kg per administration, preferably at a dose of 0.8 to 12.4 mg / kg per administration. For example, the anti-HER2 antibody-drug conjugate may be administered at a dose of 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 5.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg once every 3 weeks, preferably at a dose of 5.4 mg / kg or 6.4 mg / kg once every 3 weeks.

[0209] RASG12C selective inhibitors can be administered in suitable doses by any suitable route of administration. The size of the dose required for therapeutic treatment of a particular condition necessarily varies according to the subject being treated, the route of administration and the severity of the disease being treated. For further information on routes of administration and dosing regimens, refer to Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, Volume 5, Chapter 25.3.

[0210] The compounds of formula (I) or (II) or their pharma- ceutically acceptable salts are usually administered in a pharma- ceutically acceptable dosage form, in the form of a pharmaceutical preparation containing the active ingredient or its pharma- ceutical acceptable salts or solvates or solvates of such salts, via the oral route, parenterally, intravenously, intramuscularly, subcutaneously or other injection methods, buccal, rectal, vaginal, transdermal and / or intranasal routes and / or by inhalation. Depending on the disorder and the patient to be treated and the route of administration, the compositions may be administered in various doses, for example in oral doses of 1 mg to 1,000 mg or 100 mg to 2,000 mg. The pharmaceutical preparations of the compounds of formula (I) or (II) described above may be prepared, for example, for parenteral, subcutaneous, intramuscular or intravenous administration. The pharmaceutical formulations of the compounds of formula (I) or (II) above may be conveniently administered in unit dosage form and may be prepared by any method well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA. (1985). Pharmaceutical formulations suitable for oral administration may contain one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binders, fillers, lubricants and surfactants. Liquid compositions may contain conventional additives such as suspending agents, emulsifiers and preservatives. Liquid compositions may be encapsulated, for example, in gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. An exemplary oral composition would comprise a compound of Formula (I) or (II) and at least one pharma- ceutically acceptable excipient loaded into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule. EXAMPLES

[0211] The present disclosure will be specifically described with reference to the following examples. However, the present disclosure is not limited thereto. Moreover, the examples should not be interpreted as being limiting in any way.

[0212] Example 1: Preparation of antibody-drug conjugates According to the production method described in WO 2015 / 115091, and using an anti-HER2 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO:11 (amino acid residues 1 to 449 of SEQ ID NO:1) and a light chain consisting of the amino acid sequence consisting of all amino acid residues 1 to 214 of SEQ ID NO:2), a compound represented by the following formula: [ka] (wherein A represents the attachment position to the antibody). An anti-HER2 antibody-drug conjugate was prepared in which the drug-linker represented by the formula: was conjugated to the anti-HER2 antibody via a thioether bond (DS-8201: trastuzumab deruxtecan). The DAR of the antibody-drug conjugate is 7.7 or 7.8.

[0213] Example 2: Preparation of RASG12C inhibitors The RASG12 inhibitor of formula (I) is prepared according to known manufacturing methods, specifically, 1-[(6aS,9R)-3-chloro-1-fluoro-2-(2-fluoro-6-hydroxyphenyl)-9-methyl-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1',2':5,6][1,5]oxazocino[4,3,2-de]quinazolin-8-yl]prop-2-en-1-one [ka] may be prepared according to Example 39 of WO 2019 / 215203.

[0214] Example 3: Antitumor Testing Combination of antibody-drug conjugate DS-8201 (trastuzumab deruxtecan (Enhertu®)) with a KRAS G12C inhibitor To evaluate the benefit of combining KRAS G12C inhibitors with DS-8201, G12CIn vitro cell proliferation assays in mutant human cell lines were performed. A 5-day cell proliferation assay using a range of inhibitor doses was used to investigate the potential for synergistic combinations of KRAS G12C inhibitors with DS-8201. A long-term (20-day) cell proliferation assay, including monitoring proliferation after cessation of drug treatment, was utilized to investigate the depth and duration of combination benefit of Compound A as a KRAS G12C inhibitor with DS-8201. The antitumor combination benefit of KRAS G12C inhibitors with DS-8201 was investigated in vivo in KRAS G12C mutant lung xenograft models and colorectal patient-derived graft models.

[0215] method Preclinical Models NCI-H358 (CRL-5807), NCI-H2122 (CRL-5985), NCI-H1792 (CRL-5895), SW1573 (CRL-2170), and SW837 (CCL-235) cells were obtained from the American Type Culture Collection (ATCC). LIM2099 (12062002) and KYSE410 (94072023) cells were from the European Collection of Authenticated Cell Cultures (ECACC). LU99 cells (JCRB0080) were obtained from the Japanese Collection of Research Bioresources (JCRB), and HCC44 (70044) was from the Korean Cell line bank (KCLB). Cell lines were authenticated by short tandem repeat analysis (STR). CTG-1489 and CTG-0387 are Champions Oncology colorectal cancer patient-derived xenograft (PDX) models.

[0216] In vitro studies Cell lines were routinely cultured in Growth Media (RPMI-1640 without Ferrous Red, 10% FCS, 2 mM L-glutamine). To seed cells onto assay plates, cells were detached with 0.25% trypsin solution and then passed through a blunt 18G needle and syringed in and out three times to completely disperse the cells.

[0217] To determine synergistic combination effects, cells were seeded in 384-well plates at 500-1000 cells / well in 70 μl of growth medium. Plates were incubated for 24 hours and either immediately treated (day 0) or treated with KRAS G12C inhibitor (compound A) and DS-8201 using an 8×8 dosing matrix with an ECHO 555 liquid handler (Labcyte) and incubated for an additional 5 days. Cell proliferation was assessed by adenosine triphosphate content using CellTiter-Glo (Promega). 35 μl of CellTiter-Glo reagent was added and incubated for 1 hour at room temperature. Luminescence was measured with a SpectraMax i3 (Molecular Devices) plate reader. Data were normalized to day 0 and 2-dimensional dose-response matrices and curve fitting were processed with the combination extension of Genedata Screener12™ (Genedata, Basel, Switzerland). Combination activity (synergy) was calculated using the Loewe dose additivity model. This model of additivity provides a null reference predicted by the expected response if the two agents were the same drug. The predicted 3-dimensional model surface from the two single agent response curves is subtracted from the experimentally derived 3-dimensional dose-effect surface to generate a differential volume. This excess matrix volume can be integrated to generate a synergy score. Synergistic combinations are defined as having a Loewe score of 5 or greater. The results as a combination matrix are shown in FIG. 12.

[0218] For time to regrowth assay, cells were seeded in 48-well tissue culture plates in growth medium and left to attach overnight. After 24 hours, cells were dosed with KRAS G12C inhibitor (Compound A) and / or DS-8201. On days 4 and 7, cells were re-treated with fresh medium containing inhibitor, and on day 10, fresh medium without inhibitor was added. Cell confluency was monitored using an Incucyte Zoom live cell imaging platform (Sartorius). Results are shown graphically in Figure 13.

[0219] Loewe synergy scores were obtained for the combination treatment of KRAS G12C inhibitors (Compound A; AMG510; MRTX849) and DS-8201 in a panel of KRAS G12C mutant cancer cell lines. Synergy scores were obtained from independent combination experiments. Synergistic combinations are defined as having a Loewe score of 5 or more. The results are shown in Table 1 below.

[0220] [Table 1]

[0221] From the results in Figure 12, KRAS G12C Lung cancer cell lines H358 and H2122 and KRAS G12C It is found that compound A exhibits synergistic combination activity with DS-8201 in vitro in the esophageal cancer cell line KYSE410.

[0222] The results in FIG. 13 show that the combination of Compound A and DS-8201 increases tumor growth inhibition in vivo and delays regrowth upon cessation of treatment in lung, colorectal and esophageal cancer cell lines.

[0223] From the results in Table 1, AMG510 and MRTX849 were G12C The study showed synergistic combination activity with DS-8201 in lung, colorectal and esophageal cancer cell lines in vitro, and that DS-8201 and Compound A inhibited the KRAS G12CIt is found that the combination exhibits synergistic activity in lung cancer cell lines.

[0224] In vivo studies In vivo studies were performed in Athymic Nude-Foxn1nu mice (Envigo) at AstraZeneca (xenograft model) or Champions Oncology (PDX model) in accordance with local regulations. For NCI-H358, NCI-H2122 or LU99 xenograft studies, cells were cultured at 3 × 10 cells / mL, respectively, in a 50:50 ratio of Matrigel:cells on the day of implantation. 6 , 2.5×10 5 Or 5 x 10 6 The cells were prepared at a concentration of 0.1 x 10 cells / mouse. The cell suspension was implanted subcutaneously in the left flank at 0.1 ml / mouse. Animals with actively growing tumors were selected until the mean tumor volume reached approximately 0.2–0.3 cm. 3 When the animals reached a mean tumor volume of 0.15-0.3 cm, they were randomly assigned to the relevant treatment group. For patient-derived xenograft (PDX) studies, animals were implanted with the appropriate PDX tumor fragments in the left flank and tumor volumes were recorded 7-10 days after implantation. 3 Once the tumors reached a mean age of 10 days, actively growing tumors were randomly assigned to the relevant treatment group.

[0225] Treatment began the day after randomization. Animals were orally administered a single daily dose of vehicle control or 100 mg / kg Compound A for the designated treatment period. DS-8201 was administered as a single intravenous dose. Compound A was formulated in 0.5% HPMC / 0.1% Tween 80. DS-8201 was formulated in 25 mM histidine buffer-9% sucrose, pH 5.5. Tumors were measured twice weekly with calipers and volumes were calculated using the ellipse formula (pi / 6 x width x width x length). Animal weights and tumor status were also recorded twice weekly throughout the study.

[0226] The results are shown in the graphs of Figures 14 to 18. As can be seen from the results, the combination of Compound A and DS-8201 inhibited KRAS G12C Mutant lung cancer xenograft models NCI-H358, NCI-H2122, and LU99 and KRAS G12C1 shows enhanced and prolonged tumor growth inhibition in vivo in mutant colorectal cancer patient-derived xenograft models CTG-1489 and CTG-0387.

[0227] Therefore, the results of Example 3 (Figures 12-18; Table 1) demonstrate that KRAS G12C inhibition using a KRAS G12C inhibitor (Compound A) enhances the anti-tumor effect of an anti-HER2 antibody-drug conjugate (DS-8201) in HER2-expressing cell lines in vitro and in vivo.

[0228] Example 4: Antitumor Testing Combination of the antibody-drug conjugate T-DM1 (trastuzumab emtansine (Kadcyla®)) with a KRAS G12C inhibitor. To evaluate the benefit of combining a KRAS G12C inhibitor with T-DM1, G12C In vitro cell proliferation assays in mutant human cell lines were performed. A 5-day cell proliferation assay using a dose range of inhibitors was used to investigate the potential for synergistic combinations of KRAS G12C inhibitors with DS-8201.

[0229] method Preclinical Models NCI-H358 (CRL-5807) and NCI-H2122 (CRL-5985) cells were obtained from the American Type Culture Collection (ATCC). Cell lines were authenticated by short tandem repeat analysis (STR).

[0230] In vitro studies Cell lines were routinely cultured in Growth Media (RPMI-1640 without Ferrous Red, 10% FCS, 2 mM L-glutamine). To seed cells onto assay plates, cells were detached with 0.25% trypsin solution and then passed through a blunt 18G needle and syringed in and out three times to completely disperse the cells.

[0231] To determine synergistic combination effects, cells were seeded in 384-well plates at 500-1000 cells / well in 70 μl of growth medium. Plates were incubated for 24 h and either immediately treated (day 0) or treated with KRAS G12C inhibitor (compound A) and T-DM1 or trastuzumab using an 8×8 dosing matrix with an ECHO 555 liquid handler (Labcyte) and incubated for an additional 5 days. Cell proliferation was assessed by adenosine triphosphate content using CellTiter-Glo (Promega). 35 μl of CellTiter-Glo reagent was added and incubated for 1 h at room temperature. Luminescence was measured with a SpectraMax i3 (Molecular Devices) plate reader. Data were normalized to day 0 and 2-dimensional dose-response matrices and curve fitting were processed with the combination extension of Genedata Screener12™ (Genedata, Basel, Switzerland). Combination activity (synergy) was calculated using the Loewe dose additivity model. This model of additivity provides a null reference predicted by the expected response if the two agents were the same drug. The predicted three-dimensional model surface from the two single agent response curves is subtracted from the experimentally obtained three-dimensional dose-effect surface to generate a differential volume. This excess matrix volume can be integrated to generate a synergy score. Synergistic combinations are defined as having a Loewe score of 5 or more. The results as a combination matrix are shown in Figures 19A and 19B.

[0232] In NCI-H358 and NCI-H2122 cancer cell lines, Loewe synergy scores were obtained for the combination treatment of KRAS G12C inhibitors (compound A; AMG510; MRTX849) with T-DM1 or trastuzumab. The synergy scores were obtained from independent combination experiments. Synergistic combinations are defined as having a Loewe score of 5 or more. The results are shown in Table 2 below.

[0233] [Table 2]

[0234] From the results of Figures 19A and 19B, KRAS G12C In the lung cancer cell line H358, compound A, AMG510 and MRTX849 are found to exhibit synergistic combination activity with T-DM1, but not with trastuzumab, in vitro.

[0235] From the results in Table 2, KRAS G12C In the lung cancer cell lines NCI-H358 and NCI-H2122, compound A, AMG510 and MRTX849 are shown to exhibit synergistic combination activity with T-DM1 in vitro.

[0236] Thus, the results of Example 4 (Figure 19A; Table 2) demonstrate that KRAS G12C inhibition using KRAS G12C inhibitors (Compound A; AMG510; MRTX849) enhances the anti-tumor effect of an anti-HER2 antibody-drug conjugate (T-DM1) in HER2-expressing lung cancer cell lines in vitro.

[0237] The above specification is deemed sufficient to enable those skilled in the art to practice the embodiments. The above description and examples detail certain embodiments and explain the best mode contemplated by the inventors. However, regardless of how detailed the above description is, it should be understood that the embodiments can be practiced in many ways, and the claims include any equivalents thereof.

[0238] Free text in sequence listing SEQ ID NO:1 - Amino acid sequence of the heavy chain of the anti-HER2 antibody SEQ ID NO:2 - Amino acid sequence of the light chain of the anti-HER2 antibody SEQ ID NO:3 - amino acid sequence of heavy chain CDRH1 [= amino acid residues 26 to 33 of SEQ ID NO:1] SEQ ID NO:4 - amino acid sequence of heavy chain CDRH2 [= amino acid residues 51 to 58 of SEQ ID NO:1] SEQ ID NO:5 - amino acid sequence of heavy chain CDRH3 [= amino acid residues 97 to 109 of SEQ ID NO:1] SEQ ID NO:6 - Amino acid sequence of light chain CDRL1 [= amino acid residues 27-32 of SEQ ID NO:2] SEQ ID NO:7 - Amino acid sequence (SAS) including the amino acid sequence of light chain CDRL2 [= amino acid residues 50 to 56 of SEQ ID NO:2] SEQ ID NO:8 - Amino acid sequence of light chain CDRL3 [= amino acid residues 89-97 of SEQ ID NO:2] SEQ ID NO:9 - Amino acid sequence of the heavy chain variable region [= amino acid residues 1 to 120 of SEQ ID NO:1] SEQ ID NO:10 - Amino acid sequence of the light chain variable region [= amino acid residues 1 to 107 of SEQ ID NO:2] SEQ ID NO:11 - amino acid sequence of the heavy chain [= amino acid residues 1 to 449 of SEQ ID NO:1]

Claims

1. A pharmaceutical product comprising an antibody-drug conjugate, wherein the antibody is an anti-HER2 antibody, and a RASG12C inhibitor for combined administration.

2. The RASG12C inhibitor has the following formula (I): 【Chemistry 1】 (In the formula, A is phenyl or a bicyclic heteroaryl group; X and Y are connected by a double bond, and i) X is CR ７ and Y is CR ８ or ii) X is N and Y is CR ８ or iii) X is CR ７ and Y is N, or X and Y are both C(O)NR ９ or X and Y are adjacent ring atoms of an optionally substituted 5- or 6-membered N-heterocycle that is fused to an aromatic ring substituted with Z, and X and Y are both C or C and N; Z is O, NH or NMe; R １ are independently F, Cl, Br, OH, CH ２ OH, OMe, CH ２ OMe, C １ ~C ３ Alkyl and C １ ~C ３ fluoroalkyl; n is 0, 1, 2 or 3; R ２ are H, F, Cl, CCH, CCMe, CN, Br, C １ ~C ３ Alkyl, C １ ~C ３ fluoroalkyl, OMe or OEt; R ３ａ and R ３ｂ are both ═O or R ３ａ and R ３ｂ is H, R ４ is H or Me, R ５ is H or Me, R ６ is H or CH ２ NMe ２ and R ７ and R ８ are independently H, F, Cl, CCH, CC(C １ ~C ３ Alkyl), CCCH ２ NMe ２ , C.C.C.H. ２ O (C １ ~C ３ Alkyl), CN, Me, C １ ~C ６ Alkyl, OH, OMe, O(C １ ~C ３ alkyl), O(C １ ~C ３ Deuteroalkyl), O(C １ ~C ３ Fluoroalkyl), O(C ３ ~C ６ Cycloalkyl), C １ ~C ３ Fluoroalkyl, OCH ２ CH ２ NMe ２ , O.C.H. ２ CH ２ OMe, CH ２ OMe, OCH ２ CH ２ N (CH ２ CH ２ ) ２ C.H., O.C.H. ２ CH ２ N (CH ２ CH ２ ) ２ O, OCH ２ CH ２ (2-pyridyl) or an optionally substituted 3-, 4-, 5- or 6-membered carbocyclic or heterocyclic ring; or R ７ and R ８ are joined to form an optionally substituted 5- or 6-membered carbocyclic or heterocyclic ring; R ９ is H, Me, Et, C ３ H ７ and C １ ~C ３ fluoroalkyl) The pharmaceutical agent according to claim 1, which is a compound represented by:

3. In formula (I), i) X is CR ７ and Y is CR ８ or ii) X is N and Y is CR ８ or iii) X is CR ７ and Y is N.

4. The pharmaceutical agent according to claim 2 or 3, wherein in formula (I), Z is O.

5. In formula (I), R ３ａ and R ３ｂ The pharmaceutical agent according to any one of claims 2 to 4, wherein is H.

6. In formula (I), R ４ The pharmaceutical agent according to any one of claims 2 to 5, wherein is H.

7. In formula (I), R ６ The pharmaceutical agent according to any one of claims 2 to 6, wherein is H.

8. The pharmaceutical agent according to any one of claims 2 to 7, wherein in formula (I), A is phenyl.

9. The RASG12C inhibitor is (12aS)-2-Acryloyl-10-chloro-9-(5-methyl-1H-indazol-4-yl)-1,2,3,4,12,12a-hexahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-6-one; 1-((12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; (12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-((12aR)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; (12aR)-10-chloro-8-fluoro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-7-hydroxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-imidazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-7-carbonitrile; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-7-(1H-pyrazol-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-10-chloro-8-fluoro-9-(5-methyl-1H-benzo[d]imidazol-4-yl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; (12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; (12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methyl-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-6-one; 1-[(12aR)-8,10-dichloro-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 8-[(12aR)-10-chloro-8-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-9-yl]-7-methylisoquinolin-1(2H)-one; 1-[(12aR)-10-chloro-9-(2-fluoro-6-hydroxyphenyl)-8-methoxy-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aS)-10-chloro-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepin-6(2H)-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aS)-10-chloro-11-methyl-9-(5-methyl-1H-indazol-4-yl)-2-(prop-2-enoyl)-1,3,4,11,12,12a-hexahydropyrazino[2,1-c][1,4]benzodiazepin-6(2H)-one; 1-[(12aR)-10-chloro-9-(2,3-difluoro-6-hydroxyphenyl)-8-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-10-chloro-9-(2-hydroxy-6-methylphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-[2-fluoro-6-(hydroxymethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8,10-difluoro-9-[2-hydroxy-6-(trifluoromethyl)phenyl]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-ethyl-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-[2-(difluoromethyl)-6-hydroxyphenyl]-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; (12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-2-(prop-2-enoyl)-1,2,3,4,12,12a-hexahydro-6H-pyrazino[2,1-c][1,4]benzoxazepine-8-carbonitrile; 1-[(12aR)-9-(2-bromo-6-hydroxyphenyl)-8,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-10-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-10-ethynyl-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-ethynyl-8-fluoro-9-(2-hydroxy-6-methylphenyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-2-methyl-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-1-one; 1-[(6aR)-1,4-dichloro-3-(2-fluoro-6-hydroxyphenyl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; (6aR)-4-chloro-3-(2-fluoro-6-hydroxyphenyl)-8-(prop-2-enoyl)-2,6,6a,7,8,9,10,12-octahydro-1H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-1-one; 1-[(8aR)-6-chloro-5-(2-fluoro-6-hydroxyphenyl)-8a,9,11,12-tetrahydro-14H-pyrazino[2,1-c][1,2,4]triazolo[4',3':1,2]pyrido[3,4-f][1,4]oxazepin-10(8H)-yl]prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazol-9(7H)-yl]prop-2-en-1-one; and 1-[(7aR)-5-chloro-4-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,7a,8,10,11,13-hexahydropyrazino[2',1':3,4][1,4]oxazepino[7,6-g]indazol-9(7H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-10-chloro-8-ethynyl-9-(2-fluoro-6-hydroxyphenyl)-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(7aR)-5-chloro-4-(2-chloro-6-hydroxyphenyl)-1-methyl-1,7a,8,10,11,13-hexahydroimidazo[4,5-g]pyrazino[2,1-c][1,4]benzoxazepin-9(7H)-yl]prop-2-en-1-one; 1-[(12aR)-8-chloro-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-methyl-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-7,8-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-7,10-difluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(difluoromethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(cyclopropyloxy)-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-((12aR)-9-(2-chloro-6-hydroxyphenyl)-8-(3-(dimethylamino)prop-1-yn-1-yl)-10-fluoro-3,4,12,12a-tetrahydro-6H-benzo[f]pyrazino[2,1-c][1,4]oxazepin-2(1H)-yl)prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[(pyridin-4-yl)methoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(2-methoxyethoxy)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-[2-(piperidin-1-yl)ethoxy]-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-2-[( ２ H ３ methyloxy]-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[2,3-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; 1-[(12aR)-10-chloro-9-(2-chloro-6-hydroxyphenyl)-8-(methoxymethyl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-7-[2-(dimethylamino)ethoxy]-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one; 1-[(6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-(prop-1-yn-1-yl)-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl]prop-2-en-1-one; and 1-((6aR)-4-chloro-3-(2-chloro-6-hydroxyphenyl)-1-ethynyl-6a,7,9,10-tetrahydro-12H-pyrazino[2,1-c]pyrido[3,4-f][1,4]oxazepin-8(6H)-yl)prop-2-en-1-one; or Pharmaceutically acceptable salts thereof The pharmaceutical composition of claim 2, which is a compound selected from the group consisting of:

10. The pharmaceutical product of claim 2, wherein the RASG12C inhibitor is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-8-ethynyl-10-fluoro-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one.

11. The pharmaceutical product of claim 2, wherein the RASG12C inhibitor is 1-[(12aR)-9-(2-chloro-6-hydroxyphenyl)-10-fluoro-8-(prop-1-yn-1-yl)-3,4,12,12a-tetrahydro-6H-pyrazino[2,1-c][1,4]benzoxazepin-2(1H)-yl]prop-2-en-1-one.

12. 2. The pharmaceutical product of claim 1, wherein the RASG12C inhibitor is selected from LY3537982 (Loxo / Lilly), AZD4625 (AstraZeneca), sotorasib (AMG510), adagrasib (MRTX849), JDQ443 (Novartis), GDC-6036 (Genentech), BI 1,823,911 (Boehringer Ingelheim), D1553 (InventisBio), and JNJ-74699157 (Johnson and Johnson) or a pharma- ceutical acceptable salt thereof.

13. The RASG12C inhibitor has the following formula: 【Chemistry 2】 The pharmaceutical composition according to claim 1, which is compound A represented by:

14. The pharmaceutical according to any one of claims 1 to 13, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3, a CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4, and a CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5, and a light chain comprising a CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6, a CDRL2 consisting of the amino acid sequence consisting of amino acid residues 1 to 3 of SEQ ID NO: 7, and a CDRL3 consisting of the amino acid sequence represented by SEQ ID NO:

8.

15. The pharmaceutical according to any one of claims 1 to 13, wherein the anti-HER2 antibody is an antibody comprising a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9, and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO:

10.

16. The pharmaceutical according to any one of claims 1 to 13, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 1 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

2.

17. The pharmaceutical according to any one of claims 1 to 13, wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

2.

18. The antibody-drug conjugate has the following formula: 【Chemistry 3】 (wherein A represents the attachment position to the antibody). The pharmaceutical agent according to any one of claims 1 to 17, which is an antibody-drug conjugate in which a drug-linker represented by the formula:

19. The anti-HER2 antibody-drug conjugate has the following formula: 【Chemistry 4】 (wherein "antibody" refers to the anti-HER2 antibody conjugated to the drug-linker via a thioether bond, and n refers to the average number of units of the drug-linker conjugated per antibody molecule in the antibody-drug conjugate, where n ranges from 7 to 8). The pharmaceutical product according to any one of claims 1 to 18, wherein the pharmaceutical product is represented by:

20. The pharmaceutical product of any one of claims 1 to 13, wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201) or trastuzumab emtansine (T-DM1).

21. The pharmaceutical product of claim 20, wherein the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan (DS-8201).

22. The pharmaceutical product of any one of claims 1 to 21, which is a composition comprising said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor for separate simultaneous administration.

23. The pharmaceutical product according to any one of claims 1 to 21, which is a combined preparation comprising the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor for sequential administration.

24. The pharmaceutical product according to any one of claims 1 to 23, which is for treating cancer.

25. 25. The pharmaceutical product of claim 24, wherein the cancer is at least one selected from the group consisting of breast cancer, gastric cancer, colorectal cancer, lung cancer, esophageal cancer, head and neck cancer, gastroesophageal junction adenocarcinoma, biliary tract cancer, Paget's disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma.

26. The pharmaceutical agent of claim 25, wherein the cancer is breast cancer.

27. 27. The method of claim 26, wherein the breast cancer has a HER2 status score of IHC 3+.

28. The pharmaceutical agent of claim 26, wherein the breast cancer is HER2 low-expressing breast cancer.

29. 27. The method of claim 26, wherein the breast cancer has a HER2 status score of IHC 2+.

30. 27. The method of claim 26, wherein the breast cancer has a HER2 status score of IHC 1+.

31. 27. The method of claim 26, wherein the breast cancer has an IHC>0 and a HER2 status score of <1+.

32. The method of claim 26, wherein the breast cancer is triple-negative breast cancer.

33. The pharmaceutical product of claim 24, wherein the cancer is gastric cancer.

34. The method of claim 24, wherein the cancer is colorectal cancer.

35. The pharmaceutical agent of claim 24, wherein the cancer is lung cancer.

36. The pharmaceutical product of claim 35, wherein the lung cancer is non-small cell lung cancer.

37. The pharmaceutical agent of claim 24, wherein the cancer is pancreatic cancer.

38. The pharmaceutical agent of claim 24, wherein the cancer is ovarian cancer.

39. The pharmaceutical agent of claim 24, wherein the cancer is prostate cancer.

40. The pharmaceutical agent of claim 24, wherein the cancer is renal cancer.

41. A pharmaceutical product according to any one of claims 1 to 23 for use in the treatment of cancer.

42. The method of claim 41, wherein the cancer is as defined in any one of claims 25 to 40.

43. 22. Use of an anti-HER2 antibody-drug conjugate in the manufacture of a medicament for use in combination with a RASG12C inhibitor to treat cancer, wherein said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor are as defined in any one of claims 1 to 21.

44. 44. The use of claim 43, wherein the medicament is for use in combination with the RASG12C inhibitor by sequential administration.

45. 44. The use of claim 43, wherein the medicament is for use in combination with the RASG12C inhibitor by separate co-administration.

46. 22. Use of a RASG12C inhibitor in the manufacture of a medicament for use in combination with an anti-HER2 antibody-drug conjugate to treat cancer, wherein said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor are as defined in any one of claims 1 to 21.

47. 47. The use of claim 46, wherein the medicament is for use in combination with the anti-HER2 antibody-drug conjugate by sequential administration.

48. 47. The use of claim 46, wherein said agent is for use in combination with said anti-HER2 antibody-drug conjugate by separate co-administration.

49. The use according to any one of claims 43 to 48, wherein the cancer is as defined in any one of claims 25 to 40.

50. 22. An anti-HER2 antibody-drug conjugate for use in combination with a RASG12C inhibitor in the treatment of cancer, wherein said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor are as defined in any one of claims 1 to 21.

51. The anti-HER2 antibody-drug conjugate for use according to claim 50, wherein the cancer is as defined in any one of claims 25 to 40.

52. 52. The anti-HER2 antibody-drug conjugate for use according to claim 50 or 51, wherein said use comprises sequential administration of said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor.

53. 52. The anti-HER2 antibody-drug conjugate for use according to claim 50 or 51, wherein said use comprises separate and simultaneous administration of said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor.

54. 22. An anti-HER2 antibody-drug conjugate for use in the treatment of cancer in a subject, said treatment comprising the sequential or separate simultaneous administration to said subject of i) said anti-HER2 antibody-drug conjugate and ii) a RASG12C inhibitor, said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor being as defined in any one of claims 1 to 21.

55. 22. A RASG12C inhibitor for use in combination with an anti-HER2 antibody-drug conjugate in the treatment of cancer, wherein said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor are as defined in any one of claims 1 to 21.

56. The RASG12C inhibitor for use according to claim 50, wherein the cancer is as defined in any one of claims 25 to 40.

57. 57. The RASG12C inhibitor for use according to claim 55 or 56, wherein said use comprises sequential administration of said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor.

58. 57. The RASG12C inhibitor for use according to claim 55 or 56, wherein said use comprises separate and simultaneous administration of said anti-HER2 antibody-drug conjugate and said RASG12C inhibitor.

59. 22. A RASG12C inhibitor for use in the treatment of cancer in a subject, said treatment comprising the sequential or separate simultaneous administration to said subject of i) said RASG12C inhibitor and ii) an anti-HER2 antibody-drug conjugate, said RASG12C inhibitor and said anti-HER2 antibody-drug conjugate being as defined in any one of claims 1 to 21.

60. A method for treating cancer, comprising administering to a subject in need thereof a combination of an anti-HER2 antibody-drug conjugate according to any one of claims 1 to 21 and a RASG12C inhibitor.

61. The method of claim 60, wherein the cancer is as described in any one of claims 25 to 40.

62. 62. The method of claim 60 or 61, comprising administering the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor sequentially.

63. 62. The method of claim 60 or 61, comprising administering the anti-HER2 antibody-drug conjugate and the RASG12C inhibitor separately and simultaneously.

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