Combination of antibody-drug conjugates with ATR inhibitors

Abstract

A pharmaceutical product is provided for administering an anti-TROP2 antibody-drug conjugate in combination with an ATR inhibitor. The anti-TROP2 antibody-drug conjugate has the formula: wherein A represents the attachment position to the anti-TROP2 antibody, is conjugated to the anti-TROP2 antibody via a thioether bond. Therapeutic uses and methods are also provided in which the anti-TROP2 antibody-drug conjugate and the ATR inhibitor are administered in combination to a subject: Formula (I). [Formula 1] JPEG2025501175000057.jpg45170

Description

[Technical field]

[0001] The present disclosure relates to pharmaceutical products for administering a specific antibody-drug conjugate having an anti-TROP2 antibody conjugated via a linker structure in combination with an ATR inhibitor, as well as therapeutic uses and methods in which a specific antibody-drug conjugate and an ATR inhibitor are administered in combination to a subject. [Background technology]

[0002] ATR (ataxia telangiectasia and rad3-related kinase) is a serine / threonine protein kinase and a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. During normal DNA replication, ATR is recruited at stalled replication forks, which, if left unrepaired, can develop into double-stranded breaks. ATR is recruited to single-stranded DNA coated with replication protein A (RPA) after single-stranded DNA damage or resection of double-stranded breaks during DNA replication. Recruitment and activation of ATR leads to cell cycle arrest at S phase, where DNA is repaired and stalled replication forks are degraded, or nuclear fragmentation and initiation of programmed cell death (apoptosis).

[0003] As a result, ATR inhibitors are expected to cause growth inhibition in tumor cells that depend on ATR for DNA repair, such as ATM-deficient tumors.In addition to these monotherapy activities, ATR inhibitors are also expected to enhance the activity of DNA damage-inducing therapy (through the inhibition of ATR-dependent DNA repair process) when used in combination.Examples of ATR inhibitors are disclosed, for example, in WO2011 / 154737.

[0004] Inactivation of Schlafen 11 (SLFN11) in cancer cells has also been shown to result in resistance to anticancer drugs that cause DNA damage and replication stress. Thus, SLFN11 may act as a determinant of sensitivity to various classes of DNA damaging agents, including but not limited to topoisomerase I inhibitors. See Zoppoli et al., PNAS 2012;109:15030-35; Murai et al., Oncotarget 2016;7:76534-50; Murai et al., Mol. Cell 2018;69:371-84.

[0005] Antibody-drug conjugates (ADCs), which consist of a cytotoxic drug conjugated to an antibody, can be expected to selectively deliver drugs 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).

[0006] One such antibody-drug conjugate is datopotamab deruxtecan, which is composed of an antibody targeting TROP2 and a derivative of exatecan. In particular, WO 2015 / 098099 and WO 2020 / 240467 provide details of representative TROP2-targeting antibody-drug conjugates, including datopotamab deruxtecan (DS-1062). Datopotamab deruxtecan has demonstrated clinical efficacy in multiple major types of cancer, including lung and breast cancer. However, there remains a need to identify combination partners for anti-TROP2 antibody-drug conjugates such as datopotamab deruxtecan to promote their therapeutic potential.

[0007] Despite the therapeutic potential of anti-TROP2 antibody-drug conjugates such as datopotamab deruxtecan (DS-1062) and ATR inhibitors, there remains a need for improved therapeutic compositions and methods that may enhance the efficacy of existing cancer therapeutics, prolong the durability of therapeutic responses, improve patient tolerability, reduce dose-dependent toxicity, and / or provide alternative treatments for cancers that are resistant or refractory to previous cancer treatments, for example, previous treatments with PARP inhibitors such as olaparib, rucaparib, niraparib, talazoparib or veliparib. Summary of the Invention [Means for solving the problem]

[0008] The antibody-drug conjugate used in the present disclosure (anti-TROP2 antibody-drug conjugate containing a derivative of the topoisomerase I inhibitor exatecan as a component) has been confirmed to show excellent antitumor effects when administered alone in the treatment of certain cancers such as breast cancer and gastric cancer. However, it is desirable to provide drugs and treatments that can obtain excellent antitumor effects in the treatment of cancer, such as enhanced efficacy, extended duration of therapeutic response, and / or reduced dose-dependent toxicity. By inhibiting the DNA damage response to replication stress and double-strand breaks induced by the antibody-drug conjugate of the present disclosure, ATR inhibitors can further enhance antitumor efficacy when administered in combination with the antibody-drug conjugate.

[0009] The present disclosure provides a pharmaceutical product that can show excellent antitumor effects in the treatment of cancer through the administration of an anti-TROP2 antibody-drug conjugate in combination with an ATR inhibitor. The present disclosure also provides therapeutic uses and methods in which an anti-TROP2 antibody-drug conjugate and an ATR inhibitor are administered in combination to a subject.

[0010] Specifically, the present disclosure relates to the following [1] to

[74] . [1] A pharmaceutical product comprising an anti-TROP2 antibody-drug conjugate and an ATR inhibitor for administration in combination, wherein the anti-TROP2 antibody-drug conjugate has the following formula: [ka] wherein A represents the attachment position relative to the antibody, is conjugated to the anti-TROP2 antibody via a thioether bond; [2] The ATR inhibitor has the following formula (I): [ka] (In the formula, R 1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; R2 teeth, [ka] and; n is 0 or 1; R 2A , R 2C , R 2E and R 2F are each independently hydrogen or methyl; R 2B and R 2D are each independently hydrogen or methyl; R 2G -NHR 7 and -NHCOR 8 Selected from; R 2H is fluoro; R 3 is methyl; R 4 and R 5 are each independently hydrogen or methyl, or R 4 and R 5 form ring A together with the atoms to which they are attached; Ring A is a C ring containing one heteroatom selected from O and N. 3~6 cycloalkyl or a saturated 4-6 membered heterocycle; R 6 is hydrogen, R 7 is hydrogen or methyl; R 8 is methyl) A compound represented by or a pharma- ceutical product according to [1], which is a pharma- ceutical product according to [1], [3] In formula (I), R 4 and R 5 together with the atoms to which they are attached form a ring A, and ring A contains one heteroatom selected from O and N. 3~6 The pharmaceutical product according to [2], which is cycloalkyl or saturated 4-6 heterocycles; [4] The pharmaceutical product according to [2] or [3], wherein in formula (I), ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring; [5] In formula (I), R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; [6] In formula (I), R 1 is 3-methylmorpholin-4-yl; [7] The compound of formula (I) has the formula (Ia): [ka] Compound or a pharma- ceutical product according to any one of [2] to [6], which is a pharma- ceutical product comprising: [8] In formula (Ia), Ring A is a cyclopropyl ring; R 2 but, [ka] and; n is 0 or 1; R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; R 2G But -NHR 7 and; R 2H is fluoro; R 3 is a methyl group; R 6 is hydrogen; R 7 is hydrogen or methyl; [7] Medicinal products as described in the above; [9] The ATR inhibitor has the following formula: [ka] AZD6738, also known as selarasertib or AZ13386215, represented by or a pharma- ceutical product according to [2], which is a pharma- ceutical product according to [2],

[10] The pharmaceutical product according to any one of [1] to [9], wherein the anti-TROP2 antibody comprises a heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3 [= amino acid residues 50 to 54 of SEQ ID NO: 1], CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4 [= amino acid residues 69 to 85 of SEQ ID NO: 1], and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5 [= amino acid residues 118 to 129 of SEQ ID NO: 1], and a light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6 [= amino acid residues 44 to 54 of SEQ ID NO: 2], CDRL2 consisting of the amino acid sequence represented by SEQ ID NO: 7 [= amino acid residues 70 to 76 of SEQ ID NO: 2], and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 8 [= amino acid residues 109 to 117 of SEQ ID NO: 2];

[11] The pharmaceutical product according to

[10] , wherein the anti-TROP2 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 [= amino acid residues 20 to 140 of SEQ ID NO: 1] and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10 [= amino acid residues 21 to 129 of SEQ ID NO: 2];

[12] The pharmaceutical product according to

[11] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of an amino acid sequence represented by SEQ ID NO: 12 [= amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2];

[13] The pharmaceutical product according to

[11] , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 [= amino acid residues 20 to 469 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2];

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

[13] , wherein the average number of drug-linker units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 2 to 8.

[15] The pharmaceutical product according to

[14] , wherein the average number of drug-linker units conjugated per antibody molecule in the antibody-drug conjugate is in the range of 3.5 to 4.5;

[16] The pharmaceutical product according to

[15] , wherein the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062);

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

[16] , which is a combined preparation comprising an anti-TROP2 antibody-drug conjugate and an ATR inhibitor for separate simultaneous administration;

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

[16] , which is a combined preparation comprising an anti-TROP2 antibody-drug conjugate and an ATR inhibitor for sequential administration;

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

[18] , wherein the anti-TROP2 antibody-drug conjugate is administered at a dose of 6 mg / kg body weight;

[20] The pharmaceutical product according to

[19] , wherein the dose of the anti-TROP2 antibody-drug conjugate is administered once every three weeks;

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

[20] , wherein the ATR inhibitor is administered daily for the first, second and / or third weeks of a three-week cycle;

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

[20] , wherein the ATR inhibitor is administered from days 3 to 17 of a 3-week cycle;

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

[22] , which is for treating cancer;

[24] The pharmaceutical product according to

[23] , wherein the cancer is at least one selected from the group consisting of breast cancer, lung cancer, colorectal cancer, gastric 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 body carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma multiforme, osteosarcoma, sarcoma, and melanoma;

[25] The pharmaceutical product according to

[24] , wherein the cancer is breast cancer;

[26] The pharmaceutical product according to

[25] , wherein the breast cancer is triple-negative breast cancer;

[27] The pharmaceutical product according to

[25] , wherein the breast cancer is hormone receptor (HR)-positive, HER2-negative breast cancer;

[28] The pharmaceutical product according to

[24] , wherein the cancer is lung cancer;

[29] The pharmaceutical product according to

[28] , wherein the lung cancer is non-small cell lung cancer;

[30] The pharmaceutical product according to

[29] , wherein the non-small cell lung cancer is non-small cell lung cancer having actionable genomic alterations;

[31] The pharmaceutical product according to

[29] , wherein the non-small cell lung cancer is non-small cell lung cancer without actionable genomic alterations;

[32] The pharmaceutical product according to

[24] , wherein the cancer is colorectal cancer;

[33] The pharmaceutical product according to

[24] , wherein the cancer is gastric cancer;

[34] The pharmaceutical product according to

[24] , wherein the cancer is pancreatic cancer;

[35] The pharmaceutical product according to

[24] , wherein the cancer is ovarian cancer;

[36] The pharmaceutical product according to

[24] , wherein the cancer is prostate cancer;

[37] The pharmaceutical product according to

[24] , wherein the cancer is renal cancer;

[38] The pharmaceutical product according to any one of

[24] to

[37] , wherein the cancer lacks homologous recombination (HR)-dependent DNA DSB repair activity;

[39] A pharmaceutical product according to any one of

[24] to

[37] , wherein the cancer does not lack homologous recombination (HR)-dependent DNA DSB repair activity;

[40] The pharmaceutical product according to any one of

[24] to

[37] , wherein the cancer is resistant or refractory to previous treatment with a PARP inhibitor;

[41] The pharmaceutical product of

[40] , wherein the previous treatment is with a PARP inhibitor selected from olaparib, rucaparib, niraparib, talazoparib and veliparib;

[42] The pharmaceutical product according to any one of

[24] to

[38] , wherein the cancer cells of the cancer are SLFN11-deficient;

[43] the pharmaceutical product of

[42] , wherein SLFN11 expression is lower in cancer cells of the patient compared to non-cancerous cells expressing SLFN11 of the patient;

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

[22] for use in the treatment of cancer;

[45] The pharmaceutical product for use according to

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

[24] to

[43] ;

[46] Use of an anti-TROP2 antibody-drug conjugate in the manufacture of a medicament for use in combination with an ATR inhibitor to treat cancer, wherein the anti-TROP2 antibody-drug conjugate and the ATR inhibitor are as defined in any one of [1] to

[16] ;

[47] The use according to

[46] , wherein the medicament is for use in combination with an ATR inhibitor by sequential administration;

[48] ​​The use according to

[46] , wherein the agent is for use in combination with an ATR inhibitor by separate co-administration;

[49] Use of an ATR inhibitor in the manufacture of a medicament for use in combination with an anti-TROP2 antibody-drug conjugate for treating cancer, wherein the anti-TROP2 antibody-drug conjugate and the ATR inhibitor are as defined in any one of [1] to

[16] ;

[50] The use according to

[49] , wherein the agent is for use in combination with an anti-TROP2 antibody-drug conjugate by sequential administration;

[51] The use according to

[49] , wherein the agent is for use in combination with an anti-TROP2 antibody-drug conjugate by separate simultaneous administration;

[52] The use according to any one of

[46] to

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

[24] to

[43] ;

[53] An anti-TROP2 antibody-drug conjugate for use in combination with an ATR inhibitor in the treatment of cancer, wherein the anti-TROP2 antibody-drug conjugate and the ATR inhibitor are as defined in any one of [1] to

[16] ;

[54] The anti-TROP2 antibody-drug conjugate for use according to

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

[24] to

[43] ;

[55] The anti-TROP2 antibody-drug conjugate for use according to

[53] or

[54] , wherein the use comprises sequentially administering the anti-TROP2 antibody-drug conjugate and an ATR inhibitor;

[56] The anti-TROP2 antibody-drug conjugate for use according to

[53] or

[54] , wherein the use comprises administering the anti-TROP2 antibody-drug conjugate and the ATR inhibitor separately and simultaneously;

[57] An anti-TROP2 antibody-drug conjugate for use in treating cancer in a subject, said treatment comprising sequential or separate co-administration to said subject of i) said anti-TROP2 antibody-drug conjugate and ii) an ATR inhibitor, wherein said anti-TROP2 antibody-drug conjugate and said ATR inhibitor are as defined in any one of [1] to

[16] ;

[58] The anti-TROP2 antibody-drug conjugate for use according to any one of

[53] to

[57] , which is administered at a dose of 6 mg / kg body weight;

[59] An anti-TROP2 antibody-drug conjugate for use according to

[58] , wherein the dose of the anti-TROP2 antibody-drug conjugate is administered once every three weeks;

[60] The anti-TROP2 antibody-drug conjugate for use according to any one of

[53] to

[59] , wherein the ATR inhibitor is administered daily for the first, second and / or third weeks of a three-week cycle;

[61] The anti-TROP2 antibody-drug conjugate for use according to any one of

[53] to

[59] , wherein the ATR inhibitor is administered on days 3 to 17 of a 3-week cycle;

[62] An ATR inhibitor for use in combination with an anti-TROP2 antibody-drug conjugate in the treatment of cancer, wherein the anti-TROP2 antibody-drug conjugate and the ATR inhibitor are as defined in any one of [1] to

[16] ;

[63] The ATR inhibitor for use according to

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

[24] to

[43] ;

[64] An ATR inhibitor for use according to

[62] or

[63] , wherein the use comprises sequentially administering an anti-TROP2 antibody-drug conjugate and an ATR inhibitor;

[65] The ATR inhibitor for use according to

[62] or

[63] , wherein the use comprises administering the anti-TROP2 antibody-drug conjugate and the ATR inhibitor separately and simultaneously;

[66] An ATR inhibitor for use in treating cancer in a subject, the treatment comprising sequential or separate co-administration to the subject of i) the ATR inhibitor and ii) an anti-TROP2 antibody-drug conjugate, wherein the ATR inhibitor and the TROP2 antibody-drug conjugate are as defined in any one of [1] to

[16] ;

[67] The ATR inhibitor for use according to any one of

[62] to

[66] , wherein the anti-TROP2 antibody-drug conjugate is administered at a dose of 6 mg / kg body weight;

[68] The ATR inhibitor for use according to

[67] , wherein the dose of the anti-TROP2 antibody-drug conjugate is administered once every three weeks;

[69] An ATR inhibitor for use according to any one of

[62] to

[68] , which is administered daily for the first, second and / or third weeks of a three-week cycle;

[70] An ATR inhibitor for use according to any one of

[62] to

[68] , which is administered on days 3 to 17 of a 3-week cycle;

[71] A method for treating cancer, comprising administering to a subject in need thereof an anti-TROP2 antibody-drug conjugate as defined in any one of [1] to

[16] and an ATR inhibitor in combination;

[72] The method according to

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

[24] to

[43] ;

[73] The method according to

[71] or

[72] , comprising sequentially administering an anti-TROP2 antibody-drug conjugate and an ATR inhibitor;

[74] The method according to

[71] or

[72] , comprising administering an anti-TROP2 antibody-drug conjugate and an ATR inhibitor separately and simultaneously.

[0011] [Favorable effects of disclosure] The present disclosure provides a pharmaceutical product in which an anti-TROP2 antibody-drug conjugate having an antitumor drug conjugated to the anti-TROP2 antibody via a linker structure and an ATR inhibitor are combined and administered, as well as a therapeutic use and method in which an anti-TROP2 antibody-drug conjugate and an ATR inhibitor are combined and administered to a subject. Thus, the present disclosure can provide drugs and treatments that can achieve excellent antitumor effects in the treatment of cancer. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is a diagram showing the amino acid sequence of the heavy chain of an anti-TROP2 antibody (SEQ ID NO:1). [Diagram 2] FIG. 2 is a diagram showing the amino acid sequence of the light chain of an anti-TROP2 antibody (SEQ ID NO:2). [Diagram 3] FIG. 3 is a diagram showing the amino acid sequence of heavy chain CDRH1 (SEQ ID NO:3 [=amino acid residues 50-54 of SEQ ID NO:1]). [Figure 4] FIG. 4 is a diagram showing the amino acid sequence of heavy chain CDRH2 (SEQ ID NO:4 [=amino acid residues 69-85 of SEQ ID NO:1]). [Diagram 5] FIG. 5 is a diagram showing the amino acid sequence of heavy chain CDRH3 (SEQ ID NO:5 [=amino acid residues 118-129 of SEQ ID NO:1]). [Figure 6] FIG. 6 is a diagram showing the amino acid sequence of light chain CDRL1 (SEQ ID NO:6 [=amino acid residues 44-54 of SEQ ID NO:2]). [Figure 7] FIG. 7 is a diagram showing the amino acid sequence of light chain CDRL2 (SEQ ID NO:7 [=amino acid residues 70-76 of SEQ ID NO:2]). [Figure 8] FIG. 8 is a diagram showing the amino acid sequence of light chain CDRL3 (SEQ ID NO:8 [=amino acid residues 109-117 of SEQ ID NO:2]). [Figure 9] FIG. 9 is a diagram showing the amino acid sequence of the heavy chain variable region (SEQ ID NO:9 [=amino acid residues 20 to 140 of SEQ ID NO:1]). [Figure 10]FIG. 10 is a diagram showing the amino acid sequence of the light chain variable region (SEQ ID NO: 10 [=amino acid residues 21-129 of SEQ ID NO: 2]). [Figure 11] FIG. 11 is a diagram showing the amino acid sequence of the heavy chain (SEQ ID NO:11 [=amino acid residues 20-469 of SEQ ID NO:1]). [Figure 12A-12B] 12A and 12B are charts showing combination matrices obtained using a high throughput screen combining DS-1062 with AZD6738 (an ATR inhibitor) in TROP2-expressing lung cancer cell lines. [Figure 13A-13B] Figures 13A and 13B are charts showing combination matrices obtained using a high throughput screen combining DS-1062 with AZD6738 in TROP2-expressing breast cancer cell lines. [Figure 14] FIG. 14 is a chart showing combination Emax and Loewe synergy scores in cell lines treated with DS-1062 in combination with AZD6738. [Figure 15] Figure 15 is a graph showing tumor volumes for in vivo treatment with DS-1062 or AZD6738 alone, or in combination with DS-1062 with AZD6738. The dotted line indicates the end of the AZD6738 administration period. [Figure 16A-16B] Figure 16A is a graph showing tumor volumes for in vivo treatment with DS-1062 or AZD6738 alone, or in combination with DS-1062 and AZD6738. The dotted line indicates the end of the AZD6738 administration period. Figure 16B is a graph of the percentage of mice that achieved a complete response in each treatment group from this study. [Figure 17A-17B] 17A and 17B are diagrams showing combination matrices resulting from a high throughput screen combining DS-1062 and AZD6738 in primary CD34+ hematopoietic stem cells and progenitor cells differentiated along the erythroid lineage. [Figure 18]FIG. 18 is a graph showing tumor volume for in vivo treatment with DS-1062 or AZD6738 alone, or DS-1062 in combination with AZD6738. [Figure 19] Figure 19 is a graph showing tumor volumes for in vivo treatment with DS-1062 or AZD6738 alone, or in combination with DS-1062 with AZD6738. The dotted line indicates the end of the dosing period. [Figure 20] Figure 20 is a graph showing tumor volumes for in vivo treatment with DS-1062 or AZD6738 alone, or in combination with DS-1062 with AZD6738. The dotted line indicates the end of the dosing period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In order that this disclosure may be more readily understood, certain terms are first defined. Further definitions are set forth throughout the detailed description.

[0014] 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, which 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") and "one or more" and "at least one" may be used interchangeably herein.

[0015] Furthermore, as used herein, "and / or" should be considered 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" when used in phrases such as "A and / or B" herein 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).

[0016] 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 the 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.

[0017] 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.

[0018] Whenever an embodiment is described herein with the word "comprising," it is to be understood that otherwise similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0019] The terms "inhibit," "block," and "suppress" are used interchangeably herein and refer to any statistically significant decrease in biological activity, including complete blockage of activity. For example, "inhibition" can refer to about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease in biological activity. Cell proliferation can be assayed using art-recognized techniques that measure the rate of cell division and / or the proportion of cells within 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).

[0020] The term "subject" refers to any animal (e.g., a 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.

[0021] The term "pharmaceutical product" refers to a preparation 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, more preferably less than 2 hours.

[0022] Terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refer to both (1) therapeutic measures that cure, slow, alleviate, 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 already with the disorder, those prone to having the disorder, and those in whom the disorder is to be prevented. In certain aspects, a subject is successfully "treated" for cancer according to the methods of the present disclosure when the patient exhibits, for example, a complete, partial, or temporary remission of a particular type of cancer.

[0023] The terms "cancer", "tumor", "cancerous" and "malignant" refer to or describe a physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, breast cancer, lung cancer, colorectal cancer, gastric 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.

[0024] As used herein, the term "cytotoxic agent" is broadly defined and refers to a substance that inhibits or prevents the function of cells and / or causes the destruction of cells (cell death) and / or exerts antineoplastic / antiproliferative effects. 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 TROP2 antagonists, antiangiogenic 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. The term "chemotherapeutic agent" is a subset of the term "cytotoxic agent," which includes natural or synthetic compounds.

[0025] 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 the treatment of cancer 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 response" refers to the absence of clinically detectable disease with normalization of any prior test results. Alternatively, an improvement in the disease may be classified as a partial response. A "positive therapeutic response" encompasses a reduction or inhibition of the progression and / or duration of cancer, 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) reduced cancer formation; (4) eradication, removal, or control of primary, regional, and / or metastatic cancer; (5) reduced mortality; (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 in remission; (8) A decrease in hospitalization rates, (9) Reduction in hospital stays, (10) The size of the cancer is maintained and does not expand or expands 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 other adjuvant therapies (e.g., chemotherapy or hormonal therapy agents) required to treat the cancer.

[0026] Clinical response may be assessed using screening techniques such as PET, magnetic resonance imaging (MRI) scans, X-ray imaging, computed tomography (CT) scans, flow cytometry or fluorescence activated cell sorter (FACS) analysis, histology, macroscopic findings, and changes detectable by blood chemistry tests such as, but not limited to, ELISA, RIA, chromatography, etc. In addition to these positive therapeutic responses, subjects undergoing treatment may experience the beneficial effect of amelioration of symptoms associated with the disease.

[0027] As used herein, the term "SLFN11 expression level" at a certain amount, e.g., 0%, means that the described amount of cancer cells in the patient's cancer tissue expresses SLFN11.Similarly, as used herein, the term "SLFN11 expression level at <" a certain amount, e.g., <10%, means that less than the described amount of cancer cells in the patient's cancer tissue expresses SLFN11.The SLFN11 expression level can be, for example, <25%, <20%, <15%, <10%, <9%, <8%, <7%, <6%, <5%, <4%, <3%, <2%, <1% or 0%.

[0028] As used herein, the term "SLFN11 deficiency" refers to an expression level of SLFN11 in a relevant patient, animal, tissue, cell, etc. that exhibits a normal phenotype associated with the gene or is insufficient for the protein to exhibit its physiological function. In the context of a preclinical model, a cell or animal in which the SLFN11 gene has been knocked out (KO) is an example of "SLFN11 deficiency."

[0029] In this specification, the general term "C p~q "Alkyl" includes both straight-chain and branched-chain alkyl groups. However, references to individual alkyl groups such as "propyl" are specific only to the straight-chain versions (i.e., n-propyl and isopropyl) and references to individual branched-chain alkyl groups such as "tert-butyl" are specific only to the branched-chain versions.

[0030] C p~q The prefix C in alkyl and other terms (where p and q are integers) p~q indicates the range of carbon atoms present in the group, e.g., C 1~4 Alkyl includes C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl (propyl, as n-propyl and isopropyl) and C4 alkyl (n-butyl, sec-butyl, isobutyl and tert-butyl).

[0031] C p~q The term alkoxy means -OC p~q Contains an alkyl group.

[0032] C p~q The term alkanoyl includes -C(O)alkyl groups.

[0033] The term "halo" includes fluoro, chloro, bromo and iodo.

[0034] "Carbocyclyl" refers to a saturated, unsaturated or partially saturated monocyclic ring system containing 3 to 6 ring atoms in which the ring CH2 group may be replaced by a C=O group.p~q Cycloalkyl" and "C p~q "Cycloalkenyl" is included.

[0035] "Aryl" means an aromatic monocyclic carbocyclyl ring system.

[0036] "C p~q "Cycloalkenyl" is an unsaturated or partially saturated monocyclic carbocyclyl ring system containing at least one C=C bond, in which the ring CH2 group may be replaced by a C=O group.

[0037] "C p~q "Cycloalkyl" is a saturated monocyclic carbocyclyl ring system in which the ring CH2 group may be replaced by a C=O group.

[0038] "Heterocyclyl" refers to a saturated, unsaturated or partially saturated monocyclic ring system containing from 3 to 6 ring atoms, of which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen, the ring may be carbon- or nitrogen-linked, the ring nitrogen or sulfur atoms may be oxidized, and the ring CH2 groups may be replaced with C=O groups. "Heterocyclyl" includes "heteroaryl", "cycloheteroalkyl" and "cycloheteroalkenyl".

[0039] "Heteroaryl" refers specifically to an aromatic monocyclic heterocyclyl having five or six ring atoms, of which one, two or three ring atoms are selected from nitrogen, sulfur or oxygen, and where the ring nitrogen or sulfur can be oxidized.

[0040] "Cycloheteroalkenyl" refers specifically to an unsaturated or partially saturated monocyclic heterocyclyl ring system having five or six ring atoms, of which one, two or three ring atoms are selected from nitrogen, sulfur or oxygen, the ring may be carbon- or nitrogen-linked, the ring nitrogen or sulfur atoms may be oxidized, and the ring CH2 groups may be replaced with C=O groups.

[0041] "Cycloheteroalkyl" refers specifically to a saturated monocyclic heterocyclic ring system having five or six ring atoms, of which one, two or three ring atoms are selected from nitrogen, sulfur or oxygen, the ring may be carbon- or nitrogen-linked, the ring nitrogen or sulfur atoms may be oxidized, and the ring CH2 groups may be replaced with C=O groups.

[0042] The present specification may use synthetic terms to describe groups that contain multiple functional groups. Unless otherwise stated in the specification, such terms are to be interpreted as understood in the art. For example, carbocyclyl C p~q Alkyl is substituted by carbocyclyl p~q Contains alkyl, heterocyclyl C p~q Alkyl is a C substituted by heterocyclyl p~q Contains alkyl, bis(C p~q Alkyl)amino is a substituted or unsubstituted aryl group having two C p~q Contains amino substituted by alkyl groups. p~q Alkyl is a C substituted by one or more halo substituents and in particular by one, two or three halo substituents. p~q Similarly, haloC p~q Other generic terms containing halo, such as alkoxy, may contain one or more halo substituents and particularly 1, 2 or 3 halo substituents.

[0043] Hydroxy C p~q Alkyl is a C substituted with one or more hydroxyl substituents and in particular with one, two or three hydroxyl substituents. p~q Similarly, hydroxy C p~q Other generic terms containing hydroxy, such as alkoxy, may contain one or more and particularly one, two or three hydroxy substituents.

[0044] C p~q Alkoxy C p~q Alkyl is one or more C p~q Alkoxy substituents and in particular 1, 2 or 3 C p~q C substituted by alkoxy substituents p~qIt is an alkyl group. Similarly, C p~q Alkoxy C p~q Alkoxy etc. C p~q Other general terms containing alkoxy include one or more C p~q Alkoxy substituents and in particular 1, 2 or 3 C p~q It may contain alkoxy substituents.

[0045] When optional substituents are selected from "one or two," "one, two or three," or "one, two, three or four" groups or substituents, this definition is understood to include either all substituents selected from one of the specified groups, i.e., all of the substituents are the same, or the substituents are selected from two or more of the specified groups, i.e., the substituents are not the same.

[0046] The compounds of the present disclosure were named using computer software (ACD / Name version 10.06).

[0047] Suitable values ​​for any R group or any moiety or substituent of such a group include the following: C 1~3 For alkyl: methyl, ethyl, propyl and isopropyl; C 1~6 For alkyl: C 1~3 Alkyl, butyl, 2-methylpropyl, tert-butyl, pentyl, 2,2-dimethylpropyl, 3-methylbutyl and hexyl; C 3~6 For cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C 3~6 Cycloalkyl C 1~3 For alkyl: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl; For aryl: phenyl; Aryl C 1~3 For alkyl: benzyl and phenethyl; Carbocylyl: aryl, cyclohexenyl and C 3~6 Cycloalkyl; For halo: fluoro, chloro, bromo and iodo; C 1~3 For alkoxy: methoxy, ethoxy, propoxy and isopropoxy; C 1~6 For alkoxy: C 1~3 Alkoxy, butoxy, tert-butoxy, pentyloxy, 1-ethylpropoxy and hexyloxy; C 1~3 For alkanoyl: acetyl and propanoyl; C 1~6 For alkanoyl: acetyl, propanoyl and 2-methylpropanoyl; For heteroaryl: pyridinyl, imidazolyl, pyrimidinyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, thiazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, pyridazinyl and pyrazinyl; Heteroaryl C 1~3 For alkyl: pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolylmethyl, pyrazolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, pyridinylmethyl, pyridinylethyl, pyrazinylmethyl, pyrazinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylpropyl, pyrimidinylbutyl, imidazolylpropyl, imidazolylbutyl, 1,3,4-triazolylpropyl and oxazolylmethyl; For heterocyclyl: heteroaryl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, dihydro-2H-pyranyl, tetrahydropyridine and tetrahydrofuranyl; For saturated heterocyclyl: oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, tetrahydropyranyl and tetrahydrofuranyl.

[0048] It should be noted that the examples given for the terms used in the detailed description are non-limiting.

[0049] As used herein, the phrase "effective amount" refers to an amount of a compound or composition that is sufficient to significantly and positively alter the symptoms and / or pathology being treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical product will vary within the knowledge and expertise of the attending physician depending on factors such as the specific pathology being treated, the severity of the pathology, the duration of treatment, the nature of the co-therapy, the specific active ingredient being used, the specific pharmaceutically acceptable excipient / carrier utilized, etc. In particular, an effective amount of a compound of formula (I) for use in the treatment of cancer in combination with an antibody-drug conjugate is an amount that is sufficient for the combination to alleviate the symptoms of cancer in a warm-blooded animal such as a human, delay the progression of cancer, or reduce the risk of progression in a patient with a cancer condition.

[0050] As used herein, the term "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals, commensurate with a reasonable benefit / risk ratio and without excessive toxicity, irritation, allergic response or other problem or complication.

[0051] Certain compounds of formula (I) can exist in stereoisomeric forms. It is understood that the present disclosure encompasses all geometric and optical isomers of compounds of formula (I) and mixtures thereof, including racemates. Tautomers and mixtures thereof also form an aspect of the present disclosure.

[0052] Solvates and mixtures thereof also form an aspect of the present disclosure. For example, a suitable solvate of a compound of formula (I) may be, for example, a hydrate, such as a hemi-hydrate, mono-hydrate, di-hydrate or tri-hydrate or alternative amounts thereof.

[0053] Insofar as any of the compounds of formula (I) as defined above may exist in optically active or racemic forms due to one or more asymmetric carbon or sulfur atoms, the present disclosure is understood to include in its definition any such optically active or racemic forms having the above-mentioned activity. The present disclosure encompasses all such stereoisomers having activity as defined herein. It is further understood that the designation of a chiral compound (R,S) represents any scalemic mixture or racemic mixture, with (R) and (S) representing enantiomers. It is understood that in the absence of (R,S), (R), or (S) in the designation, the designation refers to any scalemic mixture or racemic mixture, where a scalemic mixture contains the R and S enantiomers in any relative proportion, and a racemic mixture contains the R and S enantiomers in a 50:50 ratio. The synthesis of optically active forms can be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of racemic forms. Racemates can be separated into individual enantiomers using known procedures (see, for example, Advanced Organic Chemistry: 3rd Edition: author J March, p104-107). A suitable procedure involves the reaction of racemic material with a chiral auxiliary to form diastereomeric derivatives, followed by separation of the diastereomers, for example, by chromatography, and then cleavage of this auxiliary species. Similarly, the above-mentioned activities can be evaluated using standard laboratory techniques.

[0054] It will be understood that compounds of formula (I) may include compounds with one or more isotopic substitutions. For example, H is: 1 H, 2 H(D) and 3 H can be in any isotopic form, including T; C can be in any isotopic form, including T; 12 C. 13 C and 14 It can be in any isotopic form, including C; O is 16 O and 18 It can be any isotopic form containing O, etc.

[0055] The present disclosure may employ compounds of formula (I) as defined herein, as well as salts thereof. For use in pharmaceutical products, the salts will be pharma-ceutically acceptable salts, although other salts may be useful in the production of compounds of formula (I) and their pharma-ceutically acceptable salts.

[0056] The pharma- ceutically acceptable salts of the present disclosure may include, for example, acid addition salts of the compound of formula (I) as defined herein that are sufficiently basic to form such salts. Such acid addition salts include, but are not limited to, fumarate, methanesulfonate, hydrochloride, hydrobromide, citrate and maleate salts, and salts formed with phosphoric acid and sulfuric acid. Furthermore, when the compound of formula (I) is sufficiently acidic, the salt is a basic salt, for example, but is not limited to, alkali metal salts, such as sodium or potassium, alkaline earth metal salts, such as calcium or magnesium, or organic amine salts, such as triethylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, or amino acids, such as lysine.

[0057] The compounds of formula (I) may also be provided as in vivo hydrolyzable esters. In vivo hydrolyzable esters of compounds of formula (I) containing a carboxy or hydroxy group are, for example, pharma- ceutically acceptable esters that are cleaved in the human or animal body to produce the parent acid or alcohol. Such esters may be identified, for example, by intravenously administering the compound to a test animal under test, followed by testing the body fluids of the test animal.

[0058] Suitable pharma- ceutically acceptable esters for carboxy include C 1~6 Alkoxymethyl esters, e.g., methoxymethyl, C 1~6 Alkanoyloxymethyl esters, such as pivaloyloxymethyl, phthalidyl esters, C 3~8Cycloalkcarbonyloxy C 1~6 Alkyl esters such as 1-cyclohexylcarbonyloxyethyl, (1,3-dioxolen-2-one)ylmethyl esters such as (5-methyl-1,3-dioxolen-2-one)ylmethyl and C 1~6 Alkoxycarbonyloxyethyl esters, such as 1-methoxycarbonyloxyethyl, can be formed at any carboxy group in the compounds of the present disclosure.

[0059] Suitable pharma- ceutically acceptable esters for hydroxy include inorganic esters, such as phosphate esters (including phosphoramidite cyclic esters) and α-acyloxyalkyl ethers and related compounds which result in the parent hydroxy group upon in vivo hydrolysis of the ester decomposition. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Selection of in vivo hydrolyzable ester forming groups for hydroxy include C1- 10 Alkanoyl, for example, acetyl, benzoyl, phenylacetyl, substituted benzoyl and phenylacetyl; C 10 Alkoxycarbonyl (to give alkyl carbonate esters), such as ethoxycarbonyl; di-C1-4 alkylcarbamoyl and N-(di-C1-4 alkylaminoethyl)-N-C1-4 alkylcarbamoyl (to give carbamates); di-C1-4 alkylaminoacetyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include aminomethyl, C 1~4 These include alkylaminomethyl and di-(C1-4 alkyl)aminomethyl and morpholino or piperazino linked from the ring nitrogen atom through a methylene linking group to the 3- or 4-position of the benzoyl ring. Other in vivo hydrolyzable esters of interest include, for example, R A C(O)OC 1~6 Alkyl-CO- (wherein R A For example, benzyloxy-C 1~4Suitable substituents on the phenyl group in such esters include, for example, 4-C1-4 alkylpiperazino-C1-4 alkyl, piperazino-C1-4 alkyl and morpholino-C1-4 alkyl.

[0060] The compounds of formula (I) may also be administered in the form of a prodrug, which is broken down in the human or animal body to yield the compound of formula (I). Various forms of prodrugs are known in the art. Examples of such prodrug derivatives are listed below. a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et. al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, H. Bundgaard, p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N.Kakeya, et al., Chem Pharm Bull, 32, 692 (1984) Please refer to.

[0061] [Description of the embodiment] Hereinafter, preferred modes for carrying out the present disclosure will be described. The following embodiments 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.

[0062] 1. Antibody-drug conjugates The antibody-drug conjugates used in this disclosure have the following formula: [ka] (wherein A represents the attachment position to the antibody). is conjugated to the anti-TROP2 antibody via a thioether bond.

[0063] In the present disclosure, the partial structure consisting of the linker and the drug in the antibody-drug conjugate is called a "drug-linker". The drug-linker is 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 the antibody.

[0064] The drug-linker of the present disclosure includes exatecan (IUPAC name: (1S,9S)-1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-9-hydroxy-4-methyl-10H,13H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13-dione, (also represented as chemical name: (1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione) as a component, which is a topoisomerase I inhibitor. Exatecan has the following formula: [ka] It is a camptothecin derivative having an antitumor effect, represented by the following formula:

[0065] The anti-TROP2 antibody-drug conjugate used in this disclosure has the following formula: [ka] It can also be represented by:

[0066] Here, the drug-linker is conjugated to the anti-TROP2 antibody ("antibody-") via a thioether bond. The meaning of n is the same as that of what is called the average number of drug molecules conjugated (DAR; drug-antibody ratio), which indicates the average number of drug-linker units conjugated per antibody molecule.

[0067] After being transferred into the cancer cells, the anti-TROP2 antibody-drug conjugate used in the present disclosure is cleaved at the linker moiety to give the following formula: [ka] The compound is represented by:

[0068] 2. Anti-TROP2 antibodies in antibody-drug conjugates The anti-TROP2 antibody in the antibody-drug conjugate used in the present invention can be from any species, and is preferably from human, rat, mouse or rabbit. If the antibody is from a species other than the human species, it is preferably chimerized or humanized using well-known techniques. The antibody of the present invention can be a polyclonal antibody or a monoclonal antibody, and is preferably a monoclonal antibody.

[0069] The antibody in the antibody-drug conjugate used in the present invention is preferably an antibody having the characteristic of being able to target cancer cells, and is preferably an antibody having, for example, the property of being able to recognize cancer cells, the property of being able to bind to cancer cells, the property of being internalized into cancer cells, and / or cytocidal activity against cancer cells.

[0070] The binding activity of the antibody to cancer cells can be confirmed using flow cytometry. The internalization of the antibody into tumor cells can be confirmed using (1) an assay in which the binding of a secondary antibody (fluorescently labeled) to the therapeutic antibody is used to visualize the antibody taken up by the cell under a fluorescent microscope (Cell Death and Differentiation (2008) 15, 751-761), (2) an assay in which the binding of a secondary antibody (fluorescently labeled) to the therapeutic antibody is used to measure the intensity of the fluorescence taken up in the cell (Molecular Biology of the Cell, Vol. 15, 5268-5282, December 2004), or (3) a Mab-ZAP assay in which the binding of an immunotoxin to the therapeutic antibody is used, and the toxin is released upon uptake into the cell to inhibit cell proliferation (Bio Techniques 28: 162-165, January 2000). As the immunotoxin, a recombinant complex protein of the catalytic domain of diphtheria toxin and protein G can be used.

[0071] The antitumor activity of the antibody can be confirmed in vitro by measuring the inhibitory activity against cell growth.For example, a cancer cell line that overexpresses the target protein against the antibody is cultured, and the antibody is added to the culture system at various concentrations to measure the inhibitory activity against focus formation, colony formation and spheroid growth.For example, the antibody can be administered to nude mice transplanted with a cancer cell line that highly expresses the target protein, and the antitumor activity can be confirmed in vivo by measuring the change in the cancer cells.

[0072] Since the compound conjugated in the antibody-drug conjugate exerts an antitumor effect, it is preferable, but not essential, that the antibody itself has an antitumor effect. For the purpose of specifically and selectively exerting the cytotoxic activity of the antitumor compound on cancer cells, it is important and preferable that the antibody will have the property of being internalized and translocated into the cancer cells.

[0073] The antibody in the antibody-drug conjugate used in the present invention can be obtained by procedures known in the art.For example, the antibody of the present invention can be obtained using the method usually performed in the art, which involves immunizing animals with antigenic polypeptides and collecting and purifying the antibodies produced in vivo.The source of this antigen is not limited to humans, and animals can be immunized with antigens from non-human animals such as mice and rats.In this case, the antibody that binds to the obtained heterologous antigen can be tested for cross-reactivity with human antigens to screen for antibodies that can be applied to human diseases.

[0074] 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; Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, NY (1980)) to establish hybridomas, from which monoclonal antibodies can then be obtained.

[0075] The antigen can be obtained by genetically engineering a host cell to produce a gene encoding an antigen protein. Specifically, a vector capable of expressing the antigen gene is prepared and introduced into a host cell to express the gene. The antigen thus expressed can be purified. The antibody can also be obtained by immunizing an animal with the genetically engineered antigen-expressing cell or cell line expressing the antigen.

[0076] The antibody in the antibody-drug conjugate used in the present invention is preferably a recombinant antibody obtained by artificial modification aimed at reducing heterologous antigenicity to humans, such as a chimeric antibody or a humanized antibody, or is preferably an antibody derived from a human, i.e., an antibody having only the gene sequence of a human antibody. These antibodies can be produced using known methods.

[0077] 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 linked to the constant region of an antibody derived from a human (Proc. Natl. Acad. Sci. USA, 81, 6851-6855, (1984)).

[0078] Examples of humanized antibodies include antibodies obtained by incorporating only the complementarity determining region (CDR) 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 pamphlet), and antibodies humanized using a gene conversion mutagenesis strategy (U.S. Pat. No. 5,821,337 specification).

[0079] Examples of human antibodies include antibodies 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). As alternatives, there can be mentioned antibodies obtained by phage display and antibodies selected from human antibody libraries (see, for example, 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).

[0080] In the antibody in the antibody-drug conjugate used in the present invention, modified variants of the antibody are also included. Modified variants refer to variants obtained by subjecting the antibody according to the present invention to chemical or biological modification. Examples of chemically modified variants include variants including attachment of a chemical moiety to the amino acid backbone, variants including attachment of 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-terminal or C-terminal processing, deamidation, isomerization of aspartic acid, or oxidation of methionine) and variants in which a methionine residue is added to the N-terminus by expression in a prokaryotic host cell. Furthermore, antibodies labeled to enable detection or isolation of the antibody or antigen according to the present invention, such as enzyme-labeled, fluorescent-labeled, and affinity-labeled antibodies, are also included in the meaning of modified variants. Such modified variants of the antibody according to the present disclosure are useful for improving the stability and blood retention of the antibody, reducing its antigenicity, detection or isolation of the antibody or antigen, etc.

[0081] Furthermore, it is possible to enhance antibody-dependent cellular cytotoxicity by adjusting the modification (glycosylation, defucosylation, etc.) of the glycan linked to the antibody according to the present invention. Techniques for adjusting the modification of the glycan of an antibody are known in WO 99 / 54342, WO 00 / 61739, WO 02 / 31140, WO 2007 / 133855, WO 2013 / 120066, etc. However, this technique is not limited thereto. The antibody according to the present invention also includes an antibody in which the modification of the glycan is adjusted.

[0082] It is known that the lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in cultured mammalian cells is deleted (Journal of Chromatography A, 705:129-134 (1995)), and it is also known that 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 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 antibody according to the present invention includes an antibody subjected to such modification and a functional fragment of the antibody, and also includes a deletion variant in which one or two amino acids are deleted at the carboxyl terminus of the heavy chain, a variant obtained by amidation of the deletion variant (e.g., a heavy chain in which a proline residue at the carboxyl terminus is amidated), and the like. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present invention is not limited to the above variants, so long as the antigen-binding affinity and effector function are preserved. The two heavy chains constituting the antibody according to the present invention may be one type selected from the group consisting of a full-length heavy chain and the deletion variants described above, or a combination of two types selected from these. The ratio of the amount of each deletion variant may be influenced by the type and culture conditions of cultured mammalian cells producing the antibody according to the present invention, but a preferred example is an antibody in which one amino acid residue is deleted at the carboxyl termini of both of the two heavy chains in the antibody according to the present invention.

[0083] Examples of the isotype of the antibody according to the present invention include IgG (IgG1, IgG2, IgG3, IgG4). Preferably, IgG1 or IgG2 is mentioned.

[0084] In the present invention, the term "anti-TROP2 antibody" refers to an antibody that specifically binds to TROP2 (TACSTD2: tumor-associated calcium signal transducer 2; EGP-1), and preferably has internalization activity in TROP2-expressing cells upon binding to TROP2.

[0085] An example of an anti-TROP2 antibody is hTINA1-H1L1 (WO 2015 / 098099).

[0086] 3. Preparation of antibody-drug conjugates A drug-linker intermediate for use in making an antibody-drug conjugate according to the invention has the formula: [ka] It is expressed by:

[0087] The 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] It can be represented as indolizino[1,2-b]quinolin-1-yl]amino}-2-oxoethoxy)methyl]glycinamide, and can be produced by reference to the descriptions in International Publication Nos. 2014 / 057687, 2015 / 098099, 2015 / 115091, 2015 / 155998, and 2019 / 044947, etc.

[0088] The antibody-drug conjugates used in the present invention can be prepared by reacting the above-described drug-linker intermediates with an anti-TROP2 antibody bearing a thiol group (alternatively called a sulfhydryl group).

[0089] Anti-TROP2 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 antibody having sulfhydryl groups with partially or completely reduced interchain disulfides in the antibody can be obtained by reacting the antibody with a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) in a buffer containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA) using 0.3 to 3 molar equivalents per interchain disulfide in the antibody.

[0090] Furthermore, by using 2-20 molar equivalents of drug-linker intermediate per antibody bearing a sulfhydryl group, antibody-drug conjugates in which 2-8 drug molecules are conjugated per antibody molecule can be produced.

[0091] The average number of drug molecules conjugated per antibody molecule of the prepared antibody-drug conjugate can be determined, for example, by a calculation method based on measurement of UV absorption for the antibody-drug conjugate and a conjugated 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).

[0092] Conjugation between an antibody and a drug-linker intermediate and calculation of the average number of drug molecules conjugated per antibody molecule of an antibody-drug conjugate can be performed with reference to the descriptions in, for example, WO 2015 / 098099 and WO 2017 / 002776.

[0093] In the present invention, the term "anti-TROP2 antibody-drug conjugate" refers to an antibody-drug conjugate according to the present invention, in which the antibody in the antibody-drug conjugate according to the present invention is an anti-TROP2 antibody.

[0094] The anti-TROP2 antibody is preferably an antibody comprising a heavy chain comprising a CDRH1 consisting of the amino acid sequence represented by SEQ ID NO:3 [= the amino acid sequence consisting of amino acid residues 50 to 54 of SEQ ID NO:1], a CDRH2 consisting of the amino acid sequence represented by SEQ ID NO:4 [= the amino acid sequence consisting of amino acid residues 69 to 85 of SEQ ID NO:1], and a CDRH3 consisting of the amino acid sequence represented by SEQ ID NO:5 [= the amino acid sequence consisting of amino acid residues 118 to 129 of SEQ ID NO:1], and a light chain comprising a CDRL1 consisting of the amino acid sequence represented by SEQ ID NO:6 [= the amino acid sequence consisting of amino acid residues 44 to 54 of SEQ ID NO:2], a CDRL2 consisting of the amino acid sequence represented by SEQ ID NO:7 [= the amino acid sequence consisting of amino acid residues 70 to 76 of SEQ ID NO:2], and a CDRL3 consisting of the amino acid sequence represented by SEQ ID NO:8 [= the amino acid sequence consisting of amino acid residues 109 to 117 of SEQ ID NO:2], More preferably, the antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO:9 [= the amino acid sequence consisting of amino acid residues 20 to 140 of SEQ ID NO:1] and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO:10 [= the amino acid sequence consisting of amino acid residues 21 to 129 of SEQ ID NO:2], Even more preferably, the antibody comprises a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12 [= the amino acid sequence consisting of amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13 [= the amino acid sequence consisting of amino acid residues 21 to 234 of SEQ ID NO: 2], or the antibody comprises a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 [= the amino acid sequence consisting of amino acid residues 20 to 469 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13 [= the amino acid residues 21 to 234 of SEQ ID NO: 2].

[0095] The average number of drug-linker conjugate units per antibody molecule in the anti-TROP2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, even more preferably 3.5 to 4.5, and even more preferably about 4.

[0096] Anti-TROP2 antibody-drug conjugates can be prepared with reference to the descriptions in WO 2015 / 098099 and WO 2017 / 002776.

[0097] In a preferred embodiment, the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

[0098] 4. ATR Inhibitors In the present disclosure, the term "ATR inhibitor" refers to an agent that inhibits ATR (ataxia telangiectasia and rad3-related kinase). The ATR inhibitor of the present disclosure may selectively inhibit the kinase ATR, or may non-selectively inhibit ATR and inhibit kinases other than ATR. The ATR inhibitor in the present disclosure is not particularly limited as long as it is an agent having the described properties, and preferred examples thereof may include those disclosed in WO2011 / 154737.

[0099] Other examples of ATR inhibitors that can be used in accordance with the present disclosure are beruzosertib (M6620; VX-970), M4344 (VX-803), BAY-1895344, ETP-46464, and VE-821.

[0100] Preferably, the ATR inhibitors of the present disclosure selectively inhibit ATR.

[0101] According to a preferred embodiment of the ATR inhibitor used in the present disclosure, the ATR inhibitor has the following formula (I): [ka] (In the formula, R 1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; R 2 teeth, [ka] and; n is 0 or 1; R 2A , R 2C , R 2E and R 2F are each independently hydrogen or methyl; R 2B and R 2D are each independently hydrogen or methyl; R 2G -NHR 7 and -NHCOR 8 Selected from; R 2H is fluoro; R 3 is methyl; R 4 and R 5 are each independently hydrogen or methyl, or R 4 and R 5 form ring A together with the atoms to which they are attached; Ring A is a C ring containing one heteroatom selected from O and N. 3~6 cycloalkyl or a saturated 4-6 membered heterocycle; R 6 is hydrogen; R 7 is hydrogen or methyl; R 8 is methyl) A compound represented by or a pharma- ceutically acceptable salt thereof.

[0102] In a preferred embodiment, the ATR inhibitor is represented by formula (I): R 1 is 3-methylmorpholin-4-yl; R 2 teeth, [ka] and; n is 0 or 1; R 2A , R 2C , R 2E and R 2Fare each independently hydrogen or methyl; R 2B and R 2D are each independently hydrogen or methyl; R 2G is selected from -NH2, -NHMe, and -NHCOMe; R 2H is fluoro; R 3 is methyl; R 4 and R 5 are each independently hydrogen or methyl, or R 4 and R 5 form ring A together with the atoms to which they are attached; Ring A is a C ring containing one heteroatom selected from O and N. 3~6 cycloalkyl or a saturated 4-6 membered heterocycle; R 6 is hydrogen) A compound represented by or a pharma- ceutically acceptable salt thereof.

[0103] Further embodiments of the ATR inhibitors include those having rings A, n, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 is a compound of formula (I) as defined below, and pharma- ceutically acceptable salts thereof. Such particular substituents may be used where appropriate with any of the definitions, claims or embodiments defined herein.

[0104] n In one embodiment, n is 0. In another embodiment, n is 1.

[0105] R 1 In one embodiment, R 1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl. In a further embodiment, R 1 is 3-methylmorpholin-4-yl. In a further embodiment, R 1 teeth, [ka] It is. In a further embodiment, R 1 teeth, [ka] It is.

[0106] R 2 In one embodiment, R 2 teeth, [ka] It is. In another embodiment, R 2 teeth, [ka] It is. In another embodiment, R 2 teeth, [ka] It is. In another embodiment, R 2 teeth, [ka] It is.

[0107] R 2A In one embodiment, R 2A is hydrogen.

[0108] R 2B In one embodiment, R 2B is hydrogen.

[0109] R2C In one embodiment, R 2C is hydrogen.

[0110] R 2D In one embodiment, R 2D is hydrogen.

[0111] R 2E In one embodiment, R 2E is hydrogen.

[0112] R 2F In one embodiment, R 2F is hydrogen.

[0113] R 2G In one embodiment, R 2G NHR 7 and -NHCOR 8 is selected from. In another embodiment, R 2G -NHR 7 It is. In another embodiment, R 2G -NHCOR 8 It is. In another embodiment, R 2G is selected from -NH2, -NHMe and -NHCOMe. In another embodiment of the present disclosure, R 2G is -NH2. In another embodiment, R 2G is -NHMe. In another embodiment, R 2G is -NHCOMe.

[0114] R 4 and R 5 In one embodiment, R 4 and R 5 is hydrogen. In another embodiment, R 4 and R 5 is methyl. In another embodiment, R 4 and R 5 together with the atoms to which they are attached form ring A.

[0115] Ring A In one embodiment, ring A is a C ring containing one heteroatom selected from O and N. 3~6 It is cycloalkyl or a saturated 4-6 heterocycle. In another embodiment, ring A is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl ring. In another embodiment, ring A is a cyclopropyl, cyclobutyl, cyclopentyl, tetrahydropyranyl, or piperidinyl ring. In another embodiment, ring A is a cyclopropyl, cyclopentyl, tetrahydropyranyl, or piperidinyl ring. In another embodiment, ring A is a cyclopropyl, tetrahydropyranyl, or piperidinyl ring. In another embodiment, ring A is a cyclopropyl or tetrahydropyranyl ring. In another embodiment, ring A is a piperidinyl ring. In another embodiment, ring A is a tetrahydropyranyl ring. In another embodiment, ring A is a cyclopropyl ring.

[0116] R 6 In one embodiment, R 6 is hydrogen.

[0117] R 7 In one embodiment, R 7 is hydrogen or methyl. In another embodiment, R 7 is methyl. In another embodiment, R 7 is hydrogen.

[0118] R 8 In one embodiment, R 12 is methyl.

[0119] In one embodiment of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, R 1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; R 2G -NHR 7 and -NHCOR 8 Selected from; R 2H is fluoro; R 3 is methyl; R 4 and R 5 form ring A together with the atoms to which they are attached; Ring A is a C ring containing one heteroatom selected from O and N. 3~6 cycloalkyl or saturated 4-6 heterocycle; R 6 is hydrogen; R 7 is hydrogen or methyl; R 8 is methyl.

[0120] In another embodiment, R 1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R 2A is hydrogen; R2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; R 2G is selected from -NH2, -NHMe, and -NHCOMe; R 2H is fluoro; R 3 is methyl; R 4 and R 5 form ring A together with the atoms to which they are attached; Ring A is a C ring containing one heteroatom selected from O and N. 3~6 cycloalkyl or saturated 4-6 heterocycle; R 6 is hydrogen.

[0121] In another embodiment, R 1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; R 2G -NHR 7 and -NHCOR 8 Selected from; R 2H is fluoro; R 3 is methyl; R 4 and R 5form ring A together with the atoms to which they are attached; Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl ring; R 6 is hydrogen; R 7 is hydrogen or methyl; R 8 is methyl.

[0122] In another embodiment, R 1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; n is 0 or 1; R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; R 2G is selected from -NH2, -NHMe, and -NHCOMe; R 2H is fluoro; R 3 is methyl; R 4 and R 5 form ring A together with the atoms to which they are attached; Ring A is a cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, or piperidinyl ring; R 6 is hydrogen.

[0123] In another embodiment, the compound of formula (I) is a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring; R 2 teeth, [ka] and; n is 0 or 1; R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; R 2G -NHR 7 and -NHCOR 8 Selected from; R 2H is fluoro; R 3 is a methyl group; R 6 is hydrogen; R 7 is hydrogen or methyl; R 8 is methyl.

[0124] In another embodiment, the compound of formula (I) is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof, wherein: Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring; R 2 teeth, [ka] and; n is 0 or 1; R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; R 2G is selected from -NH2, -NHMe, and -NHCOMe; R 2H is fluoro; R 3 is a methyl group; R 6 is hydrogen.

[0125] In another embodiment, the compound of formula (I) is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof, wherein: Ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring; R 2 teeth, [ka] and; n is 0 or 1; R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; R 2G -NHR 7 and; R 2H is fluoro; R 3 is a methyl group; R 6 is hydrogen; R 7is hydrogen.

[0126] In another embodiment, the compound of formula (I) is a compound of formula (Ia) or a pharma- ceutically acceptable salt thereof, wherein: Ring A is a cyclopropyl ring; R 2 teeth, [ka] and; n is 0; R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen; R 2G -NHR 7 and; R 2H is fluoro; R 3 is a methyl group; R 6 is hydrogen; R 7 is methyl.

[0127] In other embodiments, the ATR inhibitor used in the present disclosure is 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[((R)-S-methylsulfonimidoyl)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indole; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-indole; 1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-c]pyridine; N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((R)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[4-((S)-S-methylsulfonimidoyl)tetrahydro-2H-pyran-4-yl]pyrimidin-2-yl}-1H-indole; 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 4-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((R)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 5-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 6-Fluoro-N-methyl-1-{4-[1-methyl-1-((S)-S-methylsulfonimidoyl)ethyl]-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 5-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; 6-Fluoro-N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine A compound selected from and pharma-ceutically acceptable salts thereof.

[0128] In other embodiments, the ATR inhibitor used in the present disclosure is 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[(R)-(S-methylsulfonimidoyl)methyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine; 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine; N-methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine; N-Methyl-1-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-benzimidazol-2-amine A compound selected from and pharma-ceutically acceptable salts thereof.

[0129] In a preferred embodiment, the ATR inhibitor used in the present disclosure has the following formula: [ka] The compound AZD6738, 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine, represented by or a pharma- ceutically acceptable salt thereof.

[0130] ATR inhibitors such as compounds of formula (I), including AZD6738, may be prepared by methods known in the art, such as those disclosed in WO 2011 / 154737.

[0131] 5. Combination of antibody-drug conjugates with ATR inhibitors In a first combination embodiment of the disclosure, the anti-TROP2 antibody-drug conjugate in combination with the ATR inhibitor has the following formula: [ka] wherein A represents the attachment position relative to the antibody, is conjugated to the anti-TROP2 antibody via a thioether bond.

[0132] In another combination embodiment, the anti-TROP2 antibody-drug conjugate as defined above for the first combination embodiment has the following formula (I): [ka] (In the formula, R 1 is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; R 2 teeth, [ka] and; n is 0 or 1; R 2A , R 2C , R 2E and R 2F are each independently hydrogen or methyl; R 2B and R 2D are each independently hydrogen or methyl; R 2G -NHR 7 and -NHCOR 8 Selected from; R 2His fluoro; R 3 is methyl; R 4 and R 5 are each independently hydrogen or methyl, or R 4 and R 5 form ring A together with the atoms to which they are attached; Ring A is a C ring containing one heteroatom selected from O and N. 3~6 cycloalkyl or a saturated 4-6 membered heterocycle; R 6 is hydrogen; R 7 is hydrogen or methyl; R 8 is methyl) A compound represented by or a pharma- ceutically acceptable salt thereof.

[0133] In another combination embodiment, an anti-TROP2 antibody-drug conjugate as defined above is combined with an ATR inhibitor which is a compound represented by formula (I) as defined above, wherein R 4 and R 5 together with the atom to which they are attached form a ring A, ring A containing one heteroatom selected from O and N 3~6 It is cycloalkyl or a saturated 4-6 heterocycle.

[0134] In another combination embodiment, an anti-TROP2 antibody-drug conjugate as defined above is combined with an ATR inhibitor as defined above, 4 and R 5 together with the atoms to which they are attached form ring A, ring A being a cyclopropyl, tetrahydropyranyl or piperidinyl ring.

[0135] In another combination embodiment, an anti-TROP2 antibody-drug conjugate as defined above is combined with an ATR inhibitor as defined above,2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R 2F is hydrogen.

[0136] In another combination embodiment, an anti-TROP2 antibody-drug conjugate as defined above is combined with an ATR inhibitor as defined above, 1 is 3-methylmorpholin-4-yl.

[0137] In another combination embodiment, an anti-TROP2 antibody-drug conjugate as defined above is combined with an ATR inhibitor as defined above, and the compound of formula (I) is represented by formula (Ia): [ka] Compound or a pharma- ceutically acceptable salt thereof.

[0138] In another combination embodiment, an anti-TROP2 antibody-drug conjugate as defined above is combined with an ATR inhibitor as defined above, and the compound of formula (I) is a compound of formula (Ia), wherein: Ring A is a cyclopropyl ring; R 2 teeth, [ka] and; n is 0 or 1; R 2A is hydrogen; R 2B is hydrogen; R 2C is hydrogen; R 2D is hydrogen; R 2E is hydrogen; R2F is hydrogen; R 2G -NHR 7 and; R 2H is fluoro; R 3 is a methyl group; R 6 is hydrogen; R 7 is hydrogen or methyl.

[0139] In another combination embodiment, an anti-TROP2 antibody-drug conjugate as defined above is combined with an ATR inhibitor as defined above, wherein the ATR inhibitor has the following formula: [ka] AZD6738 represented by or a pharma- ceutically acceptable salt thereof.

[0140] In each of the above combination embodiments, the anti-TROP2 antibody comprises a heavy chain comprising a CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 3 [= amino acid residues 50 to 54 of SEQ ID NO: 1], a CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 4 [= amino acid residues 69 to 85 of SEQ ID NO: 1], and a CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 5 [= amino acid residues 118 to 129 of SEQ ID NO: 1], and a light chain comprising a CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 6 [= amino acid residues 44 to 54 of SEQ ID NO: 2], a CDRL2 consisting of the amino acid sequence represented by SEQ ID NO: 7 [= amino acid residues 70 to 76 of SEQ ID NO: 2], and a CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 8 [= amino acid residues 109 to 117 of SEQ ID NO: 2]. In another embodiment of each of the above combination embodiments, the anti-TROP2 antibody comprises a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9 [= amino acid residues 20 to 140 of SEQ ID NO: 1] and a light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 10 [= amino acid residues 21 to 129 of SEQ ID NO: 2]. In another embodiment of each of the above combination embodiments, the anti-TROP2 antibody comprises a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 12 [= amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain comprising an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2]. In another embodiment of each of the above combination embodiments, the anti-TROP2 antibody comprises a heavy chain comprising an amino acid sequence represented by SEQ ID NO: 11 [= amino acid residues 20 to 469 of SEQ ID NO: 1] and a light chain comprising an amino acid sequence represented by SEQ ID NO: 13 [= amino acid residues 21 to 234 of SEQ ID NO: 2].

[0141] In a particularly preferred combination embodiment of the disclosure, the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062) and the ATR inhibitor is of the following formula: [ka] The compound is represented by the formula: which is also identified as AZD6738.

[0142] 6. Therapeutic Combination Uses and Methods Pharmaceutical products and therapeutic uses and methods in which an anti-TROP2 antibody-drug conjugate according to the present disclosure and an ATR inhibitor are administered in combination are described below.

[0143] The pharmaceutical products and therapeutic uses and methods of the present disclosure may be characterized in that the anti-TROP2 antibody-drug conjugate and the ATR inhibitor are contained separately as active ingredients in different formulations and are administered at the same time or at different times.

[0144] In the pharmaceutical products and therapeutic methods of the present disclosure, a single ATR inhibitor used in the present disclosure may be administered in combination with an anti-TROP2 antibody-drug conjugate, or two or more different ATR inhibitors may be administered in combination with an antibody-drug conjugate.

[0145] The pharmaceutical products and therapeutic methods of the present disclosure may be used to treat cancer, preferably breast cancer (including triple-negative breast cancer and hormone receptor (HR)-positive, HER2-negative breast cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), colorectal cancer (also called colon and rectal cancer, including colon and rectal cancer), gastric cancer (also called gastric adenocarcinoma), 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 tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, uterine body carcinoma, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasma cell carcinoma, leukemia, lymphoma, thyroid cancer, penile cancer, leukemia, lymphoma, thyroid cancer ... The pharmaceutical product and the method of treatment of the present disclosure may be used to treat at least one cancer selected from the group consisting of breast cancer (preferably triple-negative breast cancer and hormone receptor (HR)-positive, HER2-negative breast cancer), lung cancer (preferably non-small cell lung cancer, non-small cell lung cancer with actionable genomic alterations and non-small cell lung cancer without actionable genomic alterations, the actionable genomic alterations including EGFR, ALK, ROS1, NTRK, BRAF, RET and MET exon 14 skipping), colorectal cancer, gastric cancer, pancreatic cancer, ovarian cancer, prostate cancer and renal cancer. Furthermore, the pharmaceutical product and the method of treatment of the present disclosure may be preferably used to treat cancers that lack homologous recombination (HR)-dependent DNA DSB repair activity or cancers that do not lack homologous recombination (HR)-dependent DNA DSB repair activity. Furthermore, the pharmaceutical products and methods of treatment of the present disclosure may preferably be used to treat cancers that are resistant or refractory to previous treatment with a PARP inhibitor, particularly a PARP inhibitor selected from olaparib, rucaparib, niraparib, talazoparib and veliparib.The presence or absence of the TROP2 tumor marker can be determined, for example, by obtaining 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), for example by immunohistochemistry (IHC), flow cytometry or Western blot methods, or testing for gene transcription, for example using in situ hybridization (ISH), quantitative PCR (q-PCR) or microarray analysis, or by recovering cell-free circulating tumor DNA (ctDNA) from a cancer patient and subjecting the ctDNA to testing by methods such as next generation sequencing (NGS).

[0146] The pharmaceutical products and methods of treatment of the present disclosure may be used preferably on mammals, and more preferably on humans.

[0147] The antitumor effect of the pharmaceutical product and treatment method of the present disclosure can be confirmed, for example, by preparing a model in which cancer cells are transplanted into a test animal and measuring the reduction in tumor volume and the life-prolonging effect by applying the pharmaceutical product and treatment method of the present disclosure. Furthermore, the combined effect of the antibody-drug conjugate and the ATR inhibitor used in the present disclosure can be confirmed by comparing with the antitumor effect of a single administration of each of the antibody-drug conjugate and the ATR inhibitor used in the present disclosure.

[0148] Furthermore, the antitumor effects of the pharmaceutical products and treatment methods of the present disclosure may be confirmed in clinical trials using the Response Evaluation Criteria in Solid Tumor (RECIST) evaluation method, the WHO evaluation method, the Macdonald evaluation method, body weight measurement, and other methods; and may be determined by indicators such as complete response (CR), partial response (PR); progressive disease (PD), objective response rate (ORR), duration of response (DoR), progression-free survival rate (PFS), and overall survival rate (OS).

[0149] The aforementioned method may provide confirmation of the superiority of the pharmaceutical products and treatment methods of the present disclosure in terms of anti-tumor effects compared to existing pharmaceutical products and treatment methods for cancer treatment.

[0150] The pharmaceutical products and treatment methods of the present disclosure can delay the growth of cancer cells, inhibit their proliferation, and even kill cancer cells. These effects can enable cancer patients to be relieved from symptoms caused by cancer, or can achieve an improvement in the QOL of cancer patients, and can play a therapeutic role by prolonging the life of cancer patients. Even if the pharmaceutical products and treatment methods do not achieve the death of cancer cells, they can inhibit or control the proliferation of cancer cells, thereby achieving longer survival and at the same time improving the QOL of cancer patients.

[0151] The pharmaceutical product of the present invention is expected to exert a therapeutic effect when administered to a patient as a systemic therapy, and also when administered locally to cancer tissue.

[0152] In another aspect, the pharmaceutical products and methods 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 a therapeutically effective amount of the pharmaceutical product, either simultaneously or sequentially with ionizing radiation or other chemotherapeutic agents.

[0153] The pharmaceutical products and treatment methods of the present disclosure can be used as adjuvant chemotherapy in combination with surgery. The pharmaceutical products of the present disclosure can be administered before surgery to reduce tumor size (called neoadjuvant chemotherapy or neoadjuvant therapy), or after surgery to prevent tumor recurrence (called postoperative adjuvant chemotherapy or adjuvant therapy).

[0154] In a further aspect, the pharmaceutical product of the present disclosure can be used for the treatment of cancers with defective homologous recombination (HR)-dependent DNA DSB repair activity. The HR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA through a homologous mechanism and reforms a continuous DNA helix (KK Khanna and SP Jackson, Nat. Genet. 27(3):247-254(2001)). Components of the HR-dependent DNA DSB repair pathway include ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432). , RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE11A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the HR-dependent DNA DSB repair pathway include regulators such as EMSY (Hughes-Davies, et al., Cell, 115, pp523-535). HR components are also described in Wood, et al., Science, 291, 1284-1289 (2001). A cancer with a defect in HR-dependent DNA DSB repair may comprise or consist of one or more cancer cells that have a reduced or eliminated ability to repair DNA DSBs through the repair pathway compared to normal cells, i.e., the activity of the HR-dependent DNA DSB repair pathway may be reduced or eliminated in one or more cancer cells. The activity of one or more components of the HR-dependent DNA DSB repair pathway may be eliminated in one or more cancer cells of an individual with a cancer with a defect in HR-dependent DNA DSB repair. Components of the HR-dependent DNA DSB repair pathway have been well characterized in the art (see, for example, Wood, et al., Science, 291, 1284-1289 (2001)) and include the components listed above.

[0155] In some embodiments, the cancer cells may have a BRCA1 and / or BRCA2 deficient phenotype, i.e., BRCA1 and / or BRCA2 activity is reduced or absent in the cancer cells. Cancer cells with this phenotype may lack BRCA1 and / or BRCA2, i.e., BRCA1 and / or BRCA2 expression and / or activity may be reduced or absent in the cancer cells, for example, by mutations or polymorphisms in the encoding nucleic acid, or by amplification, mutation or polymorphisms in genes encoding regulators, such as 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 well 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, for example, in Hughes-Davies, et al., Cell, 115, 523-535).

[0156] 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.

[0157] The pharmaceutical product of the present disclosure may be administered as a pharmaceutical composition containing at least one pharma- ceutical suitable component. The pharma-ceutical suitable component may be appropriately selected and applied from formulation additives commonly used in the art, etc., depending on the dosage, administration concentration, etc., of the antibody-drug conjugate and ATR inhibitor used in the present disclosure. For example, the antibody-drug conjugate used in the present disclosure may be administered as a pharmaceutical composition containing a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as polysorbate 80 or 20. The pharmaceutical product containing the antibody-drug conjugate used in the present disclosure may be preferably used as an injection, more preferably used as an aqueous injection or a lyophilized injection, and even more preferably used as a lyophilized injection. When the pharmaceutical product containing the anti-TROP2 antibody-drug conjugate used in the present disclosure is an aqueous injection, it may be preferably diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, dextrose solution, saline, etc. may be exemplified, dextrose solution may be preferably exemplified, and 5% dextrose solution may be more preferably exemplified. When the pharmaceutical product of the present disclosure is a lyophilized injection, it can be preferably dissolved in water for injection, and then the required amount can be diluted with a suitable diluent, and then given as intravenous infusion.For the diluent, dextrose solution, saline solution, etc. can be mentioned, dextrose solution can be preferably mentioned, and 5% dextrose solution can be more preferably mentioned.

[0158] Examples of routes of administration that may be used to administer the pharmaceutical products of the present disclosure include intravenous, intradermal, subcutaneous, intramuscular and intraperitoneal routes, preferably the intravenous route.

[0159] The anti-TROP2 antibody-drug conjugate used in the present disclosure may be administered to a human once at intervals of 1 to 180 days, preferably once a week, once every two weeks, once every three weeks, or once every four weeks, and more preferably once every three weeks. The antibody-drug conjugate used in the present invention may be administered at a dose of about 0.001 to 100 mg / kg, preferably at a dose of 0.8 to 12.4 mg / kg, and more preferably at a dose of 6 mg / kg. For example, the anti-TROP2 antibody-drug conjugate may be administered at a dose of 0.27 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg once every three weeks, and preferably at a dose of 6.0 mg / kg once every three weeks.

[0160] For example, a formulation of the ATR inhibitor compound of formula (I) intended for oral administration to humans generally contains, for example, 1 mg to 1000 mg of active ingredient, which is formulated with an appropriate and convenient amount of excipients, which may vary from about 5 to about 98 weight percent of the total composition. For further information on routes of administration and dosing regimens, see Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0161] The size of the dose required for therapeutic treatment of a particular condition will necessarily vary depending on the subject being treated, the route of administration, and the severity of the disease being treated. A daily dose of the ATR inhibitor ranging from 0.1 to 50 mg / kg may be used. For example, the ATR inhibitor is preferably administered daily for weeks 1, 2, and / or 3 of a three-week cycle, such as days 3 to 17 of a three-week cycle. For example, when the ATR inhibitor used in the present disclosure is the compound AZD6738 or a pharma- ceutically acceptable salt thereof, the ATR inhibitor may be administered orally, preferably twice daily, at a dose of 20 mg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 200 mg, or 240 mg per dose. EXAMPLES

[0162] 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.

[0163] Example 1: Production of anti-TROP2 antibody-drug conjugates According to the preparation method described in WO 2015 / 098099 and WO 2017 / 002776, an anti-TROP2 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12 [amino acid residues 20 to 470 of SEQ ID NO: 1] and a light chain consisting of the amino acid sequence represented by SEQ ID NO: 13 [=amino acid residues 21 to 234 of SEQ ID NO: 2]) was prepared by the following reaction using an anti-TROP2 antibody having the following formula: [ka] An anti-TROP2 antibody-drug conjugate was prepared in which a drug-linker represented by the formula (wherein A represents the attachment position to the antibody) is conjugated to an anti-TROP2 antibody via a thioether bond (DS-1062: datopotamab deruxtecan). The DAR of this antibody-drug conjugate is about 4.

[0164] Example 2: Preparation of ATR inhibitors According to the preparation method described in WO 2011 / 154737, the ATR inhibitor of formula (I) is prepared. Specifically, 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine: [ka] can be prepared according to Example 2.02 of WO 2011 / 154737.

[0165] Example 3: Antitumor Testing Combination of antibody-drug conjugate DS-1062 (datopotamab deruxtecan) with AZD6738 (4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine) method: A high-throughput combination screen was performed in which six lung and five breast cancer cell lines (Table 1) were treated with a combination of DS-1062 and AZD6738 (an ATR inhibitor).

[0166] [Table 1]

[0167] The readout of the screen was a 7-day CellTiter-Glo cell viability assay performed as a 6x6 dose-response matrix (5-point log serial dilutions for DS-1062 and half-log serial dilutions for AZD6738). The maximum concentrations were 3 μM for AZD6738 and 10 μg / ml for DS-1062. In addition, exatecan (a DNA topoisomerase I inhibitor) was also screened in parallel with AZD6738 to aid in deconvolution of the mechanism of action of effective combinations. Combination activity was assessed based on a combination of combination Emax and Loewe synergy scores.

[0168] result: Results for the combination of DS-1062+AZD6738 are shown for TROP2-expressing lung cancer cell lines (NCIH1650, NCI-H322, NCI-H3255, HCC2935) in Figures 12A and 12B and Table 2, and for TROP2-expressing breast cancer cell lines (HCC70, HCC1806, MDA-MB-468, HCC38) in Figures 13A and 13B and Table 3.

[0169] Figures 12A and 13A show a matrix of measured cell viability signals. The X-axis represents drug A (DS-1062) and the Y-axis represents drug B (AZD6738). Values ​​in boxes represent the ratio of cells treated with drugs A+B compared to DMSO control at day 7. All values ​​are normalized to cell viability values ​​at day 0. Values ​​between 0 and 100 represent the percentage of growth inhibition, values ​​above 100 represent cell death.

[0170] 12B and 13B show the Loewe excess matrices. Values ​​in the boxes represent excess values ​​calculated by the Loewe additive model.

[0171] Tables 2 and 3 show the HSA and Loewe additive scores and the combined Emax.

[0172] [Table 2]

[0173] [Table 3]

[0174] Note: Loewe dose additivity predicts the expected response when two compounds act on the same molecular target by the same mechanism. It calculates additivity based on the assumption of zero interaction between the compounds and is independent of the nature of the dose-response relationship.

[0175] HSA (maximal single agent) [Berenbaum 1989] quantifies the higher of the effects of two single compounds at their corresponding concentrations. The combined effect is compared to the effect of each single agent at the concentration used in the combination. An excess over the maximum single agent effect indicates synergy. HSA does not require that the compounds affect the same target.

[0176] Excess Matrix: For each well in the concentration matrix, the measured or fitted value is compared to the predicted non-synergistic value for each concentration pair. This predicted value is determined by the selected model. The difference between the predicted and observed values ​​may indicate synergy or antagonism and is shown in the excess matrix. The excess matrix values ​​are summarized by a combined score of the excess amount and the synergy score.

[0177] Combination Emax: Maximum antiproliferative effect observed in the combination matrix tested. All values ​​are normalized to the cell viability value at day 0. Values ​​between 0 and 100 represent % growth inhibition, values ​​above 100 represent cell death.

[0178] FIG. 14 shows the combination Emax and Loewe synergy scores in various cell lines treated with DS-1062 in combination with AZD6738.

[0179] As can be seen from Figures 12A and 12B and Table 2, AZD6738 interacted synergistically with DS-1062 and increased cell death in TROP2-expressing lung cancer cell lines. As can be seen from Figures 13A and 13B and Table 3, AZD6738 interacted synergistically with DS-1062 and increased cell death in TROP2 breast cancer cell lines with Emax (3 μM AZD6738 and 10 μg / ml DS-1062). As can be seen from Figure 14, treatment with DS-1062 in combination with AZD6738 resulted in high combination Emax (>100) and high Loewe synergy scores (>5) in eight cell lines.

[0180] The results in Example 3 show that ATR inhibition with AZD6738 enhances the antitumor efficacy of DS-1062 in lung and breast cancer cell lines expressing TROP2 in vitro. In Example 3, AZD6738 in combination with DS-1062 showed combination benefit in four TROP2-expressing lung cancer cell lines (Figures 12A, 12B, 14 and Table 2) and four TROP2-expressing breast cancer cell lines (Figures 13A, 13B and 14 and Table 3).

[0181] Example 4: Antitumor testing - in vivo - NCI-N87 xenograft model Combination of the antibody-drug conjugate DS-1062 (datopotamab deruxtecan) with the ATR inhibitor AZD6738 (4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine) method: Female nude mice (Charles River) aged 5-8 weeks were used and were included in the study after 7 days of acclimation. 6 NCI-N87 tumor cells (gastric cancer cell line) (1:1 in Matrigel) were implanted subcutaneously into the flanks of female nude mice. Tumors grew to approximately 250 mm 3 Once tumor size was reached, equivalent sized tumors were randomly assigned to treatment groups as shown in Table 4.

[0182] [Table 4]

[0183] The dose of compound for each animal was calculated based on individual body weight on the day of dosing. DS-1062 and AZD6738 were dosed on the same day, with DS-1062 administered approximately 5 hours after AZD6738 PO administration. DS-1062 was administered as a single dose of 10 mg / kg on day 1, and AZD6738 was administered at 25 mg / kg QD for 14 days. The dosing period was 14 days.

[0184] Formulation of DS-1062 at 10mg / kg Dosing solutions for DS-1062 were prepared on the day of dosing by diluting DS-1062 stock solution (20.1 mg / ml) in 25 mM histidine buffer, 9% sucrose, pH 5.5, to 0.6 mg / ml and 2 mg / ml for the 3 mg / kg and 10 mg / kg dosing solutions, respectively. Each dosing solution was mixed thoroughly using a pipette and then administered by IV injection at a dosing volume of 5 ml / kg.

[0185] AZD6738 formulation at 25mg / kg To formulate a 25 mg / kg dosing solution, a concentration of 2.5 mg / ml AZD6738 was prepared to give a dosing volume of 10 ml / kg for PO dosing. DMSO (10% of total vehicle volume) was added to the compound and mixed thoroughly with a pellet pestle. Approximately 5 minutes of sonication was required to completely dissolve the compound. Propylene glycol (40% of total vehicle volume) was then added and mixed thoroughly using a magnetic stirrer. A volume of 10 ml of sterile water was added to a glass wheaton vial to rinse any remaining compound from the vial and then transferred to a glass bottle. All remaining amounts of sterile water (50% of final vehicle volume) were added to the glass bottle and mixed thoroughly using a magnetic stirrer. The dosing solution was kept at room temperature, protected from light, with continuous mixing for up to 7 days. The final dosing matrix for 25 mg / kg AZD6738 was a clear solution with a slight yellow hue.

[0186] measurement Tumor growth inhibition (TGI) was calculated as follows: TGI%={1-(MTV treated / MTV control)}*100 (where MTV=mean tumor volume).

[0187] On the final measurement day, statistical significance was assessed using a one-tailed t-test of (log(relative tumor volume)=log(final volume / starting volume)) compared to vehicle controls.

[0188] result Tumor volumes for treatment with DS-1062 or AZD6738 alone, or DS-1062 in combination with AZD6738 are shown in Figure 15. Data represent change in tumor volume over time for treatment groups. The dotted line in Figure 15 represents the end of the dosing period. For full dose and schedule information, see Table 4 above. Values ​​shown are geometric mean ± SEM; n=8 for all treatment groups. Mice that reached human endpoints (e.g. large tumor burden) during the study were removed from the group and the remaining mice were used for calculation of TGI.

[0189] The TGI responses (TGI% on day 33) following treatment with DS-1062 or AZD6738 alone or in combination with AZD6738 in NCI-N87 xenografts are shown in Table 5.

[0190] [Table 5]

[0191] Monotherapy with DS-1062 at 10 mg / kg showed a TGI value of 84.1% at day 33 after treatment. AZD6738 monotherapy reached a TGI of 30.1% at day 33 after treatment. Combination treatment of AZD6738 with DS-1062 at 10 mg / kg showed a better response than the individual monotherapies with a TGI of 86.4% at day 33 after treatment.

[0192] Treatment groups were generally well tolerated and mean body weights for all treatment groups remained stable throughout the study.

[0193] Example 5: Antitumor testing - in vivo - TNBC patient-derived xenograft model Combination of the antibody-drug conjugate DS-1062 (datopotamab deruxtecan) with the ATR inhibitor AZD6738 (4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine) method: Female nude mice (Charles River) aged 5-8 weeks were used and enrolled in the study after 7 days of acclimation. A human patient-derived xenograft (PDX) model, CTG-3303, was established from a freshly resected tumor fragment from a patient with triple-negative breast cancer (TNBC) that relapsed upon treatment with the PARP inhibitor talazoparib. The PDX was obtained following appropriate consent procedures. The TNBC PDX model was passaged subcutaneously in vivo as fragments from animal to animal in nude mice. Tumors were approximately 250 mm 3 Once tumor size was reached, tumors of equal size were randomly assigned to treatment groups as shown in Table 6.

[0194] [Table 6]

[0195] The dose of compound for each animal was calculated based on individual body weight on the day of dosing. DS-1062 and AZD6738 were dosed on the same day, with DS-1062 administered approximately 5 hours after PO dosing of AZD6738. DS-1062 was administered as a single dose of 10 mg / kg on day 1, and AZD6738 was administered at 25 mg / kg QD for 14 days. The dosing period was 14 days.

[0196] Formulation of DS-1062 at 10mg / kg Dosing solutions for DS-1062 were prepared on the day of dosing by diluting DS-1062 stock solution (20.1 mg / ml) in 25 mM histidine buffer, 9% sucrose, pH 5.5, to 0.6 mg / ml and 2 mg / ml for the 3 mg / kg and 10 mg / kg dosing solutions, respectively. Each dosing solution was mixed thoroughly using a pipette and then administered via IV injection at a dosing volume of 5 ml / kg.

[0197] AZD6738 formulation at 25mg / kg To formulate a 25 mg / kg dosing solution, a concentration of 2.5 mg / ml AZD6738 was prepared, resulting in a dosing volume of 10 ml / kg for PO dosing. DMSO (10% of total vehicle volume) was added to the compound and mixed thoroughly with a pellet pestle. Approximately 5 minutes of sonication was required to completely dissolve the compound. Propylene glycol (40% of total vehicle volume) was then added and mixed thoroughly using a magnetic stirrer. A volume of 10 ml of sterile water was added to a glass wheaton vial to rinse any remaining compound from the vial, which was then transferred to a glass bottle. All remaining amounts of sterile water (50% of final vehicle volume) were added to the glass bottle and mixed thoroughly using a magnetic stirrer. The dosing solution was kept at room temperature, protected from light, with continuous mixing for up to 7 days. The final dosing matrix of 25 mg / kg AZD6738 was a clear solution with a slight yellow hue.

[0198] result Tumor volumes for treatment with DS-1062 or AZD6738 alone, or DS-1062 in combination with AZD6738 are shown in Figure 16A. Data represent change in tumor volume over time for treatment groups. The dotted line in Figure 16A represents the end of the dosing period. For full dose and schedule information, see Table 6 above. Values ​​shown are geometric mean ± SEM; n=8 for all treatment groups. Mice that reached human endpoints (e.g. large tumor burden) during the study were removed from the group and the remaining mice were used for the calculation of TGI.

[0199] The TGI responses (TGI% at day 46) following treatment with DS-1062 or AZD6738 alone, or in combination with AZD6738 in CTG-3303 xenografts are shown in Table 7.

[0200] [Table 7]

[0201] Monotherapy with DS-1062 at 10 mg / kg showed a TGI value of 88.2% at day 46 after treatment. AZD6738 monotherapy reached a TGI of 2.3% at day 46 after treatment. Combination treatment with DS-1062 and AZD6738 at 10 mg / kg resulted in a TGI of 89.9% at day 46 after treatment, indicating a better response than the individual monotherapies.

[0202] Treatment groups were generally well tolerated and mean body weights for all treatment groups remained stable throughout the study.

[0203] Furthermore, a complete response was observed on the 93rd day after treatment (tumor volume = 0 mm 3 The percentage of mice in each treatment group that achieved a complete response (defined as a complete response rate) was calculated and shown in Figure 16B. 0 of 8 mice (0%) achieved a complete response at 93 days post-treatment with DS-1062 monotherapy at 10 mg / kg. 0 of 8 mice (0%) achieved a complete response at 93 days post-treatment with AZD6738 monotherapy. With combined treatment of DS-1062 and AZD6738 at 10 mg / kg, 2 of 8 mice (25%) achieved a complete response at 93 days post-treatment, a higher complete response rate than the individual monotherapies.

[0204] Example 6: Combination Dosing of Antibody-Drug Conjugate DS-1062 (Datopotamab Deruxtecan) with the ATR Inhibitor AZD6738 in Hematopoietic Stem and Progenitor Cells In Vitro method: Cryopreserved human bone marrow-derived CD34 +Hematopoietic stem and progenitor cells (HSPCs; Lonza) were thawed and allowed to recover overnight in maintenance medium (StemSpan SFEM II (Stem Cell Technologies) containing 25 ng / ml SCF, 50 ng / ml TPO, and 50 ng / ml Flt3-L human recombinant protein (all Peprotech)) in a humidified incubator at 37°C with 5% CO2. The next day, cells were resuspended at a concentration of 10,000 cells / ml in medium capable of supporting erythroid differentiation in the presence of drugs (Preferred Cell Systems, SEC-BFU1-40H). Cells (30 μl) were seeded in a 6x6 matrix pattern into black-walled, clear-bottom 384-well tissue culture plates (Perkin Elmer) supplemented with 200, 70, 20, 8.3, 3.3 or 0 μg / ml DS-1062 (equivalent to 1.333, 0.467, 0.133, 0.056, 0.022 and 0 μM, respectively) in combination with the ATR inhibitor AZD6738 (1, 0.33, 0.167, 0.033, 0.017, 0 μM). Cells were cultured for 5 days in a humidified 37°C incubator with 5% CO2.

[0205] Viability was determined using CellTiter-Glo 2.0 from Promega (using an optimized volume of 3 μl / well) and luminescence was detected using an Envision plate reader (Perkin Elmer). In Genedata Screener software (Genedata), relative luminescence signals were normalized to the percentage of control wells (both compounds at 0 μM), with control wells equaling 0 and maximum cell death equaling 100. Synergy analysis was assessed using the Loewe, Bliss and maximum single agent (HSA) models, and synergy scores and excess matrices were determined by comparing the difference between observed and predicted viability based on non-synergistic interactions for each combination dose pair.

[0206] result: Primary CD34 induced to differentiate into the erythroid lineage +The results obtained with combined dosing of DS-1062 and AZD6738 in bone marrow-derived HSPCs are shown in Figures 17A and 17B and Table 8.

[0207] In Figure 17A, the measured cell viability signals are shown, where the X-axis represents the concentration of drug A (DS-1062) and the Y-axis represents the concentration of drug B (AZD6738). The values ​​in the boxes represent the % growth inhibition of cells treated with drugs A+B, which is normalized to the control value equal to 0, and the maximum cell death equal to 100. Figure 17B shows the Loewe excess matrix, where the values ​​in the boxes represent the excess values ​​calculated by the Loewe additivity model. Table 8 shows the HSA synergy scores and the Loewe additivity scores.

[0208] [Table 8]

[0209] Primary bone marrow-derived CD34 cells can be induced to differentiate into the erythroid lineage + No synergistic toxicity was observed with simultaneous DS-1062 and AZD6738 treatment in HSPCs, and cell death in the combination occurred according to the expected Loewe additive interaction at monotherapeutic active doses.

[0210] Example 7: Antitumor testing - in vivo - dose optimization - NCI-N87 xenograft model Combination of the antibody-drug conjugate DS-1062 (datopotamab deruxtecan) with the ATR inhibitor AZD6738 (4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine) method: Female nude mice (Envigo) aged 5-8 weeks were used and were included in the study after 7 days of acclimation. 6 NCI-N87 tumor cells (gastric cancer cell line) (1:1 in Matrigel) were implanted subcutaneously into the flanks of female nude mice. Tumors grew to approximately 250 mm 3Once tumor size was reached, tumors of equal size were randomly assigned to treatment groups as shown in Table 9.

[0211] [Table 9]

[0212] The dose of compound for each animal was calculated based on individual body weight on the day of dosing. DS-1062 was administered as a single dose of 10 mg / kg on day 1 and AZD6738 was administered at 25 mg / kg BID as listed in Table 9.

[0213] Formulation of DS-1062 at 10mg / kg Dosing solutions for DS-1062 were prepared on the day of dosing by diluting DS-1062 stock solution (20.1 mg / ml) in 25 mM histidine buffer, 9% sucrose, pH 5.5, to give 2 mg / ml for a 10 mg / kg dosing solution. Each dosing solution was mixed thoroughly using a pipette and then administered via IV injection at a dosing volume of 5 ml / kg.

[0214] AZD6738 formulation at 25mg / kg To formulate a 25 mg / kg dosing solution, a concentration of 2.5 mg / ml AZD6738 was prepared to give a dosing volume of 10 ml / kg for PO dosing. DMSO (10% of total vehicle volume) was added to the compound and mixed thoroughly with a pellet pestle. Approximately 5 minutes of sonication was required to completely dissolve the compound. Propylene glycol (40% of total vehicle volume) was then added and mixed thoroughly using a magnetic stirrer. A volume of 10 ml of sterile water was added to a glass wheaton vial to rinse any remaining compound from the vial and then transferred to a glass bottle. All remaining amounts of sterile water (50% of final vehicle volume) were added to the glass bottle and mixed thoroughly using a magnetic stirrer. The dosing solution was kept at room temperature, protected from light, with continuous mixing for up to 7 days. The final dosing matrix for 25 mg / kg AZD6738 was a clear solution with a slight yellow hue.

[0215] measurement Tumor growth inhibition (TGI) was calculated as follows: TGI%={1-(MTV treated / MTV control)}*100 where MTV=mean tumor volume.

[0216] On the final measurement day, statistical significance was assessed using a one-tailed t-test of (log(relative tumor volume)=log(final volume / starting volume)) compared to vehicle controls.

[0217] result Tumor volumes for treatment with DS-1062 or AZD6738 alone, or DS-1062 in combination with AZD6738 are shown in Figure 18. Data represent change in tumor volume over time for treatment groups. For full dose and schedule information, see Table 9 above. Values ​​shown are geometric mean ± SEM; n=8 for all treatment groups. Mice that reached human endpoints (e.g. large tumor burden) during the study were removed from the group and the remaining mice were used for calculation of TGI.

[0218] The TGI responses (TGI% at day 42) following treatment with DS-1062 or AZD6738 alone, or in combination with AZD6738 in NCI-N87 xenografts are shown in Table 10.

[0219] [Table 10]

[0220] Monotherapy with 10 mg / kg DS-1062 showed a TGI value of 74.8% at 42 days after treatment. AZD6738 monotherapy reached a TGI of 23.7% at 42 days after treatment. Combination treatment with AZD6738 and DS-1062 (days 1-14) resulted in a TGI of 92.9% at 42 days after treatment, combination treatment with AZD6738 and DS-1062 (days 1-7) resulted in a TGI of 89.5% at 42 days after treatment, combination treatment with AZD6738 and DS-1062 (days 3-17) resulted in a TGI of 89.6% at 42 days after treatment, and combination treatment with AZD6738 and DS-1062 (days 1-17) resulted in a TGI of 89.6% at 42 days after treatment. Combination treatment with AZD6738 and DS-1062 (days 7-21) resulted in a TGI of 87.2% after 42 days of treatment, and combination treatment with AZD6738 and DS-1062 (days 7-14) resulted in a TGI of 80.4% after 42 days of treatment, indicating that delaying dosing of AZD6738 after DS-1062 administration does not affect combination efficacy in the N87 tumor model.

[0221] Treatment groups were generally well tolerated and mean body weights across all treatment groups remained stable throughout the study.

[0222] Example 8: Antitumor testing - in vivo - CTG3718 ovarian patient-derived xenograft model Combination of the antibody-drug conjugate DS-1062 (datopotamab deruxtecan) with the ATR inhibitor AZD6738 (4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine) method: Female nude mice (Envigo) aged 5-8 weeks were used and enrolled in the study after 7 days of acclimation. A human patient-derived xenograft (PDX) model, CTG-3718, was established from a freshly resected tumor fragment from an ovarian cancer patient who relapsed upon treatment with the PARP inhibitor talazoparib. The PDX was obtained following appropriate consent procedures. The ovarian PDX model was passaged subcutaneously in vivo as animal-to-animal fragments in nude mice. Tumors were approximately 250 mm 3Once tumor size was reached, equivalent sized tumors were randomly assigned to treatment groups as shown in Table 11.

[0223] [Table 11]

[0224] The dose of compound for each animal was calculated based on individual body weight on the day of dosing. DS-1062 and AZD6738 were dosed on the same day, with DS-1062 administered approximately 5 hours after AZD6738 PO administration. DS-1062 was administered as a single dose of 10 mg / kg on day 1, and AZD6738 was administered at 25 mg / kg BID for 14 days.

[0225] Formulation of DS-1062 at 10mg / kg Dosing solutions for DS-1062 were prepared on the day of dosing by diluting DS-1062 stock solution (20.1 mg / ml) in 25 mM histidine buffer, 9% sucrose, pH 5.5, to give 2 mg / ml for a 10 mg / kg dosing solution. The dosing solution was mixed thoroughly using a pipette and then administered via IV injection at a dosing volume of 5 ml / kg.

[0226] AZD6738 formulation at 25mg / kg To formulate a 25 mg / kg dosing solution, a concentration of 2.5 mg / ml AZD6738 was prepared to give a dosing volume of 10 ml / kg for PO dosing. DMSO (10% of total vehicle volume) was added to the compound and mixed thoroughly with a pellet pestle. Approximately 5 minutes of sonication was required to completely dissolve the compound. Propylene glycol (40% of total vehicle volume) was then added and mixed thoroughly with a magnetic stirrer. A volume of 10 ml of sterile water was added to a glass wheaton vial to rinse any remaining compound from the vial and then transferred to a glass bottle. All remaining amounts of sterile water (50% of final vehicle volume) were added to the glass bottle and mixed thoroughly with a magnetic stirrer. The dosing solution was kept at room temperature, protected from light, with continuous mixing for up to 7 days. The final dosing matrix of 25 mg / kg AZD6738 was a clear solution with a slight yellow hue.

[0227] result Tumor volumes for treatment with DS-1062 or AZD6738 alone, or DS-1062 in combination with AZD6738 are shown in Figure 19. Data represent change in tumor volume over time for treatment groups. The dotted line in Figure 19 represents the end of the dosing period. For full dose and schedule information, see Table 11 above. Values ​​shown represent geometric mean ± SEM; n=8 for all treatment groups. Mice that reached human endpoints (e.g. large tumor burden) during the study were removed from the group and the remaining mice were used for calculation of TGI.

[0228] TGI responses (TGI% on day 22) following treatment with DS-1062 or AZD6738 alone, or in combination with AZD6738 in CTG-3718 xenografts are shown in Table 12.

[0229] [Table 12]

[0230] Monotherapy with DS-1062 at 10 mg / kg showed a TGI value of 69.8% at day 22 after treatment. AZD6738 monotherapy reached a TGI of -25.7% at day 22 after treatment. Combination treatment with AZD6738 and DS-1062 at 10 mg / kg resulted in a TGI of 84.8% at day 22 after treatment, indicating a better response than the individual monotherapies.

[0231] Treatment groups were generally well tolerated and mean body weights for all treatment groups remained stable throughout the study.

[0232] Example 9: Antitumor test - in vivo - N87 (gastric cancer cell line) - DS-1062 resistance model Combination of the antibody-drug conjugate DS-1062 (datopotamab deruxtecan) with the ATR inhibitor AZD6738 (4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine) method: Female nude mice (Charles River) aged 5-8 weeks were used and were included in the study after 7 days of acclimation. 6 N87-DS-1062 resistant tumor cells (gastric cancer cell line) (1:1 in Matrigel) were implanted subcutaneously into the flanks of female nude mice. Tumors grew to approximately 250 mm 3 Once tumor size was reached, tumors of equal size were randomly assigned to treatment groups as shown in Table 13.

[0233] [Table 13]

[0234] The dose of compound for each animal was calculated based on individual body weight on the day of dosing. DS-1062 and AZD6738 were dosed on the same day, with DS-1062 administered approximately 5 hours after AZD6738 PO administration. DS-1062 was administered as a single dose of 10 mg / kg on day 1, and AZD6738 was administered at 25 mg / kg BID for 7 days.

[0235] Formulation of DS-1062 at 10mg / kg Dosing solutions for DS-1062 were prepared on the day of dosing by diluting DS-1062 stock solution (20.1 mg / ml) in 25 mM histidine buffer, 9% sucrose, pH 5.5, to give 2 mg / ml for a 10 mg / kg dosing solution. The dosing solution was mixed thoroughly using a pipette and then administered by IV injection at a dosing volume of 5 ml / kg.

[0236] AZD6738 formulation at 25mg / kg To formulate a 25 mg / kg dosing solution, a concentration of 2.5 mg / ml AZD6738 was prepared to give a dosing volume of 10 ml / kg for PO dosing. DMSO (10% of total vehicle volume) was added to the compound and mixed thoroughly with a pellet pestle. Approximately 5 minutes of sonication was required to completely dissolve the compound. Propylene glycol (40% of total vehicle volume) was then added and mixed thoroughly with a magnetic stirrer. A volume of 10 ml of sterile water was added to a glass wheaton vial to rinse any remaining compound from the vial and then transferred to a glass bottle. All remaining amounts of sterile water (50% of final vehicle volume) were added to the glass bottle and mixed thoroughly with a magnetic stirrer. The dosing solution was kept at room temperature, protected from light, with continuous mixing for up to 7 days. The final dosing matrix of 25 mg / kg AZD6738 was a clear solution with a slight yellow hue.

[0237] result Tumor volumes for treatment with DS-1062 or AZD6738 alone, or DS-1062 in combination with AZD6738 are shown in Figure 20. Data represent change in tumor volume over time for treatment groups. The dotted line in Figure 20 represents the end of the dosing period. For full dose and schedule information, see Table 13 above. Values ​​shown are geometric mean ± SEM; n=8 for all treatment groups. Mice that reached human endpoints (e.g. large tumor burden) during the study were removed from the group and the remaining mice were used for calculation of TGI.

[0238] The TGI responses (TGI% on day 21) following treatment with DS-1062 or AZD6738 alone, or in combination with DS-1062 with AZD6738 in N87-DS-1062-resistant tumor cell xenografts are shown in Table 14. [Table 14]

[0239] Monotherapy with DS-1062 at 10 mg / kg showed a TGI value of 0.77% at 21 days after treatment. AZD6738 monotherapy reached a TGI of -9.8% at 21 days after treatment. Combination treatment with AZD6738 and DS-1062 at 10 mg / kg resulted in a TGI of 49.5% at 21 days after treatment, indicating a better response than the individual monotherapies. These data suggest that ATR inhibition as demonstrated herein with AZD6738 may resensitize DS-1062-resistant tumors to DS-1062 treatment.

[0240] Treatment groups were generally well tolerated and mean body weights across all treatment groups remained stable throughout the study.

[0241] The above written specification is deemed sufficient to enable one skilled in the art to practice the embodiments. The above description and examples set forth certain embodiments in detail and set forth the best mode contemplated by the inventors. However, no matter how detailed the above description may appear in text, it should be understood that the embodiments can be practiced in many ways, and the claims include any equivalents thereof.

[0242] Free text in sequence listing SEQ ID NO:1 - Amino acid sequence of the heavy chain of the anti-TROP2 antibody SEQ ID NO:2 - Amino acid sequence of the light chain of the anti-TROP2 antibody SEQ ID NO:3 - Amino acid sequence of heavy chain CDRH1 [= amino acid residues 50-54 of SEQ ID NO:1] SEQ ID NO:4 - Amino acid sequence of heavy chain CDRH2 [= amino acid residues 69-85 of SEQ ID NO:1] SEQ ID NO:5 - Amino acid sequence of heavy chain CDRH3 [= amino acid residues 118-129 of SEQ ID NO:1] SEQ ID NO:6 - Amino acid sequence of light chain CDRL1 [= amino acid residues 44-54 of SEQ ID NO:2] SEQ ID NO:7 - Amino acid sequence of light chain CDRL2 [= amino acid residues 70-76 of SEQ ID NO:2] SEQ ID NO:8 - Amino acid sequence of light chain CDRL3 [= amino acid residues 109-117 of SEQ ID NO:2] SEQ ID NO:9 - Amino acid sequence of the heavy chain variable region [= amino acid residues 20 to 140 of SEQ ID NO:1] SEQ ID NO:10 - Amino acid sequence of the light chain variable region [= amino acid residues 21-129 of SEQ ID NO:2] SEQ ID NO:11 - Amino acid sequence of heavy chain [= amino acid residues 20 to 469 of SEQ ID NO:1] SEQ ID NO:12 - Amino acid sequence of heavy chain [= amino acid residues 20 to 470 of SEQ ID NO:1] SEQ ID NO:13 - Amino acid sequence of light chain [= amino acid residues 21-234 of SEQ ID NO:2]

Claims

1. A pharmaceutical product comprising an anti-TROP2 antibody-drug conjugate and an ATR inhibitor for administration in combination, wherein the anti-TROP2 antibody-drug conjugate has the following formula: 【Chemistry 1】 wherein A represents the attachment position to the antibody, is conjugated to an anti-TROP2 antibody via a thioether bond.

2. The ATR inhibitor has the following formula (I): 【Chemistry 2】 (In the formula, R １ is selected from morpholin-4-yl and 3-methylmorpholin-4-yl; R ２ teeth, 【Chemistry 3】 and n is 0 or 1; R ２Ａ , R ２Ｃ , R ２Ｅ and R ２Ｆ are each independently hydrogen or methyl; R ２Ｂ and R ２Ｄ are each independently hydrogen or methyl; R ２Ｇ is -NHR ７ and -NHCOR ８ Selected from: R ２Ｈ is fluoro; R ３ is methyl; R ４ and R ５ are each independently hydrogen or methyl, or R ４ and R ５ together with the atoms to which they are attached form ring A; Ring A is a C ring containing one heteroatom selected from O and N. ３～６ cycloalkyl or a saturated 4-6 membered heterocycle; R ６ is hydrogen; R ７ is hydrogen or methyl; R ８ is methyl) A compound represented by or a pharma- ceutically acceptable salt thereof.

3. In formula (I), R ４ and R ５ together with the atoms to which they are attached form a ring A, and ring A contains one heteroatom selected from O and N. ３～６ The pharmaceutical product of claim 2, which is a cycloalkyl or a saturated 4-6 heterocycle.

4. 4. The pharmaceutical product according to claim 2 or 3, wherein in formula (I), ring A is a cyclopropyl, tetrahydropyranyl or piperidinyl ring.

5. In formula (I), R ２Ａ is hydrogen, R ２Ｂ is hydrogen, R ２Ｃ is hydrogen, R ２Ｄ is hydrogen, R ２Ｅ is hydrogen, R ２Ｆ The pharmaceutical product according to any one of claims 2 to 4, wherein is hydrogen.

6. In formula (I), R １ The pharmaceutical product according to any one of claims 2 to 5, wherein is 3-methylmorpholin-4-yl.

7. The compound of formula (I) is a compound of formula (Ia): 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

8. In formula (Ia), Ring A is a cyclopropyl ring; R ２ but, 【Chemistry 5】 and n is 0 or 1; R ２Ａ is hydrogen; R ２Ｂ is hydrogen; R ２Ｃ is hydrogen; R ２Ｄ is hydrogen; R ２Ｅ is hydrogen; R ２Ｆ is hydrogen; R ２Ｇ -NHR ７ and R ２Ｈ is fluoro; R ３ is a methyl group; R ６ is hydrogen; R ７ is hydrogen or methyl; 8. The pharmaceutical product of claim 7.

9. The ATR inhibitor has the following formula: 【Chemistry 6】 3. The pharmaceutical product of claim 2, which is AZD6738 represented by: or a pharma- ceutically acceptable salt thereof.

10. The pharmaceutical product according to any one of claims 1 to 9, wherein the anti-TROP2 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 represented by SEQ ID NO:7, and a CDRL3 consisting of the amino acid sequence represented by SEQ ID NO:

8.

11. The pharmaceutical product of claim 10, wherein the anti-TROP2 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.

12. The pharmaceutical product of claim 11 , wherein the anti-TROP2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 12 and a light chain consisting of the amino acid sequence represented by SEQ ID NO:

13.

13. The pharmaceutical product of claim 11 , wherein the anti-TROP2 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:

13.

14. The pharmaceutical product of any one of claims 1 to 13, wherein the average number of drug-linker complex units per antibody molecule in the antibody-drug conjugate ranges from 2 to 8.

15. The pharmaceutical product of claim 14, wherein the average number of drug-linker complex units per antibody molecule in the antibody-drug conjugate ranges from 3.5 to 4.

5.

16. The pharmaceutical product of claim 15, wherein the anti-TROP2 antibody-drug conjugate is datopotamab deruxtecan (DS-1062).

17. The pharmaceutical product according to any one of claims 1 to 16, which is a combined preparation comprising said anti-TROP2 antibody-drug conjugate and said ATR inhibitor for separate simultaneous administration.

18. The pharmaceutical product according to any one of claims 1 to 16, which is a combined preparation comprising said anti-TROP2 antibody-drug conjugate and said ATR inhibitor for sequential or separate simultaneous administration.

19. The pharmaceutical product according to any one of claims 1 to 18, wherein the anti-TROP2 antibody-drug conjugate is administered at a dose of 6 mg / kg body weight.

20. 20. The pharmaceutical product of claim 19, wherein the dose of the anti-TROP2 antibody-drug conjugate is administered once every three weeks.

21. 21. The pharmaceutical product of any one of claims 1 to 20, wherein the ATR inhibitor is administered daily for the first, second and / or third week of a three week cycle.

22. The pharmaceutical product according to any one of claims 1 to 20, wherein the ATR inhibitor is administered on days 3 to 17 of a three-week cycle.

23. A pharmaceutical product according to any one of claims 1 to 22 for treating cancer.

24. 24. The pharmaceutical product of claim 23, wherein the cancer is at least one selected from the group consisting of breast cancer, lung cancer, colorectal cancer, gastric 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.

25. 25. The pharmaceutical product of claim 24, wherein the cancer is breast cancer.

26. 26. The pharmaceutical product of claim 25, wherein the breast cancer is triple negative breast cancer.

27. 27. The pharmaceutical product of claim 26, wherein the breast cancer is hormone receptor (HR) positive, HER2 negative breast cancer.

28. 28. The pharmaceutical product of claim 27, wherein the cancer is lung cancer.

29. 29. The pharmaceutical product of claim 28, wherein the lung cancer is non-small cell lung cancer.

30. 30. The pharmaceutical product of claim 29, wherein the non-small cell lung cancer is a non-small cell lung cancer with actionable genomic alterations.

31. 31. The pharmaceutical product of claim 30, wherein the non-small cell lung cancer is a non-small cell lung cancer without actionable genomic alterations.

32. 25. The pharmaceutical product of claim 24, wherein the cancer is colorectal cancer.

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

34. 25. The pharmaceutical product of claim 24, wherein the cancer is pancreatic cancer.

35. 25. The pharmaceutical product of claim 24, wherein the cancer is ovarian cancer.

36. 25. The pharmaceutical product of claim 24, wherein the cancer is prostate cancer.

37. 25. The pharmaceutical product of claim 24, wherein the cancer is renal cancer.

38. The pharmaceutical product of any one of claims 24 to 37, wherein the cancer lacks homologous recombination (HR) dependent DNA DSB repair activity.

39. The pharmaceutical product of any one of claims 24 to 37, wherein the cancer is not deficient in homologous recombination (HR) dependent DNA DSB repair activity.

40. The pharmaceutical product of any one of claims 24 to 37, wherein the cancer is resistant or refractory to previous treatment with a PARP inhibitor.

41. 41. The pharmaceutical product of claim 40, wherein the previous treatment is with a PARP inhibitor selected from olaparib, rucaparib, niraparib, talazoparib, and veliparib.

42. The pharmaceutical product of any one of claims 24 to 37, wherein the cancer cells of the cancer are SLFN11 deficient.

43. 43. The pharmaceutical product of claim 42, wherein SLFN11 expression is lower in cancer cells of the patient compared to SLFN11-expressing non-cancerous cells of said patient.

44. A pharmaceutical product according to any one of claims 1 to 22 for use in the treatment of cancer.

45. The pharmaceutical product for use according to claim 44, wherein said cancer is as defined in any one of claims 24 to 43.

46. 17. Use of an anti-TROP2 antibody-drug conjugate in the manufacture of a medicament for use in combination with an ATR inhibitor for treating cancer, wherein the anti-TROP2 antibody-drug conjugate and the ATR inhibitor are as defined in any one of claims 1 to 16.

47. 47. The use according to claim 46, wherein said medicament is for use in combination with said ATR inhibitor by sequential administration.

48. 47. The use according to claim 46, wherein said medicament is for use in combination with said ATR inhibitor by separate co-administration.

49. 17. Use of an ATR inhibitor in the manufacture of a medicament for use in combination with an anti-TROP2 antibody-drug conjugate for treating cancer, wherein the anti-TROP2 antibody-drug conjugate and the ATR inhibitor are as defined in any one of claims 1 to 16.

50. The use of claim 49, wherein the medicament is for use in combination with the anti-TROP2 antibody-drug conjugate by sequential administration.

51. The use according to claim 49, wherein the medicament is for combined use with the anti-TROP2 antibody-drug conjugate by separate co-administration.

52. The use according to any one of claims 46 to 51, wherein the cancer is as defined in any one of claims 24 to 43.

53. 17. An anti-TROP2 antibody-drug conjugate for use in combination with an ATR inhibitor in the treatment of cancer, wherein said anti-TROP2 antibody-drug conjugate and said ATR inhibitor are as defined in any one of claims 1 to 16.

54. The anti-TROP2 antibody-drug conjugate for use according to claim 53, wherein the cancer is as defined in any one of claims 24 to 43.

55. The anti-TROP2 antibody-drug conjugate for use according to claim 53 or 54, wherein said use comprises sequential administration of said anti-TROP2 antibody-drug conjugate and said ATR inhibitor.

56. 55. The anti-TROP2 antibody-drug conjugate for use according to claim 53 or 54, wherein said use comprises administering said anti-TROP2 antibody-drug conjugate and said ATR inhibitor separately and simultaneously.

57. 17. An anti-TROP2 antibody-drug conjugate for use in the treatment of cancer in a subject, said treatment comprising sequential or separate co-administration to said subject of i) said anti-TROP2 antibody-drug conjugate and ii) an ATR inhibitor, said anti-TROP2 antibody-drug conjugate and said ATR inhibitor being as defined in any one of claims 1 to 16.

58. The anti-TROP2 antibody-drug conjugate for use according to any one of claims 53 to 57, which is administered at a dose of 6 mg / kg body weight.

59. The anti-TROP2 antibody-drug conjugate for use according to claim 58, wherein the dose of the anti-TROP2 antibody-drug conjugate is administered once every three weeks.

60. 60. The anti-TROP2 antibody-drug conjugate for use according to any one of claims 53 to 59, wherein the ATR inhibitor is administered daily for the first, second and / or third week of a three-week cycle.

61. The anti-TROP2 antibody-drug conjugate for use according to any one of claims 53 to 59, wherein the ATR inhibitor is administered on days 3 to 17 of a three-week cycle.

62. 17. An ATR inhibitor for use in combination with an anti-TROP2 antibody-drug conjugate in the treatment of cancer, wherein said anti-TROP2 antibody-drug conjugate and said ATR inhibitor are as defined in any one of claims 1 to 16.

63. The ATR inhibitor for use according to claim 62, wherein the cancer is as defined in any one of claims 24 to 43.

64. The ATR inhibitor for use according to claim 62 or 63, wherein said use comprises sequential administration of said anti-TROP2 antibody-drug conjugate and said ATR inhibitor.

65. The ATR inhibitor for use according to claim 62 or 63, wherein said use comprises administering said anti-TROP2 antibody-drug conjugate and said ATR inhibitor separately and simultaneously.

66. 17. An ATR inhibitor for use in the treatment of cancer in a subject, said treatment comprising sequential or separate co-administration to said subject of i) said ATR inhibitor and ii) an anti-TROP2 antibody-drug conjugate, wherein said ATR inhibitor and said anti-TROP2 antibody-drug conjugate are as defined in any one of claims 1 to 16.

67. The ATR inhibitor for use according to any one of claims 62 to 66, wherein the anti-TROP2 antibody-drug conjugate is administered at a dose of 6 mg / kg body weight.

68. The ATR inhibitor for use according to claim 67, wherein the dose of the anti-TROP2 antibody-drug conjugate is administered once every three weeks.

69. The ATR inhibitor for use according to any one of claims 62 to 68, which is administered daily for the first, second and / or third week of a three-week cycle.

70. The ATR inhibitor for use according to any one of claims 62 to 68, which is administered on days 3 to 17 of a three-week cycle.

71. A method for treating cancer, comprising administering to a subject in need thereof an anti-TROP2 antibody-drug conjugate as defined in any one of claims 1 to 16 in combination with an ATR inhibitor.

72. The method of claim 71, wherein the cancer is as defined in any one of claims 24 to 43.

73. 73. The method of claim 71 or 72, comprising administering the anti-TROP2 antibody-drug conjugate and the ATR inhibitor sequentially.

74. 73. The method of claim 71 or 72, comprising administering the anti-TROP2 antibody-drug conjugate and the ATR inhibitor separately or simultaneously.

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