Cancer treatment using combination therapy of EP4 antagonists and immune checkpoint inhibitors

Abstract

To provide effective cancer treatments. [Solution] A cancer treatment agent is provided, characterized by administering a combination of standard therapy and an EP4 antagonist and an immune checkpoint inhibitor (for example, an anti-PD-1 antibody). Preferably, the standard therapy is a cancer treatment agent selected from (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, or (vi) docetaxel and ramucirumab therapy.

Description

[Technical Field]

[0001] This disclosure relates to cancer treatment methods, including the combined use of standard therapy with EP4 antagonists and immune checkpoint inhibitors. [Background technology]

[0002] Prostaglandin E2 (PGE2) is known as a metabolite in the arachidonic acid cascade and is known to have cytoprotective effects, uterine contraction effects, pain threshold reduction effects, gastrointestinal peristalsis promotion effects, stimulant effects, gastric acid secretion suppression effects, blood pressure lowering effects, and diuretic effects.

[0003] Recent research has revealed that PGE2 receptors have subtypes, each with a different role. Currently, there are four main known subtypes, referred to as EP1, EP2, EP3, and EP4 (Non-Patent Literature 1).

[0004] Of these subtypes, the EP4 receptor is thought to be involved in suppressing MCP-1 production from macrophages, suppressing TNF-α, IL-2, and IFN-γ production from lymphocytes, and enhancing IL-10 production, thereby contributing to anti-inflammatory effects, vasodilation, angiogenesis, inhibition of elastic fiber formation, and regulation of MMP-9 expression. Furthermore, the EP4 receptor is also thought to be involved in cancer immune regulation via myeloid-derived suppressor cells, regulatory T cells, and natural killer cells.

[0005] Based on these findings, compounds that strongly bind to and antagonistically affect the EP4 receptor are considered useful in treating diseases caused by activation of the EP4 receptor, such as bone diseases, cancer, systemic granulomas, immune disorders, allergies, atopic dermatitis, asthma, periodontitis, gingivitis, periodontal disease, Alzheimer's disease, Kawasaki disease, burns, multiple organ failure, chronic headaches, pain, vasculitis, venous insufficiency, varicose veins, aneurysms, aortic aneurysms, anal fistulas, diabetes insipidus, stress, endometriosis, adenomyosis, patent ductus arteriosus of the newborn, and gallstones (Non-Patent Literature 2-7).

[0006] Patent Document 1 discloses that a compound represented by general formula (I) has EP4 antagonistic activity and is useful as a cancer treatment drug (see Patent Document 1).

[0007] On the other hand, cancer cells and the tumor microenvironment contain various immune checkpoint molecules that interfere with the immune response to cancer. Immune checkpoint inhibitors are a new therapeutic approach that releases the immunosuppressive mechanism and activates the immune response to cancer. Already, immune checkpoint inhibitors such as the anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) antibody ipilimumab, and the anti-PD-1 (programmed cell death-1) antibodies nivolumab and pembrolizumab have been approved both domestically and internationally and are being used in cancer treatment.

[0008] Patent Document 2 discloses that combining a compound represented by general formula (I) with an immune checkpoint inhibitor is useful for cancer treatment (see Patent Document 2).

[0009] The main treatment for advanced or recurrent colorectal cancer that is not resectable is drug therapy, with standard treatments including fluoropyrimidine-based anti-cancer agents, oxaliplatin, and irinotecan. One such treatment is the combination therapy of XELOX and bevacizumab (hereinafter sometimes abbreviated as "XELOX + bevacizumab therapy").

[0010] Furthermore, the main treatment for unresectable pancreatic cancer with distant metastases is drug therapy. Standard therapies include FOLFIRINOX therapy (hereinafter sometimes abbreviated as "FFX therapy"), which combines a regimen containing fluorouracil (5-FU) with oxaliplatin and irinotecan; modified FOLFIRINOX therapy (hereinafter sometimes abbreviated as "mFFX therapy"), which omits the rapid administration of fluorouracil and reduces the dose of irinotecan in order to reduce toxicity from FFX therapy; or a combination of gemcitabine and nab-paclitaxel (hereinafter sometimes abbreviated as "GnP therapy").

[0011] Furthermore, the primary treatment for stage IV or recurrent non-small cell lung cancer is drug therapy, with standard therapies including combination therapy with docetaxel and ramucirumab (sometimes abbreviated as "DTX+RAM therapy") or docetaxel therapy (sometimes abbreviated as "DTX therapy").

[0012] While these treatments show some effectiveness, there is an unmet need for treatments that further extend survival time. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] WO2016 / 111347 [Patent Document 2] WO2018 / 008711 [Non-patent literature]

[0014] [Non-Patent Document 1] Journal of Lipid Mediators and Cell Signaling, Vol. 12, pp. 379-391, 1995. [Non-Patent Document 2] Pharmacological Reviews, Vol. 65, pp. 1010-1052, July, 2013. [Non-Patent Document 3] 105th American Association for Cancer Research (AACR) Meeting, Abstract Number: LB-265, Presentation Title: ONO-AE3-208 inhibits myeloid-derived suppressor cells and glioma growth, Presentation Date: April 8, 2014 [Non-Patent Document 4] FEBS Letters, Vol. 364, pp. 339-341, 1995. [Non-Patent Document 5] Cancer Science, Vol. 105, pp. 1142-1151, 2014. [Non-Patent Document 6] Cancer Research, Vol. 70, pp. 1606-1615, 2010. [Non-Patent Document 7] Cancer Research, Vol. 62, pp. 28-32, 2002. [Overview of the Initiative] [Problems that the invention aims to solve]

[0015] The object of the present invention is to provide a new treatment method for cancer (for example, colorectal cancer, pancreatic cancer, lung cancer). [Means for solving the problem]

[0016] As a result of diligent research to solve the aforementioned problems, the present inventors have found that combining an EP4 receptor antagonist and an immune checkpoint inhibitor with standard treatment can be an effective cancer treatment method, and that administering an EP4 receptor antagonist or an EP4 receptor antagonist and an immune checkpoint inhibitor to patients who have received preoperative chemoradiotherapy can also be an effective cancer treatment method (both treatment methods are sometimes abbreviated as the treatment method of the present invention).

[0017] Therefore, in a certain manner, [1] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent containing an EP4 antagonist as an active ingredient, characterized by being administered in combination with standard therapy ((i) bevacizumab and Xelox therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel therapy, or (vi) docetaxel and ramucirumab therapy) and the administration of an immune checkpoint inhibitor, or [2] Cancer progression inhibitors, recurrence inhibitors and / or treatment agents containing immune checkpoint inhibitors as active ingredients, characterized by being administered in combination with standard therapy ((i) bevacizumab and Xelox therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel therapy, or (vi) docetaxel and ramucirumab therapy) and EP4 antagonists. [3] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent containing an EP4 antagonist as an active ingredient, characterized by being administered to cancer patients who have undergone neoadjuvant chemoradiotherapy. [4] The agent described in [3] above, which is administered in combination with an immune checkpoint inhibitor, or [5] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent is provided, comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with an EP4 antagonist to cancer patients who have undergone neoadjuvant chemoradiotherapy. [Effects of the Invention]

[0018] This invention provides a novel cancer treatment method. [Brief explanation of the drawing]

[0019] [Figure 1] Figure 1 shows an overview of a multicenter, open-label, uncontrolled trial evaluating the tolerability, safety, and efficacy of compound A, nivolumab (described below), in combination with XELOX + bevacizumab therapy in patients with unresectable advanced or recurrent colorectal cancer. [Figure 2] Figure 2 shows an overview of a multicenter, open-label, uncontrolled study evaluating the safety, efficacy, and pharmacokinetics of compound A (described later) in combination with nivolumab as neoadjuvant therapy after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer that is resectable. [Figure 3] Figure 3 shows an overview of a multicenter, open-label, uncontrolled trial evaluating the tolerability, safety, and efficacy of compound A, Nivolumab (described below), in combination with mFFX therapy or GnP therapy in patients with pancreatic cancer with distant metastases. [Figure 4] Figure 4 shows an overview of a multicenter, open-label, uncontrolled trial evaluating the tolerability, safety, and efficacy of compound A, nivolumab, in combination with docetaxel and ramucirumab therapy in patients with advanced or recurrent non-small cell lung cancer who are refractory to combination therapy including anti-PD-1 antibodies or anti-PD-L1 antibodies and platinum-based agents. [Modes for carrying out the invention]

[0020] (1) EP4 antagonists In the present invention, the EP4 antagonist is not particularly limited as long as it is a compound having EP4 antagonistic activity, but in one embodiment, the general formula (I) described in WO2016 / 111347:

[0021] [ka]

[0022] (wherein R , 2 , 17 , 17 , represents COOR 8 , tetrazole, SO3H, SO2NH2, SO2NHR 8-1 , CONHSO2R 8-1 , SO2NHCOR 8-1 , or hydroxamic acid, and R 8 represents a hydrogen atom, C1-4 alkyl, or benzyl, and R 8-1 represents C1-4 alkyl, C1-4 haloalkyl, C3-10 carbocyclic ring, or 3-10 member heterocyclic ring, and each of the C3-10 carbocyclic ring and 3-10 member heterocyclic ring may be substituted with C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -O(C1-4 haloalkyl), C1-4 alkylthio, -S(C1-4 haloalkyl), halogen, or nitrile (denoted as "-CN"; the same hereinafter), L 1 represents C1-5 alkylene, C2-5 alkenylene, or C2-5 alkynylene, and R 2 represents halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C2-4 alkenyl, C2-4 alkynyl, -O(C1-4 haloalkyl), -S(C1-4 haloalkyl), -C(O)(C1-4 alkyl), -SO2(C1-4 alkyl), -CONH(C1-4 alkyl), -CON(C1-4 alkyl)2, -NHC(O)(C|4 alkyl), -N(C1-4 alkyl)C(O)(C1-4 alkyl), -NHSO2(C1-4 alkyl), -N(C1-4 alkyl)SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2, -NR 17 R 17 , nitro, nitrile, hydroxyl, aldehyde (denoted as formyl; the same hereinafter), or carboxyl, and each of the C1-4 alkyl may be substituted with halogen, The (C1-4 alkyl)2 in the R 2 represents two independent C1-4 alkyls, and each of the C1-4 alkyls may be the same or different, X1 CR 6 Or it represents a nitrogen atom, R 6 is a hydrogen atom or R 2 This represents, X 2 CR 7 Or it represents a nitrogen atom, R 7 is a hydrogen atom, R 2 , or -L 3 -R 9 Represents L 3 R represents a methylene atom, an oxygen atom, or an oxidized sulfur atom, 9 This represents a 4-10 membered heterocycle which may be substituted with substituents selected from the group consisting of halogens, C1-4 alkyls, and C1-4 haloalkyls. L 2 -CH2CH2-, -CH=CH-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -CH2S(O)-, -S(O)CH2-, -CH2SO2-, -SO2CH2-, -CH2NH-, -NHCH2-, -NHCO-, -CONH-, -NHSO2-, or -SO2NH- R 3 This represents a C1-4 alkyl or halogen, R 4 This represents a halogen, C1-4 alkyl, or C1-4 haloalkyl, X 3 is methylene, an oxygen atom, a sulfur atom which may be oxidized, or NR 10 Represents R 10 This represents C1-4 alkyl, -C(O)(C1-4 alkyl), -C(O)O(C1-4 alkyl), or -SO2(C1-4 alkyl), and each of these C1-4 alkyls may be substituted with a halogen. The term "ring" represents a benzene ring or a 5-6 membered monocyclic aromatic heterocycle.

[0023] [ka]

[0024] represents a single bond or a double bond, R5 (1) halogen, (2) C1-4 alkyl, (3) carboxyl, (4) nitrile, (5)-CONHR 11 , (6)-C(O)R 12 , (7)-OR 14 , (8)-S(O) t R 15 (9)-CH2R 16 (10)-NR 17 R 17 (11)-NHCOR 11 (12) Represents a C4-10 carbon ring, or (13) a 4-10 membered heterocycle, wherein the C4-10 carbon ring or 4-10 membered heterocycle has 1 to 3 R 18 It may also be replaced with, and the R 18 If there are multiple, R 18 Each of them may be independent, identical, or different. R 11 R represents a C1-6 alkyl, C3-6 cycloalkyl, phenyl, or 4-6 membered heterocycle. 11 1 to 3 R 13 It may also be replaced with, and the R 13 If there are multiple, R 13 Each of them may be independent, identical, or different. R 13 These include halogens, C1-6 alkyl groups, C3-6 cycloalkyl groups, C1-4 alkoxy groups, hydroxyl groups, and -NR groups. 20 R 21 , represents benzene, or a 4-6 membered heterocycle, R 20 and R 21 Each of these independently represents a hydrogen atom or a C1-4 alkyl group. R 12 This represents a C1-6 alkyl, C3-6 cycloalkyl, benzene, or 4-6 membered heterocycle, and each of these C3-6 cycloalkyl, benzene, or 4-6 membered heterocycles may be independently substituted with a halogen, a C1-4 alkyl, or a C1-4 alkoxy. R 14 R represents a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, a benzene ring, or a benzyl ring, where the C1-6 alkyl group has 1 to 3 R groups. 19It may also be replaced with, and the R 19 If there are multiple, R 19 Each of them may be independent, identical, or different. R 19 This represents a 5-6 member monocyclic aromatic heterocycle which may be substituted with substituents selected from the group consisting of C1-4 alkoxy, -CONH(C1-4 alkyl), -CON(C1-4 alkyl)2, or C1-4 alkyl and C1-4 haloalkyl. The R 19 In this context, (C1-4 alkyl)2 represents two independent C1-4 alkyl groups, which may be the same or different. R 15 This represents C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl. R 16 represents a hydroxyl group or a C1-4 alkoxy, R 17 Each of these independently represents a hydrogen atom, a C1-6 alkyl group, or a C3-6 cycloalkyl group. R 18 This represents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, oxo, nitrile, hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, (C1-4 alkyl)SO2-, 4-6 membered heterocycle, (C1-4 alkyl)NH-, or (C1-4 alkyl)2N-. The R 18 In this context, (C1-4 alkyl)2 represents two independent C1-4 alkyl groups, which may be the same or different. m represents an integer from 1 to 4, n represents an integer from 0 to 4, p represents an integer from 0 to 2, q represents an integer from 0 to 6, r represents an integer from 0 to 6, s represents an integer from 0 to 4, and t represents an integer from 0 to 2. However, if p, q, r, and s each represent an integer greater than or equal to 2, then R 2 , R 3 , R 4 , and R 5 These are compounds represented by ( ) or salts thereof, which may be the same or different, and may be independent of each other.

[0025] Furthermore, other forms of EP4 antagonists include AN0025, E7046, IK-007, RMX-1002, grapiprant, AAT-007, CR6086, INV-1120, BYD-001, TT-038, DT095895, P-001, ER-819762, MK-2894, MF498, evatanepag, CJ-042794, EP4A, BGC201531, CJ-023423, GW627368, AH23848, DT-9081, or WO2001 / 062708, WO2002 / 020462, WO2002 / 032 900, WO2002 / 050031, WO2002 / 050032, WO2002 / 050033, WO2002 / 016311, WO2003 / 086390, WO2003 / 087061, WO2003 / 099857, WO2003 / 016254, WO2005 / 0 21508, WO2004 / 067524, WO2005 / 037812, WO2005 / 061475, WO2005 / 105732, WO2005 / 105733, WO2006 / 122403, WO2007 / 121578, WO2008 / 017164, WO2008 / 104055, WO2008 / 116304, WO2008 / 123207, WO2007 / 143825, WO2009 / 005076, WO2009 / 139373, WO2010 / 019796, WO2010 / 034110, WO2012 / 039972, WO201 2 / 043634, WO2012 / 076063, WO2012 / 103071, WO2013 / 004290, WO2013 / 096496, WO2013 / 096501, WO2013 / 101733, WO2013 / 101598, WO2014 / 004229, WO2 014 / 004230, WO2014 / 086739, WO2014 / 126746, WO2014 / 186218, WO2014 / 200075, WO2015 / 094902, WO2015 / 094912, WO2015 / 091475, WO2015 / 113057, W O2015 / 147020, WO2016 / 021742, WO2016 / 088903, WO2017 / 014323, WO2017 / 066633, WO2017 / 085198, WO2018 / 195123, WO2018 / 195123, WO2018 / 210987,Examples of compounds listed include those described in WO2018 / 210988, WO2018 / 210992, WO2018 / 210994, WO2018 / 210995, WO2018 / 216640, WO2019 / 038156, WO2019 / 245590, WO2019 / 101171, WO2019 / 152982, WO2019 / 166022, CN108929281, WO2020 / 012305, WO2020 / 014465, WO2020 / 151566, WO2020 / 160075, or WO2020 / 161275.

[0026] In the present invention, "C1-4 alkyl" refers to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and isobutyl.

[0027] In the present invention, "C1-3 alkyl" refers to, for example, methyl, ethyl, n-propyl, and isopropyl.

[0028] In the present invention, "C1-5 alkylene" refers to, for example, methylene, ethylene, propylene, butylene, and pentylene.

[0029] In the present invention, "C2-5 alkenylene" refers to, for example, etenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, and 4-pentenylene.

[0030] In the present invention, "C2-5 alkynylene" refers to, for example, ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene, 1-pentynylene, 2-pentynylene, 3-pentynylene, and 4-pentynylene.

[0031] In this invention, "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0032] In the present invention, "C1-4 alkoxy" refers to, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, tert-butoxy, isobutoxy, and the like.

[0033] In the present invention, "C1-4 alkylthio" refers to, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, tert-butylthio, isobutylthio, and the like.

[0034] In the present invention, "C2-4 alkenyl" refers to, for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl.

[0035] In the present invention, "C2-4 alkynyl" refers to, for example, ethynnyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0036] In the present invention, "C1-4 haloalkyl" refers to a C1-4 alkyl group substituted with a halogen, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, 1,2,2,2-tetrafluoroethyl, 1,1,2,2-tetrafluoroethyl Roethyl, pentafluoroethyl, 1,2-dibromo-1,2,2-trifluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2-fluoropropyl, 2-chloropropyl, 1-fluoropropyl, 1-chloropropyl, 3,3-difluoropropyl, 2,3-difluoropropyl, 1,3-difluoropropyl, 1,2-difluoropropyl, 2,2-difluoropropyl, 1,1-difluoropropyl, 3,3,3 -Trifluoropropyl, 2,3,3-trifluoropropyl, 1,3,3-trifluoropropyl, 1,2,2-trifluoropropyl, 1,1,2-trifluoropropyl, 1,1,3-trifluoropropyl, 1,1,2,2-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4-fluorobutyl, 4-chlorobutyl, 3-fluorobutyl, 3-chlorobutyl, 2-fluorobutyl, 2-chlorobutyl, 1-fluorobutyl, 1-chlorobutyl, 3,3 Examples include -difluorobutyl, 2,3-difluorobutyl, 1,3-difluorobutyl, 1,2-difluorobutyl, 2,2-difluorobutyl, 1,1-difluorobutyl, 3,3,3-trifluorobutyl, 2,3,3-trifluorobutyl, 1,3,3-trifluorobutyl, 1,2,2-trifluorobutyl, 1,1,2-trifluorobutyl, 1,1,3-trifluorobutyl, 1,1,2,2-tetrafluorobutyl, and 2,2,3,3,3-pentafluorobutyl.

[0037] In the present invention, "a sulfur atom that may be oxidized" refers to sulfur (S), sulfoxide (S(O)), and sulfone (SO2).

[0038] In the present invention, "4-10 membered heterocycle" means a 4-10 membered monocyclic or bicyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, for example, oxetane, azetidine, pyrrolidine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, ox Sadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiadin, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indidine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, quinoridine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, benzodioxol, benzoxathiol, chloro Men, benzoflazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazolin, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, Tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,Tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothi Azole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiaidine, tetrahydrothiaidine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, tetrahydrotriazolopyrazine, morpholine, thiomorpholine, oxatian, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydro Dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline Dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrosinnoline, tetrahydrosinnoline, perhydrosinnoline, benzoxatian, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dioxindan, benzodioxane, thiochroman, dihydrobenzodioxinThese include dihydrobenzoxatiin, chroman, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrrolopyridine, pyrrolopyridine, pyrrolopyridine, pyrrolopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, triazolopyridine, and dihydropyridoxazine rings.

[0039] In the present invention, "3-10 membered heterocycle" means a 3-10 membered monocyclic or bicyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, such as aziridine, oxirane, thiirane, and the heterocycles described above as "4-10 membered heterocycles".

[0040] In the present invention, "5-10 membered aromatic heterocycle" means a 5-10 membered monocyclic or bicyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, such as pyrrole, imidazole, triazole, tetrazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, purine, benzoxazole, benzothiazole, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, quinoline, isoquinoline, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, and sinnoline rings.

[0041] In the present invention, "5-6 membered monocyclic aromatic heterocycle" refers to, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, and thiadiazole rings.

[0042] In the present invention, "C4-10 carbon ring" means a monocyclic or bicyclic carbon ring of C4 to C10, and includes, for example, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indan, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene rings.

[0043] In the present invention, "C3-10 carbon ring" means a monocyclic or bicyclic carbon ring of C3 to C10, such as cyclopropane and the carbon ring described above as "C4-10 carbon ring".

[0044] In the present invention, "C1-6 alkyl" refers to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 2-methyl-2-ethylpropyl, 1-ethylbutyl, and 2-ethylbutyl.

[0045] In the present invention, "C3-6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0046] In the present invention, "4-6 membered heterocycle" means a 4-6 membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and includes, for example, oxetane, azetidine, pyrrolidine, piperidine, pyrazine, pyran, thiopyran, oxazine, oxadiazine, thiadin, thiadiazine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, and thiadiazole rings.

[0047] In the present invention, R 1 Preferably COOR 8 That is the case.

[0048] In the present invention, R 8 Preferably, it is a hydrogen atom or a C1-4 alkyl group, and more preferably a hydrogen atom.

[0049] In the present invention, R 8-1 Preferably, the element is a C1-4 alkyl, benzene, or pyridine, and the benzene and pyridine may be substituted with a C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -O(C1-4 haloalkyl), C1-4 alkylthio, -S(C1-4 haloalkyl), halogen, or nitrile.

[0050] In the present invention, L 1 Preferably, the alkylene is C1-5 alkylene or C2-5 alkenylene, more preferably C1-5 alkylene, and particularly preferably propylene.

[0051] In the present invention, R 2 Preferably, it is fluorine.

[0052] In the present invention, X 1 Preferably as CR 6 That is the case.

[0053] In the present invention, R6 Preferably, it is a hydrogen atom or fluorine, and more preferably a hydrogen atom.

[0054] In the present invention, X 2 Preferably as CR 7 That is the case.

[0055] In the present invention, R 7 Preferably, fluorine, nitrile, -CH2R 9 , or -OR 9 It is more nitrile.

[0056] In the present invention, R 9 The 4-10 member heterocycle is preferably a 4-10 member heterocycle which may be substituted with methyl or trifluoromethyl, and the 4-10 member heterocycle is preferably a 5-10 member aromatic heterocycle, and more preferably a 5-10 member nitrogen-containing aromatic heterocycle (for example, pyrazole, imidazole, triazole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine, imidazopyridazine, imidazopyridine, imidazopyridine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, etc.).

[0057] In the present invention, L 2 Preferably, the compound is -CH=CH-, -NHCO-, -CONH-, -NHSO2-, or -SO2NH-, more preferably -NHCO- or -CONH-, and particularly preferably -NHCO-.

[0058] In the present invention, R 3 Preferably, it is fluorine.

[0059] In the present invention, R 4 Preferably, the compound is methyl, ethyl, or trifluoromethyl, and more preferably methyl.

[0060] In the present invention, X 3 Preferably, it is a methylene atom or an oxygen atom, and more preferably an oxygen atom.

[0061] In the present invention, R 10 is preferably methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulfonyl, ethylsulfonyl, or tert-butoxycarbonyl.

[0062] In the present invention, ring is preferably benzene, thiophene, or a pyrazole ring, and more preferably a benzene ring.

[0063] In the present invention, R 5 is preferably -CONHR 11 , fluorine, methoxy, a benzene ring, or a 4- to 10-membered heterocyclic ring, and the 4- to 10-membered heterocyclic ring is preferably azetidine, pyrrolidine, piperidine, oxazolidine, oxadiazole, triazole, thiophene, furan, pyrazole, thiazole, oxazole, imidazole, pyridine, pyrazine, pyridazine, pyrimidine, pyrazolopyrimidine, pyrrolopyrimidine, pyrazolopyridine, pyrrolopyridine, or dihydropyridooxazine ring.

[0064] In the present invention, R 11 is preferably C1-6 alkyl, C3-6 cycloalkyl, pyran, pyrrolidine, piperidine, pyrazole, thiazole, oxazole, isoxazole, pyridine, pyridazine, or a pyrimidine ring, and more preferably C1-6 alkyl.

[0065] In the present invention, R 13 is preferably halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, hydroxyl group, -NR 20 R 21, a benzene, oxetane, pyridine, pyrazole, or oxazole ring, more preferably fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, cyclopentyl, cyclobutyl, oxetane, hydroxyl group, methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, benzene, pyridine, pyrazole, or oxazole ring.

[0066] In the present invention, R 20 is preferably a hydrogen atom or methyl.

[0067] In the present invention, R 21 is preferably a hydrogen atom or methyl.

[0068] In the present invention, R 12 is preferably C1-3 alkyl, C3-6 cycloalkyl, benzene, or a 4-6 member heterocyclic ring. The 4-6 member heterocyclic ring is preferably oxetane, azetidine, pyrrolidine, piperidine, pyrazine, pyran, thiopyran, oxazine, oxadiazine, thiazine, thiadiazine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, or thiadiazole ring. The 4-6 member heterocyclic ring may be substituted with C1-4 alkoxy.

[0069] In the present invention, R 14 is preferably a hydrogen atom, methyl, ethyl, benzene, or benzyl.

[0070] In the present invention, R 19 is preferably methoxy, -CONHCH3, -CON(CH3)2, oxazole, thiazole, pyrazole, or pyridine ring.

[0071] In the present invention, R 15Preferably, the compound is methyl, cyclopropyl, or benzene.

[0072] In the present invention, R 16 Preferably, it is a hydroxyl group.

[0073] In the present invention, R 17 Preferably, the compound is methyl, ethyl, or cyclopropyl, and more preferably methyl.

[0074] In the present invention, R 18 Preferably, the compounds are fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, oxo, nitrile, hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, methylsulfonyl, pyridine, and dimethylamino.

[0075] In the present invention, m is preferably an integer between 1 and 2, and more preferably 1.

[0076] In the present invention, n is preferably an integer between 0 and 1, and more preferably 1.

[0077] In this invention, p is preferably 0.

[0078] In the present invention, q is preferably 0.

[0079] In the present invention, r is preferably an integer between 0 and 4, and more preferably an integer between 0 and 2.

[0080] In the present invention, s is preferably an integer between 0 and 2, and more preferably 1 or 2.

[0081] In this invention, t is preferably an integer between 0 and 2.

[0082] In the present invention, X3a Preferably, it is an oxygen atom.

[0083] In the present invention, na is preferably an integer between 0 and 1, and more preferably 1.

[0084] In the present invention, qa is preferably 0.

[0085] In the present invention, ra is preferably an integer between 0 and 2.

[0086] In the present invention, the general formula (I) is preferably the ring, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8-1 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , L 1 , L 2 , L 3 , X 1 , X 2 , X 3 This is a combination of preferred definitions for each of m, n, p, q, r, s, and t.

[0087] In the present invention, the compound represented by general formula (I) is preferably general formula (Ia)

[0088] [ka]

[0089] A compound represented by (wherein na represents an integer from 0 to 1, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and other symbols have the same meaning as above), or a salt thereof, more preferably a compound represented by general formula (I-1)

[0090] [ka]

[0091] (In the formula, na represents an integer from 0 to 1, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, X 3a represents a methylene or oxygen atom, and the other symbols have the same meaning as above. ) This refers to the compound or salt thereof.

[0092] In the present invention, another embodiment of the compound represented by general formula (I) is more preferably general formula (Ib)

[0093] [ka]

[0094] A compound represented by (wherein na represents an integer from 0 to 1, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and other symbols have the same meaning as above), or a salt thereof, more preferably a compound represented by general formula (Ic)

[0095] [ka]

[0096] A compound represented by (wherein na represents an integer from 0 to 1, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and other symbols have the same meaning as above), or a salt thereof, more preferably a compound represented by general formula (Id)

[0097] [ka]

[0098] A compound represented by (wherein na represents an integer from 0 to 1, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and other symbols have the same meaning as above), or a salt thereof, and more preferably a compound represented by general formula (Ie)

[0099] [ka]

[0100] A compound represented by (wherein na represents an integer from 0 to 1, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and other symbols have the same meaning as above), or a salt thereof, particularly preferably of general formula (I-2)

[0101] [ka]

[0102] (In the formula, R 2a represents halogen, R 6a represents a hydrogen atom or halogen, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and other symbols have the same meaning as above. The compound is represented by ) or a salt thereof, most preferably by general formula (I-4)

[0103] [ka]

[0104] (In the formula, R 2a represents halogen, R 6a represents a hydrogen atom or halogen, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and other symbols have the same meaning as above. ) This refers to the compound or salt thereof.

[0105] In the present invention, a further alternative embodiment of the compound represented by general formula (I) is more preferably general formula (If)

[0106] [Chemical formula]

[0107] (In the formula, R 5a represents a C4-10 carbocyclic ring or a 4-10 member heterocyclic ring which may be substituted with 1 to 3 R 18 . When there are a plurality of R 18 , R 18 may be the same or different independently of each other. na represents an integer of 0 to 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, and other symbols represent the same meaning as described above.) A compound represented by, or a salt thereof, and more preferably a general formula (I-g)

[0108] [Chemical formula]

[0109] (In the formula, R 5a represents a C4-10 carbocyclic ring or a 4-10 member heterocyclic ring which may be substituted with 1 to 3 R 18 . When there are a plurality of R 18 , R 18 may be the same or different independently of each other. na represents an integer of 0 to 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, and other symbols represent the same meaning as described above.) A compound represented by, or a salt thereof, and still more preferably a general formula (I-h)

[0110] [Chemical formula]

[0111] (In the formula, R 5a represents a C4-10 carbocyclic ring or a 4-10 member heterocyclic ring which may be substituted with 1 to 3 R 18 ​​​​Each of these may be independent, identical, or different, where na represents an integer from 0 to 1, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and the other symbols have the same meaning as above. The compound represented by ) or a salt thereof, and more preferably general formula (Ii)

[0112] [ka]

[0113] (In the formula, R 5a 1 to 3 R 18 A C4-10 carbon ring or a 4-10 membered heterocycle which may be substituted with, and the R 18 If there are multiple, R 18 Each of these may be independent, identical, or different, na represents an integer from 0 to 1, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and the other symbols have the same meaning as above. The compound is represented by ) or a salt thereof, and is particularly preferably of general formula (I-3)

[0114] [ka]

[0115] (In the formula, R 2a represents halogen, R 6a represents a hydrogen atom or halogen, and R 5a 1 to 3 R 18 A C4-10 carbon ring or a 4-10 membered heterocycle which may be substituted with, and the R 18 If there are multiple, R 18 Each of these may be independent, identical, or different, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and the other symbols have the same meaning as above. The compound is represented by ) or a salt thereof, most preferably by general formula (I-5)

[0116] [ka]

[0117] (In the formula, R 2a represents halogen, R 6a represents a hydrogen atom or halogen, and R 5a 1 to 3 R 18 A C4-10 carbon ring or a 4-10 membered heterocycle which may be substituted with, and the R 18 If there are multiple, R 18 Each of these can be independent, identical, or different; qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and the other symbols have the same meaning as above. ) This refers to the compound shown, or a salt thereof.

[0118] In the present invention, in the general formula selected from the group of general formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), and (I-1) above, each is independently preferably L 1 It is propylene, and L 2 is -CH=CH-, -NHCO-, -CONH-, -NHSO2-, or -SO2NH-. More preferably, L 1 It is propylene, and L 2 is -NHCO- or -CONH-. More preferably, L 1 It is propylene, and L 2 It is -NHCO-.

[0119] In the present invention, in the general formula selected from the group of general formulas (I-2), (I-3), (I-4), and (I-5) above, each is independently preferably L 1 That is propylene.

[0120] In the present invention, the EP4 antagonist is more preferably a compound described in the examples of WO2016 / 111347, or a salt thereof. Even more preferably, (1) 4-[4-Cyano-2-({[(2’R,4S)-6-(Methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1’-cyclopropane]-2’-yl]carbonyl}amino)phenyl]butanoic acid, (2) 4-{4-Cyano-2-[({(2’R,4S)-6-[(Cyclopropylmethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1’-cyclopropane]-2’-yl}carbonyl)amino]phenyl}butanoic acid, (3) 4-{4-Cyano-2-[({(2’R,4S)-6-[(2-Methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1’-cyclopropane]-2’-yl}carbonyl)amino]phenyl}butanoic acid, (4) 4-{4-Cyano-2-[({(2’R,4S)-6-[(2-Methyl-2-propanyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1’-cyclopropane]-2’-yl}carbonyl)amino]phenyl}butanoic acid, (5) 4-[4-Cyano-2-({[(2’R,4S)-6-{[(2S)-1-Methoxy-2-propanyl]carbamoyl}-2,3-dihydrospiro[chromene-4,1’-cyclopropane]-2’-yl]carbonyl}amino)phenyl]butanoic acid, (6) 4-{4-Cyano-2-[({(2’R,4S)-6-[(1-Methyl-1H-pyrazol-3-yl)carbamoyl]-2,3-dihydrospiro[chromene-4,1’-cyclopropane]-2’-yl}carbonyl)amino]phenyl}butanoic acid, (7) 4-[4-Cyano-2-({[(2’R,4S)-6-(Cyclopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1’-cyclopropane]-2’-yl]carbonyl}amino)phenyl]butanoic acid, (8) 4-[4-Cyano-2-({(2’R,4S)-6-[(Propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1’-cyclopropane]-2’-carbonyl}amino)phenyl]butanoic acid, (9) 4-[4-cyano-2-({[(2'R,4S)-6-(cyclopentylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (10) 4-{2-[({(2'R,4S)-6-[(2S)-2-butanylcarbamoyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]-4-cyanophenyl}butanoic acid, (11) 4-{4-cyano-2-[({(2'R,4S)-6-[(trans-4-hydroxycyclohexyl)carbamoyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (12) 4-{4-cyano-2-[({(2'R,4S)-6-[(cis-4-hydroxycyclohexyl)carbamoyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (13) 4-[4-cyano-2-({[(2'R,4S)-6-(2-pyridinylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (14) 4-[4-cyano-2-({[(2'R,4S)-6-(3-pyridazinylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (15) 4-[4-cyano-2-({[(2'R,4S)-6-(cyclobutylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (16) 4-[4-cyano-2-({[(2'R,4S)-6-{[1-(2-methyl-2-propanyl)-1H-pyrazole-4-yl]carbamoyl}-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (17) 4-[4-cyano-2-({[(2'R,4S)-6-(tetrahydro-2H-pyran-4-ylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (18) 4-[4-cyano-2-({[(2'R,4S)-6-(propylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (19) 4-{4-cyano-2-[({(2'R,4S)-6-[(2-ethoxyethyl)carbamoyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, or (20) 4-[4-cyano-2-({[(2'R,4S)-6-(ethylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (21) 4-[4-cyano-2-({[(1R,2R)-6'-(methylcarbamoyl)-2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-yl]carbonyl}amino)phenyl]butanoic acid, (22) 4-{4-cyano-2-[({(1R,2R)-6'-[(2-methoxyethyl)carbamoyl]-2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-yl}carbonyl)amino]phenyl}butanoic acid, (23) 4-{4-cyano-2-[({(1R,2R)-6'-[(1-methyl-1H-pyrazole-4-yl)carbamoyl]-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl}carbonyl)amino]phenyl}butanoic acid, (24) 4-[4-cyano-2-({[(2'R,4S)-7-fluoro-6-(methylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (25) 4-{4-cyano-2-[({(2'R,4S)-7-fluoro-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (26) 4-[4-cyano-2-({[(2'R,4S)-7-fluoro-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (27) 4-[4-cyano-2-({[(2'R,4S)-7-(methylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (28) 4-{4-cyano-2-[({(2'R,4S)-7-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (29) 4-[4-cyano-2-({[(2'R,4S)-7-methoxy-6-(methylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (30) 4-{4-cyano-2-[({(2'R,4S)-7-methoxy-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (31) 4-[4-cyano-2-({[(2'R,3S)-5-(methylcarbamoyl)-2H-spiro[1-benzofuran-3,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (32) 4-{4-cyano-2-[({(2'R,3S)-5-[(2-methoxyethyl)carbamoyl]-2H-spiro[1-benzofuran-3,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (33) 4-[4-cyano-2-({[(1S,2R)-6'-[(2-methoxyethyl)carbamoyl]-3',3'-dimethyl-2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-yl]carbonyl}amino)phenyl]butanoic acid, or (34) 4-[4-cyano-2-({[(1S,2R)-3',3'-dimethyl-6'-(methylcarbamoyl)-2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-yl]carbonyl}amino)phenyl]butanoic acid, or a salt thereof.

[0121] Alternatively, in the present invention, the EP4 antagonist is preferably (1) 4-[4-cyano-2-({[(2'R,4S)-6-(5-methyl-1,3,4-oxadiazole-2-yl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}aminophenyl]butanoic acid, (2) 4-[4-cyano-2-({[(2'R,4S)-6-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (3) 4-[4-cyano-2-({[(2'R,4S)-6-(3-methyl-1,2,4-oxadiazole-5-yl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (4) 4-[4-cyano-2-({[(2'R,4S)-6-(3-pyridinyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (5) 4-[4-cyano-2-({[(2'R,4S)-6-(1H-pyrazole-1-yl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (6) 4-[4-cyano-2-({[(2'R,4S)-6-(1H-pyrazole-5-yl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (7) 4-[4-cyano-2-({[(2'R,4S)-6-(4-pyridazinyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (8) 4-[4-cyano-2-({[(2'R,4S)-6-(2-oxo-1-pyrrolidinyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (9) 4-[4-cyano-2-({[(2'R,4S)-6-(6-methoxy-3-pyridinyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (10) 4-{4-cyano-2-[({(2'R,4S)-6-[6-(1H-pyrazole-1-yl)-3-pyridinyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (11) 4-{4-cyano-2-[({(2'R,4S)-6-[6-(dimethylamino)-3-pyridinyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (12) 4-[4-cyano-2-({[(2'R,4S)-6-(6-methyl-3-pyridinyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (13) 4-{4-cyano-2-[({(2'R,4S)-6-[6-(methylamino)-3-pyridinyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (14) 4-[4-cyano-2-({[(2'R,4S)-6-(2-pyridinyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (15) 4-[4-cyano-2-({[(2'R,4S)-6-(1,3-thiazole-2-yl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (16) 4-[4-cyano-2-({[(2'R,4S)-6-(1,3-oxazol-2-yl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (17) 4-[4-cyano-2-({[(2'R,4S)-6-(1-methyl-1H-1,2,3-triazole-4-yl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (18) 4-[4-cyano-2-({[(2'R,4S)-6-(3-pyridazinyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (19) 4-[4-cyano-2-({[(2'R,3S)-5-(3-pyridinyl)-2H-spiro[1-benzofuran-3,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid, or (20) 4-[4-cyano-2-({[(1S,2R)-3',3'-dimethyl-6'-(3-pyridinyl)-2',3'-dihydrospiro[cyclopropane-1,1'-inden]-2-yl]carbonyl}amino)phenyl]butanoic acid, or a salt thereof.

[0122] Particularly preferred is the following structural formula

[0123] [ka]

[0124] It is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid (hereinafter sometimes abbreviated as compound A), or a salt thereof. Note that 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid is sometimes named 4-[4-cyano-2-({[(2'R,4S)-6-(isopropylcarbamoyl)-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butanoic acid. Compound A can be prepared by known methods, for example, by the method described in Example 2-13 of WO2016 / 111347.

[0125] Particularly preferred is the following structural formula

[0126] [ka]

[0127] The compound is 4-{4-cyano-2-[({(2'R,4S)-6-[(2-methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromen-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butanoic acid (hereinafter sometimes abbreviated as Compound B), or a salt thereof. Compound B can be prepared by known methods, for example, by the method described in Example 2-2 of WO2016 / 111347.

[0128] In this invention, isomers are encompassed unless otherwise specified. For example, alkyl groups, alkoxy groups, and alkylene groups include both linear and branched forms. Furthermore, isomers at double bonds, rings, and fused rings (E, Z, cis, and trans isomers), isomers due to the presence of chiral carbons (R, S, α, β, enantiomers, and diastereomers), optically active isomers exhibiting optical rotation (D, L, d, and l isomers), polar forms separated by chromatography (highly polar and low polar forms), equilibrium compounds, rotational isomers, mixtures of these in any proportion, and racemic mixtures are all included in this invention. In addition, isomers due to tautomerism are also encompassed in this invention.

[0129] In this invention, unless otherwise specified, symbols will be used as will be obvious to those skilled in the art.

[0130] [ka]

[0131] This indicates that it is coupled to the other side of the paper (i.e., in an α-configuration).

[0132] [ka]

[0133] This indicates that it is bonded to the front side of the paper (i.e., in a β-configuration).

[0134] [ka]

[0135] This indicates any mixture of α-configuration and β-configuration.

[0136] [salt] Compounds represented by general formula (I) can be converted to salts by known methods. A pharmaceutically acceptable salt is preferred as the salt used. A water-soluble salt is preferable. Examples of pharmaceutically acceptable salts include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts. Examples of acid addition salts include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and nitrate, or organic salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, or gluconate. Examples of alkali metal salts include salts with potassium and sodium. Examples of alkaline earth metal salts include salts with calcium and magnesium. Examples of ammonium salts include salts with tetramethylammonium, for instance. Examples of amine salts include salts with triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, and N-methyl-D-glucamine. Furthermore, the compounds used in this invention can be converted into N-oxide compounds by any method. An N-oxide compound refers to a compound in which the nitrogen atom of the compound represented by general formula (I) has been oxidized. Compounds represented by general formula (I) and their salts may exist in an unsolvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. Hydrates are preferred as the solvates. Compounds represented by general formula (I) can form cocrystals with suitable cocrystal-forming agents. Preferably, the cocrystals are pharmaceutically acceptable and formed with pharmaceutically acceptable cocrystal-forming agents. A cocrystal is typically defined as a crystal formed by two or more different molecules through intermolecular interactions other than ionic bonding. A cocrystal may also be a complex of a neutral molecule and a salt. Cocrystals can be prepared by known methods, such as by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable cocrystal-forming agents include those described in WO2006 / 007448. In the present invention, all references to the compound represented by general formula (I) include the compound represented by general formula (I), its salt, its N-oxide, its solvate (e.g., hydrate), or its cocrystal, or the N-oxide, solvate (e.g., hydrate), or cocrystal of a salt of the compound represented by general formula (I). In other words, in the present invention, the compound represented by general formula (I), or a salt thereof, includes the solvate (e.g., hydrate) of the compound represented by general formula (I), its N-oxide, or its cocrystal, or the N-oxide, solvate (e.g., hydrate), or its cocrystal of a salt of the compound represented by general formula (I).

[0137] [Prodrug] Furthermore, compounds represented by general formula (I) can be administered as prodrugs. A prodrug of a compound represented by general formula (I) is a compound that is converted in the body by reactions involving enzymes or gastric acid to represent the compound represented by general formula (I). Examples of prodrugs of compounds represented by general formula (I) include, if the compound represented by general formula (I) has an amino group, compounds in which the amino group is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of the compound represented by general formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); and if the compound represented by general formula (I) has a hydroxyl group, compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of the compound represented by general formula (I) is acetylated, palmitoylated, or propanoylated). Examples include compounds that have been esterified, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated; and if the compound represented by general formula (I) has a carboxyl group, examples include compounds in which the carboxyl group has been esterified or amidized (for example, compounds in which the carboxyl group of the compound represented by general formula (I) has been ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolenn-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, or methylamidized). These compounds can be produced by known methods. Furthermore, the prodrug of the compound represented by general formula (I) may be either a hydrate or an unhydrated form. Furthermore, the prodrug of the compound represented by general formula (I) may be one that transforms into the compound represented by general formula (I) under physiological conditions, as described on pages 163-198 of "Molecular Design," Volume 7 of "Pharmaceutical Development," published by Hirokawa Shoten in 1990. Furthermore, each atom constituting the compound represented by general formula (I) is its isotope (for example, 2 H, 3 H, 13 C, 14 C, 15 N, 16 N, 17 O, 18 O, 18 F, 35 S, 36 Cl, 77 Br, 125 It may be replaced with something like I.

[0138] [Method for producing the compound used in the present invention] In the present invention, the EP4 antagonist can be produced by known methods; for example, the compound represented by general formula (I) can be produced according to the method described in WO2016 / 111347.

[0139] [Formulation and method of administration] In the present invention, the EP4 antagonist is usually formulated with various pharmaceutically acceptable carriers, such as additives or solvents, and then administered systemically or topically, orally or parenterally. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient that is generally used in the formulation of pharmaceuticals. A pharmaceutically acceptable carrier is preferably one that does not exhibit pharmacological effects at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. Furthermore, a pharmaceutically acceptable carrier can also be used for purposes such as enhancing the usefulness of the active ingredient and formulation, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances such as those listed in "Dictionary of Pharmaceutical Additives 2016" (edited by the Japan Pharmaceutical Additives Association), published by Yakuji Nippo Co., Ltd. in 2016, can be appropriately selected according to the purpose.

[0140] Dosage forms used for administration include, for example, oral preparations (e.g., tablets, capsules, granules, powders, oral solutions, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, semi-solid oral preparations, gargles, etc.), injectable preparations (e.g., injectable preparations, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations (e.g., inhalants, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otological preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal sprays, etc.), rectal preparations (e.g., suppositories, semi-solid rectal preparations, enema preparations, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., external solid preparations, external solutions, sprays, ointments, creams, gels, patches, etc.).

[0141] The dosage of the EP4 antagonist used in this invention varies depending on age, weight, symptoms, therapeutic effect, administration method, processing time, etc. However, typically, for adults, it is administered orally once to several times a day in a range of 1 ng to 1000 mg per dose, or parenterally once to several times a day in a range of 0.1 ng to 100 mg per dose, or continuously intravenously for a range of 1 to 24 hours per day. Of course, as mentioned above, the dosage will vary depending on various conditions, so in some cases a smaller dose than the above may be sufficient, and in other cases it may be necessary to administer a dose exceeding the range.

[0142] In one embodiment, when compound A is used, one embodiment of the dosage is administered orally in doses of approximately 1 to 100 mg once to three times a day, preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg once to three times a day, more preferably 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg once to three times a day, even more preferably 5 mg, 10 mg, 20 mg, or 40 mg once a day, and more preferably 20 mg or 40 mg once a day.

[0143] (2) Immune checkpoint inhibitors In this invention, an immune checkpoint molecule refers to a molecule that exerts an immunosuppressive function by transmitting an inhibitory co-signal. Known immune checkpoint molecules include CTLA-4, PD-1, PD-L1 (programmed cell death-ligand 1), PD-L2 (programmed cell death-ligand 2), LAG-3 (Lymphocyte activation gene 3), TIM3 (T cell immunoglobulin and mucin-3), BTLA (B and T lymphocyte attenuator), B7H3, B7H4, CD160, CD39, CD73, A2aR (adenosine A2a receptor), KIR (killer inhibitory receptor), VISTA (V-domain Ig-containing suppressor of T cell activation), IDO1 (Indoleamine 2,3-dioxygenase), Arginase I, TIGIT (T cell immunoglobulin and ITIM domain), and CD115 (Nature Reviews Cancer, 12, pp. 252-264, 2012, Cancer). (See Cell, 27, pp. 450-461, 2015), it is not particularly limited as long as it is a molecule that has a function consistent with the definition.

[0144] In this invention, an immune checkpoint inhibitor is a substance that inhibits the function of immune checkpoint molecules. The immune checkpoint inhibitor is not particularly limited as long as it is a substance that can suppress the function (signaling) of immune checkpoint molecules.

[0145] Examples of immune checkpoint inhibitors include anti-PD-1 antibodies (e.g., Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartalizumab (PDR-001), Tislelizumab (BGB-A317), AMP-514 (MEDI0680), Dostarlimab (ANB011 / TSR-042), Toripalimab (JS001), Camrelizumab (SHR-1210), Genolimzumab (CBT-501), Sintilimab (IBI308), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, Retifanlimab (MGA012), Balstilimab (AGEN2034), CS1003, Serplulimab (HLX10), BAT-1306, AK105, AK103, BI754091, LZM009, CMAB819, Sym021, Geptanolimab (GB226), SSI-361, JY034, HX008, ISU106, Budigalim ab (ABBV181), Prolgolimab (BCD-100), Sasanlimab (PF-06801591), CX-188, Cetrelimab (JNJ-6372328) 3) and Zimberelimab (AB122), etc.), anti-PD-L1 antibodies (e.g., Atezolizumab (RG7446 / MPDL3280A), Avelumab (PF-06834635 / MSB0010718C), Durvalumab (MEDI4736), BMS-936559, STI-1014, Envafolimab (KN035), Lodapol imab(LY3300054), HLX20, SHR-1316, CS1001(WBP3155), MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502(TQB2450), JS003 and CX-072, etc.) or anti-CTLA-4 antibodies (e.g., Ipilimumab(MDX- Examples include 010), Zalifrelimab (AGEN1884) and Tremelimumab, anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224), anti-Tim-3 antibodies (e.g., MBG453), anti-LAG-3 antibodies (e.g., BMS-986016, LAG525), and anti-KIR antibodies (e.g., Lirilumab). Furthermore, antibodies containing the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of the above known antibodies are also a form of immune checkpoint inhibitor. For example, a further form of an anti-PD-1 antibody is an antibody containing the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of Nivolumab, for example.

[0146] In the present invention, the immune checkpoint inhibitor is preferably an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody, and more preferably an anti-PD-1 antibody or an anti-PD-L1 antibody. Preferred anti-PD-1 antibodies are Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, Toripalimab, Sintilimab, and Camrelizumab; preferred anti-PD-L1 antibodies are Atezolizumab, Avelumab, Durvalumab, and BMS-936559; and preferred anti-CTLA-4 antibodies are Ipilimumab and Tremelimumab. Furthermore, more preferably anti-PD-1 antibodies are Nivolumab, Cemiplimab, and Pembrolizumab, and more preferably Nivolumab. In the present invention, the immune checkpoint inhibitor is preferably an anti-PD-1 antibody, and more preferably Nivolumab.

[0147] In the present invention, immune checkpoint inhibitors can be manufactured by known methods. Nivolumab can be manufactured according to the method described in WO2006 / 121168, Pembrolizumab can be manufactured according to the method described in WO2008 / 156712, BMS-936559 can be manufactured according to the method described in WO2007 / 005874, and Ipilimumab can be manufactured according to the method described in WO2001 / 014424.

[0148] In this invention, one or any combination of these immune checkpoint inhibitors can be used in combination with the administration of an EP4 antagonist and standard therapy.

[0149] The dosage of the immune checkpoint inhibitors used in the combination of this invention varies depending on age, weight, symptoms, therapeutic effect, administration method, processing time, etc., but is adjusted to produce the optimal desired effect.

[0150] For example, an immune checkpoint inhibitor can be administered intravenously (e.g., by intravenous infusion) at intervals of 2 to 4 weeks, at a dose of approximately 1 to 10 mg / kg (body weight) or approximately 200 to 1200 mg, over a period of approximately 30 minutes, 60 minutes, or more than 60 minutes. Here, examples of dosages per administration based on body weight include 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg. On the other hand, examples of dosages per administration include 200 mg, 240 mg, 250 mg, 280 mg, 300 mg, 320 mg, 350 mg, 360 mg, 400 mg, 420 mg, 450 mg, 480 mg, 500 mg, 540 mg, 560 mg, 600 mg, 640 mg, 700 mg, 720 mg, 750 mg, 800 mg, 840 mg, 900 mg, 1000 mg, 1080 mg, 1100 mg, 1120 mg, or 1200 mg. Furthermore, the administration interval may be, for example, two weeks, three weeks, or four weeks, and the duration of a single administration may be, for example, approximately 30 minutes, approximately 60 minutes, or approximately 60 minutes or more.

[0151] When the immune checkpoint inhibitor is the anti-PD-1 antibody Nivolumab, it is administered according to the following dosage and administration instructions: For patients with malignant melanoma, Nivolumab is administered intravenously at a dose of 3 mg / kg (body weight) every two weeks or 2 mg / kg (body weight) every three weeks, or 240 mg every two weeks or 480 mg every four weeks. For patients with non-small cell lung cancer, renal cell carcinoma, classical Hodgkin lymphoma, head and neck cancer, gastric cancer, and malignant pleural mesothelioma, Nivolumab is administered intravenously at a dose of 3 mg / kg (body weight) every two weeks. Additionally, for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, MSI-H or dMMR-positive colorectal cancer (including patients aged 12 years and older), gastric cancer, hepatocellular carcinoma, small cell lung cancer, and malignant pleural mesothelioma, nivolumab is administered intravenously at a dose of 240 mg every two weeks or at a dose of 480 mg every four weeks. Furthermore, alternative dosages and administrations include, for example, in patients with malignant melanoma, Nivolumab may be administered in combination with Ipilimumab, with 1 mg / kg (body weight) intravenously infusion four times at 3-week intervals, followed by 3 mg / kg (body weight) intravenously infusion every two weeks, or 80 mg of Nivolumab may be administered in combination with Ipilimumab, followed by 240 mg of Nivolumab every two weeks or 480 mg of Nivolumab every four weeks. Also, for example, in patients with renal cell carcinoma or colorectal cancer, Nivolumab may be administered in combination with Ipilimumab, with 240 mg of Nivolumab administered in combination with Ipilimumab, followed by 240 mg of Nivolumab every two weeks or 480 mg of Nivolumab every four weeks.

[0152] Furthermore, in the case of Pembrolizumab, which is also an anti-PD-1 antibody, it is administered according to the following dosage and administration: For patients with malignant melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, MSI-H or dMMR-positive solid tumors or colorectal cancer, urothelial carcinoma, cervical cancer, primary mediastinal B-cell lymphoma, hepatocellular carcinoma, gastric cancer, and Merkel cell carcinoma, Pembrolizumab is administered by intravenous infusion at a dose of 200 mg every 3 weeks or 400 mg every 6 weeks. Alternatively, for example, for children aged 2 years or older with classical Hodgkin lymphoma, MSI-H or dMMR-positive solid tumors or colorectal cancer, and primary mediastinal B-cell lymphoma, Pembrolizumab is administered by intravenous infusion at a dose of 2 mg / kg (body weight) (up to 200 mg) every 3 weeks.

[0153] Furthermore, in the case of the immune checkpoint inhibitor Avelumab, which is an anti-PD-L1 antibody, patients with Merkel cell carcinoma and urothelial carcinoma are administered 10 mg / kg (body weight) of Avelumab intravenously every two weeks. For patients with non-small cell lung cancer, urothelial carcinoma, and hepatocellular carcinoma, Atezolizumab is administered 1200 mg every three weeks by intravenous infusion, and in combination with paclitaxel, patients with triple-negative breast cancer are administered 840 mg of Atezolizumab every two weeks by intravenous infusion. Furthermore, Durvalumab, which is also a PD-L1 antibody, is administered intravenously at a dose of 10 mg / kg (body weight) every two weeks to patients with non-small cell lung cancer and urothelial carcinoma, respectively, while Durvalumab is administered intravenously at a dose of 1500 mg every four weeks to patients with advanced small cell lung cancer.

[0154] In addition, for patients with malignant melanoma, ipilimumab is administered by intravenous infusion at 3 mg / kg (body weight) once daily at 3-week intervals for 4 doses, either alone or in combination with nivolumab. For patients with renal cell carcinoma and MSI-H or dMMR-positive colorectal cancer, ipilimumab is administered by intravenous infusion at 1 mg / kg (body weight) once daily at 3-week intervals for 4 doses, in combination with nivolumab. For patients with non-small cell lung cancer, ipilimumab is administered by intravenous infusion at 1 mg / kg (body weight) once every 6 weeks.

[0155] In this invention, parenteral administration is preferred for the immune checkpoint inhibitor. Parenteral administration methods include subcutaneous, intradermal, intraperitoneal, intramuscular, and intravenous administration, with subcutaneous or intravenous administration being preferred. Intravenous administration is even more preferred. Intravenous administration is preferably administered by intravenous drip infusion.

[0156] In the present invention, the above-mentioned dosage and administration method may also be used in the treatment method of the present invention.

[0157] (3) XELOX + bevacizumab therapy in combination with EP4 antagonists and immune checkpoint inhibitors (hereinafter sometimes abbreviated as this combination-1). In this invention, "XELOX therapy" refers to a cancer treatment method using a combination of capecitabine and oxaliplatin (L-OHP).

[0158] In this invention, "XELOX + bevacizumab therapy" refers to a cancer treatment method using a combination of three drugs: capecitabine, oxaliplatin, and bevacizumab. In one embodiment, bevacizumab 7.5 mg / kg is administered intravenously over approximately 30 to 90 minutes, followed by oxaliplatin 130 mg / m². 2 (Body surface area) is administered intravenously over 2 hours, and this series of administrations is carried out at 3-week intervals, with capecitabine 1000 mg / m². 2 / times (body surface area 1.36m 2 Less than: 1200 mg / dose, body surface area 1.36-1.66 m²2 Less than: 1500 mg / dose, body surface area 1.66~1.96 m² 2 Less than: 1800 mg / dose, body surface area 1.96 m² 2 The above is a therapy involving oral administration of 2100 mg / dose twice daily for 14 days, followed by a 7-day rest period. In one embodiment, in any administration from the second cycle onward in the XELOX + bevacizumab therapy, depending on the severity of the patient's adverse reactions, bevacizumab administration may be discontinued, the dose of capecitabine may be reduced or discontinued to 1800 mg / dose, 1500 mg / dose, 1200 mg / dose, 900 mg / dose, or 600 mg / dose depending on the initial dose and body surface area, and oxaliplatin may be reduced to 100 mg / m². 2 (body surface area) or 85 mg / m² 2 The dosage may be reduced or the treatment discontinued based on (body surface area). The discontinuation, reduction, and resumption of XELOX + bevacizumab therapy should be done at the physician's discretion, referring to the latest package insert.

[0159] In combination with XELOX + bevacizumab therapy, compound A, an EP4 antagonist, is administered orally at a dose of 5 mg once daily, 10 mg once daily, 20 mg once daily, or 40 mg once daily in one embodiment. Preferably, it is administered orally at a dose of 20 mg once daily or 40 mg once daily. Depending on the severity of the patient's adverse reactions, the dose of compound A may be reduced or administration may be discontinued. If the criteria for resumption are met, administration of compound A can be resumed, and if resumed, the dose of compound A may be reduced one step at a time at the discretion of the physician. In one embodiment, when compound A as an EP4 antagonist is administered at an initial dose of 40 mg, the first step reduction is 20 mg, and the second step reduction is 10 mg. When compound A as an EP4 antagonist is administered at an initial dose of 20 mg, the first step reduction is 10 mg, and the second step reduction is 5 mg.

[0160] In combination with XELOX + bevacizumab therapy, nivolumab, as an immune checkpoint inhibitor, is administered by intravenous infusion at a dose of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks in one embodiment. Preferably, 360 mg of nivolumab is administered by intravenous infusion every three weeks. Depending on the severity of the patient's adverse reactions, administration of nivolumab may be discontinued. Furthermore, administration of nivolumab can be resumed if the criteria for resumption are met.

[0161] The cancers to which this combination therapy-1 can be applied are not particularly limited as long as this combination therapy-1 is effective, but in one embodiment it is colorectal cancer, preferably colon and rectal cancer. More preferably it is advanced or recurrent colon and rectal cancer that is not resectable.

[0162] In one embodiment, this combination therapy-1 is administered to patients who have no prior treatment history for colorectal cancer.

[0163] In this combination therapy-1, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered on the same day as XELOX + bevacizumab therapy, in one embodiment, the EP4 antagonist and the immune checkpoint inhibitor are administered first. In one embodiment, after the administration of the EP4 antagonist and the immune checkpoint inhibitor, bevacizumab, oxaliplatin, and capecitabine are administered in that order. In another embodiment, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered on the same day as XELOX + bevacizumab therapy, XELOX + bevacizumab therapy may be performed first, or simultaneously with the administration of the EP4 antagonist and the immune checkpoint inhibitor. In one embodiment, the order in which the EP4 antagonist, immune checkpoint inhibitor, bevacizumab, oxaliplatin, and capecitabine are administered may be any order in which they are administered, unless otherwise defined, and two or more drugs may be administered simultaneously.

[0164] (4) EP4 antagonists as neoadjuvant therapy after neoadjuvant chemoradiotherapy, or combination therapy of EP4 antagonists and immune checkpoint inhibitors (hereinafter sometimes abbreviated as this combination-2). In this invention, "preoperative chemoradiotherapy" refers to a therapy that combines radiation therapy with chemotherapy such as fluorouracil (5-FU) or capecitabine. In this invention, a combination of radiation therapy and capecitabine administration is preferred.

[0165] In one embodiment, the preoperative chemoradiotherapy in the present invention involves 45 Gy / 25 fractions of irradiation to the pelvic cavity and 5.4 Gy / 3 fractions of boost irradiation to the primary tumor, and capecitabine at 825 mg / m². 2The starting dose is twice daily (based on the dosage and administration instructions for Xeloda® 300mg tablets). When used in combination with radiation therapy, capecitabine is administered orally for a period equivalent to 75% of the 28 radiation sessions (e.g., 21 days or 42 or more doses, taken morning and evening, in the case of 50.4 Gy / 28 sessions). The dose can be reduced as appropriate depending on the severity of the patient's adverse reactions.

[0166] Compound A, used as an EP4 antagonist in neoadjuvant therapy after neoadjuvant chemoradiotherapy, is administered orally at doses of 5 mg once daily, 10 mg once daily, 20 mg once daily, or 40 mg once daily in one embodiment. Preferably, it is administered orally at doses of 20 mg once daily or 40 mg once daily. More preferably, compound A is administered orally at doses of 40 mg once daily. Depending on the degree of adverse reactions experienced by the patient, the dose of compound A may be reduced or administration may be discontinued. Furthermore, if the criteria for resumption are met, administration of compound A can be resumed, and if resumption is made, the dose of compound A may be reduced one step at a time at the discretion of the physician. In one embodiment, when compound A as an EP4 antagonist is administered at an initial dose of 40 mg, the first step reduction is 20 mg, and the second step reduction is 10 mg.

[0167] Nivolumab, an immune checkpoint inhibitor used as neoadjuvant therapy after neoadjuvant chemoradiotherapy, is administered in one embodiment as 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks by intravenous infusion. Preferably, 240 mg of nivolumab is administered by intravenous infusion every two weeks. Depending on the severity of the patient's adverse reactions, administration of nivolumab may be discontinued. Administration of nivolumab can also be resumed if the criteria for resumption are met.

[0168] One embodiment of this combination therapy-2 involves the administration of an EP4 antagonist, and another embodiment involves the combined administration of an EP4 antagonist and an immune checkpoint inhibitor.

[0169] The cancers to which this combination therapy-2 is applicable are not particularly limited as long as this neoadjuvant therapy can be effective, but in one embodiment it is colorectal cancer, preferably colon and rectal cancer. More preferably it is locally advanced rectal cancer that can be curatively resected.

[0170] In one embodiment, it is administered to patients who do not show distant metastases on imaging after preoperative chemoradiotherapy and who are eligible for curative resection.

[0171] In one embodiment, this preoperative adjuvant therapy is administered to patients for whom (curative) resection is possible.

[0172] (5) FFX therapy or its weight-loss regimen In this invention, "FFX therapy" refers to a cancer treatment method using a combination of four drugs: oxaliplatin (L-OHP), irinotecan hydrochloride hydrate (irinotecan, CPT-11), levofolinate calcium (levofolinate, l-LV), and fluorouracil (5-FU). The recommended dosage is, for example, oxaliplatin 85 mg / m². 2 (Body surface area) was administered intravenously over 2 hours, followed by levofolinate 200 mg / m². 2 The drug is administered intravenously over two hours, and irinotecan 180 mg / m² is administered 30 minutes after the start of levofolinate administration. 2 It is administered intravenously over 1.5 hours, and after the completion of levofolinate administration, fluorouracil 400 mg / m² is administered. 2 Rapid intravenous administration is performed, followed by fluorouracil 2400 mg / m². 2 This treatment involves intravenous administration over a 46-hour period, with this series of administrations performed at two-week intervals.

[0173] A "dose reduction regimen" for FFX therapy refers to a prescription in which the dosage of any of the four drugs administered in FFX therapy is reduced from the initial dose or discontinued entirely, or the dosage is reduced in subsequent cycles (from the second cycle onward) or the administration of any of the four drugs is discontinued, depending on the degree of adverse events observed in any of the drugs administered after the first cycle. For example, this regimen may not require rapid intravenous administration of fluorouracil from the initial dose, and the dose of oxaliplatin may be 65 mg / m². 2 50 mg / m² 2 Or 85-50 mg / m² 2 Any dose between these two ranges, and the dose of irinotecan may be 150 mg / m². 2 , 120 mg / m² 2 90 mg / m² 2 Or 180-90 mg / m² 2 Any dose between these two values ​​may be administered, and the amount of fluorouracil administered intravenously is 1800 mg / m². 2 , 1200 mg / m² 2 Or 2400-1200 mg / m² 2 Any dose between these two ranges may be used.

[0174] Furthermore, as another aspect of the dose reduction regimen, in any administration from the second cycle onward in the FFX therapy, the rapid intravenous administration of fluorouracil may be discontinued depending on the severity of the patient's adverse reactions, and the dose of oxaliplatin may be reduced to 65 mg / m² depending on the severity of the patient's adverse reactions. 2 50 mg / m² 2 Or 85-50 mg / m² 2 The dose of irinotecan may be reduced to any dose during this period or discontinued, depending on the severity of the patient's adverse reactions, starting from 150 mg / m². 2 , 120 mg / m² 2 90 mg / m² 2 Or 180-90 mg / m² 2 The dose may be reduced to any dose during this period or irinotecan may be discontinued, and the dose of fluorouracil administered intravenously may be 1800 mg / m² depending on the severity of the patient's adverse reactions.2 , 1200 mg / m² 2 Or 2400-1200 mg / m² 2 The dose may be reduced to any dose during that period, or the administration of fluorouracil may be discontinued.

[0175] Another aspect of this dose reduction regimen, recognized as modified FOLFIRINOX therapy (mFFX therapy), is a recommended dosage, for example, oxaliplatin 85 mg / m². 2 (Body surface area) was administered intravenously over 2 hours, followed by levofolinate 200 mg / m². 2 The drug is administered intravenously over 2 hours, and irinotecan 150 mg / m² is started 30 minutes after the start of levofolinate administration. 2 It is administered intravenously over 1.5 hours, and after the completion of levofolinate administration, fluorouracil 2400 mg / m² is administered. 2 This treatment involves intravenous administration over a 46-hour period, with this series of administrations performed at two-week intervals.

[0176] As a further dose reduction regimen for the mFFX therapy, for example, the dose of oxaliplatin from the initial dose could be reduced to 65 mg / m². 2 50 mg / m² 2 Or 85-50 mg / m² 2 Any dose between these two ranges, and the dose of irinotecan may be 140 mg / m². 2 , 120 mg / m² 2 Or 140-120 mg / m² 2 Any dose between these two values ​​may be used, and the amount of fluorouracil administered intravenously is 2400 mg / m². 2 , 1800 mg / m² 2 , 1200 mg / m² 2 Or 2400-1200 mg / m² 2 Any dose between these two ranges may be used.

[0177] Furthermore, in any administration from the second cycle onward in the mFFX therapy, the dose of oxaliplatin may be adjusted to 65 mg / m² depending on the severity of the patient's side effects. 2 50 mg / m² 2Or 85-50 mg / m² 2 The dose of irinotecan may be reduced to any dose during this period or discontinued, depending on the severity of the patient's adverse reactions, starting from 120 mg / m². 2 90 mg / m² 2 Or 150-90 mg / m² 2 The dose may be reduced to any dose during this period or irinotecan may be discontinued, and the dose of fluorouracil administered intravenously may be 1800 mg / m² depending on the severity of the patient's adverse reactions. 2 , 1200 mg / m² 2 Or 2400-1200 mg / m² 2 The dose may be reduced to any dose during that period, or the administration of fluorouracil may be discontinued.

[0178] Furthermore, the interval between administrations of the FFX therapy or its dose reduction regimen (e.g., mFFX therapy) may be temporarily or permanently set to a 3-week or 4-week interval, depending on the severity of the patient's side effects. Discontinuation, dose reduction, and resumption of FFX therapy or its dose reduction regimen (e.g., mFFX therapy) should be carried out at the physician's discretion, referring to the latest package insert.

[0179] (6) In combination with FFX therapy or its weight-reducing regimen (hereinafter sometimes abbreviated as "Combination-3"). In combination with FFX therapy or a dose reduction regimen (e.g., mFFX therapy), an EP4 antagonist is administered in one embodiment according to the dosage and administration described in (1) EP4 antagonist. Compound A, which is an EP4 antagonist, is administered orally at a dose of 5 mg once daily, 10 mg once daily, 20 mg once daily, or 40 mg once daily in one embodiment. Preferably, it is administered orally at a dose of 20 mg once daily or 40 mg once daily. More preferably, it is administered orally at a dose of 20 mg once daily. Depending on the degree of adverse reactions experienced by the patient, the dose of compound A may be reduced or administration may be discontinued. Furthermore, if the criteria for resumption are met, administration of compound A can be resumed, and if resumption is made, the dose of compound A may be reduced one step at a time at the discretion of the physician. In one embodiment, when compound A as an EP4 antagonist is administered at an initial dose of 40 mg, the first dose reduction is 20 mg and the second dose reduction is 10 mg. When compound A as an EP4 antagonist is administered at an initial dose of 20 mg, the first dose reduction is 10 mg and the second dose reduction is 5 mg.

[0180] In this combination therapy-3, the immune checkpoint inhibitor is administered in one embodiment according to the dosage and administration described in (2) Immune Checkpoint Inhibitor. In one embodiment, Nivolumab as the immune checkpoint inhibitor is administered by intravenous infusion at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks. Preferably, Nivolumab is administered by intravenous infusion at doses of 480 mg every four weeks. Depending on the severity of the patient's adverse reactions, Nivolumab administration may be discontinued. Furthermore, if the criteria for resumption are met, Nivolumab administration can be resumed.

[0181] In this combination therapy-3, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered on the same day, in one embodiment, the EP4 antagonist and the immune checkpoint inhibitor are administered first. In another embodiment, FFX therapy or its dose reduction regimen (preferably mFFX therapy) is performed after the administration of the EP4 antagonist and the immune checkpoint inhibitor. In yet another embodiment, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered on the same day, FFX therapy or its dose reduction regimen (preferably mFFX therapy) may be performed first, or simultaneously with the administration of the EP4 antagonist and the immune checkpoint inhibitor. In one embodiment, the order in which EP4 antagonists, immune checkpoint inhibitors, FFX therapy, or dose reduction regimens (e.g., mFFX therapy) are administered may be any order unless otherwise defined, and two or more drugs may be administered simultaneously.

[0182] (7)GnP therapy In this invention, "GnP therapy" refers to a therapy combining gemcitabine and nab-paclitaxel. In one embodiment, the recommended dosage of GnP therapy is, for example, 1000 mg / m² of gemcitabine. 2 (body surface area) is administered intravenously over 30 minutes, with nab-paclitaxel at a dose of 125 mg / m². 2 This therapy involves intravenously administering (body surface area) over 30 minutes, repeating this series of administrations at one-week intervals for three weeks, followed by a one-week rest period. In one embodiment, during any administration from the second cycle onward in this GnP therapy, gemcitabine is administered at 800 mg / m² depending on the severity of the patient's side effects. 2 Alternatively, 600 mg / m² 2 The dosage may be reduced to 100 mg / m² of nab-paclitaxel. 2 Alternatively, 75 mg / m² 2The dosage may be reduced. Discontinuation, reduction, and resumption of GnP therapy should be done at the physician's discretion, referring to the latest package insert.

[0183] (8) Concomitant use with GnP therapy (hereinafter sometimes abbreviated as this concomitant use-4). In this combination therapy-4, the EP4 antagonist is administered in one embodiment according to the dosage and administration described in (1) EP4 antagonist. Compound A, which is the EP4 antagonist, is administered orally at a dose of 5 mg once daily, 10 mg once daily, 20 mg once daily, or 40 mg once daily in one embodiment. Preferably, it is administered orally at a dose of 20 mg once daily or 40 mg once daily. More preferably, compound A is administered orally at a dose of 40 mg once daily. Depending on the degree of adverse reactions experienced by the patient, the dose of compound A may be reduced or administration may be discontinued. Furthermore, if the criteria for resumption are met, administration of compound A can be resumed, and if resumption is made, the dose of compound A may be reduced one step at a time at the discretion of the physician. In one embodiment, when compound A as the EP4 antagonist is administered at an initial dose of 40 mg, the first step reduction is 20 mg, and the second step reduction is 10 mg. When compound A, an EP4 antagonist, is administered at an initial dose of 20 mg, the first dose reduction is 10 mg, and the second dose reduction is 5 mg.

[0184] In this combination therapy-4, the immune checkpoint inhibitor is administered in one embodiment according to the dosage and administration described in (2) Immune Checkpoint Inhibitor. In one embodiment, Nivolumab as the immune checkpoint inhibitor is administered by intravenous infusion at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks. Preferably, Nivolumab is administered by intravenous infusion at doses of 480 mg every four weeks. Depending on the severity of the patient's adverse reactions, Nivolumab administration may be discontinued. Furthermore, if the criteria for resumption are met, Nivolumab administration can be resumed.

[0185] (9)DTX+RAM therapy In this invention, "docetaxel and ramucirumab therapy" refers to a cancer treatment method using docetaxel and ramucirumab in combination, with a recommended dosage of, for example, docetaxel 60 mg / m². 2 This treatment involves intravenously administering (body surface area) over 60 minutes or more, followed by intravenous administration of ramucirumab 10 mg / kg over 60 minutes, with this series of administrations performed at 3-week intervals. In one embodiment, in any administration from the second cycle onward in this DTX+RAM therapy, depending on the severity of the patient's side effects, docetaxel may be administered at 75 mg / m². 2 Alternatively, 50 mg / m² 2 The dosage of docetaxel may be increased or decreased, or docetaxel may be discontinued. Ramucirumab may be reduced to 8 mg / kg or 6 mg / kg, or ramucirumab may be discontinued. The administration time of ramucirumab may be shortened to 30-60 minutes. The discontinuation, reduction, and resumption of DTX+RAM therapy should be carried out at the discretion of the physician, referring to the latest package insert. In one embodiment, docetaxel and ramucirumab are started on the same day.

[0186] (10) Concomitant use with DTX+RAM therapy (hereinafter sometimes abbreviated as this combination-5). In this combination therapy-5, the EP4 antagonist is administered in one embodiment according to the dosage and administration described in (1) EP4 antagonist. Compound A, which is the EP4 antagonist, is administered orally at a dose of 5 mg once daily, 10 mg once daily, 20 mg once daily, or 40 mg once daily in one embodiment. Preferably, it is administered orally at a dose of 20 mg once daily or 40 mg once daily. Depending on the degree of adverse reactions experienced by the patient, the dose of compound A may be reduced or administration may be discontinued. Furthermore, if the criteria for resumption are met, administration of compound A can be resumed, and if resumption is made, the dose of compound A may be reduced one step at a time at the discretion of the physician. In one embodiment, when compound A as an EP4 antagonist is administered at an initial dose of 40 mg, the first dose reduction is 20 mg and the second dose reduction is 10 mg. When compound A as an EP4 antagonist is administered at an initial dose of 20 mg, the first dose reduction is 10 mg and the second dose reduction is 5 mg.

[0187] In this combination therapy-5, the immune checkpoint inhibitor is administered in one embodiment according to the dosage and administration described in (2) Immune Checkpoint Inhibitor. In one embodiment, Nivolumab as the immune checkpoint inhibitor is administered by intravenous infusion at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks. Preferably, Nivolumab is administered by intravenous infusion at doses of 360 mg every three weeks. Depending on the severity of the patient's adverse reactions, Nivolumab administration may be discontinued. Furthermore, if the criteria for resumption are met, Nivolumab administration can be resumed.

[0188] In one embodiment, DTX+RAM therapy, immune checkpoint inhibitors, and EP4 antagonists are administered on the same day.

[0189] In this combination therapy-5, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered with DTX+RAM therapy on the same day, in one embodiment, the EP4 antagonist and the immune checkpoint inhibitor are administered first. In one embodiment, DTX+RAM therapy is performed after the administration of the EP4 antagonist and the immune checkpoint inhibitor. In another embodiment, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered with DTX+RAM therapy on the same day, DTX+RAM therapy may be performed first, or simultaneously with the administration of the EP4 antagonist and the immune checkpoint inhibitor. In one embodiment, unless otherwise defined, the order of administration of the EP4 antagonist, immune checkpoint inhibitor, docetaxel, and ramucirumab may be any order, and two or more drugs may be administered simultaneously.

[0190] (11)DTX therapy In this invention, "docetaxel therapy" refers to a cancer treatment method using docetaxel, and in one embodiment, the recommended dosage is, for example, 60 mg / m² of docetaxel. 2 This therapy involves intravenous administration of (body surface area) over a period of 60 minutes or more, with such administrations performed at 3-week intervals. In one embodiment, in any administration from the second cycle onward in this DTX therapy, docetaxel is administered at 75 mg / m² depending on the patient's condition. 2 Alternatively, 50 mg / m² 2 The dosage may be increased or decreased, or docetaxel administration may be discontinued. The discontinuation, reduction, or resumption of DTX therapy should be done at the physician's discretion, referring to the latest package insert.

[0191] (12) Concomitant use with DTX therapy (hereinafter sometimes abbreviated as this concomitant use-6). In this combination therapy-6, the EP4 antagonist is administered in one embodiment according to the dosage and administration described in (1) EP4 antagonist. Compound A, which is the EP4 antagonist, is administered orally at a dose of 5 mg once daily, 10 mg once daily, 20 mg once daily, or 40 mg once daily in one embodiment. Preferably, it is administered orally at a dose of 20 mg once daily or 40 mg once daily. Depending on the degree of adverse reactions experienced by the patient, the dose of compound A may be reduced or administration may be discontinued. Furthermore, if the criteria for resumption are met, administration of compound A can be resumed, and if resumption is made, the dose of compound A may be reduced one step at a time at the discretion of the physician. In one embodiment, when compound A as the EP4 antagonist is administered at an initial dose of 40 mg, the first step reduction is 20 mg, and the second step reduction is 10 mg. When compound A, an EP4 antagonist, is administered at an initial dose of 20 mg, the first dose reduction is 10 mg, and the second dose reduction is 5 mg.

[0192] In this combination therapy-6, the immune checkpoint inhibitor is administered in one embodiment according to the dosage and administration described in (2) Immune Checkpoint Inhibitor. In one embodiment, Nivolumab as the immune checkpoint inhibitor is administered by intravenous infusion at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks. Preferably, Nivolumab is administered by intravenous infusion at doses of 360 mg every three weeks. Depending on the severity of the patient's adverse reactions, Nivolumab administration may be discontinued. Furthermore, if the criteria for resumption are met, Nivolumab administration can be resumed.

[0193] In one embodiment, DTX therapy, immune checkpoint inhibitors, and EP4 antagonists are administered on the same day.

[0194] In this combination therapy-6, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered with DTX therapy on the same day, in one embodiment, the EP4 antagonist and the immune checkpoint inhibitor are administered first. In another embodiment, DTX therapy is performed after the administration of the EP4 antagonist and the immune checkpoint inhibitor. In yet another embodiment, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered with DTX therapy on the same day, DTX therapy may be performed first, or simultaneously with the administration of the EP4 antagonist and the immune checkpoint inhibitor. In one embodiment, unless otherwise defined, the order of administration of the EP4 antagonist, the immune checkpoint inhibitor, and docetaxel may be any order, and two or more drugs may be administered simultaneously.

[0195] (13)RAM therapy In the present invention, "ramucirumab therapy (hereinafter sometimes abbreviated as "RAM therapy")" refers to a cancer treatment method using ramucirumab, and in one embodiment, the recommended dosage is, for example, 10 mg / kg of ramucirumab administered intravenously over 60 minutes, with this series of administrations performed at 3-week intervals. In one embodiment, in any of the administrations from the second cycle onward in the RAM therapy, depending on the patient's condition, the dose of ramucirumab may be reduced to 8 mg / kg or 6 mg / kg or the administration of ramucirumab may be discontinued, and depending on the degree of side effects in the patient, the administration time of ramucirumab may be shortened to 30 to 60 minutes.

[0196] (14) Concomitant use with RAM therapy (hereinafter sometimes abbreviated as this concomitant use-7). In this combination therapy-7, the EP4 antagonist is administered in one embodiment according to the dosage and administration described in (1) EP4 antagonist. Compound A, which is the EP4 antagonist, is administered orally at a dose of 5 mg once daily, 10 mg once daily, 20 mg once daily, or 40 mg once daily in one embodiment. Preferably, it is administered orally at a dose of 20 mg once daily or 40 mg once daily. Depending on the degree of adverse reactions experienced by the patient, the dose of compound A may be reduced or administration may be discontinued. Furthermore, if the criteria for resumption are met, administration of compound A can be resumed, and if resumption is made, the dose of compound A may be reduced one step at a time at the discretion of the physician. In one embodiment, when compound A as the EP4 antagonist is administered at an initial dose of 40 mg, the first step reduction is 20 mg, and the second step reduction is 10 mg. When compound A, an EP4 antagonist, is administered at an initial dose of 20 mg, the first dose reduction is 10 mg, and the second dose reduction is 5 mg.

[0197] In this combination therapy-7, the immune checkpoint inhibitor is administered in one embodiment according to the dosage and administration described in (2) Immune Checkpoint Inhibitor. In one embodiment, Nivolumab as the immune checkpoint inhibitor is administered by intravenous infusion at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks. Preferably, 360 mg of Nivolumab is administered by intravenous infusion every three weeks. Depending on the severity of the patient's adverse reactions, Nivolumab administration may be discontinued. Furthermore, if the criteria for resumption are met, Nivolumab administration can be resumed.

[0198] In one embodiment, RAM therapy, immune checkpoint inhibitors, and EP4 antagonists are administered on the same day.

[0199] In this combination therapy-7, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered with RAM therapy on the same day, in one embodiment, the EP4 antagonist and the immune checkpoint inhibitor are administered first. In another embodiment, RAM therapy is performed after the EP4 antagonist and the immune checkpoint inhibitor have been administered. In yet another embodiment, when an EP4 antagonist (preferably compound A) and an immune checkpoint inhibitor (preferably an anti-PD-1 antibody (preferably Nivolumab)) are administered with RAM therapy on the same day, RAM therapy may be performed first, or simultaneously with the administration of the EP4 antagonist and the immune checkpoint inhibitor. In one embodiment, unless otherwise defined, the order of administration of the EP4 antagonist, the immune checkpoint inhibitor, and ramucirumab may be any order, and two or more drugs may be administered simultaneously.

[0200] [Applicable diseases and patients] The disease to which the present invention's treatment method can be applied is cancer.

[0201] More specifically, cancers include, for example, leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), malignant lymphoma (Hodgkin lymphoma, non-Hodgkin lymphoma (e.g., adult T-cell leukemia, follicular lymphoma, diffuse large B-cell lymphoma)), multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, stomach cancer, gastric junction cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer (e.g., hepatocellular carcinoma), gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer (e.g., pancreatic ductal carcinoma, insulinoma, intraductal papillary mucinous neoplasm), thyroid cancer, lung cancer. Examples include cancer (e.g., non-small cell lung cancer (e.g., squamous cell non-small cell lung cancer, non-squamous cell non-small cell lung cancer), small cell lung cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer), cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer (e.g., renal cell carcinoma), renal pelvis and ureteral cancer, urothelial cancer (e.g., bladder cancer, upper urinary tract cancer), penile cancer, prostate cancer, testicular tumors (e.g., germ cell tumors), bone and soft tissue sarcomas, malignant bone tumors, skin cancers (e.g., uveal melanoma, malignant melanoma, Merkel cell carcinoma), thymoma, mesothelioma, malignant pleural mesothelioma, glioblastoma, hematological cancers, and cancers of unknown primary origin.

[0202] Preferably, the treatment method of the present invention is applicable to colorectal cancer, pancreatic cancer, and lung cancer, and more preferably to advanced or recurrent colorectal cancer that is unresectable, locally advanced rectal cancer that is resectable, pancreatic cancer with distant metastases, and lung cancer that has progressed or recurred unresponsively after receiving combination therapy including an anti-PD-1 antibody or anti-PD-L1 antibody and a platinum-based agent. Even more preferably, the treatment is applicable to advanced or recurrent colorectal cancer that is unresectable, locally advanced rectal cancer that is resectable, pancreatic ductal carcinoma with distant metastases, and non-small cell lung cancer that has progressed or recurred unresponsively after receiving combination therapy including an anti-PD-1 antibody or anti-PD-L1 antibody and a platinum-based agent. In this specification, “treatment” of cancer includes, for example, treatments performed to (i) reduce the growth of tumor cells, (ii) reduce symptoms caused by cancer, (iii) improve the quality of life of cancer patients, (iv) reduce the dose of other anticancer drugs or adjuvant cancer treatments already being administered, and / or (v) extend the survival of cancer patients; “suppression of cancer progression” means delaying the progression of cancer, stabilizing symptoms caused by cancer, and reversing the progression of symptoms; and “suppression of cancer recurrence” means prophylactically preventing the recurrence of cancer in patients whose cancerous lesions have been completely or substantially eliminated or removed by cancer treatment or surgical resection.

[0203] The treatment method of the present invention may be prescribed to the following cancer patients, namely: (a) patients whose treatment response to anticancer drugs is insufficient or inadequate, or patients whose disease has worsened after treatment with anticancer drugs; (b) patients with curative or unresectable, metastatic, recurrent, refractory, and / or distant metastatic cancer; (c) patients with cancer whose Tumor Proportion Score (hereinafter abbreviated as "TPS") is 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more; (d) patients with cancer whose Combined Positive Score (hereinafter abbreviated as "CPS") is 20% or more, 10% or more, 5% or more, or 1% or more; (e) patients with cancer who have mismatch repair deficiency (hereinafter abbreviated as "dMMR") and / or high-frequency microsatellite instability (hereinafter abbreviated as "MSI-H"); and (f) patients with cancer who have a high frequency of tumor mutational burden (hereinafter abbreviated as "TMB"). On the other hand, the treatment method of the present invention may be more in demand for the following cancer patients, namely (g) patients with no prior treatment history with anticancer drugs, (h) cancer patients with a TPS of less than 50%, less than 25%, less than 10%, less than 5%, or less than 1%, (i) cancer patients with a CPS of less than 20%, less than 10%, less than 5%, or less than 1%, (j) cancer patients who do not have dMMR and / or MSI-H, or who have low-frequency microsatellite instability (hereinafter abbreviated as "MSI-L"), or (k) cancer patients with low-frequency TMB. In particular, cancer patients for whom the treatment method of the present invention is required include (i) patients with advanced or recurrent cancer that is not curatively resectable, especially patients with colorectal cancer; (ii) patients with locally advanced cancer that is curatively resectable, especially patients with rectal cancer; (iii) patients with cancer that has not been treated with anticancer drugs and / or has distant metastases, especially patients with pancreatic cancer; or (iv) patients with cancer that has received combination therapy including an anti-PD-1 antibody or anti-PD-L1 antibody and a platinum-based agent and has shown refractory progression or recurrence, especially patients with lung cancer.

[0204] In one embodiment, patients with unresectable advanced or recurrent colorectal cancer may be included. In another embodiment, patients with no prior treatment history for colorectal cancer may be included. Preferably, patients with no prior treatment history with systemic anti-cancer agents for colorectal cancer may be included. Even more preferably, patients with unresectable advanced or recurrent colorectal cancer with no prior treatment history with systemic anti-cancer agents may be included.

[0205] One embodiment includes a patient with locally advanced rectal cancer that is curatively resectable. Another embodiment includes a patient with no prior treatment history for rectal cancer.

[0206] One embodiment includes patients with pancreatic cancer who have not received prior treatment with anticancer drugs and / or have distant metastases.

[0207] In one embodiment, patients with no prior treatment history for pancreatic cancer are included. Preferably, patients with no prior treatment history with systemic anti-cancer agents for pancreatic cancer are included. More preferably, patients with no prior treatment history with systemic anti-cancer agents for pancreatic cancer with distant metastases are included.

[0208] One embodiment includes a patient with lung cancer who has received combination therapy including an anti-PD-1 antibody or an anti-PD-L1 antibody and a platinum-based agent, and has experienced refractory progression or recurrence.

[0209] One embodiment includes patients who have been confirmed to have non-small cell lung cancer. Preferably, patients with stage IV or recurrent non-small cell lung cancer. More preferably, patients who have received combination therapy including an anti-PD-1 antibody or anti-PD-L1 antibody and a platinum-based agent as first-line treatment and have experienced refractory progression or recurrence.

[0210] Among these, for example, in cancer patients for whom the therapeutic effect of immune checkpoint inhibitors or EP4 receptor antagonists alone is insufficient, the treatment method of the present invention is particularly expected to maximize their antitumor effect. Furthermore, the treatment method of the present invention makes it possible to administer each drug at a lower dose, which is expected to reduce side effects.

[0211] In one embodiment, the treatment method of the present invention exhibits a synergistic effect. In another embodiment, it exhibits a synergistic effect compared to the therapeutic effect of an immune checkpoint inhibitor or an EP4 receptor antagonist or standard therapy alone, or the therapeutic effect of a combination of an immune checkpoint inhibitor and standard therapy, an EP4 receptor antagonist and standard therapy, or an immune checkpoint inhibitor and an EP4 receptor antagonist.

[0212] In one embodiment, the treatment method of the present invention reduces side effects. In another embodiment, it reduces side effects compared to the therapeutic effect of an immune checkpoint inhibitor or an EP4 receptor antagonist, or standard therapy alone, or the therapeutic effect of an immune checkpoint inhibitor and standard therapy, an EP4 receptor antagonist and standard therapy, or an immune checkpoint inhibitor and an EP4 receptor antagonist in combination.

[0213] Unless otherwise defined, the timing of administration of each drug used in the combination therapy of the present invention may be simultaneous or separate.

[0214] In one embodiment, the treatment method of the present invention can also be applied to the treatment of metastatic cancer and the suppression of metastasis.

[0215] In one embodiment, the treatment method of the present invention suppresses recurrence.

[0216] In the present invention, treatment means producing at least one of the following: a reduction in tumor size, inhibition (delay or cessation) of tumor growth, inhibition (delay or cessation) of tumor metastasis, inhibition (prevention or delay) of recurrence, and relief of one or more symptoms associated with cancer.

[0217] In the present invention, the treatment method of the present invention may be used in combination with other drugs (e.g., known anti-cancer treatments) for (1) to complement and / or enhance the therapeutic effect, (2) to improve kinetics and absorption, reduce dosage, and / or (3) to reduce side effects.

[0218] In this specification, "approximately" means that the displayed value may vary by a factor of 10% or less, or by a factor of 10% or less. For example, approximately 30 minutes means 30 minutes ± 5 minutes, and approximately 60 minutes means 60 minutes ± 5 minutes.

[0219] In this specification, “standard therapy” means a standard treatment recommended for a typical patient with a particular condition based on scientific evidence, such as chemotherapy. One embodiment of this is (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or its reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel therapy, or (vi) docetaxel and ramucirumab therapy.

[0220] The present invention provides, for example, the following embodiments.

[0221] [1] Standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, or (v) docetaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel therapy, and A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an EP4 antagonist as an active ingredient, characterized by being administered in combination with (vi) docetaxel and ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a dose reduction regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, or (vi) docetaxel and ramucirumab therapy), and the administration of an immune checkpoint inhibitor.

[0222] [2] Standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, or (v) docetaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel therapy, and A cancer progression inhibitor, recurrence inhibitor and / or treatment agent containing an immune checkpoint inhibitor as an active ingredient, characterized by being administered in combination with (vi) docetaxel and ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a dose reduction regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, or (vi) docetaxel and ramucirumab therapy), and the administration of an EP4 antagonist.

[0223] [3] EP4 antagonists are given by the general formula (I):

[0224] [ka]

[0225] (In the formula, R 1 COOR 8 tetrazole, SO3H, SO2NH2, SO2NHR 8-1 CONHSO2R 8-1 SO2NHCOR 8-1 , or represents hydroxamic acid, R 8 represents a hydrogen atom, a C1-4 alkyl group, or a benzyl group. R 8-1 represents a C1-4 alkyl, C1-4 haloalkyl, C3-10 carbon ring, or 3-10 membered heterocycle, and each of the C3-10 carbon ring and 3-10 membered heterocycle may be substituted with a C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -O(C1-4 haloalkyl), C1-4 alkylthio, -S(C1-4 haloalkyl), halogen, or nitrile (represented by "-CN"; the same applies hereinafter). L 1 This represents C1-5 alkylene, C2-5 alkenylene, or C2-5 alkynylene. R 2 These include halogens, C1-4 alkyls, C1-4 alkoxys, C1-4 alkylthios, C2-4 alkenyls, C2-4 alkynyls, -O(C1-4 haloalkyl), -S(C1-4 haloalkyl), -C(O)(C1-4 alkyl), -SO2(C1-4 alkyl), -CONH(C1-4 alkyl), -CON(C1-4 alkyl)2, -NHC(O)(C1-4 alkyl), -N(C1-4 alkyl)C(O)(C1-4 alkyl), -NHSO2(C1-4 alkyl), -N(C1-4 alkyl)SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1-4 alkyl)2, and -NR 17 R 17 , represents nitro, nitrile, hydroxyl group, aldehyde (representing formyl; the same applies hereinafter), or carboxyl, and each of the C1-4 alkyl groups may be substituted with a halogen. The R 2In this context, (C1-4 alkyl)2 represents two independent C1-4 alkyl groups, which may be the same or different. X 1 CR 6 Or it represents a nitrogen atom, R 6 is a hydrogen atom or R 2 This represents, X 2 CR 7 Or it represents a nitrogen atom, R 7 is a hydrogen atom, R 2 , or -L 3 -R 9 Represents L 3 R represents a methylene atom, an oxygen atom, or an oxidized sulfur atom, 9 This represents a 4-10 membered heterocycle which may be substituted with substituents selected from the group consisting of halogens, C1-4 alkyls, and C1-4 haloalkyls. L 2 -CH2CH2-, -CH=CH-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -CH2S(O)-, -S(O)CH2-, -CH2SO2-, -SO2CH2-, -CH2NH-, -NHCH2-, -NHCO-, -CONH-, -NHSO2-, or -SO2NH- R 3 This represents a C1-4 alkyl or halogen, R 4 This represents a halogen, C1-4 alkyl, or C1-4 haloalkyl, X 3 is methylene, an oxygen atom, a sulfur atom which may be oxidized, or NR 10 Represents R 10 This represents C1-4 alkyl, -C(O)(C1-4 alkyl), -C(O)O(C1-4 alkyl), or -SO2(C1-4 alkyl), and each of these C1-4 alkyls may be substituted with a halogen. The term "ring" represents a benzene ring or a 5-6 membered monocyclic aromatic heterocycle.

[0226] [ka]

[0227] represents a single bond or a double bond, R 5 (1) halogen, (2) C1-4 alkyl, (3) carboxyl, (4) nitrile, (5)-CONHR 11 , (6)-C(O)R 12 , (7)-OR 14 , (8)-S(O) t R 15 (9)-CH2R 16 (10)-NR 17 R 17 (11)-NHCOR 11 (12) Represents a C4-10 carbon ring, or (13) a 4-10 membered heterocycle, wherein the C4-10 carbon ring or 4-10 membered heterocycle has 1 to 3 R 18 It may also be replaced with, and the R 18 If there are multiple, R 18 Each of them may be independent, identical, or different. R 11 R represents a C1-6 alkyl, C3-6 cycloalkyl, phenyl, or 4-6 membered heterocycle. 11 1 to 3 R 13 It may also be replaced with, and the R 13 If there are multiple, R 13 Each of them may be independent, identical, or different. R 13 These include halogens, C1-6 alkyl groups, C3-6 cycloalkyl groups, C1-4 alkoxy groups, hydroxyl groups, and -NR groups. 20 R 21 , represents benzene, or a 4-6 membered heterocycle, R 20 and R 21 Each of these independently represents a hydrogen atom or a C1-4 alkyl group. R 12 This represents a C1-6 alkyl, C3-6 cycloalkyl, benzene, or 4-6 membered heterocycle, and each of these C3-6 cycloalkyl, benzene, or 4-6 membered heterocycles may be independently substituted with a halogen, a C1-4 alkyl, or a C1-4 alkoxy. R 14R represents a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, a benzene ring, or a benzyl ring, where the C1-6 alkyl group has 1 to 3 R groups. 19 It may also be replaced with, and the R 19 If there are multiple, R 19 Each of them may be independent, identical, or different. R 19 This represents a 5-6 member monocyclic aromatic heterocycle which may be substituted with substituents selected from the group consisting of C1-4 alkoxy, -CONH(C1-4 alkyl), -CON(C1-4 alkyl)2, or C1-4 alkyl and C1-4 haloalkyl. The R 19 In this context, (C1-4 alkyl)2 represents two independent C1-4 alkyl groups, which may be the same or different. R 15 This represents C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl. R 16 represents a hydroxyl group or a C1-4 alkoxy, R 17 Each of these independently represents a hydrogen atom, a C1-6 alkyl group, or a C3-6 cycloalkyl group. R 18 This represents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, oxo, nitrile, hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, (C1-4 alkyl)SO2-, 4-6 membered heterocycle, (C1-4 alkyl)NH-, or (C1-4 alkyl)2N-. The R 18 In this context, (C1-4 alkyl)2 represents two independent C1-4 alkyl groups, which may be the same or different. m represents an integer from 1 to 4, n represents an integer from 0 to 4, p represents an integer from 0 to 2, q represents an integer from 0 to 6, r represents an integer from 0 to 6, s represents an integer from 0 to 4, and t represents an integer from 0 to 2. However, if p, q, r, and s each represent an integer greater than or equal to 2, then R 2 , R 3 , R 4, and R 5 The agents described in [1] or [2] above, which are compounds represented by () or salts thereof, which may be independent of each other and may be the same or different. [4] The agent according to any one of [1] to [3] above, wherein the standard therapy is bevacizumab and XELOX therapy. [5] The agent according to any one of [1] to [4] above, wherein the cancer is colorectal cancer. [6] The agent described in [5] above, wherein the colorectal cancer is colon or rectal cancer. [7] The agent according to [6] above, wherein the colorectal cancer is advanced or recurrent colorectal cancer that is unresectable (preferably advanced or recurrent colorectal cancer that is unresectable and has not been treated).

[0228] [8] EP4 antagonists, general formula (I-2)

[0229] [ka]

[0230] (In the formula, R 2a represents halogen, R 6a The agent according to any one of [1] to [7], wherein represents a hydrogen atom or halogen, qa represents an integer from 0 to 3, ra represents an integer from 0 to 4, and the other symbols have the same meaning as in claim 1. [9] The agent according to any one of [1] to [8], wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof.

[10] The agent according to [9], characterized in that it is administered orally once a day at a dose of 5 mg to 40 mg as an EP4 antagonist.

[11] The agent according to [9], characterized in that it is administered orally once daily at a dose of 20 mg or 40 mg as an EP4 antagonist.

[12] The agent according to any one of [1] to

[11] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[13] The agent according to

[12] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0231]

[14] Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, AMP-514, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (Retifanlimab), AGEN2034 (Balstilimab), CS1003, HLX10 (Serplulimab), BAT-1306, AK105, AK103, BI The agent described in

[13] above, which is 754091, LZM009, CMAB819, Sym021, GB226 (Geptanolimab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalimab), BCD-100 (Prolgolimab), PF-06801591 (Sasanlimab), CX-188, JNJ-63723283 (Cetrelimab), or AB122 (Zimberelimab).

[15] The agent according to

[12] , wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolimab), HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003, or CX-072.

[16] The agent according to

[12] , wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipilimumab, AGEN1884, or tremelimumab.

[17] The agent according to

[13] , wherein the anti-PD-1 antibody is nivolumab.

[0232]

[18] The agent according to

[13] , wherein the anti-PD-1 antibody is Pembrolizumab.

[19] The agent according to

[13] , wherein the anti-PD-1 antibody is cemplimab.

[20] The agent according to

[15] , wherein the anti-PD-L1 antibody is avelumab.

[21] The agent according to

[15] , wherein the anti-PD-L1 antibody is atezolizumab.

[22] The agent according to

[15] , wherein the anti-PD-L1 antibody is Durvalumab.

[23] The agent according to

[16] , wherein the anti-CTLA-4 antibody is ipilimumab.

[24] The agent according to

[17] , characterized in that it is administered as nivolumab at a dose of 3 mg / kg (body weight) or 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks).

[25] The agent according to

[17] , characterized in that 360 mg of nivolumab is administered intravenously at 3-week intervals.

[26] The agent according to

[17] , characterized in that 360 mg of nivolumab is administered intravenously over approximately 30 minutes at intervals of three weeks.

[27] The agent according to

[18] , characterized in that pembrolizumab is administered at a dose of 2 mg / kg (body weight) or 200 mg every 3 weeks or 400 mg every 6 weeks.

[28] The agent according to

[19] , characterized in that 350 mg of cemiplimab is administered at 3-week intervals.

[29] The agent according to

[20] , characterized in that it is administered at a dose of 10 mg / kg (body weight) of avelumab at intervals of two weeks.

[30] The agent according to

[21] , characterized in that 1200 mg of atezolizumab is administered at 3-week intervals.

[31] The agent according to

[22] , characterized in that 10 mg / kg (body weight) of Durvalumab is administered once every two weeks.

[32] The agent according to

[23] , characterized by being administered intravenously four times at 3 mg / kg (body weight) or 1 mg / kg (body weight) of ipilimumab at 3-week intervals.

[0233]

[33] The bevacizumab and XELOX regimen is (i) Administer bevacizumab at a dose of 7.5 mg / kg every three weeks. (ii) Oxaliplatin 130 mg / m² 2 Administer at 3-week intervals, and (iii) Capecitabine 1000 mg / m² 2 Administer orally twice a day for 14 days, followed by a 7-day rest period. A therapeutic agent as described in any of the above [1] to

[32] .

[34] The agent described in any of [1] to

[33] above, which is a therapy in which bevacizumab, oxaliplatin, and capecitabine are administered on the same day.

[35] The agent described in any of [1] to

[34] above, which is a therapy in which bevacizumab, oxaliplatin, capecitabine, an immune checkpoint inhibitor, and an EP4 antagonist are administered on the same day.

[36] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an EP4 antagonist as an active ingredient, characterized in that it is administered in combination with bevacizumab and XELOX therapy and an immune checkpoint inhibitor, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 360 mg every three weeks). (iii) The bevacizumab and XELOX therapy consists of administering bevacizumab 7.5 mg / kg once every three weeks and oxaliplatin 130 mg / m². 2 Administer this at 3-week intervals, and capecitabine 1000 mg / m² 2 Administer orally twice a day for 14 days, followed by a 7-day rest period. A therapeutic agent.

[0234]

[37] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an immune checkpoint inhibitor as an active ingredient, characterized by being administered in combination with bevacizumab and XELOX therapy and an EP4 antagonist, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 360 mg every three weeks). (iii) The bevacizumab and XELOX therapy consists of administering bevacizumab 7.5 mg / kg once every three weeks and oxaliplatin 130 mg / m². 2 Administer this at 3-week intervals, and capecitabine 1000 mg / m² 2 Administer orally twice a day for 14 days, followed by a 7-day rest period. A therapeutic agent.

[38] The agent described in

[36] or

[37] , which is a therapy in which administration of bevacizumab, oxaliplatin, capecitabine, 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof and nivolumab is initiated on the same day.

[39] The agent according to any one of

[36] to

[38] above, wherein the cancer is colorectal cancer.

[40] The agent described above

[39] , wherein colorectal cancer is colon and rectal cancer.

[41] The agent according to

[40] , wherein the colorectal cancer is advanced or recurrent colorectal cancer that is unresectable (preferably advanced or recurrent colorectal cancer that has not been treated).

[0235] [2-1] A cancer progression inhibitor, recurrence inhibitor, and / or treatment agent containing an EP4 antagonist as an active ingredient, characterized by being administered to cancer patients who have undergone neoadjuvant chemoradiotherapy. [2-2] The agent described in [2-1] above, which is further administered in combination with an immune checkpoint inhibitor. [2-3] A cancer progression inhibitor, recurrence inhibitor, and / or treatment agent containing an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with an EP4 antagonist to cancer patients who have undergone neoadjuvant chemoradiotherapy. [2-4] The agent according to any one of [2-1] to [2-3], wherein the EP4 antagonist is a compound represented by the general formula (I) described in [3] above, or a salt thereof. [2-5] The agent according to any one of [2-1] to [2-4] above, wherein the cancer is colorectal cancer (preferably colon / rectal cancer). [2-6] The agent described in [2-5] above, wherein the colorectal cancer is locally advanced rectal cancer that is resectable. [2-7] Any of the agents described in [2-1] to [2-6] above, wherein an immune checkpoint inhibitor and / or EP4 antagonist is used as neoadjuvant therapy after neoadjuvant chemoradiotherapy (CRT). [2-8] The agent according to any one of [2-1] to [2-7], wherein the EP4 antagonist is a compound represented by the general formula (I-2) described in [8] above, or a salt thereof. [2-9] The agent according to any one of [2-1] to [2-8] above, wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof. [2-10] The agent described in [2-9] above, characterized by being administered orally once daily at a dose of 5 mg to 40 mg as an EP4 antagonist. [2-11] The agent according to [2-9], characterized in that 20 mg or 40 mg (preferably 40 mg) of an EP4 antagonist is administered orally once daily. [2-12] The agent according to any one of [2-2] to [2-11] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody. [2-13] The agent according to [2-12], wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0236] [2-14] Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, AMP-514, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (Retifanlimab), AGEN2034 (Balstilimab), CS1003, HLX10 (Serplulimab), BAT-1306, AK105, AK103, BI The agent described in [2-13] above, which is 754091, LZM009, CMAB819, Sym021, GB226 (Geptanolimab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalimab), BCD-100 (Prolgolimab), PF-06801591 (Sasanlimab), CX-188, JNJ-63723283 (Cetrelimab), or AB122 (Zimberelimab).

[0237] [2-15] The agent according to [2-12], wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolimab), HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003, or CX-072. [2-16] The agent according to [2-12], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipilimumab, AGEN1884, or tremelimumab. [2-17] The agent according to [2-13], wherein the anti-PD-1 antibody is nivolumab. [2-18] The agent according to [2-13], wherein the anti-PD-1 antibody is Pembrolizumab. [2-19] The agent according to [2-13], wherein the anti-PD-1 antibody is cemplimab. [2-20] The agent according to [2-15], wherein the anti-PD-L1 antibody is avelumab. [2-21] The agent according to [2-15], wherein the anti-PD-L1 antibody is atezolizumab. [2-22] The agent according to [2-15], wherein the anti-PD-L1 antibody is Durvalumab. [2-23] The agent according to [2-16], wherein the anti-CTLA-4 antibody is ipilimumab.

[0238] [2-24] The agent according to [2-17], characterized in that it is administered as nivolumab at a dose of 3 mg / kg (body weight) or 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks). [2-25] The agent described in [2-17] above, characterized by being administered intravenously at a dose of 240 mg of nivolumab every two weeks. [2-26] The agent described in [2-17], characterized by being administered intravenously at a dose of 240 mg of nivolumab over approximately 30 minutes at two-week intervals. [2-27] The agent according to [2-18], characterized by being administered as pembrolizumab at doses of 2 mg / kg (body weight) or 200 mg at intervals of 3 weeks. [2-28] The agent described in [2-19] above, characterized by being administered at a dose of 350 mg of cemiplimab every three weeks. [2-29] The agent according to [2-20], characterized in that 10 mg / kg (body weight) of avelumab is administered at intervals of two weeks. [2-30] The agent according to [2-21], characterized by being administered at a dose of 1200 mg of atezolizumab at 3-week intervals. [2-31] The agent described in [2-22] above, characterized by being administered at a dose of 10 mg / kg (body weight) of Durvalumab every two weeks. [2-32] The agent according to [2-23], characterized by being administered intravenously four times at 3-week intervals as ipilimumab, either 3 mg / kg (body weight) or 1 mg / kg (body weight). [2-33] The agent described in any of [2-1] to [2-32] above, which is administered starting within 14 days of the completion of preoperative chemoradiotherapy.

[0239] [2-34] The agent described in any of [2-2] to [2-33] above, wherein the surgery is performed at least 7 days after the last administration of the EP4 antagonist and at least 14 days after the last administration of the immune checkpoint inhibitor, and within 14 weeks after the completion of preoperative chemoradiotherapy. [2-35] The agent described in any of [2-1] to [2-34] above, which is administered to patients who have not shown distant metastases on imaging after the completion of preoperative chemoradiotherapy. [2-36] The agent described in any of [2-1] to [2-35] above, which is administered to patients who do not show distant metastases on imaging after the completion of preoperative chemoradiotherapy and who are eligible for curative resection. [2-37] The agent according to any of [2-1] to [2-36] above, wherein the preoperative chemoradiotherapy is a combination of radiotherapy and capecitabine. [2-38] Preoperative chemoradiotherapy consisted of 45 Gy / 25 fractions of pelvic irradiation and 5.4 Gy / 3 fractions of boost irradiation to the primary tumor, and capecitabine at 825 mg / m². 2 The agent described in any of [2-1] to [2-37] above, which is administered twice a day for 21 days or 42 times or more. [2-39] A cancer treatment agent comprising an EP4 antagonist as an active ingredient, characterized by being administered to cancer patients who have undergone neoadjuvant chemoradiotherapy, for inhibiting progression, preventing recurrence, and / or treating cancer (preferably colorectal cancer, more preferably colorectal cancer (preferably locally advanced rectal cancer that can be curatively resected)), (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg, more preferably 40 mg). (ii) Preoperative chemoradiotherapy is a combination of radiotherapy and capecitabine (preferably 45 Gy / 25 fractions of pelvic irradiation and 5.4 Gy / 3 fractions of boost irradiation to the primary tumor, and capecitabine at 825 mg / m²). 2 This therapy involves administering the drug twice a day for 21 days or 42 or more doses. Agent. [2-40] The agent described in [2-39] above, which is further administered in combination with an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is Nivolumab, and the agent is administered as anti-Nivolumab at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 240 mg every two weeks).

[0240] [2-41] A treatment for colorectal cancer, comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with an EP4 antagonist to cancer patients who have undergone neoadjuvant chemoradiotherapy, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg, more preferably 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 240 mg every two weeks), and (iii) Preoperative chemoradiotherapy is a combination of radiotherapy and capecitabine (preferably 45 Gy / 25 fractions of pelvic irradiation and 5.4 Gy / 3 fractions of boost irradiation to the primary tumor, and capecitabine at 825 mg / m² 2 This therapy involves administering the drug twice a day for 21 days or 42 or more doses. Agent.

[0241] [3-1] The agent according to [1] or [2] above, wherein the standard therapy is FOLFIRINOX therapy or a dose reduction regimen thereof. [3-2] The agent according to [3-1], wherein the EP4 antagonist is a compound represented by the general formula (I) described in [3] above, or a salt thereof. [3-3] The agent according to [3-1] or [3-2], wherein the cancer is pancreatic cancer (preferably pancreatic ductal carcinoma, more preferably invasive pancreatic ductal carcinoma). [3-4] The agent described in [3-3] above, wherein the pancreatic cancer is pancreatic cancer with distant metastasis. [3-5] The agent according to any one of [3-1] to [3-4] above, characterized in that it is administered to patients who have not received prior treatment with systemic anti-cancer agents for pancreatic cancer with distant metastases. [3-6] The agent according to any one of [3-1] to [3-5], wherein the EP4 antagonist is a compound represented by the general formula (I-2) described in [8] above, or a salt thereof. [3-7] The agent according to any one of [3-1] to [3-6] above, wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof. [3-8] The agent described in [3-7] above, characterized by being administered orally once daily at a dose of 5 mg to 40 mg as an EP4 antagonist. [3-9] The agent according to [3-7], characterized by being administered orally once daily at a dose of 20 mg or 40 mg as an EP4 antagonist. [3-10] The agent according to any one of [3-1] to [3-9] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody. [3-11] The agent according to [3-10], wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0242] [3-12] Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, AMP-514, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (Retifanlimab), AGEN2034 (Balstilimab), CS1003, HLX10 (Serplulimab), BAT-1306, AK105, AK103, BI The agent described in [3-11] above, which is 754091, LZM009, CMAB819, Sym021, GB226 (Geptanolimab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalimab), BCD-100 (Prolgolimab), PF-06801591 (Sasanlimab), CX-188, JNJ-63723283 (Cetrelimab), or AB122 (Zimberelimab). [3-13] The agent according to [3-10], wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolimab), HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003, and CX-072. [3-14] The agent according to [3-10], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipilimumab, AGEN1884, or tremelimumab. [3-15] The agent according to [3-11], wherein the anti-PD-1 antibody is nivolumab. [3-16] The agent according to [3-11], wherein the anti-PD-1 antibody is Pembrolizumab. [3-17] The agent according to [3-11], wherein the anti-PD-1 antibody is cemplimab. [3-18] The agent according to [3-13], wherein the anti-PD-L1 antibody is avelumab. [3-19] The agent according to [3-13], wherein the anti-PD-L1 antibody is atezolizumab. [3-20] The agent according to [3-13], wherein the anti-PD-L1 antibody is Durvalumab. [3-21] The agent according to [3-14], wherein the anti-CTLA-4 antibody is ipilimumab.

[0243] [3-22] The agent according to [3-15], characterized in that it is administered as nivolumab at a dose of 3 mg / kg (body weight) or 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks). [3-23] The agent described in [3-15], characterized by being administered intravenously at a dose of 480 mg of nivolumab every four weeks. [3-24] The agent described in [3-15] above, characterized in that 480 mg of nivolumab is administered intravenously over approximately 30 minutes at intervals of 4 weeks. [3-25] The agent according to [3-16], characterized by being administered as pembrolizumab at a dose of 2 mg / kg (body weight) or 200 mg every 3 weeks or 400 mg every 6 weeks. [3-26] The agent described in [3-17], characterized by being administered at a dose of 350 mg of cemiplimab every three weeks. [3-27] The agent described in [3-18] above, characterized by being administered at a dose of 10 mg / kg (body weight) of avelumab every two weeks. [3-28] The agent described in [3-19], characterized by being administered at a dose of 1200 mg of atezolizumab at 3-week intervals. [3-29] The agent according to [3-20], characterized in that Durvalumab is administered intravenously at a dose of 10 mg / kg (body weight) every two weeks or at a dose of 1500 mg every four weeks for four doses.

[0244] [3-30] The agent according to [3-21], characterized in that ipilimumab is administered intravenously at a dose of 3 mg / kg (body weight) or 1 mg / kg (body weight) at 3-week intervals for 4 doses, or at a dose of 1 mg / kg (body weight) at 6-week intervals. [3-31] The agent according to any of [3-1] to [3-30] above, wherein FOLFIRINOX therapy or a dose reduction regimen is administered in combination with (i) oxaliplatin, (ii) leucovorin calcium, (iii) irinotecan hydrochloride hydrate, and (iv) fluorouracil. [3-32] FOLFIRINOX therapy, (i) Oxaliplatin 50-85 mg / m² 2 (Preferably 50 mg / m²) 2, 65 mg / m² 2 , 85 mg / m² 2 More preferably, 85 mg / m² 2 ) is administered intravenously. (ii) Leucovorin calcium 200 mg / m² 2 Administer intravenously. (iii) Irinotecan hydrochloride hydrate 90-180 mg / m² 2 (Preferably 90 mg / m²) 2 , 120 mg / m² 2 , 150 mg / m² 2 , 180 mg / m² 2 More preferably, 180 mg / m² 2 ) is administered intravenously. (iv) Fluorouracil 400 mg / m² 2 Administer rapidly intravenously. (v) In addition, fluorouracil 1200-2400 mg / m² 2 (Preferably 1200 mg / m²) 2 , 1800 mg / m² 2 , 2400 mg / m² 2 More preferably, 2400 mg / m² 2 A therapy comprising administering the agent described in any of [3-1] to [3-31] above by continuous intravenous administration.

[0245] [3-33] The FOLFIRINOX therapy dose reduction regimen is (i) Oxaliplatin 50-85 mg / m² 2 (Preferably 50 mg / m²) 2 , 65 mg / m² 2 , 85 mg / m² 2 More preferably, 85 mg / m² 2 ) is administered intravenously. (ii) Leucovorin calcium 200 mg / m² 2 Administer intravenously. (iii) Irinotecan hydrochloride hydrate 120-140 mg / m² 2 (Preferably 140 mg / m²) 2 ) is administered intravenously. (iv) Fluorouracil 1200-2400 mg / m² 2(Preferably 1200 mg / m²) 2 , 1800 mg / m² 2 , 2400 mg / m² 2 More preferably, 2400 mg / m² 2 A therapy comprising administering the agent described in any of [3-1] to [3-31] above by continuous intravenous administration. [3-34] The agent according to any one of [3-1] to [3-33], wherein FOLFIRINOX therapy or a dose reduction regimen is administered in a series of doses at intervals of 2 to 4 weeks (preferably at intervals of 2 weeks, 3 weeks, 4 weeks, more preferably at intervals of 2 weeks). [3-35] FOLFIRINOX therapy, (i) Oxaliplatin 85 mg / m² 2 It is administered intravenously over a period of 2 hours. (ii) After discontinuation of oxaliplatin administration, levofolinate calcium 200 mg / m² 2 It is administered intravenously over a period of 2 hours. (iii) Irinotecan hydrochloride hydrate 180 mg / m² starting 30 minutes after the start of administration of levofolinate calcium. 2 It is administered intravenously over 1.5 hours. (iv) After discontinuing administration of levofolinate calcium, administer fluorouracil 400 mg / m². 2 Administer rapidly intravenously. (v) In addition, fluorouracil 2400 mg / m² 2 The agent described in any of [3-1] to [3-32] or [3-34] above, which is administered intravenously over a period of 46 hours, with this series of administrations being carried out at 2-week intervals. [3-36] The FOLFIRINOX therapy dose reduction regimen is (i) Oxaliplatin 85 mg / m² 2 It is administered intravenously over a period of 2 hours. (ii) Leucovorin calcium 200 mg / m² 2 It is administered intravenously over a period of 2 hours. (iii) Irinotecan hydrochloride hydrate 150 mg / m² starting 30 minutes after the start of levofolinate calcium administration. 2It is administered intravenously over 1.5 hours. (iv) Furthermore, after the discontinuation of administration of levofolinate calcium, fluorouracil 2400 mg / m² 2 The agent described in any of [3-1] to [3-31] or [3-33] or [3-34] above, which is administered intravenously over a period of 46 hours, with this series of administrations being carried out at 2-week intervals. [3-37] A therapy comprising FOLFIRINOX therapy or a dose reduction regimen thereof, administration of an immune checkpoint inhibitor and an EP4 antagonist, initiated on the same day, the agent described in any of [3-1] to [3-36] above.

[0246] [3-38] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an EP4 antagonist as an active ingredient, characterized in that it is administered in combination with FOLFIRINOX therapy or a dose reduction regimen thereof, and an immune checkpoint inhibitor, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) The FOLFIRINOX therapy is (a) Oxaliplatin 85 mg / m² 2 It is administered intravenously over a period of 2 hours. (b) Leucovorin calcium 200 mg / m² 2 It is administered intravenously over a period of 2 hours. (c) Irinotecan hydrochloride hydrate 180 mg / m² starting 30 minutes after the start of administration of levofolinate calcium. 2 It is administered intravenously over 1.5 hours. (d) After discontinuing administration of levofolinate calcium, fluorouracil 400 mg / m² 2 Administer rapidly intravenously. (e) In addition, fluorouracil 2400 mg / m² 2 This therapy involves continuous intravenous administration over 46 hours, with this series of administrations performed at 2-week intervals, and the dose reduction regimen for this FOLFIRINOX therapy is (a) Oxaliplatin 85 mg / m² 2 It is administered intravenously over a period of 2 hours. (b) Leucovorin calcium 200 mg / m² 2 It is administered intravenously over a period of 2 hours. (c) Irinotecan hydrochloride hydrate 150 mg / m² starting 30 minutes after the start of levofolinate calcium administration. 2 Administer intravenously over a 1.5x multiplier. (d) Furthermore, after the discontinuation of administration of levofolinate calcium, fluorouracil 2400 mg / m² 2 This therapy involves administering a drug intravenously over a 46-hour period, with this series of administrations performed at two-week intervals.

[0247] [3-39] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with FOLFIRINOX therapy or a dose reduction regimen thereof, and an EP4 antagonist, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) The FOLFIRINOX therapy is (a) Oxaliplatin 85 mg / m² 2 It is administered intravenously over a period of 2 hours. (b) Leucovorin calcium 200 mg / m² 2 It is administered intravenously over a period of 2 hours. (c) Irinotecan hydrochloride hydrate 180 mg / m² starting 30 minutes after the start of administration of levofolinate calcium. 2 It is administered intravenously over 1.5 hours. (d) After discontinuing administration of levofolinate calcium, fluorouracil 400 mg / m² 2 Administer rapidly intravenously. (e) In addition, fluorouracil 2400 mg / m² 2 This therapy involves continuous intravenous administration over 46 hours, with this series of administrations performed at 2-week intervals, and the dose reduction regimen for this FOLFIRINOX therapy is (a) Oxaliplatin 85 mg / m² 2 It is administered intravenously over a period of 2 hours. (b) Leucovorin calcium 200 mg / m² 2 It is administered intravenously over a period of 2 hours. (c) Irinotecan hydrochloride hydrate 150 mg / m² starting 30 minutes after the start of levofolinate calcium administration. 2 Administer intravenously over a 1.5x multiplier. (d) Furthermore, after the discontinuation of administration of levofolinate calcium, fluorouracil 2400 mg / m² 2 This therapy involves administering a drug intravenously over a 46-hour period, with this series of administrations performed at two-week intervals.

[0248] [3-40] The agent described in [3-38] or [3-39], which is a regimen of FOLFIRINOX therapy or a dose reduction regime thereof, 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid, or a salt thereof, and Nivolumab, initiated on the same day. [3-41] The agent according to [3-38] to [3-40] above, wherein the cancer is pancreatic cancer (preferably pancreatic ductal carcinoma, more preferably invasive pancreatic ductal carcinoma). [3-42] The agent described in [3-41] above, wherein the pancreatic cancer is pancreatic cancer with distant metastasis. [3-43] The agent according to any one of [3-38] to [3-42] above, characterized by being administered to a patient who has not received prior treatment with a systemic anti-cancer agent for pancreatic cancer with distant metastases.

[0249] [4-1] The agent according to [1] or [2] above, wherein the standard therapy is gemcitabine and nab-paclitaxel therapy. [4-2] The agent according to [4-1], wherein the EP4 antagonist is a compound represented by the general formula (I) described in [3] above, or a salt thereof. [4-3] The agent according to [4-1] or [4-2], wherein the cancer is pancreatic cancer (preferably pancreatic ductal carcinoma, more preferably invasive pancreatic ductal carcinoma). [4-4] The agent described in [4-3] above, wherein the pancreatic cancer is pancreatic cancer with distant metastasis. [4-5] The agent according to any one of [4-1] to [4-4] above, characterized in that it is administered to patients who have not received prior treatment with systemic anti-cancer agents for pancreatic cancer with distant metastases. [4-6] The agent according to any one of [4-1] to [4-5], wherein the EP4 antagonist is a compound represented by the general formula (I-2) described in [8] above, or a salt thereof. [4-7] The agent according to any one of [4-1] to [4-6] above, wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof. [4-8] The agent described in [4-7] above, characterized by being administered orally once daily at a dose of 5 mg to 40 mg as an EP4 antagonist. [4-9] The agent according to [4-7], characterized in that 20 mg or 40 mg (preferably 40 mg) of an EP4 antagonist is administered orally once daily. [4-10] The agent according to any one of [4-1] to [4-9] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody. [4-11] The agent according to [4-10], wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0250] [4-12] Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, AMP-514, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (Retifanlimab), AGEN2034 (Balstilimab), CS1003, HLX10 (Serplulimab), BAT-1306, AK105, AK103, BI The agent described in [4-11] above, which is 754091, LZM009, CMAB819, Sym021, GB226 (Geptanolimab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalimab), BCD-100 (Prolgolimab), PF-06801591 (Sasanlimab), CX-188, JNJ-63723283 (Cetrelimab), or AB122 (Zimberelimab). [4-13] The agent according to [4-10], wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolimab), HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003, and CX-072.

[0251] [4-14] The agent according to [4-10], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipilimumab, AGEN1884, or tremelimumab. [4-15] The agent according to [4-11], wherein the anti-PD-1 antibody is nivolumab. [4-16] The agent according to [4-11], wherein the anti-PD-1 antibody is Pembrolizumab. [4-17] The agent according to [4-11], wherein the anti-PD-1 antibody is cemplimab. [4-18] The agent according to [4-13], wherein the anti-PD-L1 antibody is avelumab. [4-19] The agent according to [4-13], wherein the anti-PD-L1 antibody is atezolizumab. [4-20] The agent according to [4-13], wherein the anti-PD-L1 antibody is Durvalumab. [4-21] The agent according to [4-14], wherein the anti-CTLA-4 antibody is ipilimumab. [4-22] The agent according to [4-15], characterized in that it is administered as nivolumab at a dose of 3 mg / kg (body weight) or 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks). [4-23] The agent described in [4-15], characterized by being administered intravenously at a dose of 480 mg of nivolumab every four weeks. [4-24] The agent described in [4-15] above, characterized by being administered intravenously at a dose of 480 mg of nivolumab over approximately 30 minutes at intervals of 4 weeks.

[0252] [4-25] The agent according to [4-16], characterized by being administered as pembrolizumab at doses of 2 mg / kg (body weight) or 200 mg at intervals of 3 weeks. [4-26] The agent described in [4-17], characterized by being administered at a dose of 350 mg of cemiplimab every three weeks. [4-27] The agent described in [4-18] above, characterized by being administered at a dose of 10 mg / kg (body weight) of avelumab every two weeks. [4-28] The agent according to [4-19], characterized by being administered at a dose of 1200 mg of atezolizumab at 3-week intervals. [4-29] The agent described in [4-20] above, characterized by being administered at a dose of 10 mg / kg (body weight) of Durvalumab every two weeks. [4-30] The agent according to [4-21], characterized by being administered intravenously four times at 3-week intervals, with ipilimumab at a dose of 3 mg / kg (body weight) or 1 mg / kg (body weight). [4-31] Gemcitabine and nab-paclitaxel therapy, (i) Gemcitabine 600-1000 mg / m² 2 (Preferably 600 mg / m²) 2 , 800 mg / m² 2 1000 mg / m² 2 , comfortable, 1000 mg / m² 2 ) is administered intravenously. (ii) Nab-paclitaxel 75-125 mg / m² 2 (Preferably 75 mg / m²) 2 , 100 mg / m² 2 , 125 mg / m² 2More preferably 125 mg / m² 2 ) is administered intravenously. A therapeutic agent as described in any of the above [4-1] to [4-30]. [4-32] The agent described in any of [4-1] to [4-31] above, wherein gemcitabine and nab-paclitaxel therapy is administered in a series of doses at one-week intervals for three weeks, followed by a one-week rest period. [4-33] Gemcitabine and nab-paclitaxel therapy, (i) Gemcitabine 1000 mg / m² 2 It is administered intravenously over 30 minutes. (ii) Nab-paclitaxel 125 mg / m² 2 The drug is administered intravenously over 30 minutes, and this series of administrations is repeated at one-week intervals for three weeks, followed by a one-week break. A therapeutic agent as described in any of the above [4-1] to [4-32]. [4-34] A therapy in which gemcitabine and nab-paclitaxel are administered on the same day, the agent described in any of [4-1] to [4-33] above. [4-35] The agent described in any of [4-1] to [4-34] above, which is a therapy in which the administration of gemcitabine, nab-paclitaxel, an immune checkpoint inhibitor, and an EP4 antagonist is initiated on the same day.

[0253] [4-36] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an EP4 antagonist as an active ingredient, characterized by being administered in combination with gemcitabine and nab-paclitaxel therapy and an immune checkpoint inhibitor, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) The gemcitabine and nab-paclitaxel therapy is (a) gemcitabine 1000 mg / m² 2 (b) Nab-paclitaxel 125 mg / m² is administered intravenously over 30 minutes. 2 This therapy involves intravenously administering the drug over 30 minutes, repeating this series of administrations at one-week intervals for three weeks, followed by a one-week break. [4-37] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an immune checkpoint inhibitor as an active ingredient, characterized by being administered in combination with gemcitabine and nab-paclitaxel therapy and an EP4 antagonist, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 480 mg every four weeks). (iii) The gemcitabine and nab-paclitaxel therapy is (a) gemcitabine 1000 mg / m² 2 (b) Nab-paclitaxel 125 mg / m² is administered intravenously over 30 minutes. 2 This therapy involves intravenously administering the drug over 30 minutes, repeating this series of administrations at one-week intervals for three weeks, followed by a one-week break. [4-38] The agent according to [4-36] or [4-37], wherein the cancer is pancreatic cancer (preferably pancreatic ductal carcinoma, more preferably invasive pancreatic ductal carcinoma). [4-39] The agent described in [4-38] above, wherein the pancreatic cancer is pancreatic cancer with distant metastasis. [4-40] The agent according to any one of [4-36] to [4-39] above, characterized by being administered to a patient who has not received prior treatment with a systemic anti-cancer agent for pancreatic cancer with distant metastases.

[0254] [5-1] The agent according to [1] or [2] above, wherein the standard therapy is docetaxel and / or ramucirumab therapy. [5-2] The agent described in [5-1] above, wherein the standard therapy is docetaxel therapy. [5-3] The agent described in [5-1] above, wherein the standard therapy is ramucirumab therapy. [5-4] The agent described in [5-1] above, wherein the standard therapy is docetaxel and ramucirumab therapy. [5-5] The agent according to [5-1] to [5-4] above, wherein the EP4 antagonist is a compound represented by the general formula (I) described in [3] above, or a salt thereof. [5-6] The agent according to any one of [5-1] to [5-5] above, wherein the cancer is lung cancer (preferably non-small cell lung cancer). [5-7] The agent according to [5-6] above, wherein the lung cancer is stage IV or recurrent non-small cell lung cancer (preferably advanced or recurrent non-small cell lung cancer that is refractory to combination therapy including an anti-PD-1 antibody or anti-PD-L1 antibody and a platinum-based agent). [5-8] The agent according to any one of [5-1] to [5-7] above, characterized in that it is administered to patients who have received combination therapy including an anti-PD-1 antibody or an anti-PD-L1 antibody and a platinum-based agent and have shown refractory progression or relapse. [5-9] The agent according to any one of the above [5-1] to [5-8], wherein the EP4 antagonist is a compound represented by the general formula (I-2) described in [8] above, or a salt thereof. [5-10] The agent according to any one of the above [5-1] to [5-9], wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof. [5-11] The agent according to [5-10], characterized in that it is administered orally once a day at a dose of 5 mg to 40 mg as an EP4 antagonist. [5-12] The agent according to [5-10], characterized in that it is administered orally once daily at a dose of 20 mg or 40 mg as an EP4 antagonist.

[0255] [5-13] The agent according to any one of [5-1] to [5-12] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody. [5-14] The agent according to [5-13], wherein the immune checkpoint inhibitor is an anti-PD-1 antibody. [5-15] Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartalizumab, Tislelizumab, AMP-514, Dostarlimab, Toripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (Retifanlimab), AGEN2034 (Balstilimab), CS1003, HLX10 (Serplulimab), BAT-1306, AK105, AK103, BI The agent described in [5-14] above, which is 754091, LZM009, CMAB819, Sym021, GB226 (Geptanolimab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalimab), BCD-100 (Prolgolimab), PF-06801591 (Sasanlimab), CX-188, JNJ-63723283 (Cetrelimab), or AB122 (Zimberelimab). [5-16] The agent according to [5-13], wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035 (Envafolimab), LY3300054 (Lodapolimab), HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003, and CX-072.

[0256] [5-17] The agent according to [5-13], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipilimumab, AGEN1884, or tremelimumab. [5-18] The agent according to [5-14], wherein the anti-PD-1 antibody is nivolumab. [5-19] The agent according to [5-14], wherein the anti-PD-1 antibody is Pembrolizumab. [5-20] The agent according to [5-14], wherein the anti-PD-1 antibody is cemplimab. [5-21] The agent according to [5-16], wherein the anti-PD-L1 antibody is avelumab. [5-22] The agent according to [5-16], wherein the anti-PD-L1 antibody is atezolizumab. [5-23] The agent according to [5-16], wherein the anti-PD-L1 antibody is Durvalumab. [5-24] The agent according to [5-17], wherein the anti-CTLA-4 antibody is ipilimumab. [5-25] The agent according to [5-18], characterized in that it is administered as nivolumab at a dose of 3 mg / kg (body weight) or 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks). [5-26] The agent described in [5-18] above, characterized by being administered intravenously at a dose of 360 mg of nivolumab every three weeks. [5-27] The agent described in [5-18] above, characterized by being administered intravenously at a dose of 360 mg of nivolumab over approximately 30 minutes at intervals of 3 weeks. [5-28] The agent described in [5-19] above, characterized by being administered as pembrolizumab at a dose of 2 mg / kg (body weight) once, or 200 mg once every 3 weeks, or 400 mg once every 6 weeks.

[0257] [5-29] The agent according to [5-20], characterized by being administered at a dose of 350 mg of cemiplimab every three weeks. [5-30] The agent described in [5-21] above, characterized by being administered at a dose of 10 mg / kg (body weight) of avelumab every two weeks. [5-31] The agent according to [5-22], characterized by being administered at a dose of 1200 mg of atezolizumab at 3-week intervals. [5-32] The agent according to [5-23], characterized by administering 10 mg / kg (body weight) of Durvalumab once every two weeks, or 1500 mg once every four weeks intravenously four times. [5-33] The agent according to [5-24], characterized in that ipilimumab is administered intravenously at a dose of 3 mg / kg (body weight) or 1 mg / kg (body weight) at 3-week intervals for 4 doses, or at a dose of 1 mg / kg (body weight) at 6-week intervals. [5-34] Docetaxel therapy involves docetaxel 50-75 mg / m². 2 (Preferably 50 mg / m²) 2 , 60 mg / m² 2 75 mg / m² 2 More comfortably 60 mg / m² 2 Therapy involves intravenous administration of the agent as described in any of [5-1], [5-2], [5-4] to [5-33] above. [5-35] Docetaxel therapy involves docetaxel 50-75 mg / m².2 (Preferably 50 mg / m²) 2 , 60 mg / m² 2 75 mg / m² 2 More comfortably 60 mg / m² 2 The agent described in any of [5-1], [5-2], [5-4] to [5-34] above, which is administered intravenously over a period of 60 minutes or more, with the administration performed at 3-week intervals. [5-36] The agent according to any one of [5-1], [5-3], [5-4] to [5-33], wherein ramucirumab therapy is a therapy in which ramucirumab 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) is administered intravenously. [5-37] The agent according to any one of [5-1], [5-3], [5-4] to [5-33], or [5-36], wherein ramucirumab therapy is a therapy in which ramucirumab 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) is administered intravenously over 30 to 60 minutes (preferably 60 minutes), and this series of administrations is carried out at 3-week intervals.

[0258] [5-38] Docetaxel and ramucirumab therapy, (i) Docetaxel 50-75 mg / m² 2 (Preferably 50 mg / m²) 2 , 60 mg / m² 2 75 mg / m² 2 More comfortably, 60 mg / m² 2 ) is administered intravenously. (ii) Ramucirumab 6-10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) is administered intravenously. A therapeutic agent as described in any of the above [5-1], [5-4] to [5-33]. [5-39] Docetaxel and ramucirumab therapy, (i) Docetaxel 50-75 mg / m² 2 (Preferably 50 mg / m²) 2 , 60 mg / m² 2 75 mg / m²2 More comfortably, 60 mg / m² 2 ) is administered intravenously over a period of 60 minutes or more. (ii) Ramucirumab 6-10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) is administered intravenously over 30-60 minutes (preferably 60 minutes), and this series of administrations is carried out at 3-week intervals. A therapeutic agent as described in any of the above [5-1], [5-4] to [5-33], or [5-38]. [5-40] The agent described in any of [5-1] to [5-39] above, which is a therapy in which docetaxel and / or ramucirumab therapy, an immune checkpoint inhibitor and an EP4 antagonist are initiated on the same day. [5-41] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an EP4 antagonist as an active ingredient, characterized in that it is administered in combination with docetaxel therapy and an immune checkpoint inhibitor, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 360 mg every three weeks). (iii) Docetaxel therapy involves docetaxel 50-75 mg / m². 2 (Preferably 50 mg / m²) 2 , 60 mg / m² 2 75 mg / m² 2 More comfortably 60 mg / m² 2 This therapy involves administering the drug intravenously over a period of 60 minutes or more, with the administration being repeated at 3-week intervals.

[0259] [5-42] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with docetaxel therapy and an EP4 antagonist, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 360 mg every three weeks). (iii) Docetaxel therapy involves docetaxel 50-75 mg / m². 2 (Preferably 50 mg / m²) 2 , 60 mg / m² 2 75 mg / m² 2 More comfortably 60 mg / m² 2 This therapy involves administering the drug intravenously over a period of 60 minutes or more, with the administration being repeated at 3-week intervals.

[0260] [5-43] A therapy comprising administering docetaxel, 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid, or a salt thereof, and Nivolumab on the same day (if administered on the same day, preferably docetaxel is administered after administration of 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid, or a salt thereof, and Nivolumab), the agent described in [5-41] or [5-42] above. [5-44] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an EP4 antagonist as an active ingredient, characterized in that it is administered in combination with ramucirumab therapy and an immune checkpoint inhibitor, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 360 mg every three weeks). (iii) A drug in which ramucirumab therapy is administered intravenously at a dose of ramucirumab 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) over 30 to 60 minutes (preferably 60 minutes), and this series of administrations is carried out at 3-week intervals.

[0261] [5-45] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an immune checkpoint inhibitor as an active ingredient, characterized in that it is administered in combination with ramucirumab therapy and an EP4 antagonist, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 360 mg every three weeks). (iii) A drug in which ramucirumab therapy is administered intravenously at a dose of ramucirumab 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) over 30 to 60 minutes (preferably 60 minutes), and this series of administrations is carried out at 3-week intervals. [5-46] A therapy comprising administering ramucirumab, 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid, or a salt thereof, and Nivolumab on the same day (when administered on the same day, preferably ramucirumab is administered after administration of 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid, or a salt thereof, and Nivolumab), the agent described in [5-44] or [5-45] above. [5-47] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent comprising an EP4 antagonist as an active ingredient, characterized by being administered in combination with docetaxel and ramucirumab therapy and an immune checkpoint inhibitor, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 360 mg every three weeks). (iii) Docetaxel and ramucirumab therapy, (a) Docetaxel 50-75 mg / m² 2 (Preferably 50 mg / m²) 2 , 60 mg / m² 2 75 mg / m² 2 More comfortably, 60 mg / m² 2 ) is administered intravenously over a period of 60 minutes or more. (b) A drug comprising a regimen in which ramucirumab 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) is administered intravenously over 30 to 60 minutes (preferably 60 minutes), and this series of administrations is carried out at 3-week intervals.

[0262] [5-48] A cancer progression inhibitor, recurrence inhibitor and / or treatment agent containing an immune checkpoint inhibitor as an active ingredient, characterized by being administered in combination with docetaxel and ramucirumab therapy and an EP4 antagonist, (i) The EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid or a salt thereof, and the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is Nivolumab, and Nivolumab is administered at doses of 240 mg every two weeks, 360 mg every three weeks, or 480 mg every four weeks (preferably 360 mg every three weeks). (iii) Docetaxel and ramucirumab therapy, (a) Docetaxel 50-75 mg / m² 2 (Preferably 50 mg / m²)2 , 60 mg / m² 2 75 mg / m² 2 More comfortably, 60 mg / m² 2 ) is administered intravenously over a period of 60 minutes or more. (b) A drug comprising a regimen in which ramucirumab 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) is administered intravenously over 30 to 60 minutes (preferably 60 minutes), and this series of administrations is carried out at 3-week intervals.

[0263] [5-49] A therapy comprising administering docetaxel, ramucirumab, 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid, or a salt thereof, and Nivolumab on the same day (when administered on the same day, preferably docetaxel and ramucirumab are administered after administration of 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid, or a salt thereof, and Nivolumab), as described in [5-47] or [5-48] above. [5-50] The agent according to any one of [5-41] to [5-49] above, wherein the cancer is lung cancer (preferably non-small cell lung cancer). [5-51] The agent according to [5-50], wherein the lung cancer is stage IV or recurrent non-small cell lung cancer (preferably advanced or recurrent non-small cell lung cancer that is refractory to combination therapy including an anti-PD-1 antibody or anti-PD-L1 antibody and a platinum-based agent). [5-52] The agent according to any one of [5-41] to [5-51] above, characterized in that it is administered to patients who have received combination therapy including an anti-PD-1 antibody or an anti-PD-L1 antibody and a platinum-based agent and have experienced refractory progression or relapse.

[0264] [6-1] Standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a dose reduction regimen, (iv) gemcitabine and nab-paclitaxel therapy, or (v) docetaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a dose reduction regimen, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel EP4 antagonists used for suppressing cancer progression, preventing recurrence and / or treatment, administered in combination with (i) bevacizumab and Xelox therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, or (vi) docetaxel and ramucirumab therapy) and immune checkpoint inhibitors. [6-2] Standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, or (v) docetaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel An immune checkpoint inhibitor used to suppress cancer progression, prevent recurrence and / or treatment, administered in combination with (i) bevacizumab and Xelox therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, or (vi) docetaxel and ramucirumab therapy) and an EP4 antagonist.

[0265] [6-3] Standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, or (v) docetaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel therapy) The use of EP4 antagonists in the manufacture of cancer progression suppression, recurrence suppression and / or therapeutic agents, administered in combination with (i) docetaxel and ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, or (vi) docetaxel and ramucirumab therapy) and immune checkpoint inhibitors. [6-4] Standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, or (v) docetaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel therapy) The use of immune checkpoint inhibitors in the manufacture of cancer progression suppression, recurrence suppression and / or therapeutic agents, administered in combination with (i) docetaxel and ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, or (vi) docetaxel and ramucirumab therapy) and EP4 antagonists. [6-5] Standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a dose reduction regimen, (iv) gemcitabine and nab-paclitaxel therapy, or (v) docetaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a dose reduction regimen, (iv) gemcitabine and nab-paclitaxel therapy, (vii) docetaxel therapy, or (vi) A method for suppressing cancer progression, preventing recurrence and / or treatment, comprising administering an effective dose of cetaxel and ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose regimen thereof, (iv) gemcitabine and nab-paclitaxel therapy, or (vi) docetaxel and ramucirumab therapy) along with an effective dose of an immune checkpoint inhibitor and an effective dose of an EP4 antagonist to a patient in need of cancer treatment, either separately or simultaneously.

[0266] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meanings as those commonly understood by those skilled in the art.

[0267] Furthermore, all patent and non-patent documents or references explicitly cited herein may be incorporated herein by reference as part of this specification. [Examples]

[0268] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. As the EP4 receptor antagonist represented by general formula (I), 4-[4-cyano-2-({(2'R,4S)-6-[(propan-2-yl)carbamoyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butanoic acid (compound A) was used. Compound A can be prepared by known methods, for example, the method described in Example 2-13 of WO2016 / 111347.

[0269] Example 1 This is an open-label, uncomparable trial in patients with unresectable advanced or recurrent colorectal cancer, comparing compound A, nivolumab, and the standard treatment of XELOX plus bevacizumab as first-line therapy. This study aims to investigate the tolerability, safety, and efficacy of compound A, nivolumab, and XELOX + bevacizumab as a first-line treatment in patients with unresectable advanced or recurrent colorectal cancer. This trial will allow for the evaluation of the combined effects of compound A, nivolumab, and XELOX + bevacizumab. (1) Target patients Patients with advanced or recurrent colorectal cancer that is not resectable (2) Patient selection criteria At the time of enrollment, patients were selected who had no prior treatment with systemic anti-cancer agents for unresectable advanced or recurrent colorectal cancer, and who met all of the prescribed patient selection criteria determined by considering the patient selection criteria in each clinical trial conducted to date for compound A, nivolumab, and XELOX + bevacizumab therapy. If it became clear that a patient did not meet these criteria between enrollment and the first dose of the investigational drug, the administration of the investigational drug would not be started, and the trial would be terminated. (3) Patient exclusion criteria At the time of enrollment, patients who were deemed to meet any of the following criteria were excluded: the patient exclusion criteria for each clinical trial for compound A, nivolumab, and XELOX + bevacizumab therapy, or the prescribed patient exclusion criteria determined in consideration of the appropriate use guidelines or appropriate use information for compound A, nivolumab, and XELOX + bevacizumab therapy. If it became clear that a patient did not meet these criteria between enrollment and the first dose of the investigational drug, the administration of the investigational drug was not started, and the trial was terminated.

[0270] (4) Dosage and administration and duration of administration [Compound A] Compound A was administered orally at a dose of 20 mg or 40 mg once daily, and continued until the prescribed discontinuation criteria for Compound A were met. When Compound A, Nivolumab, and XELOX + bevacizumab therapy were administered on the same day, Compound A and Nivolumab were administered first, followed by the initiation of XELOX + bevacizumab therapy. [Nivolumab] Nivolumab 360 mg was administered intravenously over 30 minutes at 3-week intervals, and continued until the prescribed discontinuation criteria for Nivolumab were met. Note that Nivolumab administration was performed at least 14 days after the previous dose, starting on the 15th day or later. [XELOX + Bevacizumab therapy] Bevacizumab was administered intravenously at a dose of 7.5 mg / kg over 90 minutes. If well tolerated, the second dose was administered intravenously over 60 minutes, and subsequent cycles were administered over 30 minutes. Oxaliplatin was administered at a dose of 130 mg / m². 2 (Body surface area) was administered intravenously over 2 hours. Capecitabine was administered at a dose of 1000 mg / m². 2 The drug was administered orally twice daily, after breakfast and after dinner, for 14 days, followed by a 7-day rest period. Bevacizumab, oxaliplatin, and capecitabine were commercially available products. [Clinical Trial Schedule] This trial consists of a screening phase, a treatment phase, and a follow-up observation phase. Figure 1 shows an overview of the trial schedule. The screening period was within 28 days prior to administration of the investigational drug. The principal investigator or co-investigator enrolled patients who met the above selection criteria, did not violate the above exclusion criteria, and were deemed eligible to participate in this clinical trial.

[0271] Each treatment cycle consisted of 21 days, with the first administration of the investigational drug designated as day 1 of cycle 1. Day 1 of each subsequent cycle was designated as [21X(number of cycles-1)+1] days. Administration of compound A, nivolumab, and XELOX+bevacizumab therapy was initiated according to the above-described dosage and administration guidelines, and continued according to the administration criteria, dose reduction criteria, and dose reduction levels for compound A, nivolumab, and XELOX+bevacizumab therapy. The treatment period ended when the evaluation at the end of administration (discontinuation) of compound A, nivolumab, and XELOX+bevacizumab therapy was completed. Of all subjects who received the investigational drug, those who discontinued or terminated administration of compound A, nivolumab, and XELOX+bevacizumab therapy underwent an evaluation at the end of administration (discontinuation) and proceeded to the post-observation period. Follow-up surveys were conducted after the end of the post-observation period.

[0272] [Dosage criteria for compound A and nivolumab] At the start of each administration, subjects must meet all of the prescribed administration criteria, which are determined by considering the administration criteria from previous clinical trials for compound A and nivolumab. If any of these criteria are not met, the scheduled administration of compound A and nivolumab will be discontinued. However, even if any of the criteria are not met, administration of compound A and nivolumab may be continued only if there is no worsening of clinical symptoms judged to be due to disease progression, a clinical benefit from continued administration is expected, and it is determined that it is safe to continue administration of compound A and nivolumab considering the subject's baseline and the effects of concomitant medications. [Criteria for discontinuing administration of compound A] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined by considering the discontinuation criteria from clinical trials conducted to date with respect to compound A, will have their administration of compound A discontinued. [Criteria for discontinuing Nivolumab administration] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined based on the discontinuation criteria from previous clinical trials of Nivolumab, will have Nivolumab discontinued. [Dosage Criteria for XELOX + Bevacizumab Therapy] At the start of each administration, subjects must meet all of the prescribed administration criteria, which are determined by considering the administration criteria from previous clinical trials of XELOX + bevacizumab therapy. Administration will be postponed until the clinical laboratory values ​​on the scheduled administration date return to a state that meets the criteria, and administration will be performed only after confirming that there are no contraindications for each drug. [Dose reduction and criteria for XELOX + bevacizumab therapy] The dosage reduction will be carried out in accordance with the latest package insert. [Discontinuation Criteria for XELOX + Bevacizumab Therapy] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined by considering the discontinuation criteria in each clinical trial conducted to date with regard to XELOX + bevacizumab therapy, will discontinue XELOX + bevacizumab therapy. [Efficacy Evaluation Criteria] (Image diagnosis) CT / magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis were performed. In addition, during the screening period (within 28 days prior to administration of the investigational drug), if brain metastasis was suspected based on clinical symptoms, CT / MRI scans of the head, fluorodeoxyglucose-positron emission tomography (FDG-PET) (or bone scintigraphy) were performed to confirm the presence or absence of brain or bone metastasis.

[0273] The principal investigator or co-investigator measured the tumor diameter of the target lesion and determined the antitumor effect in accordance with the RECIST Guideline 1.1. Baseline assessment was performed using the most recent imaging examination within 28 days prior to administration of the investigational drug, confirming the presence of at least one measurable lesion as defined in the RECIST Guideline 1.1. Imaging during the treatment period was measured at 6-week intervals from day 1 of cycle 1 to 6 weeks (+7 days) and 54 weeks (+7 days), and thereafter at 12-week intervals (±7 days).

[0274] The overall effect and best overall effect were defined as the image diagnostic results evaluated based on RECIST guideline version 1.1. (Evaluation criteria) (1) Objective response rate (ORR), (2) Disease control rate (DCR), (3) Overall survival (OS), (4) Progression-free survival (PFS), (5) Duration of response (DOR), (6) Time to response (TTR), (7) Best overall response (BOR), (8) Percentage change in the sum of tumor diameters of target lesions, (9) Maximum percentage change in the sum of tumor diameters of target lesions, (10) Changes in tumor markers (CEA and CA19-9) (1) Performance The response rate indicates the percentage of subjects whose best overall effect was determined to be a complete response (CR) or a partial response (PR). (2) Disease control rate The disease control rate represents the percentage of subjects whose best overall response was determined to be CR, PR, or stable disease (hereinafter abbreviated as "SD"). (3) Overall survival period Overall survival time is calculated using the following formula. Overall survival (days) = "Date of death from any cause" - "Date of commencement of investigational drug administration" + 1 For subjects who become untrackable or who have not died by the data cutoff date, the last date of survival confirmation will be considered the termination date. (4) Progression-free survival Progression-free survival is calculated using the following formula. Progression-free survival (days) = "The earlier of the day on which overall efficacy was determined to be PD, or the day of death due to any cause" - "Start date of investigational drug administration" + 1 For subjects whose overall response has not been determined to be progression (progressive disease, hereafter abbreviated as "PD") and who have not died, the censorship date will be the date on which the last evaluable imaging diagnosis was performed. For subjects whose overall response has not been determined to be PD and who have not died, the censorship date will be the date on which the investigational drug administration began. For subjects who received subsequent treatment for cancer before their overall response was determined to be PD or before they died, the censorship date will be the date on which the last evaluable imaging diagnosis was performed before the start of subsequent treatment for cancer. (5) Duration of effectiveness The duration of effectiveness is calculated using the following formula. Duration of response (days) = "The earlier of the date on which the overall response was first determined to be PD after the confirmation of response, or the date of death from any cause" - "The date on which the first confirmed CR or PR was determined" + 1 The subjects to be evaluated are those who demonstrated a confirmed complete response (CR) or partial response (PR) during the clinical trial. (6) Time to achieve results The time required to achieve a response is calculated using the following formula. Time to response (days) = "First date of confirmed CR or PR" - "Start date of investigational drug administration" + 1 (7) Percentage change in tumor diameter of target lesion For subjects with target lesions, the percentage change in the sum of tumor diameter of the target lesion was calculated using the following formula. However, the percentage change in the sum of tumor diameter of the target lesion after subsequent treatment was not calculated.

[0275]

number

[0276] (8) Maximum change in the sum of tumor diameters of the target lesion The maximum percentage change in the sum of tumor diameter of the target lesion is defined as the percentage change at the point when the sum of tumor diameter of the target lesion is smallest. However, the sum of tumor diameter of the target lesion after the overall effect is determined to be PD or after subsequent treatment is performed is not used in calculating the maximum percentage change.

[0277]

number

[0278] [Safety evaluation criteria] The following items were measured, examined, and investigated by the principal investigator and other relevant personnel at predetermined times. (1) Dose-limiting toxicity, (2) Adverse events, (3) Clinical laboratory tests (hematological tests, blood biochemical tests, hormone tests, blood coagulation tests, urinalysis, immunological tests), (4) Vital signs (systolic / diastolic blood pressure, pulse rate, body temperature), transcutaneous oxygen saturation (SpO2), body weight, (5) 12-lead electrocardiogram, (6) ECOG Performance Status, (7) Chest X-ray, (8) Ophthalmic examination (visual acuity test, intraocular pressure test, slit-lamp microscopy, and (9) CT scan) [Efficacy Evaluation Results] Ten months after the enrollment of the first subject, two cases were judged to have achieved a partial response (PR).

[0279] Example 2 This is an open-label, uncontrolled trial in which compound A or compound A in combination with nivolumab is used as neoadjuvant therapy after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer that is resectable. This study aims to investigate the efficacy, pharmacokinetics, and safety of compound A administered as monotherapy and / or in combination with nivolumab as neoadjuvant therapy following neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer that is resectable. This trial will allow for the evaluation of the effects of compound A and / or compound A in combination with nivolumab as neoadjuvant therapy. (1) Target Locally advanced rectal cancer that can be curatively resected (2) Patient selection criteria At the time of enrollment, patients were selected who met all of the predetermined patient selection criteria, which were determined by considering the patient selection criteria in each clinical trial conducted to date for Nivolumab and Compound A. If it becomes clear that a patient does not meet the criteria between enrollment and the first dose of the investigational drug, the administration of the investigational drug will not be started and the trial will be terminated.

[0280] It was administered to patients who received preoperative CRT treatment meeting the following conditions. The patient received 25 fractions of 45 Gy of irradiation to the pelvic cavity and 3 boost fractions of 5.4 Gy to the primary lesion. • 1,650 mg / m² of capecitabine per day 2 (825 mg / m²) 2 Treatment was initiated at a dose of twice daily. The starting dose was determined based on Method D of the Dosage and Administration guidelines for Xeloda® Tablets 300mg. • When used in combination with radiation therapy, capecitabine was administered orally for a period equivalent to 75% of the 28 radiation sessions (e.g., 21 days or 42 or more doses if administered morning and evening in the case of 50.4 Gy / 28 sessions). Dosage reduction was not considered.

[0281] The investigational drug will be administered to patients who can begin administration of the investigational drug within 14 days after the completion of preoperative CRT treatment with capecitabine and radiation therapy.

[0282] This drug is administered to patients who show no distant metastases on imaging after the completion of preoperative CRT and who are eligible for curative resection. Pre-registration imaging will be based on images taken from 14 days prior to the completion of preoperative CRT until the registration date. (3) Patient exclusion criteria At the time of registration, patients who were deemed to meet any of the patient exclusion criteria determined in consideration of the patient exclusion criteria for each clinical trial for compound A and nivolumab, or the patient selection precautions in the appropriate use guidelines or appropriate use information for compound A and nivolumab, were excluded. If it became clear that a patient did not meet the criteria between registration and the first dose of the investigational drug, administration of the investigational drug was not started, and the trial was terminated. (4) Dosage and administration and duration of administration [Compound A] Compound A was administered orally at a dose of 40 mg once daily, and administration was continued until the prescribed criteria for discontinuing administration of Compound A were met. [Nivolumab] Nivolumab was administered intravenously at a dose of 240 mg over 30 minutes at two-week intervals, and continued until the prescribed discontinuation criteria for Nivolumab were met. Nivolumab administration was performed at least 10 days after the previous dose, starting from the 11th day. [Clinical Trial Schedule] This clinical trial consists of a screening phase, a treatment phase, a perioperative phase, and a follow-up observation phase. An overview of the trial design is shown in Figure 2.

[0283] During the screening phase, patients with locally advanced rectal cancer that is resectable and has undergone preoperative CRT, and who are deemed eligible for this clinical trial, will be enrolled and proceed to the treatment phase.

[0284] During the treatment phase, administration of the investigational drug was initiated within 14 days of the completion of preoperative CRT. Two groups were established: Cohort 1, which received compound A (40 mg, once daily (QD), orally) as monotherapy for a certain period, followed by a combination of compound A (40 mg, QD, orally) and nivolumab (240 mg, every two weeks (Q2W), intravenously) for a certain period; and Cohort 2, which received compound A (40 mg, QD, orally) and nivolumab (240 mg, Q2W, intravenously) for a certain period. After enrollment in Cohort 1 was completed, enrollment in Cohort 2 would begin. After completion of investigational drug administration, all subjects underwent end-of-treatment (discontinuation) examinations and transitioned from the treatment phase to the perioperative phase.

[0285] In the perioperative period, surgery will, in principle, be performed at least 7 days after the last administration of compound A and at least 14 days after the last administration of nivolumab, and within 14 weeks after the completion of preoperative CRT. However, the timing of surgery will be determined with the subject's condition as the top priority, and this rule will not apply if surgery becomes urgently necessary due to exacerbation of the underlying disease, or if surgery needs to be postponed due to treatment for adverse events. In the post-observation period, various final examinations will be conducted starting at the later of 30 days after the completion of surgical treatment or when the principal investigator or co-investigator determines that surgical complications have subsided. However, if subsequent treatment for the underlying disease (rectal cancer) is initiated due to clinical necessity before the starting date, the final examinations will be conducted before the commencement of subsequent treatment. Follow-up will also be conducted thereafter. [Dosage criteria for compound A and nivolumab] At the start of each administration, subjects must meet all of the prescribed administration criteria, which are determined based on the administration criteria from previous clinical trials for compound A and nivolumab. If any of these criteria are not met, the scheduled administration of compound A and nivolumab will be discontinued. However, if the principal investigator or co-investigator determines, after considering the benefit-risk balance, that continued administration is expected to be beneficial, administration of the investigational drug may be continued. [Criteria for discontinuing administration of compound A] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined by considering the discontinuation criteria from clinical trials conducted to date with respect to compound A, will have their administration of compound A discontinued. [Criteria for discontinuing Nivolumab administration] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined based on the discontinuation criteria from previous clinical trials of Nivolumab, will have Nivolumab discontinued.

[0286] [Effectiveness evaluation items] (Diagnostic imaging and endoscopic examinations) Imaging studies and endoscopic examinations were performed to determine whether tumor progression had occurred based on colonoscopy, CT, or MRI images. The timing of these examinations was not affected by the discontinuation of the investigational drug. In addition, if brain metastasis was suspected based on clinical symptoms during the screening period (within 14 days before administration of the investigational drug), CT / MRI scans of the head, FDG-PET (or bone scintigraphy), etc. were performed to confirm the presence or absence of brain or bone metastasis. (Evaluation criteria) (1) Pathological complete response (pCR) rate, (2) Major pathological response (MPR) rate, (3) Overall survival (OS), (4) Recurrence-free survival (RFS), (5) Event-free survival (EFS), (6) Changes in tumor markers (CEA and CA19-9) (1) pCR rate The pCR rate was calculated as the percentage of subjects who were determined to have an AJCC Tumor regression grade of 0 by pathologists at each participating medical institution. pCR was defined as the absence of viable tumor cells in both the primary tumor and the regional lymph nodes (ypT0N0). (2)MPR rate The percentage of subjects who were determined to have an AJCC Tumor regression grade of 0 or 1 by a pathologist at each participating medical institution is calculated as the MPR rate. [Surgical evaluation criteria] (1) Rate of radical resection, (2) Rate of treatment completion up to radical resection, (3) Rate of radical resection during the period specified in the clinical trial protocol, (4) Macroscopic evaluation of the resected specimen. [Safety evaluation criteria] The following items were measured, examined, and investigated by the principal investigator and other relevant personnel at predetermined times. (1) Adverse events, (2) Perioperative complications, (3) Clinical tests (hematological tests, blood biochemical tests, hormone tests, blood coagulation tests, urinalysis, immunological tests), (4) Vital signs (systolic / diastolic blood pressure, pulse rate, body temperature), transcutaneous oxygen saturation (SpO2), body weight, (5) 12-lead electrocardiogram, (6) ECOG Performance Status, (7) Chest X-ray, (8) Ophthalmic examination (visual acuity test, intraocular pressure test, slit-lamp microscopy, and (9) CT scan) [Efficacy Evaluation Results] Ten months after the enrollment of the first subject, three cases were judged to have achieved a pathological complete response (pCR).

[0287] Example 3 This is an open-label, uncontrolled trial in patients with pancreatic cancer with distant metastases, comparing compound A, nivolumab, and standard therapy (mFFX or GnP) as first-line treatment. This study aims to investigate the tolerability, safety, and efficacy of compound A, nivolumab, and mFFX therapy or GnP therapy as a first-line treatment in patients with pancreatic cancer with distant metastases. This trial will allow for the evaluation of the combined effects of compound A, nivolumab, and mFFX therapy or GnP therapy. (1) Target patients Pancreatic cancer patients with distant metastases (2) Patient selection criteria At the time of enrollment, patients were selected who had no prior treatment history with systemic anti-cancer agents for pancreatic cancer with distant metastases, and who met all of the prescribed patient selection criteria determined by considering the patient selection criteria in each clinical trial conducted to date for compound A, nivolumab, and either mFFX therapy or GnP therapy. If it became clear that a patient did not meet these criteria between enrollment and the first dose of the investigational drug, the administration of the investigational drug was not started, and the trial was terminated. (3) Patient exclusion criteria At the time of enrollment, patients who were deemed to meet any of the patient exclusion criteria for each clinical trial concerning Compound A, Nivolumab, and mFFX therapy or GnP therapy, or the prescribed patient exclusion criteria determined in consideration of the appropriate use guidelines or appropriate use information for Compound A, Nivolumab, and mFFX therapy or GnP therapy, were excluded. If it became clear that a patient did not meet the criteria between enrollment and the first dose of the investigational drug, the administration of the investigational drug was not started, and the trial was terminated.

[0288] (4) Dosage and administration and duration of administration [Compound A] Compound A was administered orally at a dose of 20 mg or 40 mg once daily, and continued until the prescribed discontinuation criteria for Compound A were met. When Compound A, Nivolumab, and mFFX therapy or GnP therapy were administered on the same day, Compound A and Nivolumab were administered first, followed by the initiation of mFFX therapy or GnP therapy. [Nivolumab] Nivolumab 480 mg was administered intravenously over 30 minutes at 4-week intervals, and continued until the prescribed discontinuation criteria for Nivolumab were met. Note that Nivolumab administration was performed at least 24 days after the previous dose, starting on the 25th day or later. [mFFX therapy] Oxaliplatin is 85 mg / m² 2 (Body surface area) was administered intravenously over 2 hours. Irinotecan was administered at a dose of 150 mg / m². 2 The dose (based on body surface area) was administered intravenously over 90 minutes. Leucovorin was administered at a dose of 200 mg / m². 2 (Body surface area) was administered intravenously over 2 hours. Fluorouracil was administered at a dose of 2400 mg / m². 2 The (body surface area) dose was administered intravenously over 46 hours. This series of administrations was carried out at 2-week intervals. Oxaliplatin, irinotecan, leucovorin, and fluorouracil were all commercially available products. [GnP therapy] Gemcitabine is 1000 mg / m² 2 The drug was administered intravenously over 30 minutes (based on body surface area), followed by a drug-free period of at least 6 days. Nab-paclitaxel was administered at a dose of 125 mg / m². 2 The drug (based on body surface area) was administered intravenously over 30 minutes, followed by a drug-free period of at least 6 days. This series of administrations was carried out at 1-week intervals for 3 weeks, followed by a 1-week drug-free period. [Clinical Trial Schedule] This trial consists of a screening phase, a treatment phase, and a follow-up observation phase. An overview of the trial schedule is shown in Figure 3. The screening period was within 28 days prior to administration of the investigational drug. The principal investigator or co-investigator enrolled patients who met the above selection criteria, did not violate the above exclusion criteria, and were deemed eligible to participate in this clinical trial.

[0289] The treatment period consisted of 28-day cycles, with the first administration of the investigational drug designated as day 1 of cycle 1. Day 1 of each subsequent cycle was designated as [28 × (number of cycles - 1) + 1] days. Administration of compound A, nivolumab, and mFFX therapy or GnP therapy was initiated according to the above-mentioned dosage and administration instructions, and continued according to the administration criteria, dose reduction criteria, and dose reduction dosage for compound A, nivolumab, and mFFX therapy or GnP therapy. The treatment period ended when the evaluation at the end of administration (discontinuation) of compound A, nivolumab, and mFFX therapy or GnP therapy was completed. Of all subjects who received the investigational drug, those who discontinued or terminated administration of compound A, nivolumab, and mFFX therapy or GnP therapy underwent an evaluation at the end of administration (discontinuation) and proceeded to the post-observation period. Follow-up surveys were conducted after the end of the post-observation period. [Dosage criteria for compound A and nivolumab] At the start of each administration, subjects must meet all of the prescribed administration criteria, which are determined by considering the administration criteria from previous clinical trials for compound A and nivolumab. If any of these criteria are not met, the scheduled administration of compound A and nivolumab will be discontinued. However, even if any of the criteria are not met, administration of compound A and nivolumab may be continued only if there is no worsening of clinical symptoms judged to be due to disease progression, a clinical benefit from continued administration is expected, and it is determined that it is safe to continue administration of compound A and nivolumab considering the subject's baseline and the effects of concomitant medications.

[0290] [Criteria for discontinuing administration of compound A] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined by considering the discontinuation criteria from clinical trials conducted to date with respect to compound A, will have their administration of compound A discontinued. [Criteria for discontinuing Nivolumab administration] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined based on the discontinuation criteria from previous clinical trials of Nivolumab, will have Nivolumab discontinued. [Dosage Criteria for mFFX Therapy] At the start of each administration, subjects must meet all prescribed administration criteria determined in consideration of the administration criteria used in previous clinical trials for mFFX therapy. Administration will be postponed until clinical laboratory values ​​on the scheduled administration date return to a state that meets the criteria, and administration will only be performed after confirming that there are no contraindications for each drug. [Dose reduction and criteria for mFFX therapy] The dosage reduction will be carried out in accordance with the latest package insert. [Criteria for discontinuing mFFX therapy] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined by considering the discontinuation criteria in each clinical trial conducted to date for mFFX therapy, will have their mFFX therapy discontinued. [Guidelines for administering GnP therapy] At the start of each administration, subjects must meet all prescribed administration criteria, which are determined by considering the administration criteria from previous clinical trials of GnP therapy. Administration will be postponed until the clinical laboratory values ​​on the scheduled administration date return to a state that meets the criteria, and administration will only be performed after confirming that there are no contraindications for each drug. [Dose reduction and criteria for GnP therapy] The dosage reduction will be carried out in accordance with the latest package insert. [Criteria for discontinuing GnP therapy] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined by considering the discontinuation criteria in each clinical trial conducted to date regarding GnP therapy, will have their GnP therapy discontinued. [Efficacy Evaluation Criteria] (Image diagnosis) CT / magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis were performed. In addition, during the screening period (within 28 days prior to administration of the investigational drug), if brain metastasis was suspected based on clinical symptoms, CT / MRI scans of the head, fluorodeoxyglucose-positron emission tomography (FDG-PET) (or bone scintigraphy) were performed to confirm the presence or absence of brain or bone metastasis.

[0291] The principal investigator or co-investigator measured the tumor diameter of the target lesion and determined the antitumor effect in accordance with the RECIST Guideline 1.1. Baseline evaluation was performed using the most recent imaging examination within 28 days prior to administration of the investigational drug, confirming the presence of at least one measurable lesion as defined in the RECIST Guideline 1.1. Imaging during the treatment period was performed from day 1 of the first cycle to 8 weeks (+7 days), and tumor diameter was measured.

[0292] The overall effect and best overall effect were defined as the image diagnostic results evaluated based on RECIST guideline version 1.1. (Evaluation criteria) (1) Objective response rate (ORR), (2) Disease control rate (DCR), (3) Overall survival (OS), (4) Progression-free survival (PFS), (5) Duration of response (DOR), (6) Time to response (TTR), (7) Best overall response (BOR), (8) Percentage change in the sum of tumor diameters of target lesions, (9) Maximum percentage change in the sum of tumor diameters of target lesions, (10) Changes in tumor markers (CEA and CA19-9)

[0293] (1) Performance The response rate indicates the percentage of subjects whose best overall response was determined to be a complete response (CR) or partial response (PR). (2) Disease control rate The disease control rate represents the percentage of subjects whose best overall response was determined to be CR, PR, or SD. (3) Overall survival period Overall survival time is calculated using the following formula. Overall survival (days) = "Date of death from any cause" - "Date of commencement of investigational drug administration" + 1 For subjects who become untrackable or who have not died by the data cutoff date, the last date of survival confirmation will be considered the termination date. (4) Progression-free survival Progression-free survival is calculated using the following formula. Progression-free survival (days) = "The earlier of the day on which overall efficacy was determined to be PD, or the day of death due to any cause" - "Start date of investigational drug administration" + 1 For subjects whose overall response has not been determined to be PD and who have not died, the censorship date will be the date of the last evaluable imaging diagnosis performed. For subjects whose evaluable imaging diagnosis has not been performed and who have not died, the censorship date will be the date the investigational drug administration started. For subjects who received subsequent treatment for cancer before their overall response was determined to be PD or before they died, the censorship date will be the date of the last evaluable imaging diagnosis performed before the start of subsequent treatment for cancer. (5) Duration of response The duration of effectiveness is calculated using the following formula. Duration of response (days) = "The earlier of the date on which the overall response was first determined to be PD after the confirmation of response, or the date of death from any cause" - "The date on which the first confirmed CR or PR was determined" + 1 The subjects to be evaluated are those who demonstrated a confirmed complete response (CR) or partial response (PR) during the clinical trial. (6) Time to achieve a response The time required to achieve a response is calculated using the following formula. Time to response (days) = "First date of confirmed CR or PR" - "Start date of investigational drug administration" + 1 (7) Percentage change in tumor diameter of target lesion For subjects with target lesions, the percentage change in the sum of tumor diameter of the target lesion was calculated using the following formula. However, the percentage change in the sum of tumor diameter of the target lesion after subsequent treatment was not calculated.

[0294]

number

[0295] (8) Maximum change in the sum of tumor diameters of the target lesion The maximum percentage change in the sum of tumor diameter of the target lesion is defined as the percentage change at the point when the sum of tumor diameter of the target lesion is smallest. However, the sum of tumor diameter of the target lesion after the overall effect is determined to be PD or after subsequent treatment is performed is not used in calculating the maximum percentage change.

[0296]

number

[0297] (9) Changes in tumor marker rates (CEA and CA19-9) The percentage change in tumor markers is calculated using the following formula. However, the percentage change in tumor markers after subsequent treatment is not calculated.

[0298]

number

[0299] [Safety evaluation criteria] The following items were measured, examined, and investigated by the principal investigator and other relevant personnel at predetermined times. (1) Dose-limiting toxicity (DLT), (2) Adverse events, (3) Clinical laboratory tests (hematological tests, blood biochemical tests, hormone tests, blood coagulation tests, urinalysis, immunological tests), (4) Vital signs (systolic / diastolic blood pressure, pulse rate, body temperature), transcutaneous oxygen saturation (SpO2), body weight, (5) 12-lead electrocardiogram, (6) ECOG Performance Status, (7) Chest X-ray, (8) Ophthalmic examination (visual acuity test, intraocular pressure test, slit-lamp microscopy, and (9) CT scan) [Efficacy Evaluation Results] Regarding the combination therapy of compound A, nivolumab, and mFFX therapy, there was one case of partial response (PR) observed 9 months after the enrollment of the first subject.

[0300] Furthermore, regarding the combination therapy of compound A, nivolumab, and GnP therapy, there were two cases judged to have achieved a partial response (PR) nine months after the enrollment of the first subject.

[0301] Example 4 This is an open-label, uncontrolled trial in patients with advanced or recurrent non-small cell lung cancer who are refractory to combination therapy including anti-PD-1 antibodies or anti-PD-L1 antibodies and platinum-based agents, comparing compound A, nivolumab, with the standard therapy of docetaxel and ramucirumab as a second-line treatment. This study aims to investigate the tolerability, safety, and efficacy of compound A, nivolumab, docetaxel, and ramucirumab as a second-line treatment in patients with advanced or recurrent non-small cell lung cancer who are refractory to combination therapy including anti-PD-1 antibodies or anti-PD-L1 antibodies and platinum-based agents. This trial will allow for the evaluation of the combined efficacy of compound A, nivolumab, docetaxel, and ramucirumab. (1) Target patients Patients with stage IV or recurrent non-small cell lung cancer (2) Patient selection criteria At the time of enrollment, patients were selected who had received combination therapy including an anti-PD-1 antibody or anti-PD-L1 antibody and a platinum-based agent as first-line treatment, who had experienced refractory progression or relapse, and who met all of the prescribed patient selection criteria determined by considering the patient selection criteria in each clinical trial conducted to date for compound A, nivolumab, docetaxel, and ramucirumab. If it became clear that a patient did not meet these criteria between enrollment and the first dose of the investigational drug, the administration of the investigational drug was not started, and the trial was terminated. (3) Patient exclusion criteria At the time of enrollment, patients who were deemed to meet any of the following criteria were excluded: the patient exclusion criteria for each clinical trial for compound A, nivolumab, docetaxel, and ramucirumab, or the prescribed patient exclusion criteria determined in consideration of the patient selection precautions in the appropriate use guidelines or appropriate use information for each compound A, nivolumab, docetaxel, and ramucirumab. If it became clear that a patient did not meet these criteria between enrollment and the first dose of the investigational drug, the administration of the investigational drug was not started, and the trial was terminated.

[0302] (4) Dosage and administration and duration of administration [Compound A] Compound A was administered orally at a dose of 20 mg or 40 mg once daily, and continued until the prescribed discontinuation criteria for Compound A were met. When Compound A, Nivolumab, docetaxel, and ramucirumab were administered on the same day, Compound A and Nivolumab were administered first, followed by the commencement of docetaxel and ramucirumab. [Nivolumab] Nivolumab 360 mg was administered intravenously over approximately 30 minutes at 3-week intervals, and continued until the prescribed criteria for discontinuing Nivolumab were met. Note that Nivolumab administration was performed at least 14 days after the previous dose, starting on the 15th day or later. [Docetaxel and ramucirumab] The dosage and administration of docetaxel and ramucirumab should follow the procedures of the medical institution, but the recommended dosage is 60 mg / m² for docetaxel. 2 (Body surface area) was administered intravenously over a period of 60 minutes or more at 3-week intervals. Ramucirumab was administered intravenously at a dose of 10 mg / kg over 60 minutes at 3-week intervals. The 3-week interval means that the administration takes place between day 22 and day 29, counting the previous administration day of docetaxel or ramucirumab as day 1. Commercially available products were used for both docetaxel and ramucirumab. [Clinical Trial Schedule] This trial consists of a screening phase, a treatment phase, and a follow-up observation phase. An overview of the trial schedule is shown in Figure 4. The screening period was within 28 days prior to administration of the investigational drug. The principal investigator or co-investigator enrolled patients who met the above selection criteria, did not violate the above exclusion criteria, and were deemed eligible to participate in this clinical trial.

[0303] Each treatment cycle consisted of 21 days, with the first administration of the investigational drug designated as day 1 of cycle 1. Day 1 of each subsequent cycle was designated as [21 × (number of cycles - 1) + 1] days. Administration of compound A, nivolumab, docetaxel, and ramucirumab was initiated according to the above-described dosage and administration guidelines, and continued according to the administration criteria, dose reduction criteria, and dose reduction levels for compound A, nivolumab, docetaxel, and ramucirumab. The treatment period ended when the evaluation of discontinuation of compound A, nivolumab, docetaxel, and ramucirumab was completed. Of all subjects who received the investigational drug, those who discontinued or terminated administration of compound A, nivolumab, docetaxel, and ramucirumab underwent an evaluation of discontinuation and proceeded to the post-observation period. Follow-up surveys were conducted after the completion of the post-observation period. [Dosage criteria for compound A and nivolumab] At the start of each administration, subjects must meet all of the prescribed administration criteria, which are determined by considering the administration criteria from previous clinical trials for compound A and nivolumab. If any of these criteria are not met, the scheduled administration of compound A and nivolumab will be discontinued. However, even if any of the criteria are not met, administration of compound A and nivolumab may be continued only if there is no worsening of clinical symptoms judged to be due to disease progression, a clinical benefit from continued administration is expected, and it is determined that it is safe to continue administration of compound A and nivolumab considering the subject's baseline and the effects of concomitant medications. [Criteria for discontinuing administration of compound A] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined by considering the discontinuation criteria from clinical trials conducted to date with respect to compound A, will have their administration of compound A discontinued. [Criteria for discontinuing Nivolumab administration] During the treatment period, subjects who meet any of the predetermined discontinuation criteria, determined based on the discontinuation criteria from previous clinical trials of Nivolumab, will have Nivolumab discontinued. [Dosage criteria for docetaxel and ramucirumab] The drug was administered according to the latest package insert. [Dose reduction and criteria for docetaxel and ramucirumab] The dosage reduction will be carried out in accordance with the latest package insert. [Discontinuation Criteria for Docetaxel and Ramucirumab] Discontinue administration in accordance with the most recent package insert. [Efficacy Evaluation Criteria] (Image diagnosis) CT / magnetic resonance imaging (MRI) scans of the chest, abdomen, and pelvis were performed. In addition, during the screening period (within 28 days prior to administration of the investigational drug), if brain metastasis was suspected based on clinical symptoms, CT / MRI scans of the head, fluorodeoxyglucose-positron emission tomography (FDG-PET) (or bone scintigraphy) were performed to confirm the presence or absence of brain or bone metastasis.

[0304] The principal investigator or co-investigator measured the tumor diameter of the target lesion and determined the antitumor effect in accordance with the RECIST Guideline 1.1. Baseline evaluation was performed using the most recent imaging examination within 28 days prior to administration of the investigational drug, confirming the presence of at least one measurable lesion as defined in the RECIST Guideline 1.1. Imaging during the treatment period was performed at 6-week intervals (±7 days) from day 1 of cycle 1 to week 54, and thereafter at 12-week intervals (±7 days), and tumor diameter was measured.

[0305] The overall effect and best overall effect were defined as the image diagnostic results evaluated based on RECIST guideline version 1.1. (Evaluation criteria) (1) Objective response rate (ORR), (2) Disease control rate (DCR), (3) Overall survival (OS), (4) Progression-free survival (PFS), (5) Duration of response (DOR), (6) Time to response (TTR), (7) Best overall response (BOR), (8) Percentage change in the sum of tumor diameters of target lesions, (9) Maximum percentage change in the sum of tumor diameters of target lesions, (10) Changes in tumor markers (1) Performance The response rate indicates the percentage of subjects whose best overall response was determined to be a complete response (CR) or partial response (PR). (2) Disease control rate The disease control rate represents the percentage of subjects whose best overall response was determined to be CR, PR, or SD. (3) Overall survival period Overall survival time is calculated using the following formula. Overall survival (days) = "Date of death from any cause" - "Date of commencement of investigational drug administration" + 1 For subjects who become untrackable or who have not died by the data cutoff date, the last date of survival confirmation will be considered the termination date. (4) Progression-free survival Progression-free survival is calculated using the following formula. Progression-free survival (days) = "The earlier of the day on which overall efficacy was determined to be PD, or the day of death due to any cause" - "Start date of investigational drug administration" + 1 For subjects whose overall response has not been determined to be PD and who have not died, the censorship date will be the date of the last evaluable imaging diagnosis performed. For subjects whose evaluable imaging diagnosis has not been performed and who have not died, the censorship date will be the date the investigational drug administration started. For subjects who received subsequent treatment for cancer before their overall response was determined to be PD or before they died, the censorship date will be the date of the last evaluable imaging diagnosis performed before the start of subsequent treatment for cancer. (5) Duration of response The duration of effectiveness is calculated using the following formula. Duration of response (days) = "The earlier of the date on which the overall response was first determined to be PD after the confirmation of response, or the date of death from any cause" - "The date on which the first confirmed CR or PR was determined" + 1 The subjects to be evaluated are those who demonstrated a confirmed complete response (CR) or partial response (PR) during the clinical trial. (6) Time to achieve a response The time required to achieve a response is calculated using the following formula. Time to response (days) = "First date of confirmed CR or PR" - "Start date of investigational drug administration" + 1 (7) Percentage change in tumor diameter of target lesion For subjects with target lesions, the percentage change in the sum of tumor diameter of the target lesion was calculated using the following formula. However, the percentage change in the sum of tumor diameter of the target lesion after subsequent treatment was not calculated.

[0306]

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[0307] (8) Maximum change in the sum of tumor diameters of the target lesion The maximum percentage change in the sum of tumor diameter of the target lesion is defined as the percentage change at the point when the sum of tumor diameter of the target lesion is smallest. However, the sum of tumor diameter of the target lesion after the overall effect is determined to be PD or after subsequent treatment is performed is not used in calculating the maximum percentage change.

[0308]

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[0309] (9) Changes in tumor marker rates The percentage change in tumor markers is calculated using the following formula. However, the percentage change in tumor markers after subsequent treatment is not calculated.

[0310]

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[0311] [Safety evaluation criteria] The following items were measured, examined, and investigated by the principal investigator and other relevant personnel at predetermined times. (1) Dose-limiting toxicity (DLT), (2) Adverse events, (3) Clinical laboratory tests (hematological tests, blood biochemical tests, hormone tests, blood coagulation tests, urinalysis, immunological tests), (4) Vital signs (systolic / diastolic blood pressure, pulse rate, body temperature), transcutaneous oxygen saturation (SpO2), body weight, (5) 12-lead electrocardiogram, (6) ECOG Performance Status, (7) Chest X-ray, (8) Ophthalmic examination (visual acuity test, intraocular pressure test, slit-lamp microscopy, and (9) CT scan) [Efficacy Evaluation Results] Eight months after the enrollment of the first subject, there was one case that was judged to have achieved a partial response (PR). [Industrial applicability]

[0312] This invention provides a novel cancer treatment method and is useful.

Claims

[Claim 1] The invention described herein.

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