Cancer treatment with combination of ep4 antagonist and immune checkpoint inhibitor

Abstract

The objective of this invention is to provide an effective cancer treatment method. This invention provides a cancer treatment method that combines standard therapy, an EP4 antagonist, and an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody). This treatment method is useful for cancer treatment.

Description

[Technical Field]

[0001] This invention relates to a cancer treatment method, etc., which combines standard treatment with EP4 antagonists and immune checkpoint inhibitors. [Previous Technology]

[0002] Prostaglandin E2 (PGE2) is known to be a metabolite in the arachidonic acid cascade reaction and has cell protection, uterine contraction, pain threshold reduction, digestive tract peristalsis promotion, stimulation, gastric acid secretion inhibition, blood pressure reduction, and diuretic effects.

[0003] In recent studies, it has been known that there are various subtypes with different roles in the PGE2 receptor. The currently known subtypes are roughly divided into four types, which are respectively called EP1, EP2, EP3 and EP4 (Non-Patent Literature 1).

[0004] Among these subtypes, the EP4 receptor is believed to be involved in inhibiting the production of MCP-1 from macrophages, inhibiting the production of TNF-α, IL-2, and IFN-γ from lymphocytes, and inhibiting anti-inflammatory, vasodilatory, angiogenesis, elastic fiber formation, and MMP-9 expression resulting from enhanced IL-10 production. Furthermore, the EP4 receptor is also believed to be involved in cancer immune control through myeloid-derived suppressor cells, regulatory T cells, and natural killer cells.

[0005] Compounds that bind strongly to and have antagonistic effects with EP4 receptors are considered to be useful for the treatment of diseases caused by activation of EP4 receptors, such as: bone diseases, cancer, systemic granulomas, immune diseases, allergies, atopic diseases, asthma, gingivitis, periodontitis, Alzheimer's disease, Kawasaki disease, burns, multiple organ failure, chronic headaches, pain, vasculitis, venous insufficiency, venous aneurysms, aneurysms, aortic aneurysms, anal fistulas, diabetes insipidus, stress, endometriosis, adenomyosis, neonatal open ductus arteriosus, gallstones, etc. (Non-Patent Literature 2-7).

[0006] Patent Document 1 discloses that the compound represented by general formula (I) has EP4 antagonistic effect and can be used as a cancer treatment drug (see Patent Document 1).

[0007] On the other hand, various immune checkpoint molecules exist within cancer cells and the microenvironment of cancer, which hinder the immune response to cancer. Immune checkpoint inhibitors are novel therapeutic methods that relieve immunosuppression and activate the immune response to cancer. In terms of immune checkpoint inhibitors, ipilimumab (anti-CTLA-4, cytotoxic T lymphocyte-associated protein-4) antibody), nivolumab (anti-PD-1, programmed cell death protein-1) antibody), and pembrolizumab have been recognized both domestically and internationally and are used in cancer treatment.

[0008] Patent Document 2 has disclosed that the combination of the compound shown in general formula (I) with an immune checkpoint inhibitor is useful for cancer treatment (see Patent Document 2).

[0009] Drug therapy is the main treatment for unresectable and incurable advanced / recurrent colorectal cancer, including standard treatments such as the use of fluorinated pyrimidine anti-tumor agents, oxaliplatin, and irinotecan. One of these is the combination of XELOX and bevacizumab (hereinafter referred to as "XELOX + bevacizumab therapy").

[0010] Furthermore, drug therapy is the primary treatment for unresectable pancreatic cancer with distant metastases, including FOLFIRINOX therapy (hereinafter referred to as "FFX therapy"), which is a standard therapy that combines a regimen containing fluorouracil (5-FU) with oxaliplatin and irinotecan; modified FOLFIRINOX therapy (hereinafter referred to as "mFFX therapy"), which aims to reduce the toxicity of FFX therapy by omitting the rapid administration of fluorouracil and reducing the dose of irinotecan; or the combination of gemcitabine and nab-paclitaxel (hereinafter referred to as "GnP therapy").

[0011] Furthermore, drug therapy is the main treatment for stage IV or recurrent non-small cell lung cancer, including the combination therapy of docetaxel and ramucirumab as standard therapy (hereinafter referred to as "DTX+RAM therapy") or docetaxel therapy (hereinafter referred to as "DTX therapy").

[0012] Although such treatments have been recognized as having some effectiveness, there remains an unmet need for further treatments to extend survival time. [Prior Art Documents] [Patent Documents]

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

[0014] [Non-Patent Literature 1] Journal of Lipid Mediators and Cell Signalling, Vol.12, 1995, p.379-391 [Non-Patent Literature 2] Pharmacological Reviews, Vol.65, July 2013, p.1010-1052 [Non-Patent Literature 3] 105th American Association for Cancer Research (AACR) Meeting, Abstract No.: LB-265, Title: ONO-AE3-208 inhibits myeloid derived suppressor cells and glioma growth, Publication Date: April 8, 2014 [Non-Patent Literature 4] FEBS Letters, Vol.364, 1995, p.339-341 [Non-Patent Literature 5] Cancer Science, Vol.105, 2014, p.1142-1151 [Non-Patent Literature 6] Cancer Research, Vol.70, 2010, pp. 1606-1615 [Non-Patent Literature 7] Cancer Research, Vol. 62, 2002, pp. 28-32 [Summary of the Invention]

[0015] [The problem the invention aims to solve]

[0016] The subject of this invention is a novel treatment for cancer (e.g., colorectal cancer, pancreatic cancer, lung cancer). [Means for solving the subject matter]

[0017] In order to solve the aforementioned problems, the inventors, through dedicated research, discovered that combining standard treatment with EP4 receptor antagonists and immune checkpoint inhibitors can be an effective cancer treatment. Furthermore, administering EP4 receptor antagonists, or EP4 receptor antagonists combined with immune checkpoint inhibitors, to patients undergoing preoperative chemoradiotherapy can also be an effective cancer treatment (sometimes the two treatments are combined and referred to as the treatment of this invention).

[0018] Therefore, in a certain state, the following cancer progression inhibitors, recurrence inhibitors and / or therapeutic agents are provided: [1] A cancer progression inhibitor, recurrence inhibitor and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and administered in combination with a standard therapy ((i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced version thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, (vii) European paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy), and an immune checkpoint inhibitor; [2] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and administered in combination with a standard therapy ((i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced version thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, (vii) European paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy), and an EP4 antagonist; [3] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and administered to a cancer patient undergoing preoperative chemoradiotherapy; [4] The agent described above [3] is further administered in combination with an immune checkpoint inhibitor; or [5] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and administered in combination with an EP4 antagonist to a cancer patient undergoing preoperative chemoradiotherapy. [Invention Effects]

[0019] This invention provides a novel cancer treatment method.

Implementation Method

[0021] (1) EP4 antagonist In this invention, the EP4 antagonist is not particularly limited to any compound having EP4 antagonistic activity. In one embodiment, it is a compound of general formula (I) or a salt thereof as described in WO2016 / 111347:

[0022]

[0023] In the formula, R1 represents COOR8, tetrazolium, SO3H, SO2NH2, SO2NHR8-1, CONHSO2R8-1, SO2NHCOR8-1, or hydroxyxamic acid; R8 represents a hydrogen atom, C1-4 alkyl, or benzyl; R8-1 represents a C1-4 alkyl, C1-4 haloalkyl, C3-10 carbon ring, or 3-10 member heterocycle, wherein the C3-10 carbon ring and the 3-10 member heterocycle may each 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 (represented by "-CN"; the same applies below); L1 represents C1-5 alkylene, C2-5 alkenyl, or C2-5 alkyneyl. R2 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)(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, -NR17R17, nitro, nitrile, hydroxyl, aldehyde (representing formyl);The following are the same), or carboxyl groups, where each of the C1-4 alkyl groups may be substituted with a halogen. In R2, (C1-4 alkyl)2 represents two independent C1-4 alkyl groups, which may be the same or different. X1 represents CR6 or a nitrogen atom, R6 represents a hydrogen atom or R2, X2 represents CR7 or a nitrogen atom, R7 represents a hydrogen atom, R2, or -L3-R9, L3 represents a methylene group, an oxygen atom, or an oxidizable sulfur atom, and R9 represents a 4-10 member heterocycle that may be substituted with a substituent selected from the group consisting of halogens, C1-4 alkyl groups, and C1-4 haloalkyl groups. L2 represents -CH2CH2-, -CH=CH-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -CH2S(O)-, -S(O)CH2-, -CH2SO2-, -SO2CH2-, -CH2NH-, -NHCH2-, -NHCO-, -CONH-, -NHSO2-, or -SO2NH-; R3 represents C1-4 alkyl or halogen; R4 represents halogen, C1-4 alkyl, or C1-4 haloalkyl; X3 represents methylene, oxygen atom, oxidizable sulfur atom, or NR10; R10 represents C1-4 alkyl, -C(O)(C1-4 alkyl), -C(O)O(C1-4 alkyl), or -SO2(C1-4 alkyl), each of which can be substituted with halogen; ring represents benzene ring or 5-6 member monocyclic aromatic heterocycle.

[0024] indicates a single or double bond.

[0025] R5 represents (1) halogen, (2) C1-4 alkyl, (3) carboxyl, (4) nitrile, (5)-CONHR11, (6)-C(O)R12, (7)-OR14, (8)-S(O)tR15, (9)-CH2R16, (10)-NR17R17, (11)-NHCOR11, (12) C4-10 carbon ring, or (13) 4-10 member heterocycle, wherein the C4-10 carbon ring or 4-10 member heterocycle may be substituted by 1 to 3 R18s, wherein when the R18s are plural, each R18 may be independent and may be the same or different; R11 represents C1-6 alkyl, C3-6 cycloalkyl, phenyl, or 4-6 member heterocycle, wherein R11 may be substituted by 1 to 3 R13s, wherein when the R13s are plural, each R13 may be independent and may be the same or different. R13 represents a halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, hydroxyl, -NR20R21, benzene, or a 4-6 member heterocycle. R20 and R21 each independently represent a hydrogen atom or a C1-4 alkyl group. R12 represents a C1-6 alkyl, C3-6 cycloalkyl, benzene, or a 4-6 member heterocycle. Each of these C3-6 cycloalkyl, benzene, or 4-6 member heterocycles can be substituted with a halogen, C1-4 alkyl, or C1-4 alkoxy group. R14 represents a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl group. The C1-6 alkyl group can be substituted with one to three R19 groups. When there are plural R19 groups, each R19 group can be independent and may be the same or different. R19 represents a 5-6 member monocyclic aromatic heterocycle that can be substituted with a substituent 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. In R19, (C1-4 alkyl)2 represents two independent C1-4 alkyl groups, which may be the same or different. R15 represents a C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl. R16 represents a hydroxyl or C1-4 alkoxy group. R17 represents a hydrogen atom, a C1-6 alkyl, or a C3-6 cycloalkyl group. R18 represents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, oxy, nitrile, hydroxy, hydroxymethyl, 1-methyl-1-hydroxyethyl, (C1-4 alkyl)SO2-, 4-6 membered heterocycle, (C1-4 alkyl)NH-, or (C1-4 alkyl)2N-. In this R18, (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, when p, q, r, and s each represent an integer greater than 2, R2, R3, R4, and R5 are independent and may be the same or different.

[0026] 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 / 02 0462、WO2002 / 032900、WO2002 / 050031、WO2002 / 050032、WO2002 / 050033、WO2002 / 016311、WO2003 / 086390、WO2003 / 087061、WO2003 / 099857、WO2003 / 016254、WO2005 / 021508、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、WO20 12 / 039972, WO2012 / 043634, WO2012 / 076063, WO2012 / 103071, WO2013 / 004 290. WO2013 / 096496, WO2013 / 096501, WO2013 / 101733, WO2013 / 101598, WO2 014 / 004229, WO2014 / 004230, WO2014 / 086739, WO2014 / 126746, WO2014 / 18 6218、WO2014 / 200075、WO2015 / 094902、WO2015 / 094912、WO2015 / 091475、W O2015 / 113057, WO2015 / 147020, WO2016 / 021742, WO2016 / 088903, WO2017 / 014323、WO2017 / 066633、WO2017 / 085198、WO2018 / 195123、WO2018 / 195123、Compounds described in WO2018 / 210987, 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.

[0027] In this invention, the so-called "C1-4 alkyl" series includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, terbutyl, and isobutyl.

[0028] In this invention, the so-called "C1-3 alkyl" refers to, for example, methyl, ethyl, n-propyl, and isopropyl.

[0029] In this invention, the so-called "C1-5 alkyl" refers to, for example, methylene, ethyl alkyl, propyl alkyl, butyl alkyl, and pentyl alkyl.

[0030] In this invention, the so-called "C2-5 enylene" refers to, for example, vinylene, 1-enylene, 2-enylene, 1-enylbutenyl, 2-enylbutenyl, 3-enylbutenyl, 1-enylpentenyl, 2-enylpentenyl, 3-enylpentenyl, and 4-enylpentenyl.

[0031] In this invention, the so-called "C2-5 enynyl" refers to, for example, enynyl ethynyl, 1-enynyl propynyl, 2-enynyl propynyl, 1-enynyl butynyl, 2-enynyl butynyl, 3-enynyl butynyl, 1-enynyl pentyryne, 2-enynyl pentyryne, 3-enynyl pentyryne, and 4-enynyl pentyryne.

[0032] In this invention, the so-called "halogen" system includes: fluorine, chlorine, bromine, and iodine.

[0033] In this invention, the so-called "C1-4 alkoxy" series includes, for example: methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, third butoxy, isobutoxy, etc.

[0034] In this invention, the so-called "C1-4 alkylthio" group includes, for example: methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, tributylthio, isobutylthio, etc.

[0035] In this invention, the so-called "C2-4 alkenyl" system includes, for example, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 3-butenyl.

[0036] In this invention, the so-called "C2-4 ynyl" group includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0037] In this invention, the term "C1-4 haloalkyl" refers to a C1-4 alkyl group substituted with a halogen, such as 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, 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-Difluoropropyl Fluorobutyl, 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, etc.

[0038] In this invention, the term "oxidizable sulfur atom" refers to sulfur (S), monoxide (S(O)), and monoxide (SO2).

[0039] In this invention, the term "4-10 member heterocycle" refers to a 4-10 member monocyclic or bicyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, such as butane, tetrahydrozirconium, pyrrolidine, pyrrole, imidazole, triazole, tetraazole, pyrazole, pyridine, piperidine, piperazine, pyridine, pyrimidine, pyrazine, acrylonitrile, diacrylonitrile, diacrylonitrile Furan, pyran, thiophene, thiopyran, thiophene, thiophene, thiophene, isothiophene, thiazole, thiazole, isothiazole, furazan, oxazepine, oxadiazepine, thiadiazol, thiadiazol, thiadiazol, thiadiazol, thiadiazol, indole, isoindole, indole Indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, quinolizine, purine, teridine, pteridine, quinoline, quinazolin, quinoline, benzothiazole, benzoimidazole, benzodiazole, benzothiazole Alcohols (benzooxathiole), benzoene, benzofuran, benzothiadiazole, benzotriazole, pyrrolidone, pyrrolidine, imidazolinone, imidazolinone, triazoline, triazolinone, tetrazoline, tetrazoline, pyrazole, dihydropyridine, tetrahydropyridine, dihydropyridine, tetrahydropyridine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridine, tetrahydropyridine Perhydropyran, dihydropyran, tetrahydropyran, perhydropyran, dihydrodipyran, tetrahydrodipyran, perhydrodipyran, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydropyran, tetrahydropyran, dihydropyran, tetrahydropyran, perhydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiophene, tetrahydrothiophene, perhydrothiophene, dihydropyrazole, tetrahydropyrazole (P) (Azolidine), dihydroisothiazol, tetrahydroisothiazol (isothiazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazol, tetrahydroisothiazol (isothiazolidine), dihydrofuran, tetrahydrofuran, dihydroisothiazol, tetrahydroisothiazol (isothiazolidine), dihydroisothiazol, tetrahydroisothiazol, dihydroisothiazol, tetrahydroisothiazol, dihydroisothiazol, tetrahydroisothiazol, perhydroisothiazol) Dihydrothiazide, Tetrahydrothiazide, Perhydrothiazide, Dihydrothiazide, Tetrahydrothiazide (Thiazide), Dihydrothiazide, Tetrahydrothiazide, Dihydrothiazide, Tetrahydrothiazide, Dihydrothiazide, Tetrahydrothiazide, Perhydrothiazide, Dihydrothiazide, Tetrahydrothiazide, Perhydrothiazide, Tetrahydrothiazide, Perhydrothiazide, Tetrahydrotriazolpyridine, Morpholin, Thiomorpholin, Oxythiopyridine (o xathiane), indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,Dihydrophenanthrene, Tetrahydrophenanthrene, Perhydrophenanthrene, Dihydrophenidine, Tetrahydrophenidine, Perhydrophenidine, Dihydroquinoline, Tetrahydroquinoline, Perhydroquinoline, Dihydroquinazoline, Tetrahydroquinazoline, Perhydroquinazoline, Dihydroquinoline, Tetrahydroquinazoline, Perhydroquinazoline, Dihydroquinoline, Tetrahydroquinoline, Perhydroquinoline, Benzo[a]oxosulfuron, Dihydrobenzo[a]oxophenanthrene, Dihydrobenzo[a]oxosulfuron ... Dioxaindane, benzo[a]dioxane, thio[a]ane, dihydrobenzodioxin, dihydrobenzooxathiin, oxane, pyrazolidine, imidazo[a]pyridine, imidazo[a]pyridine, imidazo[a]pyridine, pyrrolo[a]pyridine, pyrrolo[a]pyridine, imidazo[a]pyridine, pyrrolo[a]pyridine, triazol[a]pyridine, and dihydropyridine[a]pyridine ring, etc.

[0040] In this invention, the term "3-10 member heterocycle" means a 3-10 member monocyclic or bicyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen, nitrogen and sulfur atoms, such as aziridine, ethylene oxide, thiirane, and the heterocycles described in the aforementioned "4-10 member heterocycle".

[0041] In this invention, the term "5-10 member aromatic heterocycle" refers to a 5-10 member monocyclic or bicyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, such as pyrrole, imidazole, triazole, tetraazole, pyrazole, furan, thiophene, acetazole, isoacetazole, thiazole, isothiazole, furazolidone, acediazole, thiadiazole, pyridine, pyridine, pyrimidine, pyridoxine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, purine, benzoacetazole, benzothiazole, benzimazole, benzofuran, benzothiadiazole, benzotriazole, quinoline, isoquinoline, terpinen, pteridine, acetidine, quinazolin, quinazolin, and aceline ring, etc.

[0042] In this invention, the so-called "5-6 member monocyclic aromatic heterocycle" includes, for example: pyrrole, imidazole, triazole, tetraazole, pyrazole, pyridine, pyridine, pyrimidine, pyridine, furan, thiophene, succinazole, isosuccinazole, thiazole, isothiazole, furazolidone, succinazole, and thiadiazole ring, etc.

[0043] In this invention, the term "C4-10 carbon ring" refers to a monocyclic or bicyclic carbon ring of C4 to 10, such as cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazine, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene, and perhydronaphthalene ring, etc.

[0044] In this invention, the term "C3-10 carbon ring" means a single or bicyclic carbon ring of C3 to 10, such as cyclopropane and the carbon ring described in the aforementioned "C4-10 carbon ring".

[0045] In this invention, the so-called "C1-6 alkyl" series includes, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, tributyl, 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, etc.

[0046] In this invention, the so-called "C3-6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0047] In this invention, the term "4-6 member heterocycle" means a 4-6 member monocyclic heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms, such as oxobutane, tetrahydrozazolinium, pyrrolidine, piperidine, pyridine, pyran, thiopyran, pyridine, pyridoxine, thiazolinium, pyrrole, pyrrole, imidazole, triazole, tetraazole, pyrazole, pyridine, pyrimidine, pyridine, furan, thiophene, pyrazole, isopyrazole, thiazole, isothiazole, furazolidone, pyridoxine, and thiadiazole ring, etc.

[0048] In this invention, R1 is preferably COOR8.

[0049] In this invention, R8 is preferably a hydrogen atom or a C1-4 alkyl group, and more preferably a hydrogen atom.

[0050] In this invention, R8-1 is preferably a C1-4 alkyl, benzene or pyridine, wherein the benzene or 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 group.

[0051] In this invention, L1 is preferably C1-5 alkyl or C2-5 alkenyl, more preferably C1-5 alkyl, and especially preferably propyl.

[0052] In this invention, R2 is preferably fluorine.

[0053] In this invention, X1 is preferably CR6.

[0054] In this invention, R6 is preferably a hydrogen atom or fluorine, and more preferably a hydrogen atom.

[0055] In this invention, X2 is preferably CR7.

[0056] In this invention, R7 is preferably fluorine, nitrile, -CH2R9, or -OR9, and more preferably nitrile.

[0057] In this invention, R9 is preferably a 4-10 member heterocycle that can be substituted with methyl or trifluoromethyl, and the 4-10 member heterocycle is preferably a 5-10 member aromatic heterocycle, more preferably a 5-10 member nitrogen-containing aromatic heterocycle (e.g., pyrazole, imidazole, triazole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridine, imidazolepyridine, imidazolepyrimidine, imidazolepyridine, pyrrolopyrimidine, etc.).

[0058] In this invention, L2 is preferably -CH=CH-, -NHCO-, -CONH-, -NHSO2-, or -SO2NH-, more preferably -NHCO- or -CONH-, and especially preferably -NHCO-.

[0059] In this invention, R3 is preferably fluorine.

[0060] In this invention, R4 is preferably methyl, ethyl, or trifluoromethyl, and more preferably methyl.

[0061] In this invention, X3 is preferably a methylene group or an oxygen atom, and more preferably an oxygen atom.

[0062] In this invention, R10 is preferably methyl, ethyl, methyl carbonyl, ethyl carbonyl, methyl sulfonyl, ethyl sulfonyl, or third butoxy carbonyl.

[0063] In this invention, the ring is preferably a benzene, thiophene, or pyrazole ring, and more preferably a benzene ring.

[0064] In this invention, R5 is preferably -CONHR11, fluorine, methoxy, benzene ring, or a 4-10 member heterocycle, wherein the 4-10 member heterocycle is preferably tetrahydropyridine, pyrrolidine, piperidine, acezoline, diazole, triazole, thiophene, furan, pyrazole, thiazole, acezoline, imidazole, pyridine, pyridine, pyrazolidine, pyrrolopyrimidine, pyrazololopyrimidine, pyrrolopyrimidine, or dihydropyridinidine acezoline ring.

[0065] In this invention, R11 is preferably a C1-6 alkyl, C3-6 cycloalkyl, pyran, pyrrolidine, piperidine, pyrazole, thiazole, acetazole, isoacetazole, pyridine, pyridine, or pyrimidine ring, and more preferably a C1-6 alkyl.

[0066] In this invention, R13 is preferably a halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, hydroxyl, -NR20R21, benzene, oxetane, pyridine, pyrazole, or acetazole ring, and more preferably fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, tributyl, isobutyl, cyclopentyl, cyclobutyl, oxetane, hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, benzene, pyridine, pyrazole, or acetazole ring.

[0067] In this invention, R20 is preferably a hydrogen atom or a methyl group.

[0068] In this invention, R21 is preferably a hydrogen atom or a methyl group.

[0069] In this invention, R12 is preferably a C1-3 alkyl, C3-6 cycloalkyl, benzene, or a 4-6 member heterocycle. The 4-6 member heterocycle is preferably an oxacyclobutane, tetrahydroxamic acid, pyrrolidine, piperidine, pyridine, pyran, thiopyran, pyridine, pyridoxine, thiamethoxam, thiamethoxam, pyrrole, imidazole, triazole, tetraazole, pyrazole, pyridine, pyridine, pyridine, pyrimidine, pyridine, furan, thiophene, pyrazole, isopyrazole, thiazole, isothiazole, furazolidone, pyridoxine, or a thiadiazole ring. The 4-6 member heterocycle may be substituted with a C1-4 alkoxy group.

[0070] In this invention, R14 is preferably a hydrogen atom, methyl, ethyl, benzene, or benzyl.

[0071] In this invention, R19 is preferably methoxy, -CONHCH3, -CON(CH3)2, acetazole, thiazole, pyrazole, or pyridine ring.

[0072] In this invention, R15 is preferably methyl, cyclopropyl, or benzene.

[0073] In this invention, R16 is preferably a hydroxyl group.

[0074] In this invention, R17 is preferably methyl, ethyl, or cyclopropyl, and more preferably methyl.

[0075] In this invention, R18 is preferably fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, tributyl, isobutyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, oxy, nitrile, hydroxy, hydroxymethyl, 1-methyl-1-hydroxyethyl, methanesulfonyl, pyridine, or dimethylamino.

[0076] In this invention, m is preferably an integer from 1 to 2, and more preferably 1.

[0077] In this invention, n is preferably an integer from 0 to 1, and more preferably 1.

[0078] In this invention, p is preferably 0.

[0079] In this invention, q is preferably 0.

[0080] In this invention, r is preferably an integer from 0 to 4, and more preferably an integer from 0 to 2.

[0081] In this invention, s is preferably an integer from 0 to 2, and more preferably 1 or 2.

[0082] In this invention, t is preferably an integer from 0 to 2.

[0083] In this invention, X3a is preferably an oxygen atom.

[0084] In this invention, na is preferably an integer from 0 to 1, and more preferably 1.

[0085] In this invention, qa is preferably 0.

[0086] In this invention, ra is preferably an integer from 0 to 2.

[0087] In this invention, general formula (I) is preferably a combination of the preferred definitions of ring, R1, R2, R3, R4, R5, R6, R7, R8, R8-1, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, L1, L2, L3, X1, X2, X3, m, n, p, q, r, s, and t.

[0088] In this invention, the compound represented by general formula (I) is preferably the compound represented by general formula (Ia) or a salt thereof:

[0089]

[0090] 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, and other symbols have the same meaning as above), preferably a compound or salt of the general formula (I-1):

[0091]

[0092] 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, X3a represents a methylene or oxygen atom, and other symbols have the same meaning as above.

[0093] In this invention, with regard to other forms of the compound represented by general formula (I), it is more preferably the compound represented by general formula (Ib) or a salt thereof:

[0094]

[0095] 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, and other symbols have the same meaning as above, and are more preferably compounds or salts of the general formula (Ic):

[0096]

[0097] 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, and other symbols have the same meaning as above, but are more preferably compounds or salts of the general formula (Id):

[0098]

[0099] 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, and other symbols have the same meaning as above, and are more preferably compounds or salts of the general formula (Ie):

[0100]

[0101] 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, and other symbols have the same meaning as above, preferably the compound or its salt shown in general formula (I-2):

[0102]

[0103] In the formula, R2a represents a halogen, R6a 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, preferably the compound or its salt shown in general formula (I-4):

[0104]

[0105] In the formula, R2a represents a halogen, R6a 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.

[0106] In this invention, with respect to another aspect of the compound represented by general formula (I), it is more preferably the compound represented by general formula (If) or a salt thereof:

[0107]

[0108] In the formula, R5a is a C4-10 carbon ring or a 4-10 member heterocycle that can be substituted by 1 to 3 R18s. When R18 is a complex number, each R18 can be independent and may be the same 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 other symbols have the same meaning as above. More preferably, it is a compound or its salt represented by the general formula (Ig):

[0109]

[0110] In the formula, R5a is a C4-10 carbon ring or a 4-10 member heterocycle that can be substituted by 1 to 3 R18s. When R18 is a complex number, each R18 can be independent and may be the same 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 other symbols have the same meaning as above. More preferably, it is a compound or its salt represented by the general formula (Ih):

[0111]

[0112] In the formula, R5a is a C4-10 carbon ring or a 4-10 member heterocycle that can be substituted by 1 to 3 R18s. When R18 is a complex number, each R18 can be independent and may be the same 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 other symbols have the same meaning as above. More preferably, it is a compound or its salt shown in general formula (Ii):

[0113]

[0114] In the formula, R5a is a C4-10 carbon ring or a 4-10 member heterocycle that can be substituted by 1 to 3 R18s. When R18 is a complex number, each R18 can be independent and may be the same 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 other symbols have the same meaning as above. Preferably, it is a compound or its salt represented by the general formula (I-3).

[0115]

[0116] In the formula, R2a represents a halogen, R6a represents a hydrogen atom or a halogen, R5a is a C4-10 carbon ring or a 4-10 member heterocycle that can be substituted by 1 to 3 R18s. When the R18 is complex, each R18 is independent and can be the same or different. 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. Preferably, it is a compound or its salt represented by the general formula (I-5).

[0117]

[0118] In the formula, R2a represents a halogen, R6a represents a hydrogen atom or a halogen, R5a is a C4-10 carbon ring or a 4-10 member heterocycle that can be substituted by 1 to 3 R18s. When R18 is a complex number, each R18 is independent and can be the same or different. 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.

[0119] In this invention, the general formulas selected from the group of general formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), and (I-1) are each independent. Preferably, L1 is endopeptide, and L2 is -CH=CH-, -NHCO-, -CONH-, -NHSO2-, or -SO2NH-. More preferably, L1 is endopeptide, and L2 is -NHCO- or -CONH-. Even more preferably, L1 is endopeptide, and L2 is -NHCO-.

[0120] In this invention, the general formulas selected from the above general formulas (I-2), (I-3), (I-4) and (I-5) are independent, and it is preferred that L1 is propyltriethionyl.

[0121] In this invention, the EP4 antagonist is preferably the compound or a salt thereof described in the embodiment of WO2016 / 111347. More preferably, it is the following compound or a salt thereof: (1) 4-[4-cyano-2-({[(2'R,4S)-6-(methylaminomethoxy)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (2) 4-{4-cyano-2-[({(2'R,4S)-6-[(cyclopropylmethyl)aminomethoxy]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid, (3) 4-{4-cyano-2-[({(2'R,4S)-6-[(2-methoxyethyl)aminomethoxy]-2,3-dihydrospiro[azobenzene-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid, (4) 4-{4-cyano-2-[({(2'R,4S)-6-[(2-methyl-2-propyl)aminomethoxy]-2,3-dihydrospiro[azobenzene-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid, (5) 4-[4-cyano-2-({[(2'R,4S)-6-{[(2S)-1-methoxy-2-propyl]aminomethoxy}-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (6) 4-{4-cyano-2-[({(2'R,4S)-6-[(1-methyl-1H-pyrazol-3-yl)aminomethoxy]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid, (7) 4-[4-cyano-2-({[(2'R,4S)-6-(cyclopropylaminomethyl)-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (8) 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid, (9) 4-[4-cyano-2-({[(2'R,4S)-6-(cyclopentylaminomethyl)-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (10) 4-{2-[({(2'R,4S)-6-[(2S)-2-butylaminomethyl]-2,3-dihydrospiro[aeno-4,1'-cyclopropane]-2'-yl}carbonyl)amino]-4-cyanophenyl}butyric acid, (11) 4-{4-cyano-2-[({(2'R,4S)-6-[(trans-4-hydroxycyclohexyl)aminomethyl]-2,3-dihydrospiro[aeno-4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid, (12) 4-{4-cyano-2-[({(2'R,](13) 4-[4-cyano-2-({[(2'R,4S)-6-(2-pyridylaminomethoxy)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl]butyric acid, (14) 4-[4-cyano-2-({[(2'R,4S)-6-(3-pyridylaminomethoxy)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (15) 4-[4-cyano-2-({[(2'R,4S)-6-(cyclobutylaminomethyl)-2,3-dihydrospiro[oen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (16) 4-[4-cyano-2-({[(2'R,4S)-6-{[1-(2-methyl-2-propyl)-1H-pyrazol-4-yl]aminomethyl}-2,3-dihydrospiro[oen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (17) 4-[4-cyano-2-({[(2'R,4S)-6-(tetrahydro-2H-pyran-4-ylaminomethyl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (18) 4-[4-cyano-2-({[(2'R,4S)-6-(propylaminomethyl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (19) 4-{4-cyano-2-[({(2'R,4S)-6-[(2-ethoxyethyl)aminomethoxy]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl]butyric acid, or (20) 4-[4-cyano-2-({[(2'R,4S)-6-(ethylaminomethoxy)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (21) 4-[4-cyano-2-({[(1R,2R)-6'-(methylaminomethoxy)-2',3'-dihydrospiro[1,1'-indene]-2-yl]carbonyl}amino)phenyl]butyric acid, (22) 4-{4-cyano-2-[({(1R,2R)-6'-[(2-methoxyethyl)aminomethyl]-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl}carbonyl)amino]phenyl}butyric acid, (23) 4-{4-cyano-2-[({(1R,2R)-6'-[(1-methyl-1H-pyrazol-4-yl)aminomethyl]-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl}carbonyl)amino]phenyl}butyric acid, (24) 4-[4-cyano-2-({[(2'R,(25) 4-{4-cyano-2-[({(2'R,4S)-7-fluoro-6-[(2-methoxyethyl)aminomethoxy]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (26) 4-[4-cyano-2-({[(2'R,4S)-7-fluoro-6-(isopropylaminomethoxy)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (27) 4-[4-cyano-2-({[(2'R,4S)-7-(methylaminomethoxy)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (28) 4-{4-cyano-2-[({(2'R,4S)-7-[(2-methoxyethyl)aminomethoxy]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl]butyric acid, (29) 4-[4-cyano-2-({[(2'R,4S)-7-methoxy-6-(methylaminomethoxy)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (30) 4-{4-cyano-2-[({(2'R,4S)-7-methoxy-6-[(2-methoxyethyl)aminomethoxy]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid, (31) 4-[4-cyano-2-({[(2'R,3S)-5-(methylaminomethoxy)-2H-spiro[1-benzofuran-3,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (32) 4-{4-cyano-2-[({(2'R,3S)-5-[(2-methoxyethyl)aminomethyl]-2H-spiro[1-benzofuran-3,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid, (33) 4-[4-cyano-2-({[(1S,2R)-6'-[(2-methoxyethyl)aminomethyl]-3',3'-dimethyl-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl]carbonyl}amino)phenyl]butyric acid, or (34) 4-[4-cyano-2-({[(1S,2R)-3',3'-dimethyl-6'-(methylaminomethyl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl]carbonyl}amino)phenyl]butyric acid.

[0122] Or, in this invention, the EP4 antagonist is preferably one of the following compounds or a salt thereof: (1) 4-[4-cyano-2-({[(2'R,4S)-6-(5-methyl-1,3,4-diazol-2-yl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (2) 4-[4-cyano-2-({[(2'R,4S)-6-(5-cyclopropyl-1,3,4-diazol-2-yl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (3) 4-[4-cyano-2-({[(2'R,4S)-6-(3-methyl-1,2,4-diazol-5-yl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (4) 4-[4-cyano-2-({[(2'R,4S)-6-(3-pyridyl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (5) 4-[4-cyano-2-({[(2'R,4S)-6-(1H-pyrazol-1-yl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (6) 4-[4-cyano-2-({[(2'R,4S)-6-(1H-pyrazole-5-yl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (7) 4-[4-cyano-2-({[(2'R,4S)-6-(4-pyrrolidyl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (8) 4-[4-cyano-2-({[(2'R,4S)-6-(2-oxy-1-pyrrolidyl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (9) 4-[4-cyano-2-({[(2'R,4S)-6-(6-methoxy-3-pyridyl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino]phenyl]butyric acid, (10) 4-{4-cyano-2-[({(2'R,4S)-6-[6-(1H-pyrazol-1-yl)-3-pyridyl]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl]butyric acid, (11) 4-{4-cyano-2-[({(2'R,4S)-6-[6-(dimethylamino)-3-pyridyl]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid, (12) 4-[4-cyano-2-({[(2'R,4S)-6-(6-methyl-3-pyridyl) ...3) 4-[4-cyano-2-({[2'R,4S)-6-(6-methyl-3-pyridyl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid,1'-Cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (13)4-{4-cyano-2-[({(2'R,4S)-6-[6-(methylamino)-3-pyridyl]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl]butyric acid, (14)4-[4-cyano-2-({[(2'R,4S)-6-(2-pyridyl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (15) 4-[4-cyano-2-({[(2'R,4S)-6-(1,3-thiazo-2-yl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (16) 4-[4-cyano-2-({[(2'R,4S)-6-(1,3-thiazo-2-yl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (17) 4-[4-cyano-2-({[(2'R,4S)-6-(1-methyl-1H-1,2,3-triazol-4-yl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (18) 4-[4-cyano-2-({[(2'R,4S)-6-(3-tertyl)-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, (19) 4-[4-cyano-2-({[(2'R,3S)-5-(3-pyridyl)-2H-spiro[1-benzofuran-3,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid, or (20) 4-[4-cyano-2-({[(1S,2R)-3',3'-dimethyl-6'-(3-pyridyl)-2',3'-dihydrospiro[cyclopropane-1,1'-indene]-2-yl]carbonyl}amino)phenyl]butyric acid.

[0123] The preferred compound is 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid (hereinafter referred to as compound A) or a salt thereof, as shown in the following structural formula.

[0124]

[0125] In addition, 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethyl]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid is sometimes named 4-[4-cyano-2-({[(2'R,4S)-6-(isopropylaminomethyl)-2,3-dihydrospiro[oen-4,1'-cyclopropane]-2'-yl]carbonyl}amino)phenyl]butyric acid. Compound A can be prepared according to known methods, such as those described in Examples 2-13 of WO2016 / 111347.

[0126] Preferably, 4-{4-cyano-2-[({(2'R,4S)-6-[(2-methoxyethyl)aminomethoxy]-2,3-dihydrospiro[4,1'-cyclopropane]-2'-yl}carbonyl)amino]phenyl}butyric acid (hereinafter referred to as compound B) or a salt thereof, as shown in the following structural formula.

[0127]

[0128] Compound B can be manufactured according to a known method, such as the method described in Example 2-2 of WO2016 / 111347.

[0129] In this invention, unless otherwise specified, all isomers are included. For example, alkyl, alkoxy, and alkylene compounds include both straight-chain and branched types. Furthermore, all isomers of double bonds, rings, fused rings (E, Z, cis, trans), isomers resulting from the presence of asymmetric carbons (R, S, α, β, mirror-image isomers, non-mirror-image isomers), optically active compounds with optical rotation (D, L, d, l), polar compounds separated by chromatography (highly polar, lowly polar), equilibrium compounds, rotational isomers, mixtures of these in any proportion, and racemic mixtures are all included in this invention. Furthermore, this invention also includes all isomers resulting from tautomerism.

[0130] In this invention, unless otherwise specified, all symbols are those that are obvious to those skilled in the art.

[0131]

[0132] indicates that the bonds are located on the back side of the paper (i.e., α-arrangement).

[0133]

[0134] indicates that the bonds are located on the front side of the paper (i.e., β-arrangement).

[0135]

[0136] represents any mixture of α-arrangements and β-arrangements.

[0137] [Salt] The compound represented by general formula (I) can be converted into a salt by conventional methods. The salt is preferably a pharmaceutically acceptable salt. The salt is preferably water-soluble. Pharmaceutically acceptable salts include, for example, acid salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts. Acid salts include, for example, inorganic acid salts such as hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate, and nitrate; or organic acid salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, 2-hydroxyethanesulfonate (isethionic acid), glucuronide, or gluconate. Alkali metal salts include, for example, salts of potassium and sodium. Alkaline earth metal salts include, for example, salts of calcium and magnesium. Ammonium salts include, for example, salts of tetramethylammonium. Examples of amine salts include salts of triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, ethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, and N-methyl-D-reduced glucosamine. Furthermore, the compounds used in this invention can be prepared as N-oxides by any method. An N-oxide indicates that the nitrogen atom of the compound represented by general formula (I) is oxidized. The compound represented by general formula (I) and its salts can exist in a solvate form or as solvates with pharmaceutically acceptable solvents such as water and ethanol. The solvate is preferably a hydrate. The compound represented by general formula (I) can form a cocrystal with a suitable cocrystal forming agent. The cocrystal is preferably a pharmaceutically acceptable cocrystal formed with a pharmaceutically acceptable cocrystal forming agent. A cocrystal is typically defined as a crystal formed by the interaction of two or more different molecules through ionic bonds. Furthermore, the eutectic can be a complex of a neutral molecule and a salt. The eutectic can be prepared by known methods, for example, by melt crystallization, by recrystallization from a solvent, or by physically crushing the components together. Suitable eutectic forming agents include those described in WO2006 / 007448. In this invention, all descriptions relating to compounds of formula (I) include compounds of formula (I), their salts, their N-oxides, their solvates (e.g., hydrates), or eutectic forms thereof, or N-oxides of salts of compounds of formula (I), their solvates (e.g., hydrates), or eutectic forms thereof. That is, in this invention, it includes compounds of formula (I) or their salts, solvates (e.g., hydrates) of compounds of formula (I), their N-oxides, or eutectic forms thereof, or N-oxides of salts of compounds of formula (I), their solvates (e.g., hydrates), or eutectic forms thereof.

[0138] [Prodrug] Furthermore, the compound represented by general formula (I) can be administered as a prodrug. The so-called prodrug of the compound represented by general formula (I) refers to a compound that can be converted into the compound represented by general formula (I) through reactions such as enzymes or gastric acid in the body. Examples of compounds represented by general formula (I) include: when a compound represented by general formula (I) has an amino group, the amino group is a compound that has undergone acetylation, alkylation, or phosphorylation (e.g., compounds represented by general formula (I) whose amino group has undergone eicosylation, propylaminoation, pentylaminocarbonylation, (5-methyl-2-oxy-1,3-dioxacyclopenten-4-yl)methoxycarbonylation, tetrahydrofuranization, pyrrolidine methylation, trimethylacetoxymethylation, acetoxymethylation, or tributylation, etc.); when a compound represented by general formula (I) has a hydroxyl group, the hydroxyl group is a compound that has undergone acetylation, alkylation, phosphorylation, or borateation (e.g., compounds represented by general formula (I) whose amino group has undergone acetylation, alkylation, phosphorylation, or borateation). Compounds with hydroxyl groups that have undergone acetylation, palmitylation, propionylation, trimethylacetylation, succinylation, transbutene diacetylation, propylamine acetylation, or dimethylaminomethylcarbonylation, etc.; when the compound shown in general formula (I) has a carboxyl group, that carboxyl group is a compound that has undergone esterification or amination (for example, compounds with carboxyl groups of the compound shown in general formula (I) that have undergone ethyl esterification, phenyl esterification, carboxylic acid methyl esterification, dimethylamino methyl esterification, trimethylacetylated oxymethyl esterification, 1-{(ethoxycarbonyl)oxy} ethyl esterification, phthaloyl esterification, (5-methyl-2-oxy-1,3-dioxacyclopenten-4-yl) methyl esterification, 1-{[(cyclohexyloxy)carbonyl]oxy} ethyl esterification, or methyl amination, etc.). These compounds can be manufactured by methods known to them. Furthermore, the prodrug of the compound represented by general formula (I) can be either a hydrate or a non-hydrate. Also, the prodrug of the compound represented by general formula (I), as described on pages 163-198 of Volume 7, "Molecular Design," of "Pharmaceutical Development," published by Hirokawa Shoten in 1990, can be transformed into the compound represented by general formula (I) under physiological conditions. Moreover, the atoms constituting the compound represented by general formula (I) can be substituted by their isotopes (e.g., 2H, 3H, 13C, 14C, 15N, 16N, 17O, 18O, 18F, 35S, 36Cl, 77Br, 125I, etc.).

[0139] [Method for manufacturing the compound used in this invention] The EP4 antagonist of this invention can be manufactured according to conventional methods, for example, the compound represented by general formula (I) can be manufactured according to the method described in WO2016 / 111347.

[0140] [Formulation and Administration Method] The EP4 antagonist of the present invention is typically formulated together with pharmaceutically acceptable carriers such as various additives or solvents and then administered orally or non-orally to the system or local area. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient in pharmaceutical formulations. A pharmaceutically acceptable carrier is preferably one that does not exhibit pharmacological effects at the dosage of its formulation, is harmless, and does not interfere with the active ingredient. Furthermore, pharmaceutically acceptable carriers may also be used for purposes such as improving the usefulness of the active ingredient and the formulation, facilitating formulation, seeking quality stability, or enhancing usability. Specifically, depending on the appropriate purpose, substances such as those described in the "Pharmaceutical Additives Encyclopedia 2016" (compiled by the Japan Pharmaceutical Additives Association), published by Pharmacy Daily in 2016, may be selected.

[0141] The dosage forms used for administration include, for example: oral administration preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semi-solid preparations, mouthwashes, etc.), injectable preparations (e.g., injections, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations (e.g., inhalers, etc.), ophthalmic preparations (e.g., eye drops, ointments, etc.), otological preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semi-solid preparations, enemas, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and skin preparations (e.g., topical solid preparations, topical liquid preparations, sprays, ointments, creams, gels, patches, etc.).

[0142] The dosage of the EP4 antagonist used in this invention varies depending on age, weight, symptoms, treatment effect, administration method, and treatment time. Generally, for adults, the dosage ranges from 1 ng to 1000 mg per dose, administered orally once or several times a day; or for adults, the dosage ranges from 0.1 ng to 100 mg per dose, administered orally once or several times a day; or for adults, administered continuously intravenously over a period of 1 hour to 24 hours a day. Of course, as mentioned above, since the dosage varies with various conditions, there are cases where a smaller dosage than the above-mentioned dosage is sufficient, and there are cases where a dosage exceeding the above-mentioned range is required.

[0143] For a particular state sample, when using compound A, the dosage of one state sample is approximately 1 to 100 mg orally 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, or 90 mg per dose. 95mg or 100mg orally once or three times a day, preferably 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, or 50mg orally once or three times a day, preferably 5mg, 10mg, 20mg, or 40mg orally once a day, and even more preferably 20mg or 40mg orally once a day.

[0144] (2) Immune checkpoint inhibitory substance In this invention, immune checkpoint molecule means a molecule that exerts an immunosuppressive function by transmitting inhibitory co-message. 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), and IDO1 (indoleamine 2,3-dioxygenase). 2,3-dioxygenase), arginase I, TIGIT (T cell immunoglobulin and ITIM domain), CD115, etc. (see Nature Reviews Cancer, Vol.12, 2012, p.252-264, Cancer Cell, Vol.27, 2015, p.450-461), there are no particular restrictions as long as the molecules have the same function as defined.

[0145] The immune checkpoint inhibitor of the present invention is a substance that inhibits the function of immune checkpoint molecules. There are no particular limitations as long as the immune checkpoint inhibitor is a substance that can inhibit the function (message) of immune checkpoint molecules.

[0146] Immune checkpoint inhibitors such as: anti-PD-1 antibodies (e.g., nivolumab, cimiplimab (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, BI 754091, LZM009, CMAB819, Sym021, geptanolimab (GB226), SSI-361, JY034, HX008, ISU106, budigalimab (ABBV181), prolgolimab (BCD-100), sasanlimab (PF-06801591), CX-188, cetrelimab (JNJ-63723283), and zimberelimab (AB122), etc.; anti-PD-L1 antibodies (e.g., atezolizumab (RG7446 / M)). PDL3280A), avelumab (PF-06834635 / MSB0010718C), durvalumab (MEDI4736), BMS-936559, STI-1014, envafolimab (KN035), lodapolimab (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-010), zalifrelimab (AGEN1884), and tremelimumab, etc.); 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), anti-KIR antibodies (e.g., lirilumab), etc. Furthermore, antibodies containing the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of the aforementioned known antibodies are also a form of immune checkpoint inhibitory substances. For example, another form of anti-PD-1 antibody could be an antibody containing the heavy and light chain complementarity-determining regions (CDRs) or variable regions (VRs) of nivolumab.

[0147] In this 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. The anti-PD-1 antibody is preferably nivolumab, cimiprimab, pembrolizumab, spartalimab, tislelizumab, toripalimab, sintilimab, and camrelizumab; the anti-PD-L1 antibody is preferably atezolizumab, avelumab, durvalumab, and BMS-936559; and the anti-CTLA-4 antibody is preferably ipralimab and trimelimab. Furthermore, the anti-PD-1 antibody is more preferably nivolumab, cimiprimab, and pembrolizumab, and even more preferably nivolumab. The immune checkpoint inhibitor of the present invention is preferably an anti-PD-1 antibody, and more preferably nivolumab.

[0148] In this invention, the immune checkpoint inhibitor can be manufactured by conventional 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 ipalimumab can be manufactured according to the method described in WO2001 / 014424.

[0149] In this invention, any one or any plurality of these immune checkpoint inhibitors may be used in combination with the administration of an EP4 antagonist and standard therapy.

[0150] The dosage of the immune checkpoint inhibitor used in the combination of the present invention varies with age, weight, symptoms, treatment effect, administration method, treatment time, etc., but can be adjusted in a way that achieves the most appropriate desired effect.

[0151] For example, the immune checkpoint inhibitor, which is the active ingredient, can be administered intravenously at a dose of about 1 to 10 mg / kg (body weight) or about 200 to 1200 mg at intervals of 2 to 4 weeks, over a period of about 30 minutes to about 60 minutes or more (e.g., intravenous drip). Therefore, the dosage per dose, converted from body weight, can be, for example, 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, the dosage per dose can be, for example, 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 throwing interval can be, for example, 2 weeks, 3 weeks or 4 weeks, and the throwing time per session can be, for example, about 30 minutes, about 60 minutes or more.

[0152] When the immune checkpoint inhibitor is nivolumab, which is an anti-PD-1 antibody, it shall be administered as follows: Specifically, for patients with malignant melanoma, nivolumab shall be administered intravenously at a dose of 3 mg / kg (body weight) every 2 weeks, or at a dose of 2 mg / kg (body weight) every 3 weeks, or at a dose of 240 mg every 2 weeks, or at a dose of 480 mg every 4 weeks. For patients with non-small cell lung cancer, renal cell carcinoma, classic Hodgkin's lymphoma, head and neck cancer, gastric cancer, and malignant pleural mesothelioma, nivolumab shall be administered intravenously at a dose of 3 mg / kg (body weight) every 2 weeks. Furthermore, for other uses / dosages, for example, in patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, MSI-H or dMMR positive colorectal cancer (including children 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 2 weeks or at a dose of 480 mg every 4 weeks. Furthermore, regarding other uses / dosages, for example, in patients with malignant melanoma, when used in combination with ipalimumab, sometimes nivolumab is administered as a single intravenous infusion of 1 mg / kg (body weight) at 3-week intervals for 4 times, followed by a single intravenous infusion of 3 mg / kg (body weight) at 2-week intervals; or sometimes nivolumab is administered as a single intravenous infusion of 80 mg at 3-week intervals for 4 times, followed by a single intravenous infusion of 240 mg at 2-week intervals, or a single intravenous infusion of 480 mg at 4-week intervals. For example, in patients with renal cell carcinoma or colorectal cancer, when used in combination with ipalimumab, nivolumab is sometimes administered intravenously at a dose of 240 mg once every 3 weeks, for a total of 4 times. After that, nivolumab is administered intravenously at a dose of 240 mg once every 2 weeks, or at a dose of 480 mg once every 4 weeks.

[0153] Furthermore, when pembrolizumab, which is also an anti-PD-1 antibody, is administered as follows: That is, for patients with malignant melanoma, non-small cell lung cancer, typical Hodgkin's 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's cell carcinoma, pembrolizumab is administered intravenously at a dose of 200 mg every 3 weeks or at a dose of 400 mg every 6 weeks. Furthermore, regarding other uses / dosages, for example, in children aged 2 years and older with typical Hodgkin's lymphoma, MSI-H or dMMR positive solid tumors, colorectal cancer, and primary mediastinal B-cell lymphoma, pembrolizumab is administered intravenously at a dose of 2 mg / kg (body weight) once (up to 200 mg once) at 3-week intervals.

[0154] Furthermore, when the immune checkpoint inhibitor is avelumab, which is an anti-PD-L1 antibody, patients with Merkel cell carcinoma and urothelial carcinoma are given avelumab at a dose of 10 mg / kg (body weight) every 2 weeks via intravenous infusion. When the PD-L1 antibody is atezolizumab, patients with non-small cell lung cancer, urothelial carcinoma, and hepatocellular carcinoma are given atezolizumab at a dose of 1200 mg every 3 weeks via intravenous infusion. For patients with triple-negative breast cancer, when used in combination with paclitaxel, atezolizumab is given at a dose of 840 mg every 2 weeks via intravenous infusion. Furthermore, when using durvalumab, which is also a PD-L1 antibody, patients with non-small cell lung cancer and urothelial carcinoma were given a single intravenous infusion of 10 mg / kg (body weight) every 2 weeks. Patients with progressive small cell lung cancer were given a single intravenous infusion of 1500 mg of durvalumab every 4 weeks.

[0155] Furthermore, when ipalimumab is an anti-CTLA-4 antibody, for patients with malignant melanoma, ipalimumab is administered intravenously at a dose of 3 mg / kg (body weight) once daily for 4 times at 3-week intervals, either alone or in combination with nivolumab. For patients with renal cell carcinoma and MSI-H or dMMR-positive colorectal cancer, ipalimumab is administered intravenously at a dose of 1 mg / kg (body weight) once daily for 4 times at 3-week intervals, when in combination with nivolumab. For patients with non-small cell lung cancer, ipalimumab is administered intravenously at a dose of 1 mg / kg (body weight) once daily for 6-week intervals.

[0156] Furthermore, the preferred administration method of the immune checkpoint inhibitor of the present invention is non-oral administration. Examples of non-oral administration include subcutaneous administration, intradermal administration, intraperitoneal administration, intramuscular administration, and intravenous administration, with subcutaneous or intravenous administration being more preferred. Intravenous administration is even more preferred. Intravenous administration is preferably administered via intravenous drip.

[0157] In this invention, the above-described usage and dosage can also be used in the treatment method of this invention.

[0158] (3) The combined use of XELOX + bevacizumab therapy with EP4 antagonist and immune checkpoint inhibitor (hereinafter referred to as the combined use-1) The "XELOX therapy" in this invention is a cancer treatment method performed by the combined use of capecitabine and oxaliplatin (L-OHP).

[0159] The "XELOX + bevacizumab therapy" of the present invention is a cancer treatment method that uses three doses of capecitabine, oxaliplatin and bevacizumab in combination. In one embodiment, bevacizumab 7.5 mg / kg is administered intravenously over approximately 30 to 90 minutes, and oxaliplatin 130 mg / m2 (body surface area) is administered intravenously over 2 hours. This series of administrations is spaced 3 weeks apart. The treatment involved administering capecitabine 1000 mg / m² / dose (1200 mg / dose for body surface area less than 1.36 m², 1500 mg / dose for body surface area between 1.36 and 1.66 m², 1800 mg / dose for body surface area between 1.66 and 1.96 m², and 2100 mg / dose for body surface area greater than 1.96 m²) twice daily orally for 14 days, followed by a 7-day withdrawal period. In any subsequent administration of XELOX + bevacizumab therapy after the second cycle, bevacizumab administration may be discontinued based on the severity of side effects experienced by the patient. The capecitabine dosage may be reduced to 1800 mg / dose, 1500 mg / dose, 1200 mg / dose, 900 mg / dose, or 600 mg / dose, or discontinued, depending on the starting dose and body surface area. Oxaliplatin may also be reduced to 100 mg / m² (body surface area) or 85 mg / m² (body surface area), or discontinued. The discontinuation / reduction / restart of XELOX + bevacizumab therapy is implemented with reference to the latest package insert and at the physician's discretion.

[0160] In combination with XELOX + bevacizumab therapy, in one implementation configuration, compound A, which is an EP4 antagonist, is administered orally at 5 mg once daily, 10 mg once daily, 20 mg once daily, or 40 mg once daily. Preferably, it is administered orally at 20 mg once daily or 40 mg once daily. The dosage of compound A may be reduced or discontinued depending on the severity of the patient's side effects. Furthermore, if the restart criteria are met, compound A can be restarted. Upon restarting, the dosage of compound A in each phase may be reduced based on the physician's judgment. In one embodiment, when compound A, as an EP4 antagonist, is administered at an initial dose of 40 mg, the dose is reduced to 20 mg in stage 1 and 10 mg in stage 2. When compound A, as an EP4 antagonist, is administered at an initial dose of 20 mg, the dose is reduced to 10 mg in stage 1 and 5 mg in stage 2.

[0161] In combination with XELOX + bevacizumab therapy, nivolumab, as an immune checkpoint inhibitor, is administered intravenously in one formulation as follows: 240 mg once every 2 weeks, 360 mg once every 3 weeks, or 480 mg once every 4 weeks. Preferably, nivolumab is administered intravenously at 360 mg once every 3 weeks. Nivolumab administration may be discontinued depending on the severity of side effects experienced by the patient. Furthermore, nivolumab administration may be restarted if the restart criteria are met.

[0162] The cancer to which this combination-1 can be applied is any cancer that can exert the effect of this combination-1, without any particular limitation. In one embodiment, it is colorectal cancer, preferably colon / rectal cancer. More preferably, it is advanced or recurrent colon / rectal cancer that cannot be resected and cured.

[0163] In one embodiment, the present invention is administered to a patient who has no history of treatment for colorectal cancer.

[0164] In this combined use-1, when the EP4 antagonist (preferably compound A) and the immune checkpoint inhibitor (preferably 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 another embodiment, after the administration of the EP4 antagonist and the immune checkpoint inhibitor, bevacizumab, oxaliplatin, and capecitabine are administered sequentially. Furthermore, in other embodiments, when the EP4 antagonist (preferably compound A) and the immune checkpoint inhibitor (preferably anti-PD-1 antibody (preferably nivolumab)) are administered on the same day as XELOX + bevacizumab therapy, XELOX + bevacizumab therapy may be administered first, or it may be administered simultaneously with the administration of the EP4 antagonist and the immune checkpoint inhibitor. In one implementation, as long as the order of administration of EP4 antagonist, immune checkpoint inhibitor, bevacizumab, oxaliplatin and capecitabine is not otherwise defined, administration can begin with any one of the drugs, and more than two drugs can be administered simultaneously.

[0165] (4) An EP4 antagonist as an adjuvant therapy following preoperative chemoradiotherapy, or a combination of an EP4 antagonist and an immune checkpoint inhibitor as part of the same therapy (hereinafter referred to as "combined therapy-2"). The "preoperative chemoradiotherapy" in this invention is a combination of radiation irradiation and chemotherapy with fluorouracil (5-FU) or capecitabine. In this invention, a combination of radiation irradiation and capecitabine administration is preferred.

[0166] In one embodiment, the preoperative chemoradiotherapy of the present invention consists of 45 Gy / 25 fractions of pelvic irradiation and 5.4 Gy / 3 fractions of boost irradiation of the primary site, and capecitabine 825 mg / m2 (the initial dosage is based on the usage / dosage of XELODA (registered trademark) tablet 300) administered twice daily. During the concurrent irradiation, capecitabine is administered orally (e.g., for 21 days or more than 42 times daily during 50.4 Gy / 28 fractions of irradiation), but the dosage may be appropriately reduced according to the severity of the patient's side effects.

[0167] In one embodiment, compound A, used as an EP4 antagonist as adjuvant therapy after preoperative chemoradiotherapy, is administered orally at a dose of 5 mg, 10 mg, 20 mg, or 40 mg once daily. Preferably, it is administered orally at a dose of 20 mg or 40 mg once daily. More preferably, compound A is administered orally at a dose of 40 mg once daily. Depending on the severity of the patient's side effects, the dosage of compound A may be reduced or discontinued. Furthermore, if the restart criteria are met, the administration of compound A may be restarted. Upon restarting, the dosage of compound A in each phase may be reduced based on the physician's judgment. In one embodiment, when compound A, which is an EP4 antagonist, is administered at an initial dose of 40 mg, the dose is reduced to 20 mg in stage 1 and 10 mg in stage 2.

[0168] Nivolumab, an immune checkpoint inhibitor used as adjuvant therapy after preoperative chemoradiotherapy, is administered intravenously in one formulation as follows: 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks. Preferably, 240 mg is administered intravenously every 2 weeks. Nivolumab administration may be discontinued depending on the severity of side effects. Furthermore, nivolumab administration may be restarted if the restart criteria are met.

[0169] One embodiment of the combined use-2 is the administration of an EP4 antagonist, and another embodiment is the combined administration of an EP4 antagonist and an immune checkpoint inhibitor.

[0170] For cancers to which this combined therapy-2 is applicable, there are no particular restrictions as long as the cancer can exert the effect of this preoperative adjuvant therapy. In one implementation form, it is colorectal cancer, preferably colon / rectal cancer. More preferably, it is locally advanced resectable rectal cancer that is curable.

[0171] In one embodiment, patients who are curable and resectable are given the treatment after imaging diagnosis confirms that there is no distant metastasis following the completion of preoperative chemoradiotherapy.

[0172] In one embodiment, this preoperative adjuvant therapy is administered to a patient whose surgery has become (radical) resectable.

[0173] (5) FFX therapy or its reduction regimen The “FFX therapy” in this invention refers to the use of oxaliplatin (L-OHP), irinotecan hydrochloride hydrate (irinotecan, CPT-11), and levofloxacin calcium (calcium) This cancer treatment regimen involves four doses of levofolinate (L-LV) and fluorouracil (5-FU). A recommended dosage and administration sequence is as follows: Oxaliplatin 85 mg / m² (body surface area) is administered intravenously over 2 hours, followed by levofolinate 200 mg / m² over 2 hours. Thirty minutes after the start of levofolinate administration, irinotecan 180 mg / m² is administered intravenously over 1.5 hours. Following the end of the levofolinate administration, fluorouracil 400 mg / m² is rapidly administered intravenously, followed by fluorouracil 2400 mg / m² over 46 hours. This series of administrations is administered at two-week intervals.

[0174] The so-called "reduction regimen" of the FFX therapy is a prescription that reduces or discontinues any of the four doses of the FFX therapy from the initial dose, or reduces or discontinues any of the four doses in any subsequent dose after the second round based on the severity of the side effects identified in any dose after the first round. In terms of its form, for example, rapid intravenous administration of fluorouracil can be omitted from the initial administration; the dosage of oxaliplatin can be any dosage between 65 mg / m2, 50 mg / m2, or 85 to 50 mg / m2; the dosage of irinotecan can be any dosage between 150 mg / m2, 120 mg / m2, 90 mg / m2, or 180 to 90 mg / m2; and the dosage of fluorouracil for continuous intravenous administration can be any dosage between 1800 mg / m2, 1200 mg / m2, or 2400 to 1200 mg / m2.

[0175] Furthermore, regarding another aspect of this dose reduction regimen, in any administration after the second round of FFX therapy, depending on the severity of the patient's side effects, the rapid intravenous administration of fluorouracil may be discontinued, and depending on the severity of the patient's side effects, the dosage of oxaliplatin may be reduced to any dosage between 65 mg / m², 50 mg / m², or 85 to 50 mg / m², or the administration of oxaliplatin may be discontinued, depending on the severity of the patient's side effects. Irinotecan dosage may be reduced to any dosage between 150 mg / m2, 120 mg / m2, 90 mg / m2 or 180 to 90 mg / m2, or irinotecan administration may be discontinued. Depending on the severity of the patient’s side effects, the dosage of fluorouracil administered intravenously may be reduced to any dosage between 1800 mg / m2, 1200 mg / m2 or 2400 to 1200 mg / m2, or fluorouracil administration may be discontinued.

[0176] Furthermore, as another form of the dose reduction regimen known as the modified FOLFIRINOX therapy (mFFX therapy), in terms of recommended dosage, for example, levofloxacin 200 mg / m2 is administered intravenously over 2 hours while oxaliplatin 85 mg / m2 (body surface area) is administered intravenously over 2 hours, irinotecan 150 mg / m2 is administered intravenously over 1.5 hours 30 minutes after the start of levofloxacin administration, and fluorouracil 2400 mg / m2 is administered intravenously over 46 hours after the end of levofloxacin administration, and this series of administrations is carried out at 2-week intervals.

[0177] Regarding further dose reduction regimens for this mFFX therapy, for example, from the initial administration, the dosage of oxaliplatin may be 65 mg / m2, 50 mg / m2 or any dosage between 85 and 50 mg / m2, the dosage of irinotecan may be 140 mg / m2, 120 mg / m2 or any dosage between 140 and 120 mg / m2, and the dosage of fluorouracil administered continuously intravenously may be 2400 mg / m2, 1800 mg / m2, 1200 mg / m2 or any dosage between 2400 and 1200 mg / m2.

[0178] Furthermore, in any subsequent administration of the mFFX therapy after the second round, depending on the severity of the patient's side effects, the dosage of oxaliplatin may be reduced to any dosage between 65 mg / m2, 50 mg / m2, or 85 to 50 mg / m2, or the administration of oxaliplatin may be discontinued. Depending on the severity of the patient's side effects, the dosage of irinotecan may be reduced to any dosage between 120 mg / m2, 90 mg / m2, or 150 to 90 mg / m2, or the administration of irinotecan may be discontinued. Depending on the severity of the patient's side effects, the dosage of fluorouracil administered intravenously may be reduced to any dosage between 1800 mg / m2, 1200 mg / m2, or 2400 to 1200 mg / m2, or the administration of fluorouracil may be discontinued.

[0179] Furthermore, depending on the severity of the patient's side effects, a series of administration intervals for the FFX therapy or its tapering regimen (e.g., mFFX therapy) may be set temporarily or continuously at 3-week or 4-week intervals. The discontinuation / tapering / restart of the FFX therapy or its tapering regimen (e.g., mFFX therapy) is implemented with reference to the latest manual and at the physician's discretion.

[0180] (6) Concomitant use with FFX therapy or a reduced version thereof (hereinafter referred to as "concomitant use-3") In one embodiment, the EP4 antagonist used in conjunction with FFX therapy or a reduced version thereof (e.g., mFFX therapy) is administered in the dosage and administration method described in (1) above for the EP4 antagonist. In one embodiment, compound A of 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. 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 severity of the patient's side effects, the dosage of compound A may be reduced or discontinued. Furthermore, if the restart criteria are met, compound A can be restarted. Upon restarting, the dosage of compound A in each stage can be reduced based on the physician's judgment. In one implementation scenario, when starting with a dose of 40 mg of compound A as an EP4 antagonist, the dose is reduced to 20 mg in stage 1 and 10 mg in stage 2. When starting with a dose of 20 mg of compound A as an EP4 antagonist, the dose is reduced to 10 mg in stage 1 and 5 mg in stage 2.

[0181] In one embodiment, the immune checkpoint inhibitor of this combination-3 is administered according to the dosage and administration method described in (2) above. Nivolumab, as the immune checkpoint inhibitor, is administered intravenously at intervals of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks, as an intravenous infusion in one embodiment. Preferably, it is administered intravenously at intervals of 480 mg every 4 weeks. Nivolumab administration may be discontinued depending on the severity of side effects experienced by the patient. Furthermore, if the restart criteria are met, nivolumab administration may be restarted.

[0182] When the EP4 antagonist (preferably compound A) and immune checkpoint inhibitor (preferably anti-PD-1 antibody (preferably nivolumab)) of this combination-3 are administered on the same day as FFX therapy or a reduced version thereof (e.g., mFFX therapy), in one embodiment, the EP4 antagonist and immune checkpoint inhibitor are administered first. In another embodiment, FFX therapy or a reduced version thereof (e.g., mFFX therapy) is administered after the EP4 antagonist and immune checkpoint inhibitor are administered. Furthermore, in other embodiments, when the EP4 antagonist (preferably compound A) and immune checkpoint inhibitor (preferably anti-PD-1 antibody (preferably nivolumab)) are administered on the same day as FFX therapy or a reduced version thereof (e.g., mFFX therapy), FFX therapy or a reduced version thereof (e.g., mFFX therapy) may be administered first, or it may be administered simultaneously with the EP4 antagonist and immune checkpoint inhibitor. In one implementation, as long as the order of administration of EP4 antagonists, immune checkpoint inhibitors, FFX therapy or their tapering regimens (e.g., mFFX therapy) is not otherwise defined, administration may begin with any one of the drugs, and more than two drugs may be administered simultaneously.

[0183] (7) GnP therapy The “GnP therapy” in this invention is a combination of gemcitabine and albumin-bound paclitaxel. In one embodiment, the recommended dosage of GnP therapy is, for example, to administer gemcitabine 1000 mg / m2 (body surface area) intravenously over 30 minutes and albumin-bound paclitaxel 125 mg / m2 (body surface area) intravenously over 30 minutes. This series of administrations is performed at 1-week intervals and continues for 3 weeks, followed by a 1-week break. In general, during any subsequent administration of GnP therapy after the second round, gemcitabine may be reduced to 800 mg / m2 or 600 mg / m2, and albumin-bound paclitaxel may be reduced to 100 mg / m2 or 75 mg / m2, depending on the severity of the patient's side effects. The discontinuation / reduction / restart of GnP therapy shall be implemented with reference to the latest manual and based on the physician's judgment.

[0184] (8) Combination with GnP therapy (hereinafter referred to as Combination-4) In one embodiment, the EP4 antagonist of Combination-4 is administered according to the dosage and administration method described above for the EP4 antagonist. In one embodiment, compound A of 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. 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 40 mg once daily. Depending on the severity of the patient's side effects, the dosage of compound A may be reduced or discontinued. Furthermore, if the restart criteria are met, the administration of compound A may be restarted. When restarting, the dosage of compound A in each stage may be reduced based on the physician's judgment. In one embodiment, when compound A, as an EP4 antagonist, is administered at an initial dose of 40 mg, the dose is reduced to 20 mg in stage 1 and 10 mg in stage 2. When compound A, as an EP4 antagonist, is administered at an initial dose of 20 mg, the dose is reduced to 10 mg in stage 1 and 5 mg in stage 2.

[0185] In one embodiment, the immune checkpoint inhibitor of this combination-4 is administered according to the dosage and administration method described in (2) above. Nivolumab, as the immune checkpoint inhibitor, is administered intravenously at intervals of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks, as an intravenous infusion. Preferably, nivolumab is administered intravenously at intervals of 480 mg every 4 weeks. Nivolumab administration may be discontinued depending on the severity of side effects experienced by the patient. Furthermore, nivolumab administration may be restarted if the restart criteria are met.

[0186] (9) DTX+RAM Therapy The “European paclitaxel and ramucirumab therapy” in this invention is a cancer treatment method that uses European paclitaxel and ramucirumab in combination. The recommended dosage is, for example, administering European paclitaxel 60 mg / m2 (body surface area) intravenously over 60 minutes and ramucirumab 10 mg / kg intravenously over 60 minutes. This series of administrations is carried out at 3-week intervals. In any subsequent administrations of the DTX+RAM therapy, depending on the severity of the patient’s side effects, European paclitaxel may be increased or decreased to 75 mg / m2 or 50 mg / m2 or the administration of European paclitaxel may be discontinued. Ramucirumab may be reduced to 8 mg / kg or 6 mg / kg or the administration of ramucirumab may be discontinued. The administration time of ramucirumab may be shortened to 30 to 60 minutes. The discontinuation / reduction / restart of DTX+RAM therapy is implemented with reference to the latest package insert and based on the physician's judgment. In one implementation mode, administration of European paclitaxel and ramucirumab can be started on the same day.

[0187] (10) Use with DTX+RAM therapy (hereinafter referred to as "combined use-5") In one embodiment, the EP4 antagonist of the combined use-5 is administered in the manner and dosage described in (1) above for the EP4 antagonist. In one embodiment, compound A of the EP4 antagonist is administered orally at 5 mg once daily, 10 mg once daily, 20 mg once daily, or 40 mg once daily. Preferably, it is administered orally at 20 mg once daily or 40 mg once daily. Depending on the severity of the patient's side effects, the dosage of compound A may be reduced or discontinued. Furthermore, if the restart criteria are met, the administration of compound A may be restarted. When restarting, the dosage of compound A in each stage may be reduced based on the physician's judgment. In one embodiment, when compound A, as an EP4 antagonist, is administered at an initial dose of 40 mg, the dose is reduced to 20 mg in stage 1 and 10 mg in stage 2. When compound A, as an EP4 antagonist, is administered at an initial dose of 20 mg, the dose is reduced to 10 mg in stage 1 and 5 mg in stage 2.

[0188] In one embodiment, the immune checkpoint inhibitor of this formulation-5 is administered according to the dosage and administration method described in (2) above. Regarding nivolumab as the immune checkpoint inhibitor, in one embodiment, nivolumab is administered intravenously at intervals of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks. Preferably, nivolumab is administered intravenously at intervals of 360 mg every 3 weeks. Nivolumab administration may be discontinued depending on the severity of side effects experienced by the patient. Furthermore, nivolumab administration may be restarted if the restart criteria are met.

[0189] In one implementation, the administration of DTX+RAM therapy, immune checkpoint inhibitors and EP4 antagonists can begin on the same day.

[0190] When the EP4 antagonist (preferably compound A) and immune checkpoint inhibitor (preferably anti-PD-1 antibody (preferably nivolumab)) are administered on the same day as DTX+RAM therapy, in one embodiment, the EP4 antagonist and immune checkpoint inhibitor are administered first. In another embodiment, DTX+RAM therapy is administered after the EP4 antagonist and immune checkpoint inhibitor are administered. Furthermore, in other embodiments, when the EP4 antagonist (preferably compound A) and immune checkpoint inhibitor (preferably anti-PD-1 antibody (preferably nivolumab)) are administered on the same day as DTX+RAM therapy, DTX+RAM therapy may be administered first, or it may be administered simultaneously with the EP4 antagonist and immune checkpoint inhibitor. In one implementation, as long as the order of administration of EP4 antagonist, immune checkpoint inhibitor, European paclitaxel and ramucirumab is not otherwise defined, administration can begin with any one of the drugs, and more than two drugs can be administered simultaneously.

[0191] (11) DTX Therapy The "European paclitaxel therapy" in this invention refers to cancer treatment using European paclitaxel. In one embodiment, the recommended dosage is, for example, administering 60 mg / m² (body surface area) of European paclitaxel intravenously over 60 minutes, with the administration intervald at 3-week intervals. In any subsequent administration of this DTX therapy, depending on the patient's condition, the dosage of European paclitaxel may be increased or decreased to 75 mg / m² or 50 mg / m², or the administration of European paclitaxel may be discontinued. The discontinuation / reduction / restart of DTX therapy is implemented with reference to the latest manual and based on the physician's judgment.

[0192] (12) Combination with DTX therapy (hereinafter referred to as Combination-6) In one embodiment, the EP4 antagonist of Combination-6 is administered according to the dosage and administration method described in (1) above for the EP4 antagonist. In one embodiment, compound A of 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. 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 side effects, the dosage of compound A may be reduced or discontinued. Furthermore, if the restart criteria are met, the administration of compound A may be restarted. When restarting, the dosage of compound A in each stage may be reduced based on the physician's judgment. In one embodiment, when compound A, as an EP4 antagonist, is administered at an initial dose of 40 mg, the dose is reduced to 20 mg in stage 1 and 10 mg in stage 2. When compound A, as an EP4 antagonist, is administered at an initial dose of 20 mg, the dose is reduced to 10 mg in stage 1 and 5 mg in stage 2.

[0193] In one embodiment, the immune checkpoint inhibitor of this formulation-6 is administered according to the dosage and administration method described in (2) above. In one embodiment, regarding the immune checkpoint inhibitor nivolumab, nivolumab is administered intravenously at intervals of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks. Preferably, nivolumab is administered intravenously at intervals of 360 mg every 3 weeks. Nivolumab administration may be discontinued depending on the severity of side effects experienced by the patient. Furthermore, nivolumab administration may be restarted if the restart criteria are met.

[0194] In one implementation, the administration of DTX therapy, immune checkpoint inhibitors and EP4 antagonists may begin on the same day.

[0195] In the combined use-6, when the EP4 antagonist (preferably compound A) and the immune checkpoint inhibitor (preferably anti-PD-1 antibody (preferably nivolumab)) are administered on the same day as DTX therapy, in one embodiment, the EP4 antagonist and the immune checkpoint inhibitor are administered first. In another embodiment, DTX therapy is administered after the EP4 antagonist and the immune checkpoint inhibitor are administered. Furthermore, in other embodiments, when the EP4 antagonist (preferably compound A) and the immune checkpoint inhibitor (preferably anti-PD-1 antibody (preferably nivolumab)) and DTX therapy are administered on the same day, DTX therapy may be administered first, or it may be administered simultaneously with the EP4 antagonist and the immune checkpoint inhibitor. In one implementation, as long as the order of administration of EP4 antagonist, immune checkpoint inhibitor, and European paclitaxel is not otherwise defined, administration can begin with any one of the drugs, and more than two drugs can be administered simultaneously.

[0196] (13) RAM Therapy The "ramucirumab therapy (hereinafter referred to as "RAM therapy")" in this invention is a cancer treatment method using ramucirumab. In one embodiment, the recommended dosage is, for example, ramucirumab 10 mg / kg is administered intravenously over 60 minutes, and this series of administrations is administered at 3-week intervals. In one embodiment, in any administration after the second round of RAM therapy, depending on the patient's condition, the ramucirumab dose may be reduced to 8 mg / kg or 6 mg / kg, or the administration of ramucirumab may be discontinued. Also, depending on the severity of the patient's side effects, the administration time of ramucirumab may be shortened to 30 to 60 minutes.

[0197] (14) Combination with RAM therapy (hereinafter referred to as Combination-7) In one embodiment, the EP4 antagonist of Combination-7 is administered according to the dosage and administration method described in (1) above for the EP4 antagonist. In one embodiment, compound A of 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. 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 side effects, the dosage of compound A may be reduced or discontinued. Furthermore, if the restart criteria are met, the administration of compound A may be restarted. When restarting, the dosage of compound A in each stage may be reduced based on the physician's judgment. In one embodiment, when compound A, as an EP4 antagonist, is administered at an initial dose of 40 mg, the dose is reduced to 20 mg in stage 1 and 10 mg in stage 2. When compound A, as an EP4 antagonist, is administered at an initial dose of 20 mg, the dose is reduced to 10 mg in stage 1 and 5 mg in stage 2.

[0198] In one embodiment, the immune checkpoint inhibitor of this formulation-7 is administered according to the dosage and administration method described in (2) above. In one embodiment, nivolumab, as the immune checkpoint inhibitor, is administered intravenously at intervals of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks. Preferably, nivolumab is administered intravenously at intervals of 360 mg every 3 weeks. Nivolumab administration may be discontinued depending on the severity of side effects experienced by the patient. Furthermore, nivolumab administration may be restarted if the restart criteria are met.

[0199] In one implementation, the administration of RAM therapy, immune checkpoint inhibitors and EP4 antagonists may begin on the same day.

[0200] When the EP4 antagonist (preferably compound A) and immune checkpoint inhibitor (preferably anti-PD-1 antibody (preferably nivolumab)) are administered on the same day as RAM therapy, in one embodiment, the EP4 antagonist and immune checkpoint inhibitor are administered first. In another embodiment, RAM therapy is administered after the EP4 antagonist and immune checkpoint inhibitor are administered. Furthermore, in other embodiments, when the EP4 antagonist (preferably compound A) and immune checkpoint inhibitor (preferably anti-PD-1 antibody (preferably nivolumab)) are administered on the same day as RAM therapy, RAM therapy may be administered first, or it may be administered simultaneously with the EP4 antagonist and immune checkpoint inhibitor. In one implementation, as long as the order of administration of the EP4 antagonist, immune checkpoint inhibitor, and ramucirumab is not otherwise defined, administration can begin with any one of the drugs, and more than two drugs can be administered simultaneously.

[0201] [Applicable Diseases and Patients] The applicable disease for the treatment method of the present invention is cancer.

[0202] More specifically, cancers may include, for example: leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), malignant lymphoma (Hodgkin's lymphoma, non-Hodgkin's lymphoma (e.g., adult T-cell leukemia, follicular lymphoma, diffuse large cell B-cell lymphoma)), multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, esophagogastric junction adenocarcinoma, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer (e.g., hepatocellular carcinoma), gallbladder and bile duct cancer, cholangiocarcinoma, pancreatic cancer (e.g., pancreatic duct cancer, insulinoma, intraductal papillary mucinous tumor), thyroid cancer, etc. Adenocarcinoma, lung cancer (e.g., non-small cell lung cancer (e.g., squamous non-small cell lung cancer, non-squamous non-small cell lung cancer), small cell lung cancer), breast cancer, ovarian cancer (e.g., serous ovarian cancer), cervical cancer, uterine corpus cancer, endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer (e.g., renal cell carcinoma), renal pelvis / urinary tract cancer, urinary tract epithelial cancer (e.g., bladder cancer, upper urinary tract cancer), penile cancer, prostate cancer, testicular tumor (e.g., germ cell tumor), bone / soft tissue sarcoma, malignant osteoma, skin cancer (e.g., uveal malignant melanoma, malignant melanoma, Merkel cell carcinoma), thymoma, mesothelioma, malignant pleural mesothelioma, glioblastoma, leukemia, and cancers of unknown primary origin, etc.

[0203] The applicable diseases for the treatment method of the present invention are preferably colorectal cancer, pancreatic cancer, and lung cancer, more preferably advanced or recurrent colorectal cancer that is unresectable and incurable, locally advanced colorectal cancer that is resectable and curable, pancreatic cancer with distant metastases, and advanced or recurrent lung cancer that has been deemed ineffective after receiving combined therapy containing anti-PD-1 antibodies or anti-PD-L1 antibodies and platinum preparations. Even more preferably, the applicable diseases are advanced or recurrent colorectal cancer that is unresectable and incurable, locally advanced colorectal cancer that is resectable and curable, pancreatic cancer with distant metastases, and advanced or recurrent lung cancer that has been deemed ineffective after receiving combined therapy containing anti-PD-1 antibodies or anti-PD-L1 antibodies and platinum preparations. The term "treatment" for cancer in this instruction manual includes treatments intended to, for example, (i) reduce the proliferation of tumor cells, (ii) reduce symptoms caused by cancer, (iii) improve the quality of life of cancer patients, (iv) reduce the dosage of other anticancer drugs or adjuvant cancer treatments already administered, and / or (v) prolong the survival of cancer patients. "Progress suppression" for cancer refers to slowing the progression of cancer, stabilizing symptoms caused by cancer, and causing the progression of symptoms to subside. Furthermore, "recurrence suppression" for cancer refers to the preventative suppression of cancer recurrence in patients whose cancerous lesions have been completely or substantially eliminated or removed through cancer treatment or surgical resection.

[0204] The treatment method of the present invention is for the following cancer patients, namely, (a) patients whose treatment effect is ineffective or insufficient due to anticancer drugs, or patients whose cancer has worsened after treatment with anticancer drugs; (b) patients with metastatic, recurrent, refractory and / or distant metastatic cancer that cannot be cured or resected; (c) cancer patients with a tumor proportion score (hereinafter abbreviated as "TPS") of 50% or more, 25% or more, 10% or more, 5% or more, or 1% or more; and (d) patients with a combined positive score. Prescriptions were administered to cancer patients with a score (hereinafter referred to as "CPS") of 20% or higher, 10% or higher, 5% or higher, or 1% or higher; (e) cancer patients with loss of mismatched repair (hereinafter referred to as "dMMR") and / or high microsatellite instability (hereinafter referred to as "MSI-H"); and (f) cancer patients with high tumor mutation burden (hereinafter referred to as "TMB"). Furthermore, the treatment method of the present invention is also suitable for the following cancer patients, namely, (g) patients with no history of anticancer drug treatment, (h) cancer patients with TPS less than 50%, 25%, 10%, 5% or 1%, (i) cancer patients with CPS less than 20%, 10%, 5% or 1%, (j) cancer patients without dMMR and / or MSI-H, or with low microsatellite instability (hereinafter abbreviated as "MSI-L"), or (k) cancer patients with low TMB. In particular, cancer patients for whom the treatment method of the present invention is required may include: (i) patients with unresectable or recurrent advanced cancer, especially colorectal cancer patients; (ii) patients with resectable and curable locally advanced cancer, especially rectal cancer patients; (iii) patients with cancer who have no history of anticancer drug treatment and / or have distant metastases, especially pancreatic cancer patients; or (iv) patients with advanced or recurrent cancer who have been deemed ineffective by combined therapy including anti-PD-1 antibody or anti-PD-L1 antibody and platinum preparations, especially lung cancer patients.

[0205] In one embodiment, patients with unresectable, advanced, or recurrent colorectal cancer may be listed. In another embodiment, patients with no prior treatment history for colorectal cancer may be listed. Preferably, patients with no prior history of systemic anti-tumor therapy for colorectal cancer may be listed. More preferably, patients with unresectable, advanced, or recurrent colorectal cancer who have no prior history of systemic anti-tumor therapy may be listed.

[0206] In one embodiment, patients with locally advanced rectal cancer that is resectable and curable may be listed. In another embodiment, patients with no prior history of treatment for rectal cancer may be listed.

[0207] In one embodiment, pancreatic cancer patients with no history of anticancer drug treatment and / or with distant metastases may be listed.

[0208] In one embodiment, patients with no prior history of treatment for pancreatic cancer may be listed. Preferably, patients with no prior history of treatment with systemic anti-tumor agents for pancreatic cancer may be listed. More preferably, patients with pancreatic cancer that has distant metastases may be listed.

[0209] In one embodiment, patients with advanced or recurrent lung cancer who have been deemed ineffective to receive concomitant therapy including anti-PD-1 antibody or anti-PD-L1 antibody and platinum preparations may be listed.

[0210] In one embodiment, patients confirmed to have non-small cell lung cancer may be listed. Preferably, patients with stage IV or recurrent non-small cell lung cancer may be listed. More preferably, patients with advanced or recurrent non-small cell lung cancer who have received concomitant therapy consisting of anti-PD-1 antibody or anti-PD-L1 antibody and platinum preparation as a first-line treatment and have been deemed ineffective may be listed.

[0211] In particular, for example, cancer patients for whom the treatment of immune checkpoint inhibitors or EP4 receptor antagonists alone is insufficient, the anti-tumor effect of the treatment method of the present invention can be expected to be maximized. Furthermore, the treatment method of the present invention can also reduce the dosage of each drug, thereby expecting a reduction in side effects.

[0212] In one aspect of the treatment method of the present invention, a synergistic effect is achieved. Furthermore, in one aspect, a synergistic effect is achieved compared to the therapeutic effects of an immune checkpoint inhibitor, an EP4 receptor antagonist, or standard therapy alone, or the therapeutic effects of using an immune checkpoint inhibitor and standard therapy, using an EP4 receptor antagonist and standard therapy, or using an immune checkpoint inhibitor and EP4 receptor antagonist together.

[0213] In one aspect of the treatment method of the present invention, side effects are reduced. Furthermore, in one aspect, compared to the therapeutic effects of immune checkpoint inhibitors, EP4 receptor antagonists, or standard therapy alone, or the therapeutic effects of combining immune checkpoint inhibitors and standard therapy, combining EP4 receptor antagonists and standard therapy, or combining immune checkpoint inhibitors and EP4 receptor antagonists, side effects are reduced.

[0214] Unless otherwise defined, the timing of administration of each agent used in the combined administration of the present invention may be simultaneous or separate.

[0215] In addition to the treatment method of the present invention, it can also be applied to the treatment of metastatic cancer and the suppression of metastasis.

[0216] In terms of one aspect of the treatment method of the present invention, it is the suppression of recurrence.

[0217] In this invention, treatment means producing at least one of the following effects: reducing tumor size, inhibiting (delaying or stopping) tumor growth, inhibiting (delaying or stopping) tumor metastasis, inhibiting (preventing or delaying) recurrence, and alleviating one or more of the symptoms associated with cancer.

[0218] In this invention, in order to (1) supplement and / or enhance the therapeutic effect, (2) improve dynamics / absorption, reduce the dosage, and / or (3) reduce side effects, the treatment method of this invention may be used in combination with other drugs (e.g., conventional anticancer treatments).

[0219] In this specification, the term "about" means a variation within a range of 10% lower or higher than the value represented. Alternatively, about 30 points means 30 points ± 5 points, and about 60 points means 60 points ± 5 points.

[0220] In this specification, the term "standard therapy" refers to a standard treatment method recommended for general patients in a certain condition based on scientific evidence, such as chemotherapy. For a single condition, examples include (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or its tapering regimen, (iv) gemcitabine and albumin-bound paclitaxel therapy, (vii) European paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy.

[0221] The present invention provides, for example, the following embodiments.

[0222] [1] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and comprising a standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) European paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy, ... or (iii) FOLFIRINOX therapy, or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) ramucirumab and / or ramucirumab therapy, or (v) ramucirumab and / or ramucirumab therapy, or (v) ramucirumab and / or ramucirumab therapy, or (v) ramucirumab and / or ramucirumab therapy, or (v) ramucirumab and / or ramucirumab therapy, or (v) ramucirumab and / or ramuci The treatment may be administered in combination with (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced version thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, (vii) European paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced version thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, and an immune checkpoint inhibitor.

[0223] [2] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and comprising a standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) European paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy, ... ramucirumab and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, or (iii) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FOLFIRINOX therapy, or (v) FO The treatment may be administered in combination with FIRINOX therapy or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, (vii) European paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, and an EP4 antagonist.

[0224] [3] The agent as described above in [1] or [2], wherein the EP4 antagonist is a compound of general formula (I) or a salt thereof:

[0225]

[0226] In the formula, R1 represents COOR8, tetrazolium, SO3H, SO2NH2, SO2NHR8-1, CONHSO2R8-1, SO2NHCOR8-1, or hydroxylamine; R8 represents a hydrogen atom, C1-4 alkyl, or benzyl; R8-1 represents a C1-4 alkyl, C1-4 haloalkyl, C3-10 carbon ring, or 3-10 member heterocycle, wherein the C3-10 carbon ring and the 3-10 member heterocycle may each 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 (represented by "-CN"; the same applies below); L1 represents C1-5 alkylene, C2-5 alkenyl, or C2-5 alkyne. R2 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)(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, -NR17R17, nitro, nitrile, hydroxyl, aldehyde (representing formyl);The following are the same), or carboxyl groups, where each of the C1-4 alkyl groups may be substituted with a halogen. In R2, (C1-4 alkyl)2 represents two independent C1-4 alkyl groups, which may be the same or different. X1 represents CR6 or a nitrogen atom, R6 represents a hydrogen atom or R2, X2 represents CR7 or a nitrogen atom, R7 represents a hydrogen atom, R2, or -L3-R9, L3 represents a methylene group, an oxygen atom, or an oxidizable sulfur atom, and R9 represents a 4-10 member heterocycle that may be substituted with a substituent selected from the group consisting of halogens, C1-4 alkyl groups, and C1-4 haloalkyl groups. L2 represents -CH2CH2-, -CH=CH-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -CH2S(O)-, -S(O)CH2-, -CH2SO2-, -SO2CH2-, -CH2NH-, -NHCH2-, -NHCO-, -CONH-, -NHSO2-, or -SO2NH-; R3 represents C1-4 alkyl or halogen; R4 represents halogen, C1-4 alkyl, or C1-4 haloalkyl; X3 represents methylene, oxygen atom, oxidizable sulfur atom, or NR10; R10 represents C1-4 alkyl, -C(O)(C1-4 alkyl), -C(O)O(C1-4 alkyl), or -SO2(C1-4 alkyl), each of which can be substituted with halogen; ring represents benzene ring or 5-6 member monocyclic aromatic heterocycle.

[0227] indicates a single or double bond.

[0228] R5 represents (1) halogen, (2) C1-4 alkyl, (3) carboxyl, (4) nitrile, (5)-CONHR11, (6)-C(O)R12, (7)-OR14, (8)-S(O)tR15, (9)-CH2R16, (10)-NR17R17, (11)-NHCOR11, (12) C4-10 carbon ring, or (13) 4-10 member heterocycle, wherein the C4-10 carbon ring or 4-10 member heterocycle may be substituted by 1 to 3 R18s, wherein when the R18s are plural, each R18 may be independent and may be the same or different; R11 represents C1-6 alkyl, C3-6 cycloalkyl, phenyl, or 4-6 member heterocycle, wherein R11 may be substituted by 1 to 3 R13s, wherein when the R13s are plural, each R13 may be independent and may be the same or different. R13 represents a halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, hydroxyl, -NR20R21, benzene, or a 4-6 member heterocycle. R20 and R21 each independently represent a hydrogen atom or a C1-4 alkyl group. R12 represents a C1-6 alkyl, C3-6 cycloalkyl, benzene, or a 4-6 member heterocycle. Each of these C3-6 cycloalkyl, benzene, or 4-6 member heterocycles can be substituted with a halogen, C1-4 alkyl, or C1-4 alkoxy group. R14 represents a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl group. The C1-6 alkyl group can be substituted with one to three R19 groups. When there are plural R19 groups, each R19 group can be independent and may be the same or different. R19 represents a 5-6 member monocyclic aromatic heterocycle that may be substituted with a substituent 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. In R19, (C1-4 alkyl)2 represents two independent C1-4 alkyl groups, which may be the same or different. R15 represents a C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl. R16 represents a hydroxyl or C1-4 alkoxy group. R17 represents a hydrogen atom, a C1-6 alkyl, or a C3-6 cycloalkyl group. R18 represents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, oxy, nitrile, hydroxy, hydroxymethyl, 1-methyl-1-hydroxyethyl, (C1-4 alkyl)SO2-, 4-6 membered heterocycle, (C1-4 alkyl)NH-, or (C1-4 alkyl)2N-. In this R18, (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, when p, q, r, and s each represent an integer greater than 2, R2, R3, R4, and R5 are independent and may be the same or different.[4] The agent described in any one of [1] to [3] above, wherein the standard therapy is bevacizumab and XELOX therapy. [5] The agent described in 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 / rectal cancer. [7] The agent described in [6] above, wherein the colon / rectal cancer is unresectable advanced or recurrent colon / rectal cancer (preferably unresectable advanced or recurrent colon / rectal cancer without prior treatment experience).

[0229] [8]) An agent as described in any of the preceding [1] to [7], wherein the EP4 antagonist is a compound of general formula (I-2) or a salt thereof:

[0230]

[0231] In the formula, R2a represents a halogen, R6a represents a hydrogen atom or a 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 in claim 1. [9] The agent described in any of the preceding [1] to [8], wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof.

[10] The agent described in the preceding [9], wherein the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg.

[11] The agent described in the preceding [9], wherein the EP4 antagonist is administered orally once daily at a dose of 20 mg or 40 mg.

[12] The agent as described in any one of [1] to

[11] above, 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 as described in

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

[0232]

[14] The agents described above in

[13] , wherein the anti-PD-1 antibody is nivolumab, cimiprizumab, pembrolizumab, spartalizumab, tislelizumab, AMP-514, doslizumab, toripalimab, camrelizumab, genozizumab, sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (refulimab), AGEN2034 (batilizumab), CS1003, HLX10 (sprullimab), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226 (Geptanumab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalizumab), BCD-100 (Progomab), PF-06801591 (Trisalizumab), CX-188, JNJ-63723283 (Cetralimab) or AB122 (Sepalimab).

[15] As described in

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

[16] As described in

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

[17] The agent described above in

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

[0233]

[18] The agent described above in

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

[19] The agent described above in

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

[20] The agent described above in

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

[21] The agent described above in

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

[22] The agent described above in

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

[23] The agent described above in

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

[24] As described in

[17] above, nivolumab is administered at a dose of 3 mg / kg (body weight) once, or at a dose of 240 mg once every 2 weeks, or at a dose of 360 mg once every 3 weeks, or at a dose of 480 mg once every 4 weeks (preferably at a dose of 240 mg once every 2 weeks, or at a dose of 360 mg once every 3 weeks, or at a dose of 480 mg once every 4 weeks).

[25] As described in

[17] above, nivolumab is administered intravenously at a dose of 360 mg once every 3 weeks.

[26] As described in

[17] above, nivolumab is administered intravenously at a dose of 360 mg once every 3 weeks, taking approximately 30 minutes.

[27] As described in

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

[28] As described in

[19] above, cimiprimab is administered at a dose of 350 mg once every 3 weeks.

[29] As described in

[20] above, avelumab is administered at a dose of 10 mg / kg (body weight) once every 2 weeks.

[30] As described in

[21] above, atezolizumab is administered at a dose of 1200 mg once every 3 weeks.

[31] As described in

[22] above, durvalumab is administered at a dose of 10 mg / kg (body weight) once every 2 weeks.

[32] As described above in

[23] , ipalimumab is administered intravenously four times at three-week intervals, either once at a dose of 3 mg / kg (body weight) or once at a dose of 1 mg / kg (body weight).

[0234]

[33] The administration of any one of the preceding [1] to

[32] , wherein the bevacizumab and XELOX therapy comprises the following administrations: (i) bevacizumab at 7.5 mg / kg once every 3 weeks, (ii) oxaliplatin at 130 mg / m2 once every 3 weeks, and (iii) capecitabine at 1000 mg / m2 twice daily for 14 days, followed by a 7-day break.

[34] The administration of any one of the preceding [1] to

[33] is a therapy initiating on the same day as the administration of bevacizumab, oxaliplatin and capecitabine.

[35] The administration of any one of the preceding [1] to

[34] is a therapy initiating on the same day as the administration of bevacizumab, oxaliplatin, capecitabine, immune checkpoint inhibitor and EP4 antagonist.

[36] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and administered in combination with bevacizumab and XELOX therapy, and an immune checkpoint inhibitor, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, 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, which is administered at a dose of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 360 mg every 3 weeks). (iii) The bevacizumab and XELOX therapy consists of bevacizumab at a dose of 7.5 mg / kg every 3 weeks, oxaliplatin at a dose of 130 mg / m2 every 3 weeks, and capecitabine at a dose of 1000 mg / m2 twice daily for 14 days, followed by a 7-day break.

[0235]

[37] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and administered in combination with bevacizumab and XELOX therapy, and an EP4 antagonist, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein 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, which is administered at a dose of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 360 mg every 3 weeks). (iii) The bevacizumab and XELOX therapy consists of bevacizumab at a dose of 7.5 mg / kg every 3 weeks, oxaliplatin at a dose of 130 mg / m2 every 3 weeks, and capecitabine at a dose of 1000 mg / m2 twice daily for 14 days, followed by a 7-day break.

[38] The agent described above in

[36] or

[37] is a treatment initiated on the same day with bevacizumab, oxaliplatin, capecitabine, 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, and nivolumab.

[39] The agent described above in any one of

[36] to

[38] , wherein the cancer is colorectal cancer.

[40] The agent described above in

[39] , wherein the colorectal cancer is colon / rectal cancer.

[41] As described above in

[40] , wherein the colorectal cancer is an unresectable advanced or recurrent colorectal cancer (preferably an unresectable advanced or recurrent colorectal cancer without prior treatment experience).

[0236] [2-1] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and administered to a cancer patient undergoing preoperative chemoradiotherapy. [2-2] The agent described in [2-1] is further administered in combination with an immune checkpoint inhibitor. [2-3] A colorectal cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and administered in combination with an EP4 antagonist to a cancer patient undergoing preoperative chemoradiotherapy. [2-4] The agent described in any one of [2-1] to [2-3], wherein the EP4 antagonist is a compound of general formula (I) described in [3] or a salt thereof. [2-5] The agent described in any one of [2-1] to [2-4], wherein the cancer is colorectal cancer (preferably colon / rectal cancer). [2-6] The agent as described in [2-5] above, wherein the colorectal cancer is resectable and curable locally advanced rectal cancer. [2-7] The agent as described in any one of [2-1] to [2-6] above, wherein the immune checkpoint inhibitor and / or EP4 antagonist is used as adjuvant therapy after preoperative chemoradiotherapy (CRT). [2-8] The agent as described in any one of [2-1] to [2-7] above, wherein the EP4 antagonist is a compound of general formula (I-2) or a salt thereof as described in [8]. [2-9] The preparation described in any one of [2-1] to [2-8] above, wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof. [2-10] The preparation described in [2-9] above, wherein the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg. [2-11] The preparation described in [2-9] above, wherein the EP4 antagonist is administered orally once daily at a dose of 20 mg or 40 mg (preferably 40 mg). [2-12] The agent as described in 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 as described in [2-12] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0237] [2-14] As described in [2-13] above, wherein the anti-PD-1 antibody is nivolumab MGA012 monoclonal antibody, cimiprizumab, pembrolizumab, spartalizumab, tislelizumab, AMP-514, doslizumab, toripalimab, camrelizumab, genozumab, sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (refulimab), AGEN2034 (batilizumab), CS1003, HLX10 (sprullimab), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226 (Geptanumab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalizumab), BCD-100 (Progomab), PF-06801591 (Trisalizumab), CX-188, JNJ-63723283 (Cetralimab) or AB122 (Sepalimab).

[0238] [2-15] The agent described above in [2-12], wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is atezolizumab, avelumumab, durvalumab, BMS-936559, STI-1014, KN035 (envorimab), LY3300054 (rodapoxetine), 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 described above in [2-12], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipalimumab, AGEN1884, or trimemumab. [2-17] The agent described above in [2-13], wherein the anti-PD-1 antibody is nivolumab. [2-18] The agent described above in [2-13], wherein the anti-PD-1 antibody is pembrolizumab. [2-19] The agent described above in [2-13], wherein the anti-PD-1 antibody is cimipril. [2-20] The agent described above in [2-15], wherein the anti-PD-1 antibody is avelumab. [2-21] The agent described above in [2-15], wherein the anti-PD-1 antibody is atezolizumab. [2-22] The agent as described above in [2-15], wherein the anti-PD-1 antibody is devalumab. [2-23] The agent as described above in [2-16], wherein the anti-CTLA-4 antibody is ipalimumab.

[0239] [2-24] As described in [2-17] above, nivolumab is administered at a dose of 3 mg / kg (body weight), or at a dose of 240 mg every 2 weeks, at a dose of 360 mg every 3 weeks, or at a dose of 480 mg every 4 weeks (preferably at a dose of 240 mg every 2 weeks, at a dose of 360 mg every 3 weeks, or at a dose of 480 mg every 4 weeks). [2-25] As described in [2-17] above, nivolumab is administered intravenously at a dose of 240 mg every 2 weeks. [2-26] As described in [2-17] above, nivolumab is administered intravenously at a dose of 240 mg every 2 weeks over approximately 30 minutes. [2-27] As described in [2-18] above, pembrolizumab is administered at a dose of 2 mg / kg (body weight) or 200 mg at a dose every 3 weeks. [2-28] As described in [2-19] above, cimiprimab is administered at a dose of 350 mg at a dose every 3 weeks. [2-29] As described in [2-20] above, avelumab is administered at a dose of 10 mg / kg (body weight) at a dose every 2 weeks. [2-30] As described in [2-21] above, atezolizumab is administered at a dose of 1200 mg at a dose every 3 weeks. [2-31] As described in [2-22] above, durvalumab is administered at a dose of 10 mg / kg (body weight) at a dose every 2 weeks. [2-32] As described above in [2-23], ipalimumab is administered intravenously four times at three-week intervals, at a dose of 3 mg / kg (body weight) or 1 mg / kg (body weight). [2-33] As described above in any one of [2-1] to [2-32], administration is initiated within 14 days after the completion of preoperative chemoradiotherapy.

[0240] [2-34] The agent described in any one of [2-2] to [2-33] above is administered more than 7 days after the last administration of the EP4 antagonist and more than 14 days after the last administration of the immune checkpoint inhibitor, and the surgery is performed within 14 weeks after the completion of preoperative chemoradiotherapy. [2-35] The agent described in any one of [2-1] to [2-34] above is administered to patients whose imaging diagnosis confirms no distant metastasis after the completion of preoperative chemoradiotherapy. [2-36] The agent described in any one of [2-1] to [2-35] above is administered to patients whose imaging diagnosis confirms no distant metastasis after the completion of preoperative chemoradiotherapy and who are curably resectable. [2-37] The agent described in any one of [2-1] to [2-36] above, wherein the preoperative chemoradiotherapy is a combination of radiation therapy and capecitabine. [2-38] The agent described in any one of [2-1] to [2-37] above, wherein the preoperative chemoradiotherapy is 45 Gy / 25 fractions of irradiation of the pelvic cavity and 5.4 Gy / 3 fractions of boost irradiation of the primary site, and capecitabine 825 mg / m2 administered twice daily for 21 days or more than 42 fractions. [2-39] A progression-inhibiting, recurrence-inhibiting, and / or therapeutic agent for cancer (preferably colorectal cancer, more preferably colon / rectal cancer (preferably resectable locally advanced rectal cancer)), comprising an EP4 antagonist as an active ingredient, and administered to cancer patients undergoing preoperative chemoradiotherapy, wherein (i) the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, the EP4 antagonist being 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 radiation therapy and capecitabine (preferably 45 Gy / 25 fractions of pelvic irradiation and 5.4 Gy / 3 fractions of boost irradiation to the primary site, and capecitabine 825 mg / m2 twice daily for 21 days or more than 42 fractions). [2-40] The agent described above [2-39] is further combined with an immune checkpoint inhibitor, namely nivolumab, wherein anti-nivolumab is administered at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 240 mg every 2 weeks).

[0241] [2-41] A colorectal cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and targeted at cancer patients undergoing preoperative chemoradiotherapy, and administered in combination with an EP4 antagonist, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein 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 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 240 mg every 2 weeks), and (iii) the preoperative chemoradiotherapy is a combination of radiation therapy and capecitabine (preferably 45 Gy / 25 fractions of pelvic irradiation and 5.4 Gy / 3 fractions of boost irradiation of the primary site, and capecitabine 825 mg / m2 twice daily for 21 days or more than 42 fractions).

[0242] [3-1] The agent as described in [1] or [2] above, wherein the standard therapy is FOLFIRINOX therapy or a reduced version thereof. [3-2] The agent as described in [3-1] above, wherein the EP4 antagonist is a compound of general formula (I) as described in [3] above, or a salt thereof. [3-3] The agent as described in [3-1] or [3-2] above, wherein the cancer is pancreatic cancer (preferably pancreatic duct cancer, more preferably invasive pancreatic duct cancer). [3-4] The agent as described in [3-3] above, wherein the pancreatic cancer is pancreatic cancer with distant metastases. [3-5] The agent as described in any one of [3-1] to [3-4] above is administered to a patient with pancreatic cancer with distant metastases who has no history of systemic anti-tumor therapy. [3-6] An agent as described in any one of [3-1] to [3-5] above, wherein the EP4 antagonist is a compound of general formula (I-2) as described in [8] above, or a salt thereof. [3-7] An agent as described in any one of [3-1] to [3-6] above, wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof. [3-8] An agent as described in [3-7] above, wherein the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg. [3-9] As described in [3-7] above, wherein the EP4 antagonist is administered orally at a dose of 20 mg or 40 mg once daily. [3-10] As described in 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] As described in [3-10] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0243] [3-12] As described in [3-11] above, wherein the anti-PD-1 antibody is nivolumab, cimiprizumab, pembrolizumab, spartalizumab, tislelizumab, AMP-514, doslizumab, toripalimab, camrelizumab, genozumab, sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (refulimab), AGEN2034 (batilizumab), CS1003, HLX10 (sprullimab), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226 (Geptanumab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalizumab), BCD-100 (Progomab), PF-06801591 (Trisalizumab), CX-188, JNJ-63723283 (Cetralimab) or AB122 (Sepalimab). [3-13] As described in [3-10] above, wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is atezolizumab, avelumumab, durvalumab, BMS-936559, STI-1014, KN035 (envorimab), LY3300054 (rodapoxetine), 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 described above in [3-10], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipalimumab, AGEN1884, or trimemumab. [3-15] The agent described above in [3-11], wherein the anti-PD-1 antibody is nivolumab. [3-16] The agent described above in [3-11], wherein the anti-PD-1 antibody is pembrolizumab. [3-17] The agent described above in [3-11], wherein the anti-PD-1 antibody is cimipril. [3-18] The agent described above in [3-13], wherein the anti-PD-1 antibody is avelumab. [3-19] The agent described above in [3-13], wherein the anti-PD-1 antibody is atezolizumab. [3-20] The agent as described above in [3-13], wherein the anti-PD-1 antibody is devalumab. [3-21] The agent as described above in [3-14], wherein the anti-CTLA-4 antibody is ipalimumab.

[0244] [3-22] As described in [3-15] above, nivolumab is administered at a dose of 3 mg / kg (body weight), or at a dose of 240 mg every 2 weeks, at a dose of 360 mg every 3 weeks, or at a dose of 480 mg every 4 weeks (preferably at a dose of 240 mg every 2 weeks, at a dose of 360 mg every 3 weeks, or at a dose of 480 mg every 4 weeks). [3-23] As described in [3-15] above, nivolumab is administered intravenously at a dose of 480 mg every 4 weeks. [3-24] As described in [3-15] above, nivolumab is administered intravenously at a dose of 480 mg every 4 weeks, taking approximately 30 minutes. [3-25] As described in [3-16] above, pembrolizumab is administered at a dose of 2 mg / kg (body weight) once, or 200 mg once at a 3-week interval, or 400 mg once at a 6-week interval. [3-26] As described in [3-17] above, cimiprimab is administered at a dose of 350 mg once at a 3-week interval. [3-27] As described in [3-18] above, avelumab is administered at a dose of 10 mg / kg (body weight) once at a 2-week interval. [3-28] As described in [3-19] above, atezolizumab is administered at a dose of 1200 mg once at a 3-week interval. [3-29] As described above in [3-20], the devalumab is administered intravenously at a dose of 10 mg / kg (body weight) every 2 weeks or at a dose of 1500 mg every 4 weeks.

[0245] [3-30] The formulation as described in [3-21] above, wherein iperalimab is administered intravenously at 3 mg / kg (body weight) once or 1 mg / kg (body weight) once at 3-week intervals for 4 times or at 1 mg / kg (body weight) once at 6-week intervals. [3-31] The formulation as described in any one of [3-1] to [3-30] above, wherein FOLFIRINOX therapy or a tapering regimen thereof is a therapy consisting of (i) oxaliplatin, (ii) leucovorin calcium, (iii) irinotecan hydrochloride hydrate, and (iv) fluorouracil. [3-32] The agent as described in any one of [3-1] to [3-31] above, wherein the FOLFIRINOX therapy comprises the following administration: (i) intravenous administration of 50 to 85 mg / m2 (preferably 50 mg / m2, 65 mg / m2, 85 mg / m2, more preferably 85 mg / m2), (ii) intravenous administration of 200 mg / m2 of levofolate calcium, (iii) intravenous administration of 90 to 180 mg / m2 (preferably 90 mg / m2, 120 mg / m2, 150 mg / m2, 180 mg / m2, more preferably 180 mg / m2) of irinotecan hydrochloride hydrate, (iv) rapid intravenous administration of 400 mg / m2 of fluorouracil. (v) Continuous intravenous administration of fluorouracil at 1200 to 2400 mg / m2 (preferably 1200 mg / m2, 1800 mg / m2, 2400 mg / m2, and even more preferably 2400 mg / m2).

[0246] [3-33] The agent described in any one of [3-1] to [3-31] above, wherein the dose reduction regimen of FOLFIRINOX therapy comprises the following administrations: (i) intravenous administration of 50 to 85 mg / m2 (preferably 50 mg / m2, 65 mg / m2, 85 mg / m2, more preferably 85 mg / m2), (ii) intravenous administration of 200 mg / m2 of leucovorin calcium, (iii) intravenous administration of 120 to 140 mg / m2 (preferably 140 mg / m2) of irinotecan hydrochloride hydrate, (iv) continuous intravenous administration of 1200 to 2400 mg / m2 (preferably 1200 mg / m2, 1800 mg / m2, 2400 mg / m2, more preferably 2400 mg / m2). [3-34] The agent as described in any of [3-1] to [3-33] above, wherein the FOLFIRINOX therapy or its tapering regimen is a series of administrations at intervals of 2 to 4 weeks (preferably 2 weeks, 3 weeks, 4 weeks, and more preferably 2 weeks). [3-35] The agent described in any of [3-1] to [3-32] and [3-34] above, wherein the FOLFIRINOX therapy is a series of administrations administered at 2-week intervals: (i) 85 mg / m2 of oxaliplatin intravenously over 2 hours; (ii) 200 mg / m2 of levofolinate calcium intravenously over 2 hours after the oxaliplatin administration; (iii) 180 mg / m2 of irinotecan hydrochloride hydrate intravenously over 1.5 hours after the levofolinate calcium administration begins 30 minutes later; (iv) 400 mg / m2 of fluorouracil intravenously rapidly after the levofolinate calcium administration ends; and (v) 2400 mg / m2 of fluorouracil intravenously continuously over 46 hours. [3-36] The agent described in any of [3-1] to [3-31] or [3-33], [3-34] above, wherein the dose reduction regimen of FOLFIRINOX therapy is to administer the following series of treatments at 2-week intervals: (i) 85 mg / m2 of oxaliplatin intravenously over 2 hours, (ii) 200 mg / m2 of levofolinic acid calcium intravenously over 2 hours, (iii) 150 mg / m2 of irinotecan hydrochloride hydrate intravenously over 1.5 hours after the start of levofolinic acid calcium administration, and (iv) 2400 mg / m2 of fluorouracil intravenously over 46 hours after the end of the levofolinic acid calcium administration. [3-37] The agent described in any of [3-1] to [3-36] above refers to the administration of FOLFIRINOX therapy or its tapering regimen, immune checkpoint inhibitors and EP4 antagonists on the same day.

[0247] [3-38] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and administered in combination with FOLFIRINOX therapy or a tapered regimen thereof, and an immune checkpoint inhibitor, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein 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, administered as a single dose of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 480 mg every 4 weeks). (iii) The FOLFIRINOX therapy is administered as a series of doses every 2 weeks: (a) Oxaliplatin 85 mg / m² intravenously over 2 hours; (b) Levofolinic acid 200 mg / m² intravenously over 2 hours; (c) Irinotecan hydrochloride 180 mg / m² intravenously over 1.5 hours, 30 minutes after the start of levofolinic acid administration; (d) After the levofolinic acid administration is completed, fluorouracil 400 mg / m² intravenously is rapidly administered. (e) 46 hours later, continue intravenous administration of fluorouracil 2400 mg / m2; The dose reduction regimen of this FOLFIRINOX therapy is to administer the following series of treatments at 2-week intervals: (a) 2 hours later, intravenous administration of oxaliplatin 85 mg / m2; (b) 2 hours later, intravenous administration of levofolinate calcium 200 mg / m2; (c) 1.5 hours later, 30 minutes after the start of levofolinate calcium administration, intravenous administration of irinotecan hydrochloride hydrate 150 mg / m2; (d) after the end of levofolinate calcium administration, continue intravenous administration of fluorouracil 2400 mg / m2 for another 46 hours.

[0248] [3-39] A colorectal cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and administered in combination with FOLFIRINOX therapy or a reduced regimen thereof, and an EP4 antagonist, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein 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, administered as a single dose of 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 480 mg every 4 weeks). (iii) The FOLFIRINOX therapy consists of the following series of administrations every 2 weeks: (a) 85 mg / m² of oxaliplatin intravenously over 2 hours; (b) 200 mg / m² of levofolate intravenously over 2 hours; (c) 180 mg / m² of irinotecan hydrochloride intravenously over 1.5 hours, 30 minutes after the start of levofolate administration; and (d) 400 mg / m² of fluorouracil intravenously rapidly after the end of the levofolate administration. (e) 46 hours later, continue intravenous administration of fluorouracil 2400 mg / m2; The dose reduction regimen of this FOLFIRINOX therapy is to administer the following series of treatments at 2-week intervals: (a) 2 hours later, intravenous administration of oxaliplatin 85 mg / m2; (b) 2 hours later, intravenous administration of levofolate calcium 200 mg / m2; (c) 1.5 hours later, 30 minutes after the start of levofolate calcium administration, intravenous administration of irinotecan hydrochloride hydrate 150 mg / m2; (d) after the end of levofolate calcium administration, continue intravenous administration of fluorouracil 2400 mg / m2 for another 46 hours.

[0249] [3-40] The agent described in [3-38] or [3-39] is a treatment initiated on the same day with FOLFIRINOX therapy or a tapering regimen thereof, 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, and nivolumab. [3-41] The agent described in [3-38] to [3-40] above, wherein the cancer is pancreatic cancer (preferably pancreatic duct cancer, more preferably invasive pancreatic duct cancer). [3-42] The agent described in [3-41] above, wherein the pancreatic cancer is pancreatic cancer with distant metastases. [3-43] The agent described in any of [3-38] to [3-42] above is administered to patients with pancreatic cancer that has distant metastases and who have no history of systemic anti-tumor therapy.

[0250] [4-1] The agent as described in [1] or [2] above, wherein the standard therapy is gemcitabine and albumin-bound paclitaxel therapy. [4-2] The agent as described in [4-1] above, wherein the EP4 antagonist is a compound of general formula (I) or a salt thereof as described in [3] above. [4-3] The agent as described in [4-1] or [4-2] above, wherein the cancer is pancreatic cancer (preferably pancreatic duct cancer, more preferably invasive pancreatic duct cancer). [4-4] The agent as described in [4-3] above, wherein the pancreatic cancer is pancreatic cancer with distant metastases. [4-5] The agent as described in any one of [4-1] to [4-4] above is administered to a patient with pancreatic cancer with distant metastases who has no history of systemic anti-tumor therapy. [4-6] An agent as described in any one of [4-1] to [4-5] above, wherein the EP4 antagonist is a compound of general formula (I-2) as described in [8] above, or a salt thereof. [4-7] An agent as described in any one of [4-1] to [4-6] above, wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof. [4-8] An agent as described in [4-7] above, wherein the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg. [4-9] As described in [4-7] above, wherein the EP4 antagonist is administered orally once daily at a dose of 20 mg or 40 mg (preferably 40 mg). [4-10] As described in 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] As described in [4-10] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0251] [4-12] The agent described above in [4-11], wherein the anti-PD-1 antibody is nivolumab, cimiprizumab, pembrolizumab, spartalizumab, tislelizumab, AMP-514, doslizumab, toripalimab, camrelizumab, genozumab, sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (refulimab), AGEN2034 (batilizumab), CS1003, HLX10 (sprullimab), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226 (Geptanumab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalizumab), BCD-100 (Progomab), PF-06801591 (Trisalizumab), CX-188, JNJ-63723283 (Cetralimab) or AB122 (Sepalimab). [4-13] As described above in [4-10], wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is atezolizumab, avelumumab, durvalumab, BMS-936559, STI-1014, KN035 (envorimab), LY3300054 (rodapoxetine), HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 and CX-072.

[0252] [4-14] The agent described above in [4-10], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipalimumab, AGEN1884, or trimemumab. [4-15] The agent described above in [4-11], wherein the anti-PD-1 antibody is nivolumab. [4-16] The agent described above in [4-11], wherein the anti-PD-1 antibody is pembrolizumab. [4-17] The agent described above in [4-11], wherein the anti-PD-1 antibody is cimipril. [4-18] The agent described above in [4-13], wherein the anti-PD-1 antibody is avelumab. [4-19] The agent described above in [4-13], wherein the anti-PD-1 antibody is atezolizumab. [4-20] As described in [4-13] above, wherein the anti-PD-1 antibody is durvalumab. [4-21] As described in [4-14] above, wherein the anti-CTLA-4 antibody is ipalimumab. [4-22] As described in [4-15] above, wherein nivolumab is administered at a single dose of 3 mg / kg (body weight), or at a single dose of 240 mg every 2 weeks, at a single dose of 360 mg every 3 weeks, or at a single dose of 480 mg every 4 weeks (preferably at a single dose of 240 mg every 2 weeks, at a single dose of 360 mg every 3 weeks, or at a single dose of 480 mg every 4 weeks). [4-23] As described in [4-15] above, wherein nivolumab is administered intravenously at a single dose of 480 mg every 4 weeks. [4-24] As described above in [4-15], nivolumab is administered intravenously at 480 mg intervals over approximately 30 minutes.

[0253] [4-25] As described in [4-16] above, wherein pembrolizumab is administered at a dose of 2 mg / kg (body weight) or 200 mg at a dose of 3 weeks. [4-26] As described in [4-17] above, wherein cimiprimab is administered at a dose of 350 mg at a dose of 3 weeks. [4-27] As described in [4-18] above, wherein avelumab is administered at a dose of 10 mg / kg (body weight) at a dose of 2 weeks. [4-28] As described in [4-19] above, wherein atezolizumab is administered at a dose of 1200 mg at a dose of 3 weeks. [4-29] As described in [4-20] above, wherein durvalumab is administered at a dose of 10 mg / kg (body weight) at a dose of 2 weeks. [4-30] As described in [4-21] above, wherein ipalimumab is administered intravenously four times at 3 mg / kg (body weight) or 1 mg / kg (body weight) once every 3 weeks. [4-31] As described in any one of [4-1] to [4-30] above, wherein gemcitabine and albumin-bound paclitaxel therapy comprises the following administrations: (i) intravenous administration of gemcitabine at 600 to 1000 mg / m2 (preferably 600 mg / m2, 800 mg / m2, 1000 mg / m2, more preferably 1000 mg / m2), and (ii) intravenous administration of albumin-bound paclitaxel at 75 to 125 mg / m2 (preferably 75 mg / m2, 100 mg / m2, 125 mg / m2, more preferably 125 mg / m2). [4-32] As described in any of [4-1] to [4-31] above, gemcitabine and albumin-bound paclitaxel therapy is a series of administrations administered at one-week intervals for three weeks, followed by a one-week break. [4-33] As described in any of [4-1] to [4-32] above, gemcitabine and albumin-bound paclitaxel therapy is a series of administrations administered at one-week intervals for three weeks, followed by a one-week break: (i) 1000 mg / m² of gemcitabine administered intravenously over 30 minutes, (ii) 125 mg / m² of albumin-bound paclitaxel administered intravenously over 30 minutes. [4-34] As described in any of [4-1] to [4-33] above, the administration of gemcitabine and albumin-bound paclitaxel is initiated on the same day. [4-35] The agent described in any of [4-1] to [4-34] above refers to the therapy initiated on the same day with the administration of gemcitabine, albumin-bound paclitaxel, immune checkpoint inhibitor and EP4 antagonist.

[0254] [4-36] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and administered in combination with gemcitabine and albumin-bound paclitaxel therapy, and an immune checkpoint inhibitor, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein 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, administered as follows: 240 mg of nivolumab every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 480 mg every 4 weeks). (iii) The gemcitabine and albumin-bound paclitaxel therapy consists of the following series of administrations every 1 week for 3 weeks, followed by a 1-week break: (a) 1000 mg / m² of gemcitabine administered intravenously over 30 minutes, and (b) 125 mg / m² of albumin-bound paclitaxel administered intravenously over 30 minutes. [4-37] A colorectal cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and administered in combination with gemcitabine and albumin-bound paclitaxel therapy, and an EP4 antagonist, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein 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, administered at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 480 mg every 4 weeks). (iii) The gemcitabine and albumin-bound paclitaxel therapy is administered at 1-week intervals for 3 weeks, followed by a 1-week break: (a) 1000 mg / m² of gemcitabine intravenously over 30 minutes, and (b) 125 mg / m² of albumin-bound paclitaxel intravenously over 30 minutes. [4-38] As described above in [4-36] or [4-37], wherein the cancer is pancreatic cancer (preferably pancreatic duct cancer, more preferably invasive pancreatic duct cancer). [4-39] The agent described above in [4-38], wherein the pancreatic cancer is pancreatic cancer with distant metastasis.[4-40] The agent described in any of [4-36] to [4-39] above is administered to a patient with pancreatic cancer that has distant metastases and has no history of systemic anti-tumor therapy.

[0255] [5-1] The preparation as described in [1] or [2] above, wherein the standard therapy is paclitaxel and / or ramucirumab therapy. [5-2] The preparation as described in [5-1] above, wherein the standard therapy is paclitaxel therapy. [5-3] The preparation as described in [5-1] above, wherein the standard therapy is ramucirumab therapy. [5-4] The preparation as described in [5-1] above, wherein the standard therapy is paclitaxel and ramucirumab therapy. [5-5] The preparation as described in [5-1] to [5-4] above, wherein the EP4 antagonist is a compound of general formula (I) as described in [3] above, or a salt thereof. [5-6] The preparation as described in 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 as described in [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 unresponsive to concomitant therapy with anti-PD-1 antibody or anti-PD-L1 antibody and platinum preparation). [5-8] The agent as described in any one of [5-1] to [5-7] above is administered to patients who are deemed unresponsive to concomitant therapy with anti-PD-1 antibody or anti-PD-L1 antibody and platinum preparation. [5-9] The agent as described in any one of [5-1] to [5-8] above, wherein the EP4 antagonist is a compound of general formula (I-2) described in [8] above or a salt thereof. [5-10] The preparation described in any one of [5-1] to [5-9] above, wherein the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof. [5-11] The preparation described in [5-10] above, wherein the EP4 antagonist is administered orally once daily in doses of 5 mg to 40 mg. [5-12] The preparation described in [5-10] above, wherein the EP4 antagonist is administered orally once daily in doses of 20 mg or 40 mg.

[0256] [5-13] The agent as described in 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 as described in [5-13] above, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody. [5-15] As described in [5-14] above, the anti-PD-1 antibody is nivolumab, cimiprizumab, pembrolizumab, spartalizumab, tislelizumab, AMP-514, doslizumab, toripalimab, camrelizumab, genozumab, sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012 (refulimab), AGEN2034 (batilizumab), CS1003, HLX10 (sprullimab), BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226 (Geptanumab), SSI-361, JY034, HX008, ISU106, ABBV181 (Budigalizumab), BCD-100 (Progomab), PF-06801591 (Trisalizumab), CX-188, JNJ-63723283 (Cetralimab) or AB122 (Sepalimab). [5-16] As described above in [5-13], wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody, and the anti-PD-L1 antibody is atezolizumab, avelumumab, durvalumab, BMS-936559, STI-1014, KN035 (envorimab), LY3300054 (rodapoxetine), HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 and CX-072.

[0257] [5-17] The agent described above in [5-13], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody, and the anti-CTLA-4 antibody is ipalimumab, AGEN1884, or trimemumab. [5-18] The agent described above in [5-14], wherein the anti-PD-1 antibody is nivolumab. [5-19] The agent described above in [5-14], wherein the anti-PD-1 antibody is pembrolizumab. [5-20] The agent described above in [5-14], wherein the anti-PD-1 antibody is cimipril. [5-21] The agent described above in [5-16], wherein the anti-PD-1 antibody is avelumab. [5-22] The agent described above in [5-16], wherein the anti-PD-1 antibody is atezolizumab. [5-23] As described in [5-16] above, wherein the anti-PD-1 antibody is durvalumab. [5-24] As described in [5-17] above, wherein the anti-CTLA-4 antibody is ipalimumab. [5-25] As described in [5-18] above, wherein nivolumab is administered at a dose of 3 mg / kg (body weight), or at a dose of 240 mg every 2 weeks, at a dose of 360 mg every 3 weeks, or at a dose of 480 mg every 4 weeks (preferably at a dose of 240 mg every 2 weeks, at a dose of 360 mg every 3 weeks, or at a dose of 480 mg every 4 weeks). [5-26] As described in [5-18] above, wherein nivolumab is administered intravenously at a dose of 360 mg every 3 weeks. [5-27] As described above in [5-18], nivolumab is administered intravenously at a dose of 360 mg every 3 weeks, taking approximately 30 minutes. [5-28] As described above in [5-19], pembrolizumab is administered at a dose of 2 mg / kg (body weight), or 200 mg every 3 weeks, or 400 mg every 6 weeks.

[0258] [5-29] As described in [5-20] above, wherein cimiprimab is administered at a single dose of 350 mg every 3 weeks. [5-30] As described in [5-21] above, wherein avelumab is administered at a single dose of 10 mg / kg (body weight) every 2 weeks. [5-31] As described in [5-22] above, wherein atezolizumab is administered at a single dose of 1200 mg every 3 weeks. [5-32] As described in [5-23] above, wherein durvalumab is administered at a single dose of 10 mg / kg (body weight) every 2 weeks, or at a single dose of 1500 mg every 4 weeks, administered intravenously 4 times. [5-33] As described in [5-24] above, wherein ipalimumab is administered intravenously at 3 mg / kg (body weight) once or 1 mg / kg (body weight) once at 3-week intervals for 4 times, or at 1 mg / kg (body weight) once at 6-week intervals. [5-34] As described in any one of [5-1], [5-2], [5-4] to [5-33] above, wherein the European paclitaxel therapy is a therapy in which European paclitaxel is administered intravenously at 50 to 75 mg / m2 (preferably 50 mg / m2, 60 mg / m2, 75 mg / m2, more preferably 60 mg / m2). [5-35] The agent described in any one of [5-1], [5-2], [5-4] to [5-34] above, wherein the European paclitaxel therapy is a treatment in which 50 to 75 mg / m2 of European paclitaxel (preferably 50 mg / m2, 60 mg / m2, 75 mg / m2, more preferably 60 mg / m2) is administered intravenously over a period of 60 minutes or more, and the administration is carried out at 3-week intervals. [5-36] The agent described in any one of [5-1], [5-3], [5-4] to [5-33] above, wherein the ramucirumab therapy is a treatment in which 6 to 10 mg / kg of ramucirumab (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) is administered intravenously. [5-37] The agent as described in any one of [5-1], [5-3], [5-4] to [5-33], [5-36] above, wherein the ramucirumab therapy is a series of intravenous administrations of ramucirumab at 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), with the series of administrations being administered at 3-week intervals.

[0259] [5-38] The agent described in any one of [5-1], [5-4] to [5-33] above, wherein the European paclitaxel and ramucirumab therapy is a therapy comprising the following administration: (i) intravenous administration of 50 to 75 mg / m2 (preferably 50 mg / m2, 60 mg / m2, 75 mg / m2, more preferably 60 mg / m2), and (ii) intravenous administration of 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg). [5-39] The agent described in any one of [5-1], [5-4] to [5-33], [5-38] above, wherein the paclitaxel and ramucirumab therapy is a therapy consisting of the following series of administrations at 3-week intervals: (i) intravenous administration of 50 to 75 mg / m2 (preferably 50 mg / m2, 60 mg / m2, 75 mg / m2, more preferably 60 mg / m2) of paclitaxel over 60 minutes or more, and (ii) intravenous administration of 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) of ramucirumab over 30 to 60 minutes (preferably 60 minutes). [5-40] The agent described in any of [5-1] to [5-39] above is a therapy in which the administration of paclitaxel and / or ramucirumab therapy, immune checkpoint inhibitors and EP4 antagonists is initiated on the same day. [5-41] A cancer progression inhibitor, relapse inhibitor and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and administered in combination with paclitaxel therapy and immune checkpoint inhibitors, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein the EP4 antagonist is administered orally once daily in doses of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) The immune checkpoint inhibitor is nivolumab, which is administered at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 360 mg every 3 weeks). (iii) The European paclitaxel therapy is administered intravenously at 50 to 75 mg / m2 (preferably 50 mg / m2, 60 mg / m2, 75 mg / m2, more preferably 60 mg / m2) over a period of 60 minutes or more, at 3-week intervals.

[0260] [5-42] A colorectal cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and administered in combination with European paclitaxel therapy and an EP4 antagonist, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein 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, which is administered at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 360 mg every 3 weeks). (iii) The European paclitaxel therapy is administered intravenously at 50 to 75 mg / m2 (preferably 50 mg / m2, 60 mg / m2, 75 mg / m2, more preferably 60 mg / m2) over a period of 60 minutes or more, at 3-week intervals.

[0261] [5-43] The agent described above in [5-41] or [5-42] is a treatment that begins on the same day as the administration of paclitaxel, 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, and nivolumab (preferably paclitaxel is administered after the administration of 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, and nivolumab). [5-44] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and administered in combination with ramucirumab therapy and an immune checkpoint inhibitor, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) Nivolumab is an immune checkpoint inhibitor administered at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 360 mg every 3 weeks). (iii) Ramucirumab therapy is administered intravenously at 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), with the series of administrations at 3-week intervals.

[0262] [5-45] A colorectal cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an immune checkpoint inhibitor as an active ingredient, and administered in combination with ramucirumab therapy and an EP4 antagonist, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein the EP4 antagonist is administered orally once daily at a dose of 5 mg to 40 mg (preferably 20 mg or 40 mg). (ii) Nivolumab is an immune checkpoint inhibitor administered at 240 mg every 2 weeks, 360 mg every 3 weeks, or 480 mg every 4 weeks (preferably 360 mg every 3 weeks). (iii) Ramucirumab therapy is administered intravenously at 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), with the series of administrations at 3-week intervals. [5-46] As described above in [5-44] or [5-45], the treatment is initiated on the same day as the administration of ramucirumab, 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, and nivolumab (preferably administered on the same day after the administration of 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, and nivolumab).[5-47] A cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprising an EP4 antagonist as an active ingredient, and administered in combination with paclitaxel and ramucirumab therapy, and an immune checkpoint inhibitor, wherein (i) the EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric 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, administered as a single dose of 240 mg every 2 weeks, a single dose of 360 mg every 3 weeks, or a single dose of 480 mg every 4 weeks (preferably a single dose of 360 mg every 3 weeks). (iii) The treatment with paclitaxel and ramucirumab is a series of administrations administered at 3-week intervals: (a) 50 to 75 mg / m² (preferably 50 mg / m², 60 mg / m², 75 mg / m², more preferably 60 mg / m²) of paclitaxel administered intravenously over 60 minutes or more; (b) 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) of ramucirumab administered intravenously over 30 to 60 minutes (preferably 60 minutes).

[0263] [5-48] A progression-inhibiting, recurrence-inhibiting, and / or therapeutic agent for colorectal cancer, comprising an immune checkpoint inhibitor as an active ingredient, and administered in combination with European paclitaxel and ramucirumab therapy, and an EP4 antagonist, (i) the EP4 antagonist being 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, wherein 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, administered as a single dose of 240 mg every 2 weeks, a single dose of 360 mg every 3 weeks, or a single dose of 480 mg every 4 weeks (preferably a single dose of 360 mg every 3 weeks). (iii) The treatment with paclitaxel and ramucirumab is a series of administrations administered at 3-week intervals: (a) 50 to 75 mg / m² (preferably 50 mg / m², 60 mg / m², 75 mg / m², more preferably 60 mg / m²) of paclitaxel administered intravenously over 60 minutes or more; (b) 6 to 10 mg / kg (preferably 6 mg / kg, 8 mg / kg, 10 mg / kg, more preferably 10 mg / kg) of ramucirumab administered intravenously over 30 to 60 minutes (preferably 60 minutes).

[0264] [5-49] As described above in [5-47] or [5-48], the agents used on the same day were European paclitaxel, ramucirumab, 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or its salts, Therapy with nivolumab (preferably administered on the same day as 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof, and nivolumab followed by paclitaxel and ramucirumab). [5-50] The agent as described in 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 as described in [5-50] above, wherein the lung cancer is stage IV or recurrent non-small cell lung cancer (preferably advanced or recurrent non-small cell lung cancer for which concomitant therapy with anti-PD-1 antibody or anti-PD-L1 antibody and platinum preparation is ineffective). [5-52] The agent described in any of [5-41] to [5-51] above is administered to patients with advanced or relapsed disease who have been deemed ineffective by concomitant therapy comprising anti-PD-1 antibody or anti-PD-L1 antibody and platinum preparation.

[0265] [6-1] An EP4 antagonist used for the inhibition of cancer progression, inhibition of recurrence and / or treatment, wherein the standard therapy is preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy. X therapy or its reduced regimen, (iv) gemcitabine and albumin-bound paclitaxel therapy, (vii) European paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or its reduced regimen, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, and a combination of administration of immune checkpoint inhibitors. [6-2] An immune checkpoint inhibitor used for the inhibition of cancer progression, recurrence, and / or treatment, comprising a standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINO X therapy or its reduced regimen, (iv) gemcitabine and albumin-bound paclitaxel therapy, (vii) European paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or its reduced regimen, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, and a combination of EP4 antagonist administration.

[0266] [6-3] The use of an EP4 antagonist in the manufacture of a cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent, wherein the standard therapy is (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced regimen thereof. (iv) FOLFIRINOX therapy or its reduced regimen, (vii) gemcitabine and albumin-bound paclitaxel therapy, or (vi) European paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or its reduced regimen, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, and a combination of administration of immune checkpoint inhibitors. [6-4] The use of an immune checkpoint inhibitor in the manufacture of a cancer progression inhibitor, recurrence inhibitor, and / or therapeutic agent comprises a standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy, or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy, or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, or (iii) FOLFIRINOX therapy, or a reduced regimen thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) paclitaxel and / or ramucirumab therapy, or ... more preferably (iv) pac (iv) FOLFIRINOX therapy or its tapered regimen, (vii) gemcitabine and albumin-bound paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or its tapered regimen, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, and a combination of EP4 antagonist administration.[6-5] A method for inhibiting cancer progression, inhibiting recurrence, and / or treating cancer, comprising administering an effective dose of standard therapy (preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose thereof, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (v) paclitaxel and / or ramucirumab therapy, more preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or a reduced dose thereof) to a patient who requires cancer treatment. The regimen may include (iv) gemcitabine and albumin-bound paclitaxel therapy, (vii) European paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, preferably (i) bevacizumab and XELOX therapy, (iii) FOLFIRINOX therapy or its tapered regimen, (iv) gemcitabine and albumin-bound paclitaxel therapy, or (vi) European paclitaxel and ramucirumab therapy, and may be administered separately or simultaneously with an effective amount of immune checkpoint inhibitor and an effective amount of EP4 antagonist.

[0267] Unless otherwise defined, all technical and scientific terms and abbreviations used in this specification shall have the same meaning as those commonly understood by one of ordinary skill in the art to which this invention pertains.

[0268] Furthermore, all patent documents, non-patent documents, or references expressly cited in this specification are incorporated herein by reference as part of this specification. [Example]

[0269] Hereinafter, the present invention will be described in detail by way of 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-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid (compound A). Compound A can be manufactured according to a known method, such as the method described in Examples 2-13 of WO2016 / 111347.

[0270] Example 1: A non-blinded, non-controlled trial of compound A, nivolumab, and XELOX + bevacizumab (a standard treatment) as first-line therapy in patients with unresectable advanced or recurrent colorectal cancer. The purpose of this trial was to examine the tolerability, safety, and efficacy of compound A, nivolumab, and XELOX + bevacizumab as first-line therapy in patients with unresectable advanced or recurrent colorectal cancer. This clinical trial aimed to evaluate the combined effects of compound A, nivolumab, and XELOX + bevacizumab therapy. (1) Patients with unresectable advanced or recurrent colorectal cancer. (2) Patient selection criteria: When registering patients, they must have no history of systemic anti-tumor therapy for unresectable advanced or recurrent colorectal cancer. Furthermore, for Compound A, nivolumab, and XELOX+bevacizumab therapy, the predetermined patient selection criteria are determined by considering the patient selection criteria of all clinical trials conducted to date. Patients meeting all patient selection criteria are selected. In addition, if a patient clearly fails to meet these criteria from registration to the initial administration of the clinical trial drug, the clinical trial drug will not be administered, and the clinical trial will be terminated. (3) Patient exclusion criteria: When registering patients, the predetermined patient exclusion criteria are determined by considering the patient exclusion criteria of each clinical trial for Compound A, nivolumab, and XELOX+bevacizumab therapy, or the precautions for patient selection in each appropriate use guideline or appropriate use information for Compound A, nivolumab, and XELOX+bevacizumab therapy. Patients deemed to meet any of these exclusion criteria are excluded. Furthermore, if the criteria are clearly not met from the time of registration to the initial administration of the clinical trial drug, the administration of the clinical trial drug will not begin, and the clinical trial will be terminated.

[0271] (4) Dosage and Administration [Compound A] 20 mg or 40 mg of Compound A shall be administered orally once daily until the predetermined discontinuation criteria for Compound A are met. Alternatively, when administering Compound A, nivolumab, and XELOX + bevacizumab on the same day, Compound A and nivolumab shall be administered first, followed by XELOX + bevacizumab therapy. [Nivolumab] 360 mg of nivolumab shall be administered intravenously over 30 minutes at 3-week intervals until the predetermined discontinuation criteria for nivolumab are met. Furthermore, nivolumab administration shall be performed on or after day 15, at least 14 days after the previous administration. [XELOX + Bevacizumab Therapy] Bevacizumab 7.5 mg / kg was administered intravenously over 90 minutes. If well tolerated, a second administration was given over 60 minutes, followed by intravenous administration over 30 minutes for circulation. Oxaliplatin 130 mg / m² (body surface area) was administered intravenously over 2 hours. Capecitabine 1000 mg / m² was administered orally twice daily after breakfast and dinner for 14 days, followed by a 7-day break. Bevacizumab, oxaliplatin, and capecitabine were administered using their respective commercially available products. [Clinical Trial Schedule] This trial includes a screening period, a treatment period, and a post-observation period. A summary of the clinical trial schedule is shown in Figure 1. The screening period was within 28 days prior to administration of the clinical trial drug. The principal investigator or co-investigator selected patients who met the above selection criteria and did not violate the above exclusion criteria, and were deemed eligible for this clinical trial.

[0272] The treatment period is 21 days per cycle, with the initial administration date of the clinical trial drug designated as day 1 of cycle 1. Day 1 of each subsequent cycle is designated as [21 x (cycle number - 1) + 1]. For Compound A, nivolumab, and XELOX + bevacizumab therapy, administration was initiated according to the above-mentioned dosage / method, and continued according to the administration baseline, reduction baseline, and reduction dosage for Compound A, nivolumab, and XELOX + bevacizumab therapy. The assessment at the end (discontinuation) of Compound A, nivolumab, and XELOX + bevacizumab therapy was based on the point of termination as the end of the treatment period. Among all subjects who received the clinical trial drug, those who discontinued or terminated Compound A, nivolumab, and XELOX + bevacizumab therapy were assessed at the end (discontinuation) of administration and moved to the post-observation period. A follow-up investigation will be conducted after the observation period ends.

[0273] [Administration Criteria for Compound A and Nivolumab] At the start of each administration, the subject must meet all predetermined administration criteria, which are determined by taking into account the administration criteria of clinical trials conducted to date concerning Compound A and nivolumab. If any criterion is not met, the predetermined administration of Compound A and nivolumab will be discontinued. However, even if any criterion is not met, if there is no assessment of clinical worsening as determined by disease progression, and the clinical benefit of continued administration is not expected, and if it is determined, considering the subject's criteria and the effects of concomitant medications, that it is safe to continue administration of Compound A and nivolumab, then administration of Compound A and nivolumab may continue. [Compound A Dosing Discontinuation Criteria] During treatment, medication to Compound A will be discontinued for subjects who meet any of the predetermined dosing discontinuation criteria, which are determined by considering the dosing discontinuation criteria of clinical trials conducted to date for Compound A. [Nivolumab Dosing Discontinuation Criteria] During treatment, medication to nivolumab will be discontinued for subjects who meet any of the predetermined dosing discontinuation criteria, which are determined by considering the dosing discontinuation criteria of clinical trials conducted to date for nivolumab. [XELOX + Bevacizumab Therapy Dosing Criteria] At the start of each dosing, subjects must meet all predetermined dosing criteria, which are determined by considering the dosing criteria of clinical trials conducted to date for XELOX + Bevacizumab therapy. The administration will be postponed until the clinical test values ​​on the scheduled administration date return to a state that meets the criteria. Administration will proceed only after confirmation that contraindications to any of the medications are not met. [Reduction and Criteria for XELOX + Bevacizumab Therapy] Reduction will be carried out according to the latest package insert. [Criteria for Discontinuation of XELOX + Bevacizumab Therapy] During the treatment period, XELOX + Bevacizumab therapy will be discontinued for subjects who meet any of the predetermined discontinuation criteria. These predetermined discontinuation criteria are determined by considering the discontinuation criteria for XELOX + Bevacizumab therapy implemented to date in clinical trials. [Criteria for Efficacy Assessment] (Imaging Diagnosis) CT / MRI scans of the chest, abdomen, and pelvis will be performed. Furthermore, during the screening period (within 28 days before the administration of the clinical trial drug), if brain metastasis is suspected based on clinical symptoms, head CT / MRI, fluorodeoxyglucose positron emission tomography (FDG-PET) (or bone scintigraphy) are performed to confirm whether there is brain or bone metastasis.

[0274] The principal investigator or co-investigator of the clinical trial determines the antitumor effect by measuring the tumor diameter of the target lesion according to the RECIST guidelines. The baseline assessment is performed using the latest imaging examination within 28 days prior to drug administration to confirm at least one measurable lesion as defined in RECIST guidelines version 1.1. Imaging diagnoses during the treatment period are measured at 6-week intervals from 6 weeks (+7 days) after the start of cycle 1 to 54 weeks (+7 days), and thereafter at 12-week intervals (±7 days).

[0275] In addition, the so-called overall efficacy and best overall efficacy are based on the imaging diagnostic results assessed by RECIST guidelines version 1.1. (Assessment items) (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) Change rate of the sum of the diameters of the target lesions, (9) Maximum change rate of the sum of the diameters of the target lesions, (10) Changes in tumor markers (CEA and CA19-9) (1) Objective response rate The objective response rate represents the proportion of subjects who are judged to have a complete response (hereinafter abbreviated as "CR") or a partial response (hereinafter abbreviated as "PR"). (2) Disease Control Rate: The disease control rate represents the proportion of subjects whose best overall response was determined to be CR, PR, or stable disease (hereinafter, "SD"). (3) Overall Survival: Overall survival is calculated as follows: Overall survival (days) = "Day of death from any cause" - "Date of administration of clinical trial drug" + 1. In addition, for subjects who could not be tracked or who had not died by the data cutoff date, the cutoff date is the date of final survival confirmation. (4) Progression-Free Survival: Progression-free survival is calculated as follows: Progression-Free Survival (days) = "Earlier of the date of determination of PD or date of death from any cause" - "Date of administration of clinical trial drug" + 1. In addition, for subjects whose overall response was not determined to be progressive disease (hereinafter, "PD") and who had not died, the cutoff date is the date of the last evaluable imaging diagnosis. For subjects who did not undergo evaluable imaging diagnosis and who had not died, the cutoff date is the date of administration of clinical trial drug. For subjects who received post-cancer treatment before their overall efficacy was determined to be PD or who died, the cutoff date was the date of the last evaluable imaging diagnosis before the start of post-cancer treatment. (5) Remission period The remission period is calculated by the following formula.Remission period (days) = "the earlier of the date on which the overall efficacy after remission is first determined to be PD or the date of death from any cause" - "the date of the initial determination of CR or PR" + 1. In addition, the subjects evaluated are those who have been determined to have CR or PR through clinical trials. (6) Time to remission The time to remission is calculated by the following formula. Time to remission (days) = "the date of the initial determination of CR or PR" - "the date of start of clinical trial drug administration" + 1 (7) Change rate of the sum of tumor diameters of the target lesion For subjects with target lesions, the change rate of the sum of tumor diameters of the target lesion is calculated using the following formula. However, the change rate of the sum of tumor diameters of the target lesion after post-treatment is not calculated.

[0276] Change rate (%) = ("Tumor diameter at each assessment time point - sum of tumor diameters before treatment") / ("sum of tumor diameters before treatment") x 100

[0277] (8) Maximum rate of change of the sum of tumor diameters of the target lesion The maximum rate of change of the sum of tumor diameters of the target lesion is the rate of change at the point in time when the sum of tumor diameters of the target lesion becomes the smallest. However, the sum of tumor diameters of the target lesion after the overall efficacy is determined to be PD or after post-treatment is performed is not used in the calculation of the maximum rate of change.

[0278] Maximum rate of change (%) = ("Sum of minimum tumor diameters after administration - Sum of tumor diameters before administration") / ("Sum of tumor diameters before administration") x 100

[0279] [Safety Assessment Items] The following items were measured, examined and investigated by the clinical trial principal investigator and others at the predetermined time: (1) dosage-limiting toxicity, (2) adverse events, (3) clinical examination (hematological examination, blood biochemistry examination, hormone survey, coagulation system examination, urine qualitative examination, immunological examination), (4) vital signs (systolic blood pressure / diastolic blood pressure, heart rate, body temperature), transcutaneous oxygen saturation (SpO2), weight, (5) 12-lead electrocardiogram, (6) ECOG performance status, (7) chest X-ray, (8) ophthalmological examination (visual acuity examination, intraocular pressure examination, slit-lamp microscopy, (9) CT scan. [Efficacy Assessment Results] Ten months after the first subject was enrolled, two cases were judged to be PR.

[0280] Example 2: A non-blinded, non-controlled trial of compound A or a combination of compound A and nivolumab as preoperative adjuvant therapy after preoperative chemoradiotherapy in patients with resectable and curable locally advanced rectal cancer. The purpose of this trial is to examine the efficacy, pharmacodynamics, and safety of compound A as a single dose and / or compound A combined with nivolumab as preoperative adjuvant therapy after preoperative chemoradiotherapy (CRT) in patients with resectable and curable locally advanced rectal cancer. Through this clinical trial, the effects of compound A and / or compound A combined with nivolumab as preoperative adjuvant therapy can be evaluated. (1) Subjects: Resectable and curable locally advanced rectal cancer (2) Patient selection criteria: Patients who meet the predetermined patient selection criteria are selected during registration. The predetermined patient selection criteria are determined with respect to nivolumab and compound A, taking into account the patient selection criteria of various clinical trials conducted to date. Furthermore, if the criteria are clearly not met from the time of registration to the initial administration of the clinical trial drug, the administration of the clinical trial drug will not begin, and the clinical trial will be terminated.

[0281] As preoperative CRT, it is administered to patients who have received treatment meeting the following criteria: • 45 Gy / 25 fractions of pelvic irradiation and 5.4 Gy / 3 fractions of boost irradiation at the primary site. • Capecitabine is started at a dose of 1,650 mg / m² daily (825 mg / m² twice daily). The starting dose is determined according to Method D of the dosage / use of XELODA (registered trademark) Tablet 300. • In combination with radiation, capecitabine is administered orally for 75% of the equivalent of 28 radiation fractions (e.g., 21 days of oral administration or 42 or more oral administrations, morning and evening, for 50.4 Gy / 28 fractions). Regardless of dose reduction.

[0282] After the completion of preoperative CRT treatment with capecitabine and radiation irradiation, the drug was administered to patients who could begin clinical trial administration within 14 days.

[0283] If the imaging diagnosis after the end of the preoperative CRT confirms that there is no distant metastasis, the patient who can be cured and resected will be given the drug. In addition, the imaging diagnosis before registration is based on the images taken from 14 days before the end of the preoperative CRT to the registration date. (3) Patient exclusion criteria When registering, the patient exclusion criteria in the various clinical trials of Compound A and nivolumab to date, or the precautions for patient selection in the appropriate use guidelines or appropriate use information of Compound A and nivolumab, are determined to exclude patients who are considered to meet any of the patient exclusion criteria. In addition, if the criteria are not clearly met from the registration to the first administration of the clinical trial drug, the administration of the clinical trial drug will not be started and the clinical trial will be terminated. (4) Dosage and administration period [Compound A] 40 mg of Compound A is administered orally once a day until the predetermined administration termination criteria for Compound A are met. [Nivolumab] Nivolumab 240 mg is administered intravenously over 30 minutes at 2-week intervals until the predetermined dosing discontinuation criteria for nivolumab are met. Nivolumab administration must be initiated at least 10 days after the day following the previous administration, starting on day 11. [Clinical Trial Schedule] This clinical trial consists of a screening phase, a treatment phase, a perioperative phase, and a post-observation phase. A summary of the clinical trial design is shown in Figure 2.

[0284] During the screening period, patients with locally advanced rectal cancer who were deemed suitable to be subjects of this clinical trial based on the preoperative resectable curable condition were registered and moved to the treatment period.

[0285] During the treatment period, administration of the clinical trial drug was initiated within 14 days after the end of the preoperative CRT. After a certain period of administration of compound A (40 mg, once daily (QD), orally), two groups were established: one group (cohort 1) administered compound A (40 mg, QD, orally) in combination with nivolumab (240 mg, Q2W, intravenously) for a certain period, and another group (cohort 2) administered compound A (40 mg, QD, orally) in combination with nivolumab (240 mg, Q2W, intravenously) for a certain period. Furthermore, after the enrollment of cohort 1 was completed, enrollment of cohort 2 began. After the completion of the clinical trial drug administration, all subjects underwent a treatment termination (discontinuation) examination, transitioning from the treatment period to the surgical period.

[0286] During the surgical period, surgery should, in principle, be performed at least 7 days after the final administration of compound A and at least 14 days after the final administration of nivolumab, and within 14 weeks after the end of preoperative CRT. However, regarding the timing of surgery, the patient's condition should be the primary consideration; however, this does not apply if surgery needs to be postponed due to further deterioration of the original disease or management of adverse events. During the post-observation period, various final examinations will be conducted starting from either 30 days after the end of surgical treatment or the later date determined by the lead physician or co-lead physician of the clinical trial to be the time when surgical complications are more moderate. However, if post-treatment of the original disease (rectal cancer) is initiated due to clinical necessity up to the starting date, final examinations will be conducted before the commencement of post-treatment. Furthermore, follow-up investigations will be conducted thereafter. [Administration Criteria for Compound A and Nivolumab] At the start of each administration, subjects must meet all predetermined administration criteria, which are determined by considering the administration criteria of clinical trials of Compound A and nivolumab conducted to date. If any criterion is not met, the predetermined administration of Compound A and nivolumab will be discontinued. However, considering the balance of benefits and risks, the clinical trial principal investigator or co-principal investigator may continue administration of the clinical trial drug if they determine that continued administration will be beneficial. [Administration Discontinuation Criteria for Compound A] During the treatment period, for subjects who meet any of the predetermined discontinuation criteria, administration of Compound A will be discontinued. These predetermined discontinuation criteria are determined by considering the discontinuation criteria of clinical trials of Compound A conducted to date. [Nivolumab Dosing Criteria] During the treatment period, nivolumab dosing will be discontinued for subjects who meet any of the predetermined dosing criteria, which are determined by taking into account the dosing criteria of nivolumab in clinical trials conducted to date.

[0287] [Efficacy Assessment Items] (Imaging Diagnosis / Endoscopy) Imaging diagnosis and endoscopy are performed to determine whether there is further tumor progression through colonoscopy, CT, or MRI imaging. The implementation period is not affected by the withdrawal of the clinical trial drug. Furthermore, during the screening period (within 14 days before the administration of the clinical trial drug), if brain metastasis is suspected based on clinical symptoms, head CT / MRI, FDG-PET (or bone scintigraphy), etc., are performed to confirm whether there is brain or bone metastasis. (Assessment Items) (1) Pathological complete response (pCR) rate, (2) Pathological 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) The pCR rate is the proportion of subjects whose AJCC tumor regression grade is determined to be 0 by pathologists at each implementing medical institution. In addition, subjects whose no viable tumor cells are identified not only at the primary site but also in the corresponding lymph nodes (ypT0N0) are also defined as pCR. (2) The MPR rate is the proportion of subjects whose AJCC tumor regression grade is determined to be 0 or 1 by pathologists at each implementing medical institution. [Surgical evaluation items] (1) Radical resection implementation rate, (2) Treatment success rate up to radical resection, (3) Radical resection implementation rate during the period specified in the clinical trial implementation plan, (4) Gross evaluation of the resected specimen. [Safety evaluation items] The following items will be measured, examined and investigated by the clinical trial principal investigator and others at the predetermined period. (1) Adverse events, (2) Surgical complications, (3) Clinical examinations (hematological examination, blood biochemistry examination, hormone survey, coagulation system examination, urine qualitative examination, immunological examination), (4) Vital signs (systolic / diastolic blood pressure, heart rate, body temperature), transcutaneous oxygen saturation (SpO2), weight, (5) 12-lead electrocardiogram, (6) ECOG performance status, (7) Chest X-ray, (8) Ophthalmological examination (visual acuity examination, intraocular pressure examination, slit-lamp microscopy, and (9) CT scan) [Efficacy assessment results] Ten months after the first subject was enrolled, three cases were judged to be pCR.

[0288] Example 3: A non-blinded, non-controlled trial of compound A, nivolumab, and mFFX or GnP therapy as a first-line treatment in patients with metastatic pancreatic cancer. The purpose of this trial was to examine the tolerability, safety, and efficacy of compound A, nivolumab, and mFFX or GnP therapy as a first-line treatment in patients with metastatic pancreatic cancer. Through this clinical trial, the combined effects of compound A, nivolumab, and mFFX or GnP therapy can be evaluated. (1) Subject Patients Patients with metastatic pancreatic cancer (2) Patient Selection Criteria At the time of registration, patients with metastatic pancreatic cancer who had no history of systemic anti-tumor agents were selected. The predetermined patient selection criteria were determined by considering the patient selection criteria of various clinical trials of compound A, nivolumab, and mFFX or GnP therapy. Patients who met all the predetermined patient selection criteria were selected. Furthermore, if the criteria are clearly not met from registration to the initial administration of the clinical trial drug, the clinical trial drug will not be administered and the clinical trial will be terminated. (3) When registering patients for exclusion criteria, the predetermined patient exclusion criteria will be determined by considering the patient exclusion criteria of each clinical trial of Compound A, nivolumab, and mFFX therapy or GnP therapy, or the considerations for patient selection in each appropriate use guideline or appropriate use information of Compound A, nivolumab, and mFFX therapy or GnP therapy, and patients deemed to meet any of the predetermined patient exclusion criteria will be selected. Furthermore, if the criteria are clearly not met from registration to the initial administration of the clinical trial drug, the clinical trial drug will not be administered and the clinical trial will be terminated.

[0289] (4) Dosage and Administration [Compound A] 20 mg or 40 mg of Compound A shall be administered orally once daily until the predetermined discontinuation criteria for Compound A are met. Furthermore, when administering Compound A, nivolumab, and mFFX or GnP therapy on the same day, Compound A and nivolumab shall be administered first, followed by mFFX or GnP therapy. [Nivolumab] 480 mg of nivolumab shall be administered intravenously over 30 minutes at 4-week intervals until the predetermined discontinuation criteria for nivolumab are met. Furthermore, nivolumab administration shall be initiated on or after day 25, at least 24 days after the previous administration. [mFFX Therapy] Oxaliplatin 85 mg / m² (body surface area) is administered intravenously over 2 hours. Irinotecan 150 mg / m² (body surface area) is administered intravenously over 90 minutes. Levofolate 200 mg / m² (body surface area) is administered intravenously over 2 hours. Fluorouracil 2400 mg / m² (body surface area) is administered intravenously over 46 hours. This series of administrations is given at 2-week intervals. Oxaliplatin, irinotecan, levofolate, and fluorouracil are all commercially available products. [GnP Therapy] Gemcitabine 1000 mg / m² (body surface area) is administered intravenously over 30 minutes, with a minimum 6-day break. Albumin-bound paclitaxel 125 mg / m² (body surface area) is administered intravenously over 30 minutes, with a minimum 6-day break. This series of administrations was conducted at 1-week intervals for 3 weeks, followed by a 1-week break. [Clinical Trial Schedule] This trial consists of a screening period, a treatment period, and a post-observation period. A summary of the clinical trial schedule is shown in Figure 3. The screening period is within 28 days prior to the administration of the clinical trial drug, during which the lead physician or co-lead physician of the clinical trial selects patients who meet the above selection criteria and do not violate the above exclusion criteria, and are deemed suitable as subjects for this clinical trial.

[0290] One cycle of treatment is 28 days, with the initial administration date of the clinical trial drug being day 1 of cycle 1. Day 1 of each subsequent cycle is [28 x (cycle number - 1) + 1]. Administration shall begin in accordance with the above-described dosage / method for each of Compound A, nivolumab, and mFFX or GnP therapy, and continue administration in accordance with the administration baseline, reduction baseline, and dosage during reduction for Compound A, nivolumab, and mFFX or GnP therapy. The assessment at the end (discontinuation) of administration of Compound A, nivolumab, and mFFX or GnP therapy shall be taken as the end of the treatment period. Among all subjects administered the clinical trial drug, those who discontinued or terminated administration of Compound A, nivolumab, and mFFX or GnP therapy shall be assessed at the end (discontinuation) of administration and moved to the post-observation period. Following the observation period, a follow-up study will be conducted. [Administration Criteria for Compound A and Nivolumab] At the start of each administration, subjects must meet all predetermined administration criteria, which are determined by considering the administration criteria of clinical trials of Compound A and nivolumab conducted to date. If any criterion is not met, the predetermined administration of Compound A and nivolumab will be discontinued. However, even if any criterion is not met, if there is no assessment of worsening clinical symptoms as determined by disease progression, and the clinical benefit of continued administration is deemed to be safe to continue, taking into account the subject's criteria and the effects of concomitant medications, then the administration of Compound A and nivolumab may continue.

[0291] [Compound A Dosing Discontinuation Criteria] During the treatment period, for subjects who meet any of the predetermined dosing discontinuation criteria, their administration of Compound A will be discontinued. These predetermined dosing discontinuation criteria are determined based on the dosing discontinuation criteria used in clinical trials of Compound A to date. [Nivolumab Dosing Discontinuation Criteria] During the treatment period, for subjects who meet any of the predetermined dosing discontinuation criteria, their administration of nivolumab will be discontinued. These predetermined dosing discontinuation criteria are determined based on the dosing discontinuation criteria used in clinical trials of mFFX therapy to date. [mFFX Therapy Dosing Criteria] At the start of each administration, subjects must meet all predetermined dosing criteria, which are determined based on the dosing criteria used in clinical trials of mFFX therapy to date. Dosing will be postponed until clinical test values ​​on the scheduled dosing date return to a state that meets the criteria. Dosing will resume only after confirmation that contraindications to any of the medications are not met. [mFFX Therapy Dosage Reduction and Reduction Criteria] Dosage reduction will be implemented according to the latest instruction manual. [mFFX Therapy Discontinuation Criteria] During the treatment period, mFFX therapy will be discontinued for subjects who meet any of the predetermined discontinuation criteria, which are determined based on the discontinuation criteria established in clinical trials of mFFX therapy to date. [GnP Therapy Dosage Criteria] At the start of each administration, subjects must meet all predetermined dosing criteria, which are determined based on the dosing criteria established in clinical trials of GnP therapy to date. Dosing will be postponed until clinical test values ​​on the scheduled dosing date return to a state that meets the criteria, and administration will resume only after confirmation that contraindications to any of the medications are not met. [GnP Therapy Dosage Reduction and Reduction Criteria] Dosage reduction will be implemented according to the latest instruction manual. [Criteria for Discontinuation of GnP Therapy] During the treatment period, GnP therapy will be discontinued for subjects who meet any of the predetermined discontinuation criteria. These predetermined discontinuation criteria are determined by considering the discontinuation criteria of clinical trials of GnP therapy to date. [Criteria for Efficacy Assessment] (Imaging Diagnosis) CT / MRI scans of the chest, abdomen, and pelvis will be performed. Furthermore, during the screening period (within 28 days prior to administration of the clinical trial drug), if brain metastases are suspected based on clinical symptoms, head CT / MRI scans, FDG-PET (or bone scintigraphy), etc., will be performed to confirm the presence or absence of brain or bone metastases.

[0292] The lead physician or co-lead physician in the clinical trial determines the antitumor effect by measuring the tumor diameter of the target lesion according to the RECIST guidelines. The baseline assessment is performed using the most recent imaging examination within 28 days prior to drug administration to confirm at least one measurable lesion as defined in RECIST guidelines version 1.1. Imaging diagnosis during the treatment period is performed 8 weeks (+7 days) after the start of day 1 of cycle 1, measuring the tumor diameter.

[0293] In addition, the so-called overall efficacy and best overall efficacy are based on the imaging diagnostic results assessed according to RECIST guidelines version 1.1. (Assessment items) (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 efficacy (BOR), (8) Rate of change of the sum of the diameters of the target lesions, (9) Maximum rate of change of the sum of the diameters of the target lesions, (10) Changes in tumor markers (CEA and CA19-9)

[0294] (1) Objective Response Rate: The objective response rate represents the proportion of subjects whose best overall response is judged to be CR or PR. (2) Disease Control Rate: The disease control rate represents the proportion of subjects whose best overall response is judged to be CR, PR, or SD. (3) Global Survival: Global survival is calculated by the following formula: Global survival (days) = "Date of death due to any cause" - "Date of administration of clinical trial drug" + 1. In addition, for subjects who cannot be tracked or who have not died by the data cutoff date, the cutoff date is the last confirmed survival date. (4) Wors-Free Survival: Wors-free survival is calculated by the following formula: Wors-Free Survival (days) = "The earlier of the date of determination of PD or date of death due to any cause" - "Date of administration of clinical trial drug" + 1. In addition, for subjects whose overall response is not determined to be PD and who have not died, the cutoff date is the date of the last evaluable imaging diagnosis. For subjects who have not undergone evaluable imaging diagnosis and who have not died, the cutoff date is the date of administration of clinical trial drug. For subjects who received post-cancer treatment before their overall response was determined to be PD or who died, the cutoff date is the date of the last evaluable imaging diagnosis before the start of post-cancer treatment. (5) Remission period The remission period is calculated by the following formula. Remission period (days) = "the earlier of the date when the overall response was first determined to be PD after remission or the date of death due to any cause" - "the date of the initial determination of CR or PR" + 1 In addition, the subjects evaluated are those who have been determined to show CR or PR through clinical trials. (6) Time to remission The time to remission is calculated by the following formula. Time to remission (days) = "the date of the initial determination of CR or PR" - "the date of the start of clinical trial drug administration" + 1 (7) Change rate of the sum of the tumor diameter of the target lesion For subjects with target lesions, the change rate of the sum of the tumor diameter of the target lesion is calculated using the following formula. However, the change rate of the sum of the tumor diameter of the target lesion after post-treatment is not included.

[0295] Change rate (%) = ("Tumor diameter at each assessment time point - sum of tumor diameters before treatment") / ("sum of tumor diameters before treatment") x 100

[0296] (8) Maximum rate of change of the sum of tumor diameters of the target lesion The maximum rate of change of the sum of tumor diameters of the target lesion is the rate of change at the point in time when the sum of tumor diameters of the target lesion becomes the smallest. However, the sum of tumor diameters of the target lesion after the overall efficacy is determined to be PD or after post-treatment is performed is not used in the calculation of the maximum rate of change.

[0297] Maximum rate of change (%) = ("Sum of minimum tumor diameters after administration - Sum of tumor diameters before administration") / ("Sum of tumor diameters before administration") x 100

[0298] (9) Changes in the rate of change of tumor markers (CEA and CA19-9) The rate of change of tumor markers was calculated using the following formula. However, the rate of change of tumor markers after subsequent treatment was not calculated.

[0299] Change rate (%) = ("Tumor markers at each assessment time point - Tumor markers before administration") / ("Tumor markers before administration") x 100

[0300] [Safety Assessment Items] The following items were measured, examined and investigated by the clinical trial principal investigator and others at the predetermined time: (1) Dose-limiting toxicity (DLT), (2) Adverse events, (3) Clinical examinations (hematological examination, blood biochemistry examination, hormone survey, coagulation system examination, urine qualitative examination, immunological examination), (4) Vital signs (systolic blood pressure / diastolic blood pressure, heart rate, body temperature), transcutaneous oxygen saturation (SpO2), weight, (5) 12-lead electrocardiogram, (6) ECOG performance status, (7) Chest X-ray, (8) Ophthalmological examination (visual acuity examination, intraocular pressure examination, slit-lamp microscopy examination, and (9) CT scan. [Efficacy Assessment Results] Regarding the combined use of compound A, nivolumab and mFFX therapy, 9 months after the first subject was enrolled, 1 case was judged to have a partial response (PR).

[0301] Furthermore, regarding the combined use of compound A, nivolumab, and GnP therapy, there were 2 cases that were judged to have PR after 9 months from the time point after the first subject was enrolled.

[0302] Example 4: A non-blinded, uncontrolled trial of compound A, nivolumab, and standard therapy (paclitaxel and ramucirumab) as secondary therapy in patients with advanced or recurrent non-small cell lung cancer who had failed concomitant therapy with anti-PD-1 or anti-PD-L1 antibodies and platinum-based formulations. The aim of this trial was to evaluate the tolerability, safety, and efficacy of compound A, nivolumab, paclitaxel, and ramucirumab as secondary therapy in patients with advanced or recurrent non-small cell lung cancer who had failed concomitant therapy with anti-PD-1 or anti-PD-L1 antibodies and platinum-based formulations. This clinical trial will assess the combined effects of compound A, nivolumab, paclitaxel, and ramucirumab. (1) Target Patients: Patients with stage IV or recurrent non-small cell lung cancer. (2) Patient Selection Criteria: At the time of registration, patients with advanced or recurrent disease who have received concomitant therapy including anti-PD-1 antibody or anti-PD-L1 antibody as a first-line treatment and platinum preparations, but have been deemed ineffective, will be selected based on the patient selection criteria of the various clinical trials conducted to date for Compound A, nivolumab, European paclitaxel, and ramucirumab. Patients meeting all of the predetermined patient selection criteria will be selected. Furthermore, if the criteria are clearly not met from registration to the initial administration of the clinical trial drug, the clinical trial drug will not be administered, and the clinical trial will be terminated. (3) When registering patients for exclusion criteria, the predetermined patient exclusion criteria are determined by considering the patient exclusion criteria of each clinical trial of Compound A, nivolumab, European paclitaxel, and ramucirumab, or the precautions for patient selection in the appropriate use guidelines or appropriate use information for Compound A, nivolumab, and European paclitaxel and ramucirumab. Patients who meet any of the predetermined patient exclusion criteria are selected. In addition, if the criteria are clearly not met from registration to the first administration of the clinical trial drug, the clinical trial drug will not be administered, and the clinical trial will be terminated.

[0303] (4) Dosage and Administration [Compound A] 20 mg or 40 mg of Compound A shall be administered orally once daily until the predetermined discontinuation criteria for Compound A are met. Furthermore, when administering Compound A, nivolumab, paclitaxel, and ramucirumab on the same day, administer Compound A and nivolumab first, followed by paclitaxel and ramucirumab. [Nivolumab] 360 mg of nivolumab shall be administered intravenously over approximately 30 minutes at 3-week intervals until the predetermined discontinuation criteria for nivolumab are met. Furthermore, nivolumab administration shall be initiated on or after the 15th day, at least 14 days after the previous administration. [European Paclitaxel and Ramucirumab] The dosage and administration of European paclitaxel and ramucirumab follow the procedures of the implementing medical institution. For the recommended dosage, 60 mg / m² (body surface area) of European paclitaxel is administered intravenously over 60 minutes at 3-week intervals. 10 mg / kg of ramucirumab is administered intravenously over 60 minutes at 3-week intervals. Furthermore, the 3-week interval refers to the date of the previous European paclitaxel or ramucirumab administration as day 1, with administration occurring between days 22 and 29. European paclitaxel and ramucirumab use their respective commercially available products. [Clinical Trial Schedule] This trial consists of a screening period, a treatment period, and a post-observation period. A summary of the clinical trial schedule is shown in Figure 4. The screening period is within 28 days prior to the administration of the clinical trial drug. Patients who meet the above selection criteria and do not violate the above exclusion criteria are selected by the clinical trial principal investigator or co-principal investigator and are deemed suitable to be subjects of this clinical trial.

[0304] One cycle of treatment is 21 days, with the initial administration date of the clinical trial drug being day 1 of cycle 1. Day 1 of each subsequent cycle is [21 × (cycle number - 1) + 1] days. Administration shall begin in accordance with the above-mentioned dosage / method for each of Compound A, nivolumab, European paclitaxel, and ramucirumab, and shall continue in accordance with the administration, reduction, and reduction dosage guidelines for Compound A, nivolumab, European paclitaxel, and ramucirumab. The assessment at the end (discontinuation) of administration of Compound A, nivolumab, European paclitaxel, and ramucirumab shall be considered the end of the treatment period. Among all subjects who received the clinical trial drug, those who discontinued or terminated administration of Compound A, nivolumab, European paclitaxel, and ramucirumab were assessed at the end (discontinuation) of administration and moved to the post-observation period. Following the observation period, a follow-up study will be conducted. [Administration Criteria for Compound A and Nivolumab] At the start of each administration, subjects must meet all predetermined administration criteria, which are determined by considering the administration criteria of clinical trials of Compound A and nivolumab conducted to date. If any criterion is not met, the predetermined administration of Compound A and nivolumab will be discontinued. However, even if any criterion is not met, if there is no assessment of worsening clinical symptoms as determined by disease progression, and the clinical benefit of continued administration is deemed to be safe to continue, taking into account the subject's criteria and the effects of concomitant medications, then the administration of Compound A and nivolumab may continue. [Compound A Discontinuation Criteria] During treatment, for subjects meeting any of the predetermined discontinuation criteria, administration of Compound A will be discontinued. These predetermined discontinuation criteria are determined based on the discontinuation criteria established in clinical trials of Compound A to date. [Nivolumab Discontinuation Criteria] During treatment, for subjects meeting any of the predetermined discontinuation criteria, administration of nivolumab will be discontinued. These predetermined discontinuation criteria are determined based on the discontinuation criteria established in clinical trials of nivolumab to date. [European Paclitaxel and Ramucirumab Administration Criteria] Administered according to the latest package insert. [European Paclitaxel and Ramucirumab Dosage Reduction and Criteria] Dosage reduction will be implemented according to the latest package insert. [European Paclitaxel and Ramucirumab Discontinuation Criteria] Administered according to the latest package insert. [Efficacy Assessment Criteria] (Imaging Diagnosis) Perform CT / MRI scans of the chest, abdomen, and pelvis. Additionally, during the screening period (within 28 days prior to drug administration), if brain metastases are suspected based on clinical symptoms, perform head CT / MRI scans, FDG-PET (or bone scintigraphy), etc., to confirm the presence or absence of brain or bone metastases.

[0305] The lead physician or co-lead physician in the clinical trial determines the antitumor effect by measuring the tumor diameter of the target lesion according to the RECIST guidelines. The baseline assessment is performed using the most recent imaging examination within 28 days prior to drug administration to confirm at least one measurable lesion as defined in RECIST guidelines version 1.1. Imaging during the treatment period is performed at 6-week (±7-day) intervals from week 1 of cycle 1 to week 54, and thereafter at 12-week (±7-day) intervals, measuring the tumor diameter.

[0306] In addition, the so-called overall efficacy and best overall efficacy are based on the imaging diagnostic results assessed in RECIST Guideline Version 1.1. (Assessment items) (1) Objective response rate (ORR), (2) Disease control rate (DCR), (3) Overall survival (OS), (4) Progression-free survival (PFS), (5) Duration of remission (DOR), (6) Time to remission (TTR), (7) Best overall efficacy (BOR), (8) Rate of change of the sum of the diameters of the target lesions, (9) Maximum rate of change of the sum of the diameters of the target lesions, (10) Changes in tumor markers (1) Objective response rate The objective response rate represents the proportion of subjects whose best overall efficacy is determined to be CR or PR. (2) Disease control rate The disease control rate represents the proportion of subjects whose best overall efficacy is determined to be CR, PR or SD. (3) Overall survival Overall survival is calculated by the following formula. Overall survival (days) = "Date of death from any cause" - "Date of administration of clinical trial drug" + 1. In addition, for subjects who could not be tracked or who had not died by the data cutoff date, the final date of survival confirmation is the cutoff date. (4) Progression-free survival Progression-free survival is calculated by the following formula. Progression-free survival (days) = "The earlier of the date of overall efficacy determination of PD or the date of death from any cause" - "Date of administration of clinical trial drug" + 1. In addition, for subjects whose overall efficacy was not determined to be PD and who had not died, the date of the last evaluable imaging diagnosis is the cutoff date. For subjects who did not undergo evaluable imaging diagnosis and who had not died, the date of administration of clinical trial drug is the cutoff date. For subjects who received post-cancer treatment before their overall efficacy was determined to be PD or who died, the date of the last evaluable imaging diagnosis before the start of post-cancer treatment is the cutoff date. (5) Remission period Remission period is calculated by the following formula. Remission period (days) = "the earlier of the date on which the overall efficacy was first determined to be PD after remission or the date of death from any cause" - "the date of the initial determination of CR or PR" + 1. In addition, the subjects evaluated were those who had demonstrated CR or PR through clinical trials. (6) Time to remission The time to remission is calculated by the following formula. Time to remission (days) = "the date of the initial determination of CR or PR" - "the date of start of clinical trial drug administration" + 1 (7) Change rate of the sum of tumor diameters of the target lesion The change rate of the sum of tumor diameters of the target lesion is calculated by the following formula for subjects with target lesions. However, the change rate of the sum of tumor diameters of the target lesion after post-treatment is not calculated.

[0307] Change rate (%) = ("Tumor diameter at each assessment time point - sum of tumor diameters before treatment") / ("sum of tumor diameters before treatment") x 100

[0308] (8) Maximum rate of change of the sum of tumor diameters of the target lesion The maximum rate of change of the sum of tumor diameters of the target lesion is the rate of change at the point in time when the sum of tumor diameters of the target lesion becomes the smallest. However, the sum of tumor diameters of the target lesion after the overall efficacy is determined to be PD or after post-treatment is performed is not used in the calculation of the maximum rate of change.

[0309] Maximum rate of change (%) = ("Sum of minimum tumor diameters after administration - Sum of tumor diameters before administration") / ("Sum of tumor diameters before administration") x 100

[0310] (9) Changes in the rate of change of tumor markers The rate of change of tumor markers is calculated using the following formula. However, the rate of change of tumor markers after subsequent treatment is not calculated.

[0311] Change rate (%) = ("Tumor markers at each assessment time point - Tumor markers before administration") / ("Tumor markers before administration") x 100

[0312] [Safety Assessment Items] The following items were measured, examined, and investigated by the clinical trial coordinator and others at the predetermined time: (1) Dose-limiting toxicity (DLT), (2) Adverse events, (3) Clinical examinations (hematological examination, blood biochemistry examination, hormone survey, coagulation system examination, urine qualitative examination, immunological examination), (4) Vital signs (systolic / diastolic blood pressure, heart rate, body temperature), transcutaneous oxygen saturation (SpO2), weight, (5) 12-lead electrocardiogram, (6) ECOG performance status, (7) Chest X-ray, (8) Ophthalmological examination (visual acuity examination, intraocular pressure examination, slit-lamp microscopy), and (9) CT scan. [Efficacy Assessment Results] Eight months after the first subject's registration, one case was determined to be a partial response (PR). [Industry Applicability]

[0313] The present invention provides a new method for cancer treatment. [Simplified Explanation of the Diagram]

[0020] Figure 1 shows the summary of a multi-institutional, unblinded, uncontrolled trial evaluating the tolerability, safety, and efficacy of compound A (described later), nivolumab, and XELOX + bevacizumab in patients with unresectable advanced or recurrent colorectal cancer. Figure 2 shows the summary of a multi-institutional, unblinded, uncontrolled trial evaluating the safety, efficacy, and pharmacodynamics of compound A (described later) in combination with nivolumab as preoperative adjuvant therapy following preoperative chemoradiotherapy in patients with resectable locally advanced rectal cancer. Figure 3 shows the summary of a multi-institutional, unblinded, uncontrolled trial evaluating the tolerability, safety, and efficacy of compound A (described later), nivolumab, and mFFX or GnP therapy in patients with distant metastatic pancreatic cancer. Figure 4 shows the summary of a multi-institutional, non-blind, non-controlled trial. This trial evaluated the tolerability, safety, and efficacy of compound A (nivolumab) in combination with European paclitaxel and ramucirumab in patients with advanced or recurrent non-small cell lung cancer who had failed concomitant therapy including anti-PD-1 or anti-PD-L1 antibodies and platinum preparations.

Claims

1. The use of a combination of an EP4 antagonist, an immune checkpoint inhibitor, and a standard therapy for the manufacture of a cancer therapeutic agent, wherein, The aforementioned EP4 antagonist is 4-[4-cyano-2-({(2'R,4S)-6-[(propane-2-yl)aminomethoxy]-2,3-dihydrospiro[1-benzopyran-4,1'-cyclopropane]-2'-carbonyl}amino)phenyl]butyric acid or a salt thereof. The aforementioned EP4 antagonist is administered in combination with standard therapy and immune checkpoint inhibitors. The aforementioned EP4 antagonist is administered orally once daily at a dose of 20 mg or 40 mg. The aforementioned immune checkpoint inhibitor is an anti-PD-1 antibody. The aforementioned anti-PD-1 antibody is nivolumab. The aforementioned standard therapy includes (1) bevacizumab, oxaliplatin and capecitabine, or (2) bevacizumab, oxaliplatin and fluorouracil. The aforementioned cancer is colorectal cancer.

2. As in the purpose of request item 1, wherein, The cancer is colon / rectal cancer.

3. The use as described in claim 1, for unresectable or recurrent advanced colorectal cancer.

4. The use as described in claim 1, wherein, The aforementioned standard treatments are bevacizumab and XELOX therapy.

5. The use as described in claim 4, wherein, The bevacizumab and XELOX therapy consists of the following administrations: (i) bevacizumab 7.5 mg / kg once every 3 weeks, (ii) oxaliplatin 130 mg / m2 once every 3 weeks, and (iii) capecitabine 1000 mg / m2 twice daily orally for 14 days, followed by a 7-day break.

6. Nivolumab is to be administered as claimed in claim 1 in the following ways: (i) 240 mg once every 2 weeks, (ii) 360 mg once every 3 weeks, or (iii) 480 mg once every 4 weeks.

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