Combined medicine

Abstract

The present invention relates to a drug, a combination agent, a pharmaceutical composition or a preparation for treating or preventing ALK fusion gene positive cancer, comprising a combination of an ALK inhibitor and a TNKS inhibitor or comprising a pan-HER inhibitor in combination therewith, and a method for treating or preventing cancer, and a drug or the like that temporarily inhibits the growth of an ALK fusion gene-positive cancer that is resistant to an ALK inhibitor.

Description

Technical Field

[0001] The present invention relates to a drug, a combination agent, a pharmaceutical composition or a preparation useful for treating or preventing ALK fusion gene-positive cancer and comprising a combination of an ALK inhibitor and a TNKS inhibitor, as well as a method and product for treating or preventing targeted cancer, a drug comprising a three-drug combination of an ALK inhibitor, a TNKS inhibitor and a pan-HER inhibitor, etc. Background Art

[0002] Anaplastic lymphoma kinase (ALK) is a receptor-type tyrosine kinase proto-oncogene identified as a fusion gene in 1994 (Science. 1994 Mar 4; 263(5151): 1281-4.: Non-Patent Document 1).

[0003] It is reported that ALK gene abnormality (translocation) leads to the production of abnormal kinases, and the kinases are involved in carcinogenesis (Non-patent Document 1). For example, it is reported that in lung cancer, ALK fuses with the microtubule-associated protein EML4 through chromosomal translocation and generates EML4-ALK with active tyrosine kinase activity, thereby acquiring carcinogenic potential (Cancer Res. 2008 July 1; 68 (13): 4971-6.: Non-patent Document 2). It is reported that compounds with ALK kinase inhibitory activity are useful for cancers with this gene abnormality (Non-patent Document 2).

[0004] Alectinib (generic name: alectinib hydrochloride) has been approved in Japan and overseas as an ALK inhibitor.

[0005] On the other hand, such inhibitors are known to have the following problem: although they show significant effects on the cancer to be treated immediately after the start of treatment, in some cases, the effects of such inhibitors weaken due to the acquisition of drug resistance by cancer cells after long-term administration (Cell 2010.141(1):69-8: Non-patent document 3).

[0006] Tankyrase (TNKS) is an enzyme, also known as tankyrase 1 and tankyrase 2, and is encoded by the human TNKS gene and TNKS2 gene. TNKS plays a variety of roles in cells, such as maintaining telomeres, Wnt signals and mitosis. It is reported that genetic abnormalities associated with Wnt signals are associated with tumor formation and tumor growth (Oncogene. March 2017; 36 (11): 1461-1473.: Non-patent literature 4). Tankyrase promotes the degradation of negative regulators of cancer-β-catenin signaling, Axin 1 and Axin 2, so as to accelerate cell proliferation (Nature Reviews Drug Discovery Vol. 11, pp. 923-936 (2012): Non-patent literature 5). TNKS inhibitors, when used alone or in combination with other anticancer agents, have been tested on a clinical / nonclinical basis in diseases such as colorectal cancer (Int J Mol Sci. 2021 Jul 8; 22(14):7330.: Non-Patent Document 6).

[0007] EGFR / ERBB family human epithelial cell proliferation factor receptor (HER) (also known as avian erythroblastic leukemia virus oncogene homolog (ERBB)), known EGFR (HER1, ERBB1), HER2 (ERBB 2), HER3 (FRBB 3) and HER4 (ERBB4) family, is considered to play an important role in the normal regulation of cell growth, proliferation, differentiation and apoptosis (Sendai Medical Center Journal, Vol. 9, 2019, 23-36: Non-patent literature 7). Pan-HER inhibitors are substances with selective inhibitory activity against HER family factors, which exhibit anti-tumor effects by inhibiting the activation of HER 3 and the dimerization of HER family factors. For example, dacomitinib is used as a therapeutic agent for inoperable or recurrent non-small cell lung cancer with positive EGFR gene mutation.

[0008] For cancer cells that temporarily acquire drug resistance through treatment with tyrosine kinase inhibitors, studies have been conducted to inhibit cell proliferation by using different inhibitors in combination. For example, for a transient drug-resistant (DTP) strain established by exposing ceritinib to an ALK lung cancer cell line from an ALK lung cancer patient, the combined effect of ceritinib, an ALK inhibitor, and an FGFR inhibitor (infigratinib) has been reported (Oncogenesis. 2013 March; 2(3): e39: Non-Patent Document 8). It has been reported that the combination of alectinib and a pan-HER inhibitor (afatinib) has a synergistic effect on reducing the cell viability of DTP cells prepared by exposing ALK-positive NSCLC to alectinib for a certain period of time (npj Precision Oncology Vol. 6, Article No.: 5(2022), 1-12.: Non-Patent Document 9).

[0009] Citation list

[0010] [Non-patent document 1] Science. 1994 Mar 4; 263(5151): 1281-4.

[0011] [Non-patent document 2] Cancer Res. 2008 Jul 1; 68(13): 4971-6.

[0012] [Non-patent document 3] Cell 2010.141(1):69-8

[0013] [Non-patent document 4] Oncogene. 2017 Mar; 36(11): 1461-1473

[0014] [Non-patent document 5] Nature Reviews Drug Discovery, Vol. 11, pp. 923-936 (2012)

[0015] [Non-patent document 6] Int J Mol Sci. 2021 Jul 8; 22(14): 7330.

[0016] [Non-patent document 7] Sendai Medical Center Journal, Vol. 9, 2019, 23-36

[0017] [Non-patent document 8] Oncogenesis. 2013 Mar; 2(3): e39

[0018] [Non-patent document 9] npj Precision Oncology, Vol. 6, Article No.: 5(2022), 1-12. Summary of the invention

[0019] Under the above circumstances, it is desirable to provide a therapeutic agent that is effective for treating ALK fusion gene-positive cancer and / or that can temporarily suppress the growth of drug-resistant ALK fusion gene-positive cancer.

[0020] The present invention provides a novel treatment method for ALK fusion gene-positive cancer, wherein the increase in the amount of β-catenin caused by the ALK inhibitor is suppressed by combining an ALK inhibitor with a terminal anchor polymerase inhibitor (TNKS inhibitor), which is discovered by screening cells obtained from ALK fusion gene-positive cancer patients and which are temporarily resistant to the ALK inhibitor due to short-term exposure to the inhibitor (drug-resistant persistent cells: DTP cells).

[0021] That is, the present invention provides a therapeutic agent which comprises a combination of an ALK inhibitor and a TNKS inhibitor and has an excellent growth inhibitory effect on ALK fusion gene-positive cancer.

[0022] Another aspect of the present invention is to provide a cancer therapeutic agent comprising a triple drug combination obtained by further combining a pan-HER inhibitor with a combination of an ALK inhibitor and a TNKS inhibitor.

[0023] That is, the present invention relates to the following inventions.

[0024] <a-1>A drug or pharmaceutical composition for treating or preventing ALK fusion gene-positive cancer, comprising a combination of an ALK inhibitor and a TNKS inhibitor.

[0025] <a-2>according to <a-1>The drug further comprises a combination of pan-HER inhibitors.

[0026] <a-3>according to <a-1>or <a-2>The drug or pharmaceutical composition, wherein the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and salts thereof.

[0027] <a-4>according to <a-1>to <a-3>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK inhibitor is selected from alectinib, lorlatinib, brigatinib and salts thereof.

[0028] <a-5>according to <a-1>to <a-4>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the TNKS inhibitor is selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof.

[0029] <a-6>according to <a-1>to <a-5>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the TNKS inhibitor is AZ6102 or G007-LK.

[0030] <a-7>according to <a-2>to <a-6>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the pan-HER inhibitor is selected from dacomitinib, neratinib, afatinib, and salts thereof.

[0031] <a-8>according to <a-2>to <a-7>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the pan-HER inhibitor is dacomitinib or a salt thereof.

[0032] <a-9>according to <a-1>to <a-8>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is selected from non-Hodgkin's lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer and lung cancer.

[0033] <a-10>according to <a-1>to <a-9>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is non-small cell lung cancer.

[0034] <a-11>according to <a-1>to <a-10>The medicament or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer has not received prior treatment with an ALK inhibitor.

[0035] <a-12>according to <a-1>to <a-11>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer has been previously treated with an ALK inhibitor.

[0036] <a-13>according to <a-1>to <a-12>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is sensitive to ALK.

[0037] <a-14>according to <a-1>to <a-13>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is temporarily resistant to the ALK inhibitor.

[0038] <b-1>A drug or pharmaceutical composition for treating or preventing ALK fusion gene-positive cancer, comprising an ALK inhibitor as an active ingredient, wherein the ALK inhibitor is used in combination with a TNKS inhibitor.

[0039] <b-2>according to <b-1>The medicament or pharmaceutical composition, wherein the ALK inhibitor is used simultaneously with the TNKS inhibitor, or before the start of administration of the TNKS inhibitor.

[0040] <b-3>A drug or pharmaceutical composition for treating or preventing ALK fusion gene-positive cancer, comprising a TNKS inhibitor as an active ingredient, wherein the TNKS inhibitor is used in combination with an ALK inhibitor.

[0041] <b-4>according to <b-3>The medicament or pharmaceutical composition, wherein the TNKS inhibitor is used simultaneously with the ALK inhibitor, or is used after the ALK inhibitor is started.

[0042] <b-5>according to <b-3>or <b-4>The medicine or pharmaceutical composition further comprises a combination of pan-HER inhibitors.

[0043] <b-6>according to <b-1>to <b-5>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and salts thereof.

[0044] <b-7>according to <b-1>to <b-6>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK inhibitor is selected from alectinib, lorlatinib, brigatinib and salts thereof.

[0045] <b-8>according to <b-1>to <b-7>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the TNKS inhibitor is selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof.

[0046] <b-9>according to <b-1>to <b-8>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the TNKS inhibitor is AZ6102 or G007-LK.

[0047] <b-10>according to <b-5>to <b-9>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the pan-HER inhibitor is selected from dacomitinib, neratinib, afatinib, and salts thereof.

[0048] <b-11>according to <b-5>to <b-10>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the pan-HER inhibitor is dacomitinib or a salt thereof.

[0049] <b-12>according to <b-1>to <b-11>The drug or pharmaceutical composition described in any one of the above, wherein the ALK fusion gene-positive cancer is selected from non-Hodgkin's lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer and lung cancer.

[0050] <b-13>according to <b-1>to <b-12>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is non-small cell lung cancer.

[0051] <b-14>according to <b-1>to <b-13>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer has not received prior treatment with an ALK inhibitor.

[0052] <b-15>according to <b-1>to <b-14>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer has been previously treated with an ALK inhibitor.

[0053] <b-16>according to <b-1>to <b-15>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is sensitive to ALK.

[0054] <b-17>according to <b-1>to <b-16>The drug or pharmaceutical composition described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is temporarily resistant to the ALK inhibitor.

[0055] <c-1>A method for treating or preventing ALK fusion gene-positive cancer, comprising administering to a subject an effective amount of an ALK inhibitor in combination with an effective amount of a TNKS inhibitor.

[0056] <c-2>according to <c-1>The method further comprises administering a pan-HER inhibitor in combination.

[0057] <c-3>according to <c-1>or <c-2>The method, wherein the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and salts thereof.

[0058] <c-4>according to <c-1>to <c-3>The method of any one of the above, wherein the ALK inhibitor is selected from alectinib, lorlatinib, brigatinib and salts thereof.

[0059] <c-5>according to <c-1>to <c-4>The method of any one of the above, wherein the TNKS inhibitor is selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof.

[0060] <c-6>according to <c-1>to <c-5>The method of any one of the preceding claims, wherein the TNKS inhibitor is AZ6102 or G007-LK.

[0061] <c-7>according to <c-2>to <c-6>The method of any one of the above, wherein the pan-HER inhibitor is selected from dacomitinib, neratinib, afatinib and salts thereof.

[0062] <c-8>according to <c-2>to <c-7>The method of any one of the above, wherein the pan-HER inhibitor is dacomitinib or a salt thereof.

[0063] <c-9>according to <c-1>to <c-8>The method of any one of the above, wherein the ALK fusion gene-positive cancer is selected from non-Hodgkin's lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer and lung cancer.

[0064] <c-10>according to <c-1>to <c-9>The method of any one of the above, wherein the ALK fusion gene-positive cancer is non-small cell lung cancer.

[0065] <c-11>according to <c-1>to <c-10>The method of any one of claims 1 to 6, wherein the ALK fusion gene-positive cancer has not received prior treatment with an ALK inhibitor.

[0066] <c-12>according to <c-1>to <c-11>The method of any one of claims 1 to 6, wherein the ALK fusion gene-positive cancer has received prior treatment with an ALK inhibitor.

[0067] <c-13>according to <c-1>to <c-12>The method of any one of the above, wherein the ALK fusion gene-positive cancer is sensitive to ALK.

[0068] <c-14>according to <c-1>to <c-13>The method of any one of the preceding claims, wherein the ALK fusion gene-positive cancer is transiently resistant to an ALK inhibitor.

[0069] <d-1>An agent for temporarily inhibiting the growth of ALK fusion gene-positive cancer that is resistant to an ALK inhibitor, comprising a combination of an ALK inhibitor and a TNKS inhibitor.

[0070] <d-1a>An agent for temporarily inhibiting the growth of ALK fusion gene-positive cancer cells that are resistant to ALK inhibitors, comprising a combination of an ALK inhibitor and a TNKS inhibitor.

[0071] <d-2>according to <d-1>or <d-1a>The growth inhibitor further comprises a pan-HER inhibitor combination.

[0072] <d-3>according to <d-1>or <d-2>The growth inhibitor, wherein the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and salts thereof.

[0073] <d-4>according to <d-1>to <d-3>The growth inhibitor of any one of the above, wherein the ALK inhibitor is selected from alectinib, lorlatinib, brigatinib and salts thereof.

[0074] <d-5>according to <d-1>to <d-4>The growth inhibitor of any one of the above, wherein the TNKS inhibitor is selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof.

[0075] <d-6>according to <d-1>to <d-5>The growth inhibitor of any one of the above, wherein the TNKS inhibitor is AZ6102 or G007-LK.

[0076] <d-7>according to <d-2>to <d-6>The growth inhibitor of any one of the above, wherein the pan-HER inhibitor is selected from dacomitinib, neratinib, afatinib and salts thereof.

[0077] <d-8>according to <d-2>to <d-7>The growth inhibitor described in any one of the preceding claims, wherein the pan-HER inhibitor is dacomitinib or a salt thereof.

[0078] <d-9>according to <d-1>to <d-8>The growth inhibitor of any one of the above, wherein the ALK fusion gene-positive cancer is selected from non-Hodgkin's lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer and lung cancer.

[0079] <d-10>according to <d-1>to <d-9>The growth inhibitor of any one of the above, wherein the ALK fusion gene-positive cancer is non-small cell lung cancer.

[0080] <d-11>according to <d-1>to <d-10>The growth inhibitor of any one of claims 1 to 6, wherein the ALK fusion gene-positive cancer has not received prior treatment with an ALK inhibitor.

[0081] <d-12>according to <d-1>to <d-11>The growth inhibitor of any one of claims 1 to 5, wherein the ALK fusion gene-positive cancer has been treated with an ALK inhibitor.

[0082] <d-13>according to <d-1>to <d-12>The growth inhibitor of any one of the above, wherein the ALK fusion gene-positive cancer is sensitive to ALK.

[0083] <d-14>according to <d-1>to <d-13>The growth inhibitor of any one of the above, wherein the ALK fusion gene-positive cancer is temporarily resistant to the ALK inhibitor.

[0084] <d2-1>A shrinkage agent for temporarily inhibiting ALK fusion gene-positive cancer that is resistant to ALK inhibitors, comprising a combination of an ALK inhibitor and a TNKS inhibitor.

[0085] <d2-2>according to <d2-1>The contraction agent further comprises a combination of pan-HER inhibitors.

[0086] <d2-3>according to <d2-1>or <d2-2>The contraction agent, wherein the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and salts thereof.

[0087] <d2-4>according to <d2-1>to <d2-3>The contraction agent described in any one of the preceding claims, wherein the ALK inhibitor is selected from alectinib, lorlatinib, brigatinib and salts thereof.

[0088] <d2-5>according to <d2-1>to <d2-4>The contraction agent described in any one of the preceding claims, wherein the TNKS inhibitor is selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof.

[0089] <d2-6>according to <d2-1>to <d2-5>The contraction agent described in any one of the preceding claims, wherein the TNKS inhibitor is AZ6102 or G007-LK.

[0090] <d2-7>according to <d2-2>to <d2-6>The contraction agent of any one of the above, wherein the pan-HER inhibitor is selected from dacomitinib, neratinib, afatinib and salts thereof.

[0091] <d2-8>according to <d2-2>to <d2-7>The contraction agent described in any one of the preceding claims, wherein the pan-HER inhibitor is dacomitinib or a salt thereof.

[0092] <d2-9>according to <d2-1>to <d2-8>The contractile agent described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is selected from non-Hodgkin's lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer, and lung cancer.

[0093] <d2-10>according to <d2-1>to <d2-9>The shrinking agent described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is non-small cell lung cancer.

[0094] <d2-11>according to <d2-1>to <d2-10>The shrinkage agent of any one of claims , wherein the ALK fusion gene-positive cancer has not received prior treatment with an ALK inhibitor.

[0095] <d2-12>according to <d2-1>to <d2-11>The shrinkage agent of any one of items , wherein the ALK fusion gene-positive cancer has received prior treatment with an ALK inhibitor.

[0096] <d2-13>according to <d2-1>to <d2-12>The shrinkage agent of any one of the above, wherein the ALK fusion gene-positive cancer is sensitive to ALK.

[0097] <d2-14>according to <d2-1>to <d2-13>The shrinking agent of any one of the above, wherein the ALK fusion gene-positive cancer is temporarily resistant to ALK inhibitors.

[0098] <f-1>A product comprising: (1) a formulation comprising an ALK inhibitor, (2) a container, and (3) instructions or labeling for administering the ALK inhibitor in combination with at least one TNKS inhibitor to a subject for treating ALK fusion gene-positive cancer.

[0099] <f-2>according to <f-1>The product comprises instructions or labels indicating further administration in combination with a pan-HER inhibitor.

[0100] <f-3>according to <f-1>or <f-2>The product, wherein the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and salts thereof.

[0101] <f-4>according to <f-1>to <f-3>The product of any one of the above, wherein the ALK inhibitor is selected from alectinib, lorlatinib, brigatinib and salts thereof.

[0102] <f-5>according to <f-1>to <f-4>The product of any one of the above, wherein the TNKS inhibitor is selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof.

[0103] <f-6>according to <f-1>to <f-5>The product of any one of the above, wherein the TNKS inhibitor is AZ6102 or G007-LK.

[0104] <f-7>according to <f-2>to <f-6>The product of any one of the above, wherein the pan-HER inhibitor is selected from dacomitinib, neratinib, afatinib and salts thereof.

[0105] <f-8>according to <f-2>to <f-7>The product of any one of the above, wherein the pan-HER inhibitor is dacomitinib or a salt thereof.

[0106] <f-9>according to <f-1>to <f-8>The product of any one of the above, wherein the ALK fusion gene-positive cancer is selected from non-Hodgkin's lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer and lung cancer.

[0107] <f-10>according to <f-1>to <f-9>In the product described in any one of the above, the ALK fusion gene-positive cancer is non-small cell lung cancer.

[0108] <f-11>according to <f-1>to <f-10>The product of any one of the above, wherein the ALK fusion gene-positive cancer has not received prior treatment with an ALK inhibitor.

[0109] <f-12>according to <f-1>to <f-11>The product of any one of the above, wherein the ALK fusion gene-positive cancer has been treated with an ALK inhibitor.

[0110] <f-13>according to <f-1>to <f-12>The product of any one of the above, wherein the ALK fusion gene-positive cancer is sensitive to ALK.

[0111] <f-14>according to <f-1>to <f-13>The product of any one of the above, wherein the ALK fusion gene-positive cancer is temporarily resistant to ALK inhibitors.

[0112] <g-1>A combination of an ALK inhibitor and a TNKS inhibitor or use thereof in the preparation of a medicament for treating or preventing ALK fusion gene-positive cancer.

[0113] <g-2>according to <g-1>The combination or use thereof, wherein the combination further comprises a pan-HER inhibitor.

[0114] <g-3>according to <g-1>or <g-2>The combination or use, wherein the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and salts thereof.

[0115] <g-4>according to <g-1>to <g-3>The combination or use thereof as described in any one of the preceding claims, wherein the ALK inhibitor is selected from alectinib, lorlatinib, brigatinib and salts thereof.

[0116] <g-5>according to <g-1>to <g-4>The combination or use thereof as described in any one of the preceding claims, wherein the TNKS inhibitor is selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof.

[0117] <g-6>according to <g-1>to <g-5>The combination or use thereof as described in any one of the preceding claims, wherein the TNKS inhibitor is AZ6102 or G007-LK.

[0118] <g-7>according to <g-2>to <g-6>The combination or use thereof as described in any one of the preceding claims, wherein the pan-HER inhibitor is selected from dacomitinib, neratinib, afatinib and salts thereof.

[0119] <g-8>according to <g-2>to <g-7>The combination or use thereof as described in any one of the preceding claims, wherein the pan-HER inhibitor is dacomitinib or a salt thereof.

[0120] <g-9>according to <g-1>to <g-8>The combination or use thereof described in any one of the preceding claims, wherein the ALK fusion gene-positive cancer is selected from non-Hodgkin's lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer and lung cancer.

[0121] <g-10>according to <g-1>to <g-9>The combination or use thereof according to any one of the preceding claims, wherein the ALK fusion gene-positive cancer is non-small cell lung cancer.

[0122] <g-11>according to <g-1>to <g-10>The combination or use thereof of any one of the above, wherein the ALK fusion gene-positive cancer has not received prior treatment with an ALK inhibitor.

[0123] <g-12>according to <g-1>to <g-11>The combination or use thereof according to any one of the preceding claims, wherein the ALK fusion gene-positive cancer has received prior treatment with an ALK inhibitor.

[0124] <g-13>according to <g-1>to <g-12>The combination or use thereof according to any one of the preceding claims, wherein the ALK fusion gene-positive cancer is sensitive to ALK.

[0125] <g-14>according to <g-1>to <g-13>The combination or use thereof according to any one of the preceding claims, wherein the ALK fusion gene-positive cancer is temporarily resistant to an ALK inhibitor.

[0126] BRIEF DESCRIPTION OF THE DRAWINGS

[0127] [ Figure 1 ] Figure 1 A graph showing the ratio of cell proliferation of DT cells to non-DT cells (15DT / 15cl) under various compounds.

[0128] [ Figure 2 ] Figure 2 A graph showing the percentage of cell proliferation in 15cl and 15DT relative to the number of cells not treated with the drug in the single agent form of alectinib as an ALK inhibitor and AZ6102, G007-LK and XAV939 as TNKS inhibitors.

[0129] [ Figure 3 ] Figure 3 Graph showing the expression levels of proteins after culture in the presence of alectinib in 15cl and 15DT.

[0130] [ Figure 4 ] Figure 4 Graph showing cytoplasmic and nuclear protein expression levels after addition of alectinib to 15cl and 15DT.

[0131] [ Figure 5 ] Figure 5 Graphs showing the percentage of cell proliferation relative to the number of untreated cells in 15cl when alectinib was used in combination with AZ6102 or G007-LK (top), lorlatinib was used in combination with AZ6102 or G007-LK (middle), or brigatinib was used in combination with AZ6102 or G007-LK (bottom).

[0132] [ Figure 6 ] Figure 6 A graph showing the expression levels of proteins in 15cl upon addition of alectinib and AZ6102.

[0133] [ Figure 7 ] Figure 7 A graph showing the percentage of cell proliferation in 15cl under the triple drug combination of alectinib, AZ6102 and dacomitinib.

[0134] [ Figure 8 ] Figure 8 A graph showing the tumor volume (mean + standard deviation) of each administration group when alectinib (2 mg / kg, orally administered once daily for 14 days) and G007-LK (10 mg / kg and 50 mg / kg, orally administered once daily for 14 days) were administered in combination to CB-17 / Icr-scid / scid / Jcl (SCID) mice transplanted with 15cl.

[0135] [ Fig. 9 ] Fig. 9 A graph showing the tumor volume (mean + standard deviation) of each administration group when alectinib (2 mg / kg, orally administered once daily for 14 days) was administered in combination with G007-LK (10 mg / kg and 50 mg / kg, orally administered once daily for 14 days) and dacomitinib (10 mg / kg, orally administered once daily for 14 days) to SCID mice transplanted with 15cl. DETAILED DESCRIPTION

[0136] The present invention relates to a drug, a combination agent, a pharmaceutical composition, a preparation and a product for treating or preventing ALK fusion gene-positive cancer, which comprises a combination of an ALK inhibitor and a TNKS inhibitor. The present invention also relates to a method for treating or preventing ALK fusion gene-positive cancer, a drug for inhibiting the growth of ALK fusion gene-positive cancer that temporarily acquires drug resistance, a drug for reducing cancer or a method for inhibiting such growth.

[0137] ALK inhibitors

[0138] The ALK inhibitor used in the present invention refers to a substance that can directly or indirectly neutralize, block, inhibit, reduce or hinder the activity of ALK. As an example of the activity of the aforementioned ALK, tyrosine kinase activity can be cited. The aforementioned substances include: low molecular weight compounds, antibodies, antisense substances, transcription inhibitors, low molecular weight interfering RNA (siRNA), etc.

[0139] As examples of the aforementioned low molecular weight compounds, the following have been approved to date: the first generation of crizotinib (compound name: 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine), the second generation of alectinib (compound name: 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)-piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile monohydrochloride), and the second generation of ceritinib (compound name: 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane -2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine), and the third-generation lorlatinib (compound name: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methanepyrazolo[4,3-h][2,5,11]benzoxadiazepinecyclotetradecine (cyclotetradecine)-3-carbonitrile), and brigatinib (compound name: {2-[(5-chloro-2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino}pyrimidin-4-yl)amino]phenyl}dimethyl-λ 5 -phosphone) as the fifth agent.

[0140] Alectinib is widely used as the first choice drug. These compounds or their salts can be produced by the methods described in WO2010 / 143664, WO2004 / 076412, WO2006 / 021881, WO2008 / 073687, etc. These compounds or their salts also include hydrates, various pharmaceutically acceptable solvates, polymorphs, etc.

[0141] Specifically, the “salt” is preferably a pharmaceutically acceptable salt, and examples thereof include hydrochlorides, hydrobromides, hydroiodides, phosphates, phosphonates, sulfates, sulfonates such as methanesulfonates (mesylate) and p-toluenesulfonates, carboxylates such as acetates, citrates, malates, tartrates, succinates and salicylates, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts.

[0142] The administration route of the ALK inhibitor used in the present invention is suitably oral or non-oral, preferably oral administration. As a dosage form for oral administration, for example, it can be appropriately selected from any dosage form such as liquid preparations, powders, granules, tablets, enteric solvents and capsules. ALK inhibitors with such a dosage form can be formulated by methods known to those skilled in the art. For example, with a pharmaceutically acceptable carrier or medium, specifically, with sterile water, saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, adhesive, etc., appropriately combined, after mixing in the unit dosage form required by the generally recognized pharmaceutical practice, it is formulated by freeze drying, tableting and other formulation operations.

[0143] ALK inhibitors can also be used non-orally in the form of injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable liquids. The amount of the active ingredient of these preparations can be appropriately selected to be able to administer an appropriate amount of the indicated range. The sterile composition for injection can be prepared in accordance with common formulation practices using a vehicle such as distilled water for injection. As aqueous solutions for injection, for example, physiological saline, isotonic solutions containing glucose or other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride can be exemplified, and can be used in combination with appropriate cosolvents, such as alcohols, specifically ethanol, polyols, such as propylene glycol, polyethylene glycol, nonionic surfactants, such as polysorbate 80 (TM), HCO-50. As oily liquids, sesame oil and soybean oil can be exemplified, and can be used in combination with benzyl benzoate and benzyl alcohol as cosolvents. Furthermore, a buffer such as a phosphate buffer and a sodium acetate buffer, a soothing agent such as procaine hydrochloride, a stabilizer such as benzyl alcohol and phenol, and an antioxidant may be appropriately blended.

[0144] As the dosage of the ALK inhibitor of the present invention, for example, the dosage can be selected within the range of 0.0001 mg to 1000 mg / 1 kg body weight per administration. Alternatively, for example, the dosage can be selected within the range of 0.001 mg to 100000 mg / body per patient. However, the dosage of the ALK inhibitor of the present invention is not limited to these dosages.

[0145] More specific dosages of the aforementioned alectinib, its salt, or hydrate thereof include: twice a day, 20 mg, 40 mg, 60 mg, 80 mg, 120 mg, 160 mg, 220 mg, 240 mg, 300 mg, 460 mg, 600 mg, 760 mg and 900 mg per dose in terms of free form.

[0146] The administration period of the ALK inhibitor of the present invention is appropriately determined according to the degree of symptoms or side effects, and can be administered until the cancer is treated or the desired therapeutic effect is achieved. Specifically, it can be administered continuously for 7 days to 3 years, or there is a method of setting a drug-free period of about 1 to 14 days during the administration period, and using 2 days to 3 months as one cycle, and administering in 1 to 36 cycles. Preferably, it is a method of administering in 14 to 30 days as one cycle, and in 3 to 24 cycles.

[0147] The Wnt / β-catenin signaling pathway is also known as the standard Wnt signaling pathway, which is involved in a variety of physiological processes such as proliferation, differentiation, apoptosis, migration, infiltration and tissue homeostasis. It is disclosed that insufficient regulation of the Wnt / β-catenin cascade leads to the development and progression of some solid tumors and hematological malignancies. It is known that impaired regulation of the Wnt / β-catenin signaling pathway is closely related to the development and progression of various cancers. The terminal anchor polymerase (TNKS) promotes the degradation of Axin 1 and Axin 2, negative regulators of the pro-oncogenic β-catenin signaling, thereby accelerating cell proliferation.

[0148] Therefore, it is known that TNKS inhibitors have a growth inhibitory effect on cancer cells.

[0149] The TNKS inhibitor used in the present invention refers to a substance that can directly neutralize, block, inhibit, reduce or hinder the activity of tankyrase. The aforementioned substances include: low molecular weight compounds, antibodies, antisense, transcription inhibitors, low molecular weight interfering RNA (siRNA, sgRNA), etc.

[0150] Examples of tankyrase inhibitors include AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582, otaparib, NVP-TNKS656, IWR-1, IWR-2, JW55, WIKI-4, JW-74, LZZ-02 ((E)-3-((4-nitrophenyl)amino)-1-phenylprop-2-en-1-one) and salts thereof. The structures of these tankyrase inhibitors are as follows.

[0151] [Formula 1]

[0152]

[0153] It is known that the compound represented by the following general formula also has TNKS enzyme inhibitory activity (Expert Opin Ther Pat. 2021 July; 31(7)645-661).

[0154] [Formula 2]

[0155]

[0156] [Formula 3]

[0157]

[0158] Specific examples of compounds encompassed by the above formula are as follows.

[0159] [Formula 4]

[0160]

[0161] [Formula 5]

[0162]

[0163] AZ6102, G007-LK, XAV939 and salts thereof are preferred.

[0164] These compounds or their salts are manufactured and sold in the form of pharmaceutical preparations, or can be obtained as research agents, or they can be prepared by conventional methods. These compounds or their salts also include salts, hydrates, various pharmaceutically acceptable solvates, polymorphs, etc. described in the "ALK inhibitor" section.

[0165] TNKS inhibitors are prepared according to conventional methods (e.g., Remington's Pharmaceutical Science, latest edition, Mack Publishing Company, Easton, USA), and may also contain pharmaceutically acceptable carriers and additives, examples of which include, but are not limited to, surfactants, excipients, colorants, flavoring agents, preservatives, stabilizers, buffers, suspending agents, isotonic agents, binders, disintegrants, lubricants, flow promoters, flavoring agents, and other commonly used carriers may be used appropriately. Specifically, suitable examples include trehalose, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylamino acetate, polyvinyl pyrrolidone, gelatin, medium chain triglycerides, polyoxyethylene hydrogenated castor oil 60, refined sugar, carboxymethyl cellulose, corn starch, inorganic salts, polysorbate, and the like.

[0166] In the present invention, the administration method of the TNKS inhibitor can be implemented by either oral or non-oral administration. Particularly preferred is the oral administration method, and specifically, suitable examples of such administration methods include administration by liquid preparations, powders, granules, tablets, enteric preparations and capsules, etc. As an example of injection administration, the therapeutic drug of the present invention can be systemically or locally administered by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, etc. In addition, the administration method can be appropriately selected according to the age and symptoms of the patient. As an administration amount, for example, in the case of an oral preparation, the administration amount can be selected in the range of 0.1 mg / kg to 100 mg / kg, preferably 0.1 mg / kg to 5 mg / kg per administration. For example, each patient can select an administration amount in the range of 9 mg to 150 mg. However, the administration amount of the TNKS inhibitor used in the present invention is not limited to these administration amounts.

[0167] The present invention has confirmed that in ALK fusion gene positive cancer, an increase in active β-catenin is observed by administering an ALK inhibitor, while the increase in β-catenin is inhibited by a TNKS inhibitor, and a growth inhibitory effect on ALK fusion gene positive cancer cells is obtained by using an ALK inhibitor and a TNKS inhibitor in combination. Therefore, inhibition of β-catenin activation and increase in β-catenin may be the main mechanism of the effect.

[0168] Based on the above findings, substances that have an inhibitory effect on the Wnt / β-catenin signaling pathway (hereinafter referred to as β-catenin pathway inhibitors) and TNKS inhibitors can be used, which help inhibit the activation of β-catenin and increase β-catenin. That is, as another aspect of the present invention, it also includes drugs, combinations, pharmaceutical compositions, preparations and products for treating or preventing ALK fusion gene-positive cancer, which contain a combination of ALK inhibitors and β-catenin pathway inhibitors. Examples of β-catenin pathway inhibitors in another aspect of the present invention include porcupine (PORCN) inhibitors, Wnt / FZD antagonists, LRP5 / 6 inhibitors, DVL inhibitors, CK1 agonists, β-catenin / TCF inhibitors and CREB binding protein (CBP) inhibitors. Specific examples include the following substances (J.Hematol.Oncol. (2020) 13: 165, Table 1 or Table 2, Figure 3 ).

[0169] Examples of PORCN inhibitors include WNT974, ETC-159, CGX1321, GNF-6231, Wnt-C59, IWP-2, RXC004, and RXC006.

[0170] Examples of Wnt / FZD antagonists include Ipafricept (OMP54F28; IPA), OMP-18R5 (vantictumab), 90 γ-OTSA-101 and Fz7-21.

[0171] Examples of LRP5 / 6 inhibitors include BMD4503-2 and salinomycin.

[0172] Examples of DVL inhibitors include NSC668036, FJ9, and 3289-8625.

[0173] Examples of CK1 agonists include pyrvinium and SSTC3.

[0174] Examples of β-catenin / TCF inhibitors include PFK115-584, CGP049090, KYA1797K / KY1220, ZINC02092166, NLS-StAx-h, CWP232291 (CWP291), iCRT3 / 5, iCRT14, and LF-3.

[0175] Examples of CBP inhibitors include PRI-724, ICG001, isoquercetin, GNE-781, 1-(1H-indol-1-yl)ethanone, JW67, JW74, NLS-StAx-h, and ep31670.

[0176] Pan-HER inhibitors

[0177] Pan-HER inhibitors refer to substances that act irreversibly on the EGFR / ERBB family to inhibit the activation and signaling of each tyrosine kinase.

[0178] The EGFR / ERBB family includes four types of receptor tyrosine kinases (RTKs): EGFR / HER1 / ErbB-1, HER2 / ErbB-2 / NEU, HER3 / ErbB-3, and HER4 / ErbB-4. The ligands of each receptor are different, and when the ligand binds, the EGFR / ERBB family forms homo- or heterodimers and activates the kinase domain, and the activation of the kinase domain phosphorylates the binding site of the Src homology 2 (SH2) domain, activating the intracellular signaling pathway.

[0179] Pan-HER inhibitors include low molecular weight compounds, antibodies, antisense, transcription inhibitors, small interfering RNA (siRNA), etc., which bind to EGFR / ERBB family receptors to inhibit the receptor, or inhibit the activation of the receptor. Examples of low molecular weight compounds include dacomitinib, neratinib and afatinib.

[0180] Dacomitinib or a salt thereof is preferred.

[0181] These compounds or their salts are manufactured and sold in the form of pharmaceutical preparations, or can be obtained as research agents, or they can be prepared by conventional methods. These compounds or their salts also include salts, hydrates, various pharmaceutically acceptable solvates, polymorphs, etc. described in the "ALK inhibitor" section.

[0182] The pan-HER inhibitor is formulated according to conventional methods (e.g., Remington's Pharmaceutical Science, latest edition, Mack Publishing Company, Easton, USA), and may also contain pharmaceutically acceptable carriers and additives, examples of which include, but are not limited to, surfactants, excipients, colorants, flavoring agents, preservatives, stabilizers, buffers, suspending agents, isotonic agents, binders, disintegrants, lubricants, fluidity promoters and flavoring agents, and other commonly used carriers may be used appropriately. Specifically, suitable examples thereof include trehalose, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylamino acetate, polyvinyl pyrrolidone, gelatin, medium chain fatty acid triglycerides, polyoxyethylene hydrogenated castor oil 60, refined sugar, carboxymethyl cellulose, corn starch, inorganic salts, polysorbate, etc.

[0183] In the present invention, the administration method of the pan-HER inhibitor can be implemented by any of oral and non-oral administration. Particularly preferred is an administration method based on oral administration, as the administration method involved, and specifically, suitable examples of such administration methods include administration by liquid preparations, powders, granules, tablets, enteric preparations and capsules, etc. As an example of injection administration, the therapeutic drug of the present invention can be systemically or locally administered by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, etc. In addition, the administration method can be appropriately selected according to the age and symptoms of the patient. As an administration amount, for example, in the case of an oral preparation, the administration amount can be selected in the range of 0.1 mg / kg to 100 mg / kg, preferably 0.1 mg / kg to 5 mg / kg per administration. For example, each patient can select an administration amount in the range of 9 mg to 150 mg. However, the administration amount of the TNKS inhibitor used in the present invention is not limited to these administration amounts.

[0184] Depending on the type and severity of the disease, for example, the preferred daily dosage of dacomitinib is in the range of 15 to 45 mg, but is not limited thereto, and can be gradually reduced according to the degree of symptoms and side effects. If side effects are observed, the dosage is reduced to 30 mg as a one-time dosage reduction, and the dosage is reduced to 15 mg as a two-time dosage reduction. In one example, osimertinib is administered once a day for 3 consecutive weeks at a dosage of 80 mg, and if side effects are observed, the dosage is reduced to 4 mg as a one-time dosage reduction, and the dosage is reduced to 75 mg as a two-time dosage reduction. However, other dosage regimens may also be useful.

[0185] The TNKS inhibitor can be administered until the targeted cancer is treated or the desired therapeutic effect is achieved, and the above 3 weeks of administration and 1 week of rest period are one cycle. Alternatively, for the frequency of administration, once a day for a predetermined period of time (e.g., 2 weeks) can generally be regarded as one cycle, followed by a predetermined rest period (e.g., 1 week), and then the cycle is repeated. The number of cycles varies according to the type and severity of the disease. By measuring according to methods known in the art, the treatment is maintained until the targeted cancer is treated or a desired therapeutic effect is achieved.

[0186] Drugs, combinations, pharmaceutical compositions, and methods of treatment and prevention

[0187] One aspect of the present invention is a drug for treating or preventing ALK fusion gene-positive cancer (hereinafter referred to as targeted cancer), which comprises a combination of an ALK inhibitor and a TNKS inhibitor.

[0188] In the above aspects, "a drug comprising a combination of an ALK inhibitor and a TNKS inhibitor for treating or preventing targeted cancer" refers to a drug comprising a combination of an ALK inhibitor and a TNKS inhibitor for treating or preventing targeted cancer, which is administered simultaneously, separately or sequentially. The drug of the present invention can also be provided in the form of a composite drug comprising both an ALK inhibitor and a TNKS inhibitor. In addition, a preparation comprising an ALK inhibitor and a preparation comprising a TNKS inhibitor can be provided separately, and these preparations can be used simultaneously or sequentially.

[0189] In the present application, the term "combination" specifically includes a statement of use in combination with other drugs in the dosage and administration of a pharmaceutical preparation. Specifically, it includes a statement of use in combination with a TNKS inhibitor in the package insert of a pharmaceutical preparation for an ALK inhibitor, or a statement of use in combination with an ALK inhibitor in the package insert of a pharmaceutical preparation for a TNKS inhibitor.

[0190] In the present invention, simultaneous administration means using the ALK inhibitor and the TNKS inhibitor by administering them simultaneously, and they may be administered as a combined drug, administered as a mixture prepared at the time of administration, or may be administered simultaneously in other forms of preparations. When used by simultaneous administration, they may be administered by different routes, or may be administered by the same route, and the administration dosage forms may be the same or different.

[0191] In the present invention, when the ALK inhibitor and the TNKS inhibitor are administered separately, the order of administration of the ALK inhibitor and the TNKS inhibitor can be: administration of the ALK inhibitor after administration of the TNKS inhibitor; simultaneous administration of the ALK inhibitor and the TNKS inhibitor; or administration of the TNKS inhibitor after administration of the ALK inhibitor.

[0192] Preferably, the ALK inhibitor and the TNKS inhibitor are administered simultaneously.

[0193] Specifically, the combined use with the TNKS inhibitor is explained in the package insert of the pharmaceutical preparation of the ALK inhibitor, and the administration is performed according to the administration amount and administration of the ALK inhibitor specified in the case of the combined use.

[0194] In another case, the package insert of the pharmaceutical preparation of the TNKS inhibitor states the combined use with the ALK inhibitor, and the administration is performed according to the prescribed administration amount and administration of the ALK inhibitor in the case of combined use.

[0195] In the above-mentioned drugs, when the ALK inhibitor and the TNKS inhibitor are contained and provided in different preparations, the dosage forms of these preparations may be the same or different, for example, the two may have a dosage form different from the other, the dosage form being selected from oral preparations, parenteral preparations, injections, drip preparations and intravenous drip preparations, or the two may have the same dosage form, the dosage form being selected from oral preparations, injections, drip preparations and intravenous drip preparations, preferably, the dosage forms of the two are oral preparations. In addition, the above-mentioned drugs may be further combined with one or more different preparations.

[0196] Note that in the present invention, the pharmaceutical composition comprises the ALK inhibitor and / or TNKS inhibitor for treatment and / or prevention of the present invention, and may further comprise a pharmaceutically acceptable carrier.

[0197] In the present invention, the term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid diluents excipients or encapsulating materials, as described above, which are suitable for administration to a mammal.

[0198] In the present invention, "combination pharmaceutical agent" refers to a form in which an ALK inhibitor and a compound, i.e., a TNKS inhibitor, can be used separately in the same subject, or a combination of these compounds in a form in which each is formulated without being mixed with them. For example, it includes a drug packaged in an administration amount so that a pharmaceutical preparation of an ALK inhibitor and a pharmaceutical preparation of a TNKS inhibitor can be taken at the same time.

[0199] In the present invention, the "pharmaceutical preparation" containing a combination of an ALK inhibitor and a TNKS inhibitor includes: preparations obtained by separately formulating these active ingredients, or solid preparations such as tablets, capsules, granules, powders, pills, etc., contained in the same preparation, aqueous and non-aqueous oral solutions and suspensions, and liquid preparations such as parenteral solutions filled in containers suitable for subdividing into individual dosages, lyophilized preparations that can be dissolved when used, or preparations obtained by combining any of these dosage forms. Each unit dosage form of the pharmaceutical preparation contains 150 mg to 800 mg, preferably 150 mg to 400 mg, and particularly preferably 150 mg to 300 mg of alectinib or a salt thereof in terms of free form. The preparations obtained by separately formulating alectinib or a salt thereof specifically include 150 mg capsule preparations, 150 mg, 300 mg, 600 mg tablets, etc.

[0200] In another viewpoint, the present invention provides a drug for treating or preventing targeted cancer, which comprises an ALK inhibitor as an active ingredient and is used in combination with a TNKS inhibitor. "A drug for treating or preventing targeted cancer, which comprises an ALK inhibitor as an active ingredient and is used in combination with a TNKS inhibitor" refers to a drug for treating or preventing targeted cancer, which comprises an ALK inhibitor as an active ingredient, but the premise is that the drug is used in combination with a TNKS inhibitor. When the drug with an ALK inhibitor as an active ingredient in the present invention is used in combination with a TNKS inhibitor, the drug can be administered simultaneously with the TNKS inhibitor, or before or after the administration of the TNKS inhibitor. If the ALK inhibitor is administered before or after the administration of the TNKS inhibitor, the administration time can be optimized by measuring the residual concentration of the TNKS inhibitor in the subject. The concentration can be determined based on the results of analyzing a sample collected from the subject using an immunoassay such as ELISA known to those skilled in the art.

[0201] In another viewpoint, the present invention provides a drug for treating or preventing targeted cancer, which comprises a TNKS inhibitor as an active ingredient and is used in combination with an ALK inhibitor. The "drug for treating or preventing targeted cancer, which comprises a TNKS inhibitor as an active ingredient and is used in combination with an ALK inhibitor" in the present invention refers to a drug for treating or preventing targeted cancer, which comprises a TNKS inhibitor as an active ingredient, but the premise is that the drug is used in combination with an ALK inhibitor. When a drug comprising a TNKS inhibitor as an active ingredient is used in combination with an ALK inhibitor, the drug can be administered simultaneously with the ALK inhibitor, or can be administered before or after the administration of the ALK inhibitor. If the TNKS inhibitor is administered before or after the administration of the ALK inhibitor, the administration time can be optimized by measuring the residual concentration of the ALK inhibitor in the subject. The concentration can be determined based on the results of separating a sample collected from a subject using a separation device such as various chromatographs, and then analyzing using analytical methods known to those skilled in the art.

[0202] The above invention refers to the simultaneous administration or use of an ALK inhibitor and a TNKS inhibitor (hereinafter referred to as "administration"), and the order of administration, the interval between administrations, etc. should not be construed as limitations. The present invention can also be used as a product in which an ALK inhibitor is combined with a TNKS inhibitor. In addition, when an ALK inhibitor is used in combination with a TNKS inhibitor in the present invention, if necessary, each can be used in a lower dosage than when either is used alone.

[0203] The combination of ALK inhibitor and TNKS inhibitor used in the medicine, combination agent, pharmaceutical composition and treatment / prevention method of the present invention is specifically a combination of ALK inhibitor, i.e., alectinib or its salt and TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and its salt, preferably a combination of ALK inhibitor, i.e., alectinib or its salt and TNKS inhibitor selected from AZ6102, G007-LK and its salt. On the other hand, it is a combination of ALK inhibitor selected from alectinib, lorlatinib and its salt and TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and its salt, preferably a combination of ALK inhibitor selected from alectinib, lorlatinib and its salt and TNKS inhibitor selected from AZ6102, G007-LK and its salt. In another aspect, it is a combination of an ALK inhibitor selected from alectinib, brigatinib and salts thereof and a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof, preferably a combination of an ALK inhibitor selected from alectinib, brigatinib and salts thereof and a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof. In another aspect, it is a combination of an ALK inhibitor selected from alectinib, lorlatinib, brigatinib and salts thereof and a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof.

[0204] In addition, the combination of ALK inhibitors, TNKS inhibitors and pan-HER inhibitors used in the drugs, combination agents, pharmaceutical compositions and treatment / prevention methods of the present invention is a combination of an ALK inhibitor, i.e., alectinib or a salt thereof, a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and their salts, and a pan-HER inhibitor selected from dacomitinib, neratinib, afatinib and their salts, preferably a combination of an ALK inhibitor, i.e., alectinib or a salt thereof, a TNKS inhibitor selected from AZ6102, G007-LK and their salts, and a pan-HER inhibitor dacomitinib or its salt. On the other hand, it is a combination of an ALK inhibitor selected from alectinib, lorlatinib and their salts, a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and their salts and a pan-HER inhibitor selected from dacomitinib, neratinib, afatinib and their salts, preferably a combination of an ALK inhibitor selected from alectinib, lorlatinib and their salts, a TNKS inhibitor selected from AZ6102, G007-LK and their salts and the pan-HER inhibitor dacomitinib or its salt. On the other hand, it is a combination of an ALK inhibitor selected from alectinib, brigatinib and their salts, a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and their salts, and a pan-HER inhibitor selected from dacomitinib, neratinib, afatinib and their salts, preferably a combination of an ALK inhibitor selected from alectinib, brigatinib and their salts, a TNKS inhibitor selected from AZ6102, G007-LK and their salts, and the pan-HER inhibitor dacomitinib or its salt.

[0205] Cancer Type

[0206] Medicine of the present invention can be used for preventing or treating diseases such as various cancers, various cancers such as leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc.), brain tumors, neuroblastoma, glioma, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, gastric cancer, intestinal cancer, large intestine cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, gallbladder cancer, skin cancer, malignant melanoma, kidney cancer, renal pelvis and ureteral cancer, bladder cancer, uterine cancer, testicular cancer and prostate cancer. In addition, compound of the present invention can be used for preventing or treating the invasion and metastasis of solid cancer.

[0207] In particular, the drug of the present invention can be used to prevent or treat ALK fusion gene positive cancer. Examples of ALK fusion gene positive cancer include, but are not limited to, non-Hodgkin's lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer and lung cancer.

[0208] In the present invention, "ALK fusion gene positive" refers to the presence of ALK fusion genes with other genes. Examples of other fusion genes include but are not limited to echinoderm microtubule-associated protein-like protein 4 (EML4, GeneBank TM Accession number NM_019063), TFG (TRK fusion gene, GeneBank TM Accession number NM_006070).

[0209] Methods for identifying ALK fusion gene-positive cancers are described in WO2008 / 127248, Japanese Patent Laid-Open No. 2008-295444, "Guidance for ALK Gene Testing" (Biomarker Committee, the Japan Lung Cancer Society), etc. As a kit for detecting such fusion genes, Vysis LSI ALK Break Apart Rearrangement Probe Kit TM (Abbott) and Histofine ALK iAEP™ Kit (Nichirei Corporation) are commercially available.

[0210] "ALK sensitivity" refers to sensitivity to ALK inhibitors. Specifically, it means that once an ALK inhibitor is administered to an ALK fusion gene-positive cancer patient or ALK fusion gene-positive cancer cell, the ALK fusion gene-positive cancer cell exhibits a certain degree of reduction or growth inhibition compared to a control such as a solvent or compared to the state before administration of the ALK inhibitor.

[0211] The term "transient drug resistance" refers to a state in which a person is temporarily resistant to an inhibitor due to short-term exposure to the inhibitor, and is a state in which there is no resistance-associated gene mutation. Here, the resistance-associated gene mutation is, for example, a gatekeeper mutation of the ALK gene.

[0212] "ALK fusion gene-positive cancer that is temporarily resistant to ALK inhibitors" refers to ALK fusion gene-positive cancer that is sensitive to ALK inhibitors when cells obtained from a subject before the start of treatment of the present invention are cultured for a certain period of time in the absence of an ALK inhibitor, although in known in vivo experiments using ALK fusion gene-positive cancer cell cultures obtained from a subject before the start of treatment of the present invention, ALK fusion gene-positive cancer obtained from a subject before the start of ALK inhibitor treatment is less sensitive to ALK inhibitors than cells of the same type that are not exposed to ALK inhibitors (e.g., Anticancer Drugs. 2022 Feb 1; 33(2): 124-131). The certain period of time refers to a period of 6 days or more and 14 days or less, and preferably at least 9 days and at most 13 days.

[0213] Specifically, ALK fusion gene-positive cancer is a cancer in which a subject suffering from ALK fusion gene-positive cancer has been treated with an ALK inhibitor for at least 6 days before starting the treatment of the present invention, and cells obtained from the ALK fusion gene-positive cancer obtained from the subject do not have a gene mutation associated with drug resistance when starting the treatment of the present invention.

[0214] The cell proliferation inhibitory effect of the combined drug of the present invention on temporarily drug-resistant ALK fusion gene-positive cancers provides therapeutic advantages such as preventing the acquisition of drug resistance associated with drug resistance gene mutations and eliminating the necessity of, for example, changing the drug withdrawal period and the drug used.

[0215] The present invention relates to a combination of an ALK inhibitor and a TNKS inhibitor for use in drugs, combination agents, pharmaceutical compositions and treatment / prevention methods for treating / preventing ALK fusion gene-positive cancer, specifically a combination of an ALK inhibitor, i.e., alectinib or a salt thereof, and a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof, wherein the ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer, preferably a combination of an ALK inhibitor, i.e., alectinib or a salt thereof, and a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof, wherein the ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer. On the other hand, it is a combination of an ALK inhibitor selected from alectinib, lorlatinib and their salts and a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and their salts, wherein the ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer, preferably a combination of an ALK inhibitor selected from alectinib, lorlatinib and their salts and a TNKS inhibitor selected from AZ6102, G007-LK and their salts, wherein the ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer. In another aspect, it is a combination of an ALK inhibitor selected from alectinib, brigatinib and salts thereof and a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof, wherein ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer, preferably a combination of an ALK inhibitor selected from alectinib, brigatinib and salts thereof and a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof, wherein ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer. In another aspect, it is a combination of an ALK inhibitor selected from alectinib, lorlatinib, brigatinib and salts thereof and a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof, wherein ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer.

[0216] The combination of an ALK inhibitor and a TNKS inhibitor for the drug, combination agent, pharmaceutical composition and treatment / prevention method for treating / preventing ALK fusion gene-positive cancer in the present invention is specifically a combination of an ALK inhibitor, i.e., alectinib or a salt thereof, and a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof, wherein the ALK fusion gene-positive cancer is an ALK fusion gene-positive lung cancer that is temporarily resistant to the ALK inhibitor, and preferably a combination of an ALK inhibitor, i.e., alectinib or a salt thereof, and a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof, wherein the ALK fusion gene-positive cancer is an ALK fusion gene-positive lung cancer that is temporarily resistant to the ALK inhibitor. In another aspect, it is a combination of an ALK inhibitor selected from alectinib, lorlatinib and their salts and a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and their salts, wherein the ALK fusion gene-positive cancer is an ALK fusion gene-positive lung cancer that is temporarily resistant to the ALK inhibitor, preferably a combination of an ALK inhibitor selected from alectinib, lorlatinib and their salts and a TNKS inhibitor selected from AZ6102, G007-LK and their salts, wherein the ALK fusion gene-positive cancer is an ALK fusion gene-positive lung cancer that is temporarily resistant to the ALK inhibitor. In another aspect, it is a combination of an ALK inhibitor selected from alectinib, brigatinib and salts thereof and a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof, wherein the ALK fusion gene-positive cancer is an ALK fusion gene-positive lung cancer that is temporarily resistant to the ALK inhibitor, preferably a combination of an ALK inhibitor selected from alectinib, brigatinib and salts thereof and a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof, wherein the ALK fusion gene-positive cancer is an ALK fusion gene-positive lung cancer that is temporarily resistant to the ALK inhibitor. In another aspect, it is a combination of an ALK inhibitor selected from alectinib, lorlatinib, brigatinib and salts thereof and a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof, wherein the ALK fusion gene-positive cancer is an ALK fusion gene-positive lung cancer that is temporarily resistant to the ALK inhibitor.

[0217] In addition, the combination of ALK inhibitors, TNKS inhibitors and pan-HER inhibitors for the drugs, combination agents, pharmaceutical compositions and treatment / prevention methods for treating / preventing ALK fusion gene-positive cancer in the present invention is an ALK inhibitor (i.e., alectinib or a salt thereof), a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof, and a combination of pan-HER inhibitors selected from dacomitinib, neratinib, afatinib and salts thereof, wherein ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer, preferably a combination of ALK inhibitors (i.e., alectinib or a salt thereof), a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof, and a pan-HER inhibitor selected from dacomitinib or a salt thereof. Wherein ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer. On the other hand, it is a combination of an ALK inhibitor selected from alectinib, lorlatinib and their salts, a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and their salts, and a pan-HER inhibitor selected from dacomitinib, neratinib, afatinib and their salts, wherein ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer, preferably a combination of an ALK inhibitor selected from alectinib, lorlatinib and their salts, a TNKS inhibitor selected from AZ6102, G007-LK and their salts, and a pan-HER inhibitor of dacomitinib or its salts, wherein ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer. On the other hand, it is a combination of an ALK inhibitor selected from alectinib, brigatinib and salts thereof, a TNKS inhibitor selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof, and a pan-HER inhibitor selected from dacomitinib, neratinib, afatinib and salts thereof, wherein ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer, preferably a combination of an ALK inhibitor selected from alectinib, brigatinib and salts thereof, a TNKS inhibitor selected from AZ6102, G007-LK and salts thereof, and a pan-HER inhibitor of dacomitinib or its salt, wherein ALK fusion gene-positive cancer is ALK fusion gene-positive lung cancer.

[0218] In another aspect of the present invention, a method for enhancing the efficacy of ALK inhibitors when using a drug to treat ALK fusion gene-positive cancer is provided, the drug comprising a combination of an ALK inhibitor and a TNKS inhibitor, or a three-drug combination of an ALK inhibitor, a TNKS inhibitor, and a pan-HER inhibitor. Here, enhancing the efficacy means that the treatment success rate is increased compared with cases where a single agent is administered; the amount of ALK inhibitors administered in combined drug treatment is reduced compared with cases where a single agent is administered; efficacy is shown in more severe cases, for example, in patients who have failed previous treatment or whose condition has worsened; the treatment time of ALK inhibitors is shorter than the expected treatment time of the compound alone or the planned treatment time before the start of combined administration of treatment due to reasons such as the disappearance of cancer; or by inhibiting disease progression, the treatment time including ALK inhibitors and / or other maintenance therapies is extended. In a preferred aspect of the present invention, the combined drug of the present invention, etc. has a synergistic effect. Here, "synergistic effect" means that the combined effect of two drugs is greater than the sum of the effects of the individual drugs. In another embodiment, the combined drug according to the present invention, etc. has an additive effect. Here, the "additive effect" of two compounds means that the combined effect of two or three drugs is the sum of the effects of the individual drugs. In addition, in another aspect of the present invention, a method for prolonging progression-free survival (PFS) of a subject is provided, comprising administering in combination an effective amount of an ALK inhibitor and an effective amount of a TNKS inhibitor. In addition, in another aspect of the present invention, a method for preparing a pharmaceutical composition for treating or preventing targeted cancer using an ALK inhibitor or a TNKS inhibitor is provided, the pharmaceutical composition comprising an ALK inhibitor and a TNKS inhibitor as active ingredients.

[0219] In the present invention, "progression-free survival (PFS)" refers to the time from treatment (or randomization) to first disease progression or death. In one aspect of the invention, PFS can be assessed by RECIST (Respiratory Response Evaluation Criteria for Solid Tumors). In one aspect of the invention, PFS can be assessed by CA-125 levels as a determinant of progression.

[0220] In the present invention, specific examples of “prolonging progression-free survival” include: using an ALK inhibitor in combination with a TNKS inhibitor to prolong PFS compared to PFS when the ALK inhibitor or the TNKS inhibitor is administered as a single agent at the same administration amount used in combination.

[0221] In the present invention, containing ALK inhibitors and / or TNKS inhibitors as active ingredients means containing ALK inhibitors and / or TNKS inhibitors as main active ingredients, and does not limit the content of ALK inhibitors and / or TNKS inhibitors. In addition, the term "treatment" refers to administering a drug according to the present invention to a subject, causing cancer cell death or a decrease in the number, weight and / or volume of those cells, inhibiting the growth of cancer cells within a certain period of time after the start of administration (i.e., compared with the number, weight and / or volume of untreated cancer cells remaining in the same period of time, the number, weight and / or volume of cancer cells within a certain period of time after the start of administration is reduced), inhibiting cancer cell metastasis, prolonging progression-free survival (PFS) compared to cases of monotherapy, or improving various symptoms caused by targeted cancer. In addition, the term "prevention" refers to preventing the number of cancer cells that have been reduced from increasing when they grow again, or preventing the growth of cancer cells that have been inhibited from growing again.

[0222] In the present invention, "effective amount" refers to the daily dosage of each inhibitor when the ALK inhibitor and the TNKS inhibitor are used in combination. The dosage in the present invention may be the same as the dosage of each inhibitor when used alone, or it may be lower than the dosage of each inhibitor when used alone. Alternatively, the effective amount in the present invention is the same as the dosage of one of the inhibitors when used alone, and it may be lower than the dosage of the other inhibitor when used alone.

[0223] Another aspect of the present invention includes: an agent for temporarily inhibiting the growth of ALK fusion gene-positive cancer that is resistant to ALK inhibitors, comprising a combination of an ALK inhibitor and a TNKS inhibitor; an agent for temporarily inhibiting the growth of ALK fusion gene-positive cancer that is resistant to ALK inhibitors, comprising an ALK inhibitor as an active ingredient, the ALK inhibitor being used in combination with a TNKS inhibitor; an agent for temporarily inhibiting the growth of ALK fusion gene-positive cancer that is resistant to ALK inhibitors, comprising a TNKS inhibitor as an active ingredient, the TNKS inhibitor being used in combination with an ALK inhibitor; and a method for temporarily inhibiting the growth of ALK fusion gene-positive cancer that is resistant to ALK inhibitors, comprising administering to a subject an effective amount of an ALK inhibitor and an effective amount of a TNKS inhibitor in combination.

[0224] The drug or method for temporarily suppressing the growth of ALK fusion gene-positive cancer that is resistant to ALK inhibitors refers to a drug or method that can suppress the growth of ALK fusion gene-positive cancer that is temporarily resistant due to previous treatment with ALK inhibitors, etc., by using an ALK inhibitor and a TNKS inhibitor in combination.

[0225] Here, inhibiting the growth of ALK fusion gene-positive cancer refers to treating a subject with ALK fusion gene-positive cancer with a combination of an ALK inhibitor and a TNKS inhibitor, so that the weight and / or volume of the ALK fusion gene-positive cancer after treatment according to the present invention is reduced or reduced compared with the weight and / or volume of the ALK fusion gene-positive cancer after the same time predicted by the growth rate before the start of treatment, or, it means that after a certain period of time of treatment of multiple subjects according to the present invention, the average value of the weight and / or volume of the ALK fusion gene-positive cancer is reduced or reduced compared with the average value of the weight and / or volume of the ALK fusion gene-positive cancer of multiple untreated subjects after the same time, preferably significantly reduced or reduced. Alternatively, it means that after a certain period of treatment of multiple subjects according to the present invention, the average value of the weight and / or volume of the ALK fusion gene-positive cancer is reduced or reduced compared with the average value of the weight and / or volume of the ALK fusion gene-positive cancer of multiple subjects who have received one of the ALK inhibitor and the TNKS inhibitor after the same time, preferably significantly reduced or reduced.

[0226] The present invention also includes a method for shrinking ALK fusion gene-positive cancer. Here, "shrinking" ALK fusion gene-positive cancer refers to treating a subject with ALK fusion gene-positive cancer with a combination of an ALK inhibitor and a TNKS inhibitor, so that the weight and / or volume of the ALK fusion gene-positive cancer after treatment according to the present invention is reduced or reduced compared to the weight and / or volume of the ALK fusion gene-positive cancer before the start of treatment. Alternatively, it means that after a certain period of time of treatment of multiple subjects according to the present invention, the average weight and / or volume of the ALK fusion gene-positive cancer is reduced or reduced, preferably significantly reduced or reduced, compared to the average weight and / or volume of the ALK fusion gene-positive cancer before the start of treatment.

[0227] Another aspect of the present invention includes: an agent for temporarily inhibiting the growth of ALK fusion gene-positive cancer cells that are resistant to ALK inhibitors, comprising a combination of an ALK inhibitor and a TNKS inhibitor; an agent for temporarily inhibiting the growth of ALK fusion gene-positive cancer cells that are resistant to ALK inhibitors, comprising an ALK inhibitor as an active ingredient used in combination with a TNKS inhibitor; an agent for temporarily inhibiting the growth of ALK fusion gene-positive cancer cells that are resistant to ALK inhibitors, comprising a TNKS inhibitor as an active ingredient used in combination with an ALK inhibitor; and a method for temporarily inhibiting the growth of ALK fusion gene-positive cancer cells that are resistant to ALK inhibitors, comprising administering to a subject an effective amount of an ALK inhibitor and an effective amount of a TNKS inhibitor in combination. Here, "inhibiting growth" of ALK fusion gene-positive cancer cells refers to treating ALK fusion gene-positive cancer cells with a combination of ALK inhibitors and TNKS inhibitors, so that after treatment according to the present invention, the weight and / or volume of ALK fusion gene-positive cancer cells is reduced or shrunk compared with the proliferation percentage of untreated ALK fusion gene-positive cancer cells after the same period of time; or, it means that after treatment according to the present invention, the average proliferation percentage of ALK fusion gene-positive cancer cells after a certain period of time is reduced, preferably significantly reduced, compared with the average proliferation percentage of ALK fusion gene-positive cancer cells treated with one of the ALK inhibitor and the TNKS inhibitor after the same period of time.

[0228] In the present invention, "subject" refers to but is not limited to a mammal that is a subject of administration of the drug of the present invention or that needs to be administered with the drug of the present invention, including humans or non-human mammals, such as cattle, horses, dogs, sheep or cats, etc. Preferably, the subject is a human. The subject includes patients (including humans and non-human mammals). Specifically, these are patients suffering from various cancers, or humans or non-human mammals that may suffer from various cancers, such as leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphoid leukemia, chronic lymphoid leukemia, etc.), malignant lymphoma (Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc.), brain tumors, neuroblastomas, gliomas, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, gallbladder cancer, skin cancer, malignant melanoma, kidney cancer, renal pelvis and ureteral cancer, bladder cancer, uterine cancer, testicular cancer, prostate cancer, and tumors transferred by these tumors.

[0229] product

[0230] As another aspect of the present invention, a product is provided. In one embodiment, a product for treating or preventing a targeted cancer in a subject is provided, and it comprises: (a) (1) a formulation comprising a TNKS inhibitor, (2) a container, and (3) instructions or labels indicating that the TNKS inhibitor is administered to a subject in combination with at least one ALK inhibitor to treat the targeted cancer in the subject; or (b) (1) a formulation comprising an ALK inhibitor, (2) a container, and (3) instructions or labels indicating that the ALK inhibitor is administered to a subject in combination with at least one TNKS inhibitor to treat the targeted cancer in the subject.

[0231] In another embodiment of the invention, (c1)(1) a formulation comprising an ALK inhibitor, (2) a container, and (3) instructions or label indicating that the formulation comprising an ALK inhibitor, at least one TNKS inhibitor, and at least one pan-HER inhibitor is to be administered to a subject in combination for treating a targeted cancer in the subject; or (c2)(1) a formulation comprising a TNKS inhibitor, (2) a container, and (3) instructions or label indicating that the formulation comprising a TNKS inhibitor, at least one ALK inhibitor, and at least one pan-HER inhibitor is to be administered to a subject in combination for treating a targeted cancer in the subject. Alternatively, (c3)(1) a formulation comprising a pan-HER inhibitor, (2) a container, and (3) instructions or label indicating that the formulation comprising a pan-HER inhibitor, at least one TNKS inhibitor, and at least one ALK inhibitor is to be administered to a subject in combination for treating a targeted cancer in the subject.

[0232] The product includes a container comprising a formulation comprising a TNKS inhibitor, a pan-HER inhibitor, or an ALK inhibitor.

[0233] The product may further include a label or instructions on or associated with the container.

[0234] In the present invention, "instructions" refers to documents usually included in the commercial packaging of the preparation, which include information on indications, usage, dosage, administration, contraindications and / or warnings regarding the use of the preparation. "Label" refers to a sheet-like item directly attached to the container, which contains the product name, dosage, dosage form, indications, etc. of the preparation containing the TNKS inhibitor or ALK inhibitor.

[0235] The label or instructions indicate the indication of the preparation, i.e., it is used to treat targeted cancers, etc. In one embodiment, the label or instructions indicate that the preparation can be used to treat targeted cancers, etc. The label or instructions may also indicate that the preparation can be used to treat other conditions.

[0236] Examples of suitable containers include PTPs, bottles, vials, syringes and blister packs. The containers can be formed from a variety of materials such as glass or plastic. These containers can be further packaged in a paper outer box on which the above-mentioned labels, etc., are printed.

[0237] Example

[0238] All patents and literature references explicitly cited herein are hereby incorporated by reference in their entirety.

[0239] Hereinafter, the present invention will be described in detail with reference to descriptions of embodiments, but the present invention should not be construed as being limited to these descriptions.

[0240] The drugs, agents and cells used in the examples are as follows.

[0241] Alectinib was synthesized by Chugai Pharmaceutical Co., Ltd. For the compound library, 3114 compounds obtained after excluding toxic drugs from 3116 compounds in the anticancer compound library (Catalog No. L2100) from TargetMol Chemicals Inc. were used. AZ6102, G007-LK, XAV939, and dacomitinib for in vitro assays were obtained from Selleck Chemicals LLC. All drugs were dissolved in dimethyl sulfoxide (DMSO: Sigma-Aldrich) for in vitro assays. G007-LK and dacomitinib for in vivo assays were obtained from ChemScene LLC and TargetMolChemicals Inc., respectively. Alectinib was dissolved in 6% captisol for in vivo assays. G007-LK and dacomitinib were dissolved in 5% DMSO, 30% PEG 300, and 5% Tween 80.

[0242] The human cancer cell line 15cl used in the embodiment is a cell line established by single cell cloning of the human cancer cell line 1510B3N (EML4-ALK variant 1) derived from a patient with ALK fusion gene-positive lung cancer, which is derived from a human cancer cell line established by the Japanese Foundation for Cancer Research under the ALCURE Observational Study (UMIN000038934) (Source: Japanese Foundation for Cancer Research, Cancer Chemotherapy Center). The culture medium of 15cl is 15% FBS in RPMI 1640 / Ham's F-12. The cells were cultured at 37°C and 5% CO2.

[0243] Example 1

[0244] 15cl cells were treated with alectinib for 9 days to prepare drug-resistant persistent (DTP) cells (15DT) with transient resistance to alectinib. DTP cells refer to cells that acquire drug resistance and have no genetic mutations through a certain period of drug exposure. The number of viable cells of 15cl and 15DT after exposure to the compound library for 6 days was measured. Exposure to each compound was performed at a final concentration of 100nM. Figure 1 Results of analyzing the percentage of cell proliferation after exposure to each compound are shown. Figure 1 In the figure, the vertical axis represents the value calculated by the following expression 1, and the horizontal axis represents each compound. The cell proliferation percentage of each compound in expression 1 was calculated by a known method (Mol Cancer Ther. 2021 June; 20(6): 1133-1141.). This indicates Figure 1 When the cell proliferation ratio (15DT / 15cl) is less than 1, the proliferation inhibition effect of the compound in DTP cells increases, and conversely, when the cell proliferation ratio is greater than 1, the proliferation inhibition effect decreases. Figure 1 Only compounds targeting TNKS (tankyrase) in L2100 from TargetMol are highlighted.

[0245] [Expression 1]

[0246]

[0247] The results showed that 4 out of 5 compounds targeting TNKS in L2100 showed values ​​less than 1 and their proliferation inhibition was increased in DTP cells.

[0248] To verify the screening results of the compound library, 15cl and 15DT were seeded in 384-well plates and the expression of 15cl and 15DT was measured. Figure 2 Viable cell numbers 6 days after treatment with the indicated concentrations of alectinib as an ALK inhibitor and AZ6102, G007-LK, and XAV939 as TNKS inhibitors. Figure 2 The results of calculating the percentage of cell proliferation relative to the number of cells not treated with the drug are shown. Figure 2 In the figure, the vertical axis represents the percentage of cell proliferation, and the horizontal axis represents the concentration of the compound.

[0249] The results showed that 15DT was less sensitive to alectinib than 15cl. In addition, the results showed that AZ6102 and G007-LK, which had increased proliferation inhibition in 15DT in the compound library screening, had no proliferation inhibition in 15cl, but had a concentration-dependent proliferation inhibition in 15DT, and their proliferation inhibition increased in 15DT. In addition, the results showed that for XAV939, at a final concentration of 100 nM, the proliferation inhibition in 15DT in the compound library was not increased, but at higher concentrations, the proliferation inhibition in 15DT increased compared with that in 15cl, as shown in FIG. Figure 2 shown.

[0250] Example 2

[0251] 15cl was inoculated on a 6-well plate, drugs were added, and cells were cultured. Figure 3 The cells were cultured for the times indicated and the proteins were purified from the cells. Figure 3 The results of observing the expression level of each protein using the capillary electrophoresis protein analysis system Sally Sue (ProteinSimple) are shown. Figure 3 In, ALC indicates alectinib, - indicates no treatment with the drug, and h and d indicate hours and days, respectively. As primary antibodies, antibodies against phosphorylated (p)-β-catenin (Ser675), non-p-β-catenin (Ser33 / 37 / Thr41), β-catenin, survivin, c-Myc / N-Myc, and actin β (ACTB) (CellSignaling Technology), antibodies against Axin 1 (Thermo Fisher Scientific), and antibodies against Axin 2 (abcam) were used. It is known that Ser675 of β-catenin is phosphorylated upon activation, while Ser33 / 37 / Thr41 is phosphorylated upon inactivation.

[0252] The results showed that the amount of active β-catenin (p-β-catenin and non-p-β-catenin) increased from 24 hours to 9 days after treatment with alectinib compared to treatment without the agent. In addition, the results showed that the amount of Axin 1 and Axin 2, which are involved in the degradation of β-catenin and targeted for degradation by the anchor polymerase, continued to decrease after treatment with alectinib. In addition, the results showed that the amount of the survival protein c-Myc / N-Myc, whose transcription is activated by β-catenin, decreased immediately after alectinib treatment, but increased as the amount of active β-catenin increased.

[0253] It is known that active β-catenin moves from the cytoplasm to the nucleus and activates the transcription of target genes. Therefore, in order to observe the amount of β-catenin located in the nucleus, 15cl and 15DT were inoculated into flasks, the drugs were added, and the cells were cultured. Figure 4 At the times indicated in , the nuclear and cytoplasmic fractions were separated using a Nuclear / Cytoplasmic Fractionation Kit (Cell Biolabs Inc.), and the proteins were purified. Figure 4 The results of using Sally Sue to observe protein expression levels are shown. Note that Figure 4 In the table, ALC indicates alectinib, NT indicates untreated, h indicates hour, and Cyt and Nuc indicate cytoplasmic fraction and nuclear fraction, respectively. As primary antibodies, antibodies against β-catenin and β-tubulin (Cell Signaling Technology) and antibodies against lamin A / C (abcam) were used. Note that β-tubulin and lamin A / C were used as marker proteins for the cytoplasmic fraction and nuclear fraction, respectively.

[0254] The results showed that the amount of β-catenin in the nucleus increased after 24 hours of treatment with alectinib compared with that without drug treatment, and further increased at 15DT, indicating that the movement of β-catenin to the nucleus was increased by alectinib treatment.

[0255] Thus, this suggests that alectinib treatment activates β-catenin.

[0256] Example 3

[0257] To investigate whether the combination of ALK inhibitors and TNKS inhibitors could enhance the cell proliferation inhibition effect of ALK inhibitors in 15cl. 15cl was seeded in 384-well plates and the Figure 5 Number of viable cells after 6 days of exposure to alectinib, lorlatinib, or brigatinib as ALK inhibitors, and AZ6102 or G007-LK as TNKS inhibitors at the indicated concentrations. Figure 5 The results of calculating the percentage of cell proliferation relative to the number of cells not treated with the drug are shown. Figure 5 In the figure, the vertical axis represents the percentage of cell proliferation, the horizontal axis represents the concentration of the compound, ALC represents alectinib, LOR represents lorlatinib, and BRG represents brigatinib.

[0258] The results showed that the TNKS inhibitor did not show a proliferation inhibitory effect as a single agent, but the combined use of the TNKS inhibitor with the ALK inhibitor enhanced the cell proliferation inhibitory effect of the ALK inhibitor, suggesting that the ALK inhibitor has a synergistic effect with the TNKS inhibitor.

[0259] Example 4

[0260] 15cl was seeded on a 6-well plate, drugs were added thereto, the cells were cultured for 48 hours, and proteins were purified from the cells. Figure 6 The results of using Sally Sue to observe protein expression levels are shown. Note that Figure 6 In the table, ALC represents alectinib, AZ represents AZ6102, - represents untreated, and + represents treated. As primary antibodies, antibodies against phosphorylated (p)-β-catenin (Ser675), non-p-β-catenin (Ser33 / 37 / Thr41), β-catenin, survivin, c-Myc / N-Myc, and actin β (ACTB) (Cell Signaling Technology) and an antibody against Axin 1 (Thermo Fisher Scientific) were used. Note that c-Myc / N-Myc is known to be involved in cell proliferation, and survivin is known to be involved in anti-apoptosis.

[0261] The results showed that the amount of active β-catenin increased by alectinib treatment was reduced by TNKS inhibitor treatment. In addition, it was shown that the combined use reduced the amount of c-Myc / N-Myc and survivin whose transcription is activated by β-catenin.

[0262] Example 5

[0263] We investigated whether the triple combination of ALK inhibitor, TNKS inhibitor and pan-HER inhibitor in 15cl enhanced the cell proliferation inhibition effect compared with the double combination of ALK inhibitor and TNKS inhibitor or ALK inhibitor and pan-HER inhibitor. Figure 7 Viable cell numbers after 6 days of exposure to alectinib as ALK inhibitor, AZ6102 as TNKS inhibitor, and dacomitinib as pan-HER inhibitor at the indicated concentrations. Figure 7 The results of calculating the percentage of cell proliferation relative to the number of cells not treated with the drug are shown. Figure 7 In the figure, the vertical axis represents the percentage of cell proliferation, the horizontal axis represents the concentration of the compound, ALC represents alectinib, Daco represents dacomitinib, and AZ represents AZ6102.

[0264] The results showed that the dual-drug combination of a TNKS inhibitor or a pan-HER inhibitor with an ALK inhibitor had enhanced cell proliferation inhibition compared with the ALK inhibitor as a single agent, and the triple-drug combination of these inhibitors further enhanced the cell proliferation inhibition, suggesting a synergistic effect.

[0265] Example 6

[0266] Alectinib (2 mg / kg, orally once daily for 14 days) and G007-LK (10 mg / kg and 50 mg / kg, orally once daily for 14 days) were combined and administered to SCID mice transplanted with 15cl (CLEA Japan, male), with 5 × 10 6 cells. Figure 8 Tumor volume (mean + standard deviation) and relative body weight (mean + standard deviation) of each administration group are shown. Alectinib (2 mg / kg, oral once daily for 14 days) and G007-LK (10 mg / kg, oral once daily for 14 days) and dacomitinib (10 mg / kg, oral once daily for 14 days) were used in combination, while Fig. 9 The volume (mean + standard deviation) and relative body weight (mean + standard deviation) of each administration group are shown.

[0267] Note that Figure 8 and Fig. 9 In the figure, the horizontal axis represents the elapsed days with the first day of drug administration being set as 1, the vertical axis represents tumor volume or relative body weight, Vehicle represents a solvent-administered control group, ALC represents alectinib, and Daco represents dacomitinib. Figure 8 Results for each group of n=6 are shown, and Fig. 9 Results for n=8 per group are shown.

[0268] The results show that in Figure 8 In the present invention, the group of alectinib and G007-LK combined administration showed a higher anti-tumor effect than each single agent administration group. On the 15th day after the start of the drug administration, the group of alectinib and 10mg / kg G007-LK combined administration showed a statistically significant higher anti-tumor effect than the solvent administration group and the 10mg / kg G007-LK single agent administration group, and the group of alectinib and 50mg / kg G007-LK combined administration showed a statistically significant higher anti-tumor effect than the solvent administration group and the 50mg / kg G007-LK single agent administration group. Compared with the solvent administration group, no weight loss was observed in both groups.

[0269] In addition, Fig. 9 In the 15th day after the administration of the drug, the three-drug combination administration group showed a significantly higher anti-tumor effect than the two-drug combination administration group of alectinib and G007-LK and the two-drug combination administration group of alectinib and dacomitinib. No weight loss was observed in both groups.

[0270] Industrial Applicability

[0271] The combined drug of the present invention can be used for the prevention or treatment of ALK fusion gene-positive cancer, etc. In addition, the combined drug of the present invention can be used as a drug for inhibiting the growth of ALK fusion gene-positive cancer that temporarily has drug resistance.

Claims

1. A drug for treating or preventing ALK fusion gene-positive cancer, comprising a combination of an ALK inhibitor and a TNKS inhibitor.

2. The medicament according to claim 1, further comprising a combination of a pan-HER inhibitor.

3. A drug for treating or preventing ALK fusion gene-positive cancer, comprising an ALK inhibitor as an active ingredient, wherein the ALK inhibitor is used in combination with a TNKS inhibitor. 4 . The medicament according to claim 1 or 3 , wherein the ALK inhibitor is used simultaneously with the TNKS inhibitor, or is used before the start of administration of the TNKS inhibitor.

5. A drug for treating or preventing ALK fusion gene-positive cancer, comprising a TNKS inhibitor as an active ingredient, wherein the TNKS inhibitor is used in combination with an ALK inhibitor. The medicament according to claim 5 , wherein the TNKS inhibitor is used simultaneously with the ALK inhibitor, or is used after the start of administration of the ALK inhibitor.

7. The medicament according to any one of claims 3, 5 and 6, further comprising a combination of a pan-HER inhibitor.

8. The medicament according to any one of claims 1 to 3, 5 and 6, wherein the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, lorlatinib, brigatinib and salts thereof.

9. The medicament according to any one of claims 1 to 3, 5 and 6, wherein the TNKS inhibitor is selected from AZ6102, G007-LK, XAV939, 2X-121, JPI-547, RK-582 and salts thereof.

10. The medicament according to any one of claims 1 to 3, 5 and 6, wherein the pan-HER inhibitor is selected from dacomitinib, neratinib, afatinib and salts thereof.

11. The medicament according to any one of claims 1 to 3, 5 and 6, wherein the ALK fusion gene-positive cancer is selected from non-Hodgkin's lymphoma, neuroblastoma, inflammatory myofibroblastic tumor, renal cancer and lung cancer.

12. The medicament according to any one of claims 1 to 3, 5 and 6, wherein the ALK fusion gene-positive cancer has not received prior treatment with an ALK inhibitor.

13. The medicament according to any one of claims 1 to 3, 5 and 6, wherein the ALK fusion gene-positive cancer is sensitive to ALK.

14. The medicament according to any one of claims 1 to 3, 5 and 6, wherein the ALK inhibitor is administered simultaneously with a TNKS inhibitor.

15. A method for treating or preventing ALK fusion gene-positive cancer, the method comprising administering to a subject an effective amount of an ALK inhibitor and an effective amount of a TNKS inhibitor in combination.

16. The method of claim 15, further comprising administering a pan-HER inhibitor in combination.

17. An agent for temporarily inhibiting the growth of ALK fusion gene-positive cancer that is resistant to an ALK inhibitor, comprising a combination of an ALK inhibitor and a TNKS inhibitor.

18. The growth inhibitor according to claim 17, further comprising a combination of a pan-HER inhibitor.

19. A product comprising: (1) a formulation comprising an ALK inhibitor, (2) a container, and (3) instructions or labeling for administering the ALK inhibitor in combination with at least one TNKS inhibitor to a subject for treating ALK fusion gene-positive cancer.

20. The product of claim 19, comprising instructions or label indicating that a pan-HER inhibitor is to be further administered in combination.

21. A combination of an ALK inhibitor and a TNKS inhibitor or use thereof in the preparation of a medicament for treating or preventing ALK fusion gene-positive cancer.

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