Pharmaceutical combination of a FAK inhibitor and a topoisomerase inhibitor, and uses thereof

Abstract

The present disclosure relates to a combination of a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor for use in treating tumors. The present disclosure also relates to a combination of a FAK inhibitor and a topoisomerase inhibitor for use in treating tumors.

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 202211129639.0, filed on September 16, 2022, and Chinese Patent Application No. 202311155482.3, filed on September 7, 2023. The disclosures of the above-referenced Chinese patent applications are incorporated herein by reference in their entirety.

[0002] The present disclosure is in the field of medicinal chemistry. Specifically, the present disclosure relates to the treatment of tumors using focal adhesion kinase (FAK) inhibitors in combination with other drugs. [Background technology]

[0003] Tumors are the second largest and most lethal threat to human health. Immunogenic cell death (ICD) is based on the superposition effect of programmed cell death. Intracellular pressure signals can be activated when cancer cells are exposed to chemotherapy or targeted drugs. These pressure signals include endoplasmic reticulum pressure (ER stress) and reactive oxygen species pressure (oxidative stress). Under the influence of pressure signals, cells first attempt to repair the stress. If the damage caused by the pressure exceeds the cell's repair capacity, the cell initiates the programmed death process. This process is often accompanied by the release of a certain class of damage-associated molecular patterns (DAMPs). These DAMPs are specifically recognized by pattern recognition receptors on antigen-presenting cells (APCs) in the body. DAMPs induce the maturation, differentiation, and activation of APCs, which then gradually present them to immune cells, such as effector T cells, thereby generating antigen memory in immune cells. If tumor cells from the same source are encountered again, the immune cells will specifically recognize and kill them. The new tumor-specific immune response initiated by ICD increases sensitivity to immune checkpoint inhibitors (ICIs), thereby enhancing the effectiveness of immune checkpoint inhibitors and generating anti-tumor responses to maintain immune memory.

[0004] FAK, also known as protein tyrosine kinase 2 (PTK2), is a non-receptor tyrosine kinase and a key component of focal adhesion complexes. FAK mediates integrin and growth factor signals and plays an important role in mediating tumor cell invasion, proliferation, and survival.

[0005] The in vivo function of topoisomerase is to release tension generated during DNA replication and transcription by breaking DNA strands, removing the positive supercoils generated in the early stages of replication and the negative supercoils generated by RNA polymerization during transcription, and then reconnecting the broken ends formed by breaking into complete DNA strands to ensure the smooth progress of the reaction. Topoisomerase inhibitors bind to easily dissociable complexes with the corresponding topoisomerase enzymes to form stable complexes that prevent replication forks from passing smoothly, thereby causing breaks in the DNA strands and interfering with DNA replication and transcription. This type of drug is widely used in tumor treatment. However, this type of drug develops some drug resistance after a certain period of use. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Patent WO2010058032 Summary of the Invention [Problem to be solved by the invention]

[0007] Combinations of chemotherapy and immunotherapy, including topoisomerase inhibitors, are widely used in clinical practice, but there remains a need to improve the therapeutic effects, particularly how to enhance efficacy and produce durable antitumor effects. [Means for solving the problem]

[0008] One aspect of the present disclosure provides the use of a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein the topoisomerase inhibitor is not an anthracycline.

[0009] Another aspect of the present disclosure provides a pharmaceutical combination product of a FAK inhibitor, a topoisomerase inhibitor and an immune checkpoint inhibitor for use in treating a tumor in a subject, wherein the topoisomerase inhibitor is not an anthracycline.

[0010] Another aspect of the present disclosure provides a method for treating a tumor, comprising administering therapeutically effective amounts of a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor to a subject in need thereof, wherein the topoisomerase inhibitor is not an anthracycline.

[0011] Another aspect of the present disclosure provides a kit or a pharmaceutically acceptable composition comprising: (a) a FAK inhibitor; (b) a topoisomerase inhibitor, wherein the topoisomerase inhibitor is not an anthracycline; and (c) an immune checkpoint inhibitor.

[0012] Another aspect of the present disclosure provides the use of a FAK inhibitor and a topoisomerase inhibitor in the manufacture of a medicament for treating a tumor, wherein the FAK inhibitor is used to enhance immunogenic cell death induced by the topoisomerase inhibitor, and the topoisomerase inhibitor is not an anthracycline.

[0013] Another aspect of the present disclosure provides a FAK inhibitor for use in enhancing immunogenic cell death induced by a topoisomerase inhibitor in the treatment of tumors, wherein the topoisomerase inhibitor is not an anthracycline.

[0014] Another aspect of the present disclosure provides a method for treating a tumor, comprising administering therapeutically effective amounts of a FAK inhibitor and a topoisomerase inhibitor to a subject in need thereof, wherein the FAK inhibitor is used to enhance immunogenic cell death induced by the topoisomerase inhibitor, and the topoisomerase inhibitor is not an anthracycline.

[0015] Another aspect of the present disclosure provides the use of a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor in the manufacture of a medicament for the combination treatment of a tumor, wherein the topoisomerase inhibitor is not an anthracycline.

[0016] Another aspect of the present disclosure provides use of a FAK inhibitor in the manufacture of a combination medicament with a topoisomerase inhibitor and an immune checkpoint inhibitor for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline.

[0017] Another aspect of the present disclosure provides use of a topoisomerase inhibitor in the manufacture of a combination medicament with a FAK inhibitor and an immune checkpoint inhibitor for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline.

[0018] Another aspect of the present disclosure provides the use of an immune checkpoint inhibitor in the manufacture of a combination medicament with a FAK inhibitor and a topoisomerase inhibitor for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline.

[0019] Another aspect of the present disclosure provides the use of a FAK inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a topoisomerase inhibitor and an immune checkpoint inhibitor, wherein the topoisomerase inhibitor is not an anthracycline.

[0020] Another aspect of the present disclosure provides the use of a topoisomerase inhibitor in the manufacture of a medicament for combined treatment of a tumor with a FAK inhibitor and an immune checkpoint inhibitor, wherein the topoisomerase inhibitor is not an anthracycline.

[0021] Another aspect of the present disclosure provides the use of an immune checkpoint inhibitor in the manufacture of a medicament for the combination treatment of a tumor with a FAK inhibitor and a topoisomerase inhibitor, wherein the topoisomerase inhibitor is not an anthracycline.

[0022] Another aspect of the present disclosure provides a kit comprising a FAK inhibitor and instructions for use, wherein the instructions indicate that the FAK inhibitor can be used in combination with a topoisomerase inhibitor and an immune checkpoint inhibitor to treat a tumor, and wherein the topoisomerase inhibitor is not an anthracycline.

[0023] Another aspect of the present disclosure provides a kit comprising a topoisomerase inhibitor and instructions for use, wherein the instructions indicate that the topoisomerase inhibitor can be used in combination with a FAK inhibitor and an immune checkpoint inhibitor to treat a tumor, and wherein the topoisomerase inhibitor is not an anthracycline.

[0024] Another aspect of the present disclosure provides a kit comprising an immune checkpoint inhibitor and instructions for use, wherein the instructions indicate that the immune checkpoint inhibitor can be used in combination with a FAK inhibitor and a topoisomerase inhibitor to treat a tumor, and wherein the topoisomerase inhibitor is not an anthracycline.

[0025] Another aspect of the present disclosure provides a method for treating a tumor, comprising administering therapeutically effective amounts of a FAK inhibitor and a topoisomerase inhibitor to a subject in need thereof, wherein the topoisomerase inhibitor is not an anthracycline.

[0026] Another aspect of the present disclosure provides a pharmaceutical combination product of a FAK inhibitor and a topoisomerase inhibitor for use in treating a tumor in a subject in need thereof, wherein the topoisomerase inhibitor is not an anthracycline.

[0027] Another aspect of the present disclosure provides the use of a FAK inhibitor and a topoisomerase inhibitor in the manufacture of a combined medicament for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline.

[0028] Another aspect of the present disclosure provides the use of a FAK inhibitor in the manufacture of a combination medicament with a topoisomerase inhibitor for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline.

[0029] Another aspect of the present disclosure provides the use of a topoisomerase inhibitor in the manufacture of a combination medicament with a FAK inhibitor for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline.

[0030] Another aspect of the present disclosure provides the use of a FAK inhibitor and a topoisomerase inhibitor in the manufacture of a medicament for the combination treatment of a tumor, wherein the topoisomerase inhibitor is not an anthracycline.

[0031] Another aspect of the present disclosure provides the use of a FAK inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a topoisomerase inhibitor, wherein the topoisomerase inhibitor is not an anthracycline.

[0032] Another aspect of the present disclosure provides the use of a topoisomerase inhibitor in the manufacture of a medicament for the combination treatment of a tumor with a FAK inhibitor, wherein the topoisomerase inhibitor is not an anthracycline.

[0033] Another aspect of the present disclosure provides a kit comprising a FAK inhibitor and instructions for use, wherein the instructions indicate that the FAK inhibitor can be used in combination with a topoisomerase inhibitor to treat a tumor, and the topoisomerase inhibitor is not an anthracycline.

[0034] Another aspect of the present disclosure provides a kit comprising a topoisomerase inhibitor and instructions for use, wherein the instructions indicate that the topoisomerase inhibitor can be used in combination with a FAK inhibitor to treat a tumor, and wherein the topoisomerase inhibitor is not an anthracycline.

[0035] Optionally, the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, or IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof, further or IN10018 or a pharmaceutically acceptable salt thereof, or IN10018 tartrate, wherein the structure of IN10018 is:

[0036] [ka]

[0037] is.

[0038] Defactinib is also known as difatini with CAS number 1345713-71-4, GSK2256098 with CAS number 1224887-10-8, PF-00562271 with CAS number 717907-75-0, VS-4718 with CAS number 1061353-68-1, APG-2449 is being developed by Ascent Pharmaceuticals, and AMP945 with CAS number 1393653-34-3.

[0039] Optionally, the topoisomerase inhibitor is a topoisomerase I inhibitor.

[0040] For example, the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67, or a pharmaceutically acceptable salt thereof.

[0041] The CAS number for topotecan is 123948-87-8, the CAS number for irinotecan is 97682-44-5, the CAS number for belotecan is 256411-32-2, the CAS number for cositecan is 401905-67-7, the CAS number for exatecan (DX-8951) is 171335-80-1, and the CAS number for indenoisoquinoline is 9750 1-75-2, the CAS number of indotecan (LMP-400) is 915303-09-2, the CAS number of indimitecan (LMP-776) is 915360-05-3, the CAS number of simmitecan is 951290-31-6, the CAS number of gimatecan (ST1481) is 292618-32-7, EC-112002 is developed by Elucida Oncology Inc., the CAS number of PLX-038 (NK012) is 86639-52-3, and the CAS number of AR-67 is 220913-32-6.

[0042] Optionally, the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

[0043] Optionally, the topoisomerase inhibitor is a topoisomerase II inhibitor.

[0044] For example, the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin, or a pharmaceutically acceptable salt thereof.

[0045] Etoposide's CAS number is 33419-42-0, teniposide's CAS number is 29767-20-2, and sabalubicin's CAS number is 211100-13-9.

[0046] Optionally, the topoisomerase II inhibitor is etoposide, teniposide, or a pharmaceutically acceptable salt thereof.

[0047] Optionally, the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

[0048] Optionally, the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and alternatively, the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181.

[0049] Optionally, the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, and alternatively, the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001.

[0050] Optionally, the immune checkpoint inhibitor is a TIGIT antibody, or alternatively, the TIGIT antibody is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321.

[0051] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor.

[0052] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

[0053] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor.

[0054] Optionally, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

[0055] Optionally, the FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

[0056] Optionally, the tumor is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, and esophageal cancer. metastases caused by pharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or hematological malignancies such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myeloid leukemia (CML).

[0057] Optionally, the tumor is breast cancer or colon cancer (including colorectal cancer).

[0058] In order to more clearly describe the exemplary technical solutions of the present disclosure, exemplary drawings are briefly introduced below. Needless to say, the drawings in the following description only relate to some examples of the present disclosure, and do not limit the present disclosure. [Brief explanation of the drawings]

[0059] [Figure 1] FIG. 1 shows that FAK silencing for 48 hours combined with 2 μM etoposide treatment enhanced apoptosis in MDA-MB-231 cells. [Figure 2] FIG. 1 shows that 48 hours of FAK silencing combined with 2 μM etoposide treatment enhanced calreticulin release and exposure. [Figure 3] FIG. 1 shows that FAK silencing for 48 hours combined with 2 μM teniposide treatment enhanced apoptosis in MDA-MB-231 cells. [Figure 4] FIG. 1 shows that 48 hours of FAK silencing combined with 2 μM teniposide treatment enhanced calreticulin release and exposure. [Figure 5] FIG. 1 shows IC50 values ​​of etoposide in combination with IN10018 in colon cancer cells CT26. [Figure 6] FIG. 1 shows white light micrographs of colon cancer CT26 cells after 48 hours of incubation with drugs. [Figure 7](Fig. 7a) shows the status of colon cancer CT26 cells after 48 hours of incubation with IN10018 and etoposide, and the percentage of CRT-positive cells after 48 hours of incubation of colon cancer CT26 cells with the drugs. (Fig. 7b) shows the status of colon cancer CT26 cells after 48 hours of incubation with IN10018 and etoposide, and the percentage of Annexin V-positive cells after 48 hours of incubation of colon cancer CT26 cells with the drugs. [Figure 8] (Fig. 8a) shows the status of colon cancer CT26 cells after 48 hours of incubation with IN10018 and irinotecan, and the percentage of CRT-positive cells after 48 hours of incubation of colon cancer CT26 cells with the drugs. (Fig. 8b) shows the status of colon cancer CT26 cells after 48 hours of incubation with IN10018 and irinotecan, and the percentage of Annexin V-positive cells after 48 hours of incubation of colon cancer CT26 cells with the drugs. [Figure 9] FIG. 1 shows the curves of the inhibitory effect of teniposide and its combination with IN10018 on the proliferation of colon cancer CT26 cells versus drug concentration. [Figure 10] (Fig. 10a) shows the status of colon cancer CT26 cells after 48 hours of incubation with IN10018 and teniposide, and the percentage of calreticulin (CRT)-positive cells after 48 hours of incubation of murine colon cancer CT26 cells with the drugs. (Fig. 10b) shows the status of colon cancer CT26 cells after 48 hours of incubation with IN10018 and teniposide, and the percentage of annexin-V-positive cells after 48 hours of incubation of murine colon cancer CT26 cells with the drugs. [Figure 11] FIG. 1 shows tumor growth curves of a C57BL / 6 mouse subcutaneous allograft tumor model of MC38 mouse colorectal cancer cells after administration; data points represent mean tumor volumes within groups, and error bars represent standard error of the mean (SEM). [Figure 12]FIG. 1 shows the weight change curve of a C57BL / 6 mouse subcutaneous allograft tumor model of MC38 mouse colorectal cancer cells after administration, where data points represent the mean weight within the group and error bars represent the standard error of the mean (SEM). [Figure 13] (Fig. 13a) shows the status of mouse breast cancer T41 cells after 48 hours of incubation with AMP945 and etoposide, and the percentage of calreticulin (CRT)-positive cells after 48 hours of incubation of mouse breast cancer T41 cells with the drugs. (Fig. 13b) shows the status of mouse breast cancer T41 cells after 48 hours of incubation with AMP945 and etoposide, and the percentage of annexin-V-positive cells after 48 hours of incubation of mouse breast cancer T41 cells with the drugs. [Figure 14] (Fig. 14a) shows the status of mouse breast cancer T41 cells after 48 hours of incubation with AMP945 and irinotecan, and the percentage of calreticulin (CRT)-positive cells after 48 hours of incubation of mouse breast cancer T41 cells with the drugs. (Fig. 14b) shows the status of mouse breast cancer T41 cells after 48 hours of incubation with AMP945 and irinotecan, and the percentage of annexin-V-positive cells after 48 hours of incubation of mouse breast cancer T41 cells with the drugs. DETAILED DESCRIPTION OF THE INVENTION

[0060] In order to make the objectives, technical solutions and advantages of the examples of the present disclosure more apparent, the technical solutions of the examples of the present disclosure are clearly and completely described in the accompanying drawings. Needless to say, the described examples are only a part of the examples of the present disclosure, but are not all of the examples. Based on the described examples of the present disclosure, all other examples obtained by those skilled in the art without creative work belong to the scope of protection of the present disclosure.

[0061] The present disclosure may be embodied in other specific forms without departing from the basic attributes of the present disclosure. It should be understood that any and all embodiments of the present disclosure may be combined with technical features of any other embodiment or embodiments to obtain additional embodiments without inconsistency. The present disclosure includes further embodiments resulting from such combinations.

[0062] All publications and patents mentioned in this disclosure are hereby incorporated by reference in their entirety. In the event that the usage in, or terminology used in, any publication or patent incorporated by reference conflicts with the usage in, or terminology used in, this disclosure, the usage and terminology of this disclosure shall control.

[0063] The section headings used in this disclosure are for organizational purposes only and are not to be construed as limitations on the subject matter.

[0064] Unless otherwise defined, all technical and scientific terms used herein have their ordinary meaning within the field to which the claimed subject matter belongs. In the event that there are a plurality of definitions for a term, those in this disclosure shall prevail.

[0065] Except in the working examples or where otherwise indicated, all numbers of quantitative nature, such as dosage amounts set forth in the description and claims, are to be understood in all instances to be modified by the term "about." It is also to be understood that any numerical range recited in this application is intended to include all subranges within the range, and any combination of the endpoints of the ranges or subranges.

[0066] As used in this disclosure, "including," "containing," "comprising," and the like mean that the elements appearing before the term cover the elements listed after the term and their equivalents, and do not exclude elements not listed. The terms "including," "containing," and "comprising" as used herein can be open, semi-open, and closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0067] definition As used in this application, the following terms and symbols have the following meanings, unless the context dictates otherwise: As used herein, the term "FAK inhibitor" refers to an effective inhibitor of FAK, which may be suitable for mammals or humans. In some embodiments, the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, AMP945, AMP886, or a pharmaceutically acceptable salt thereof, and the structure of IN10018 is:

[0068] [ka]

[0069] defactinib, also known as difatin, has a CAS number of 1345713-71-4; GSK2256098 has a CAS number of 1224887-10-8; PF-00562271 has a CAS number of 717907-75-0; VS-4718 has a CAS number of 1061353-68-1; APG-2449 is being developed by Yasheng Medicine Co., Ltd.; and AMP945 has a CAS number of 1393653-34-3. In some embodiments, the FAK inhibitor is alternatively IN10018, defactinib, AMP945, or a pharmaceutically acceptable salt thereof, and in some alternative embodiments, the FAK inhibitor is IN10018, or a pharmaceutically acceptable salt thereof, or IN10018 tartrate.

[0070] As used herein, the term "topoisomerase inhibitors" refers to a class of compounds that can inhibit the activity of DNA topoisomerases. Common topoisomerase inhibitors include topoisomerase I inhibitors and topoisomerase II inhibitors.

[0071] As used herein, the term "anthracycline" refers to a class of topoisomerase II inhibitors that includes doxorubicin, epirubicin, daunorubicin, and aclarubicin.

[0072] As used herein, the term "immune checkpoint inhibitor" refers to a pharmaceutical agent that can improve immune system activity by modulating immune checkpoint pathways (e.g., PD-1, TIGIT, CTLA-4, LAG-3, TIM-3, etc.). In some embodiments, the immune checkpoint inhibitor is a PD-1 / PD-L1 (programmed cell death protein 1) pathway antagonist (also referred to as a "PD-1 inhibitor") or a TIGIT inhibitor. PD-1 inhibitors are also referred to as PD-1 / PD-L1 inhibitors in the present disclosure. For example, in the therapeutic methods, medicaments, and uses disclosed herein, the PD-1 / PD-L1 inhibitor is a PD-1 / PD-L1 antibody, including, but not limited to, pembrolizumab (pabolizumab) (KERIDA / Keytruda / K medicament), tislelizumab (Baizean), nivolumab, toripalimab (Tuoyi), atezolizumab (Tecentriq), durvalumab (Imfinzi), avelumab (Bavencio), atezolizumab (MPDL 3280A / Tecentriq / T medicament), BMS-936559 (a fully humanized IgG4 monoclonal antibody against PD-L1), GS-4224, AN-4005, or MX-10181. In some alternative embodiments, the PD-1 inhibitor is toripalimab. In some embodiments, PD-1 inhibitors are used to treat human subjects. In some embodiments, PD-1 is human PD-1. PD-1 / PD-L1 inhibitors also include PD-1 / PD-L1 small molecule inhibitors, such as INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001. TIGIT (also known as WUCAM, Vstm3, and VSIG9) is a receptor of the Ig superfamily and a novel immune checkpoint in addition to PD-1 / PD-L1.For example, in the therapeutic methods, medicaments, and uses disclosed herein, the immune checkpoint inhibitor is a TIGIT inhibitor, including, but not limited to, osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. In some embodiments, the TIGIT inhibitor is used to treat a human subject. For the avoidance of ambiguity, all antibodies in this disclosure include biantibodies.

[0073] As used herein, "pharmaceutical combination" or "pharmaceutical combination product" may refer to the case of a fixed combination in the form of a dosage unit (e.g., all active pharmaceutical ingredients present in one dosage form), or to the case of a product that is administered in combination in a complete kit, and to the case of a combination of pharmaceuticals and instructions for use indicating that the pharmaceutical may be used in combination with one or more other pharmaceuticals.

[0074] As used herein, "combination treatment" or "combined medication" means that a medication is used in combination with one or more other medications to treat a disease, and includes both a combination of one medication and one or more other medications, and a combination of one medication and instructions indicating that the medication may be used in combination with one or more other medications.

[0075] In this application, "simultaneous or sequential administration" refers to simultaneous administration of two or more pharmaceutical agents or sequential administration of two or more pharmaceutical agents at a time interval within an administration cycle (e.g., within 4 weeks, 3 weeks, 2 weeks, 1 week, or 24 hours). The mode of administration (e.g., oral administration, intravenous administration, intramuscular administration, or subcutaneous administration) may be the same or different, and the number / cycle of administration of two or more pharmaceutical agents may be the same or different. When the therapeutic method, product, or use of the present disclosure involves two pharmaceutical agents, the two pharmaceutical agents may be administered simultaneously or separately at a certain interval. When the therapeutic method, product, or use of the present disclosure involves three pharmaceutical agents, the three pharmaceutical agents may be administered at the same time, or two pharmaceutical agents may be administered at one time and one pharmaceutical agent at another time, or each of the three pharmaceutical agents may be administered at different time points.

[0076] In some embodiments, the PD-1 / PD-L1 inhibitor is administered intravenously (e.g., as an intravenous injection), subcutaneously, or orally. Alternatively, the PD-1 / PD-L1 inhibitor is administered by intravenous injection.

[0077] In some embodiments, the TIGIT inhibitor is administered intravenously (e.g., as an intravenous injection), subcutaneously, or orally. Alternatively, the TIGIT inhibitor is administered by intravenous injection.

[0078] The ability of immune checkpoint inhibitors to treat cancer depends on the presence of tumor antigen-specific T cells in tumor tissue. This requires tumor tissue to express antigens that distinguish it from its non-transformed counterparts, for example, through new protein products called neoantigens. The neoantigen burden of a tumor is closely related to immunogenicity and susceptibility (e.g., susceptibility to checkpoint inhibitor treatment), meaning that poorly immunogenic tumors should be highly resistant to these drugs. Therapeutic agents that release tumor antigens that can be ingested by APCs, such as those that induce immunogenic cell death (ICD), or when further combined with checkpoint inhibitors, can promote effective antitumor immunity.

[0079] As used herein, the term "treatment" refers to the administration of one or more pharmaceutical agents to a subject suffering from a disease or having symptoms of a disease to cure, alleviate, relieve, alter, treat, improve, ameliorate, or affect the disease or symptoms of the disease. In some embodiments, the disease is a tumor or cancer.

[0080] The term "tumor" as used herein refers to an abnormal pathological change formed by the abnormal proliferation of clonal cells caused by the loss of normal regulation of cell growth in local tissues at the genetic level under the action of various tumorigenic factors. Tumors include bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, and the like. Cancer, including, but not limited to, ovarian cancer, salivary gland cancer, metastases caused by spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematological malignancies such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML). In some embodiments, the tumor is breast cancer or colon cancer (including colorectal cancer).

[0081] As used herein, the term "subject" or "patient" refers to mammals and non-mammals. Mammals refer to any member of the mammalian genus, including, but not limited to, humans; non-human primates, such as chimpanzees and other ape and monkey species; agricultural animals, such as cows, horses, sheep, goats, and pigs; livestock, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, and the like. The term "subject" is not limited to a particular age or sex. In some embodiments, the subject is a human.

[0082] As used herein, the term "pharmaceutically acceptable" means non-toxic, biologically tolerable and suitable for administration to a subject.

[0083] As used herein, the term "pharmaceutically acceptable salt" includes acid addition salts formed with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, and the like; and acid addition salts with organic acids, such as formates, acetates, malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, and salts of the formula HOOC-(CH) n This refers to non-toxic and biologically tolerable acid addition salts suitable for administration to a subject, including, but not limited to, salts formed with alkanedicarboxylic acids of —COOH (where n is 0 to 4).

[0084] Additionally, pharmaceutically acceptable acid addition salts can be obtained by dissolving the free base in a suitable solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine, without undue experimentation, various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts.

[0085] As used herein, the term "pharmaceutically acceptable composition" means that the composition must be chemically and / or toxicologically compatible with other ingredients included in the preparation and / or compatible with the subject being treated. As used herein, the term "therapeutically effective amount" refers to an amount generally sufficient to produce a beneficial therapeutic effect in a subject. The therapeutically effective amount of the present disclosure can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of the disease, medical history of the subject, health status of the subject, degree of response of the subject to the medication, etc.).

[0086] As used herein, the term "inhibition" refers to a decrease in the baseline activity of a biological activity or process.

[0087] As used herein, the term "kit" refers to a box containing chemical reagents for detecting chemical components, drug residues, virus types, etc. The kits of the present disclosure may include (i) one, two, or three of a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor; and (ii) instructions for use indicating that the FAK inhibitor, the topoisomerase inhibitor, and the immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit includes (i) a FAK inhibitor; and (ii) instructions for use indicating that the FAK inhibitor, the topoisomerase inhibitor, and the immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit includes (i) a topoisomerase inhibitor; and (ii) instructions for use indicating that the FAK inhibitor, the topoisomerase inhibitor, and the immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) an immune checkpoint inhibitor; and (ii) instructions for use indicating that a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor; and (ii) instructions for use indicating that a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) a FAK inhibitor; and (ii) instructions for use indicating that a FAK inhibitor and a topoisomerase inhibitor can be used to treat a tumor in a subject. In one embodiment, the kit comprises (i) a topoisomerase inhibitor; and (ii) instructions for use indicating that a topoisomerase inhibitor and a FAK inhibitor can be used to treat a tumor in a subject.

[0088] The components of the kit may be contained in separate containers. Optionally, two or more compounds are contained in the same container. For example, the kit may include a first container, a second container, a third container, and a package insert, where the first container contains at least one dose of a pharmaceutical comprising a FAK inhibitor, the second container contains at least one dose of a topoisomerase inhibitor, and the third container contains at least one dose of a pharmaceutical comprising an immune checkpoint inhibitor, and the package insert includes instructions for treating a tumor in a subject with the pharmaceutical. The first container, the second container, and the third container may contain the same or different shapes (e.g., vials, syringes, and bottles) and / or materials (e.g., plastic or glass). The kit may also include other materials that may aid in administering the pharmaceutical, such as diluents, filters, IV bags and lines, needles, and syringes.

[0089] The exact amount of FAK inhibitor, topoisomerase inhibitor, and immune checkpoint inhibitor administered to a subject will depend on a variety of factors, such as the particular drug or compound, pharmaceutical agent, route of administration, type of disease, symptoms, and identity of the subject or host being treated, but can nevertheless be routinely determined by one of ordinary skill in the art. For example, determining an effective amount also depends on the degree, severity, and type of cell proliferation. Those of ordinary skill in the art will be able to determine appropriate dosages based on these and other factors.

[0090] The FAK inhibitors, topoisomerase inhibitors and immune checkpoint inhibitors may be administered in any suitable manner, for example orally, intravenously, intramuscularly or subcutaneously.

[0091] For example, when administered orally, the medicament may be orally administered with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. These may be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or mixed directly with the patient's food. For example, the medicament may be combined with one or more excipients and used in the form of an ingestible tablet, oral tablet, lozenge, capsule, elixir, suspension, syrup, or wafer. Tablets, lozenges, pills, capsules, etc. may further contain a binder such as tragacanth gum, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid, etc.; a lubricant such as magnesium stearate; or a sweetener such as sucrose, fructose, lactose, or aspartame; or a flavoring agent.

[0092] For example, when administered intravenously or intraperitoneally by injection or infusion, pharmaceutical solutions can be prepared in water, optionally mixed with a nontoxic surfactant.

[0093] Exemplary pharmaceutical dosage forms for infusion or injection include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient suitable for temporarily preparing sterile infusion or injection solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.

[0094] Sterile injectable solutions can be prepared by mixing the required amount of the drug with various other ingredients mentioned above in a suitable solvent, and then filtering and sterilizing the mixture. For sterile powders used to prepare sterile injectable solutions, alternative preparation methods can be vacuum drying and freeze-drying techniques, which can produce powders of the active ingredient and any other ingredients required after the aforementioned sterile filtration.

[0095] The amount of FAK inhibitor, topoisomerase inhibitor, and immune checkpoint inhibitor required for treatment may vary depending not only on the particular reagent selected, but also on the route of administration, the nature of the disease being treated, and the age and condition of the patient, and can be ultimately determined by the attending physician. However, in general, the dosage can range from about 0.1 to about 50 mg / kg body weight per day.

[0096] The FAK inhibitor is administered in a dosage range of 5 mg / day to 300 mg / day in adults. In certain embodiments, IN10018 or a pharmaceutically acceptable salt thereof is administered in a dose of 5 mg / day to 100 mg / day in adults, for example, IN10018 or a pharmaceutically acceptable salt thereof is administered in a dose of 25 mg / day to 100 mg / day in adults, the dose being calculated as IN10018.

[0097] Topoisomerase inhibitors are administered in doses of 1 to 300 mg / m per week for adults. 2 In certain embodiments, irinotecan or a pharmaceutically acceptable salt thereof is administered at a dose of 1 to 300 mg / m per week for adults. 2 The dose is calculated as irinotecan; etoposide or a pharmaceutically acceptable salt thereof is administered at a dose of 1 to 300 mg / m per week for adults. 2 The dose is calculated as etoposide; teniposide is administered at a dose of 1 to 300 mg / m per week for adults. 2 and the dose is calculated as teniposide.

[0098] The immune checkpoint inhibitor is administered to an adult at a dose of 2 to 10 mg / kg or 50 to 1200 mg once every 2 to 3 weeks. In a specific embodiment, the immune checkpoint inhibitor is administered to an adult at a dose of 3 to 10 mg / kg or 100 to 1200 mg once every 2 to 3 weeks.

[0099] All technical and scientific terms used that are not specifically defined herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0100] In some embodiments, the present disclosure also discloses: 1. A FAK inhibitor, a topoisomerase inhibitor and an immune checkpoint inhibitor for use in a method for treating a tumor in a subject, wherein the topoisomerase inhibitor is not an anthracycline. 2. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof; or IN10018, defactinib, AMP945, or a pharmaceutically acceptable salt thereof; and alternatively IN10018, or a pharmaceutically acceptable salt thereof, or IN10018 tartrate, wherein the structure of IN10018 is:

[0101] [ka]

[0102] 2. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor of embodiment 1, wherein 3. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to embodiment 1 or 2, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor. 4. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor of embodiment 3, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67, or a pharmaceutically acceptable salt thereof. 5. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 3 to 4, wherein the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. 6. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 2, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor. 7. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to embodiment 6, wherein the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin or a pharmaceutically acceptable salt thereof. 8. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to embodiment 7, wherein the topoisomerase II inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof. 9. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor of any one of embodiments 1 to 8, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody. 10. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor of any one of embodiments 1 to 9, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 11. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor of any one of embodiments 1-9, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001. 12. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 9, wherein the immune checkpoint inhibitor is a TIGIT antibody, optionally wherein the TIGIT antibody is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321. 13. The FAK inhibitor, topoisomerase inhibitor, and immune checkpoint inhibitor according to embodiment 1, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 14. The FAK inhibitor, topoisomerase inhibitor, and immune checkpoint inhibitor according to embodiment 1, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 15. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 14, wherein the FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 16. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-small cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, thyroid cancer ... 16. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 15, wherein the tumor is Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or a hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML); or the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer. 17. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 1 to 16, wherein the tumor is breast cancer or colon cancer (including colorectal cancer). 18.(a) FAK inhibitors, (b) a topoisomerase inhibitor that is not an anthracycline, and (c) A kit or a pharmaceutically acceptable composition comprising an immune checkpoint inhibitor. 19. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or alternatively, the FAK inhibitor is IN10018 tartrate, and IN10018 is

[0103] [ka]

[0104] 19. The kit or composition of embodiment 18, having the structure: 20. The kit or composition of any one of embodiments 18-19, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor. 21. The kit or composition of embodiment 20, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67, or a pharmaceutically acceptable salt thereof. 22. The kit or composition according to any one of embodiments 20-21, wherein the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. 23. The kit or composition of any one of embodiments 18-19, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor. 24. The kit or composition of embodiment 23, wherein the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin, or a pharmaceutically acceptable salt thereof. 25. The kit or composition of embodiment 24, wherein the topoisomerase II inhibitor is etoposide, teniposide, or a pharmaceutically acceptable salt thereof. 26. The kit or composition of any one of embodiments 18 to 25, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody. 27. The kit or composition of any one of embodiments 18 to 26, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 28. The kit or composition of any one of embodiments 18-26, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001. 29. The kit or composition of any one of embodiments 18 to 26, wherein the immune checkpoint inhibitor is a TIGIT antibody, and optionally the TIGIT antibody is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. 30. The kit or composition of embodiment 18, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 31. The kit or composition of embodiment 18, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 32. The kit or composition according to any one of embodiments 18 to 31, wherein the kit or composition is used as a medicament. 33. The medicament is used to treat tumors, and the tumors are caused by bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, or spindle cell carcinoma. 33. The kit or composition of embodiment 32, wherein the tumor is a tumor of the breast, ovarian, colon (including colorectal), lung (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer, including metastasis due to leukemia, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML). 34. The kit or composition of embodiment 33, wherein the tumor is breast cancer or colon cancer (including colorectal cancer). 35. A method for treating a tumor in a subject, comprising administering to the subject therapeutically effective amounts of a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor, wherein the topoisomerase inhibitor is not an anthracycline. 36. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or alternatively, the FAK inhibitor is IN10018 tartrate, and IN10018 is

[0105] [ka]

[0106] 36. The method of embodiment 35, having the structure: 37. The method of any one of embodiments 35-36, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor. 38. The method of embodiment 37, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67, or a pharmaceutically acceptable salt thereof. 39. The method of embodiment 38, wherein the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. 40. The method of any one of embodiments 35-36, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor. 41. The method of embodiment 40, wherein the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin, or a pharmaceutically acceptable salt thereof. 42. The method of embodiment 41, wherein the topoisomerase II inhibitor is etoposide, teniposide, or a pharmaceutically acceptable salt thereof. 43. The method of any one of embodiments 35 to 42, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody. 44. The method of any one of embodiments 35-43, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 45. The method of any one of embodiments 35-43, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001. 46. ​​The method of any one of embodiments 35 to 43, wherein the immune checkpoint inhibitor is a TIGIT antibody, and optionally the TIGIT antibody is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. 47. The method of embodiment 35, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 48. The method of embodiment 35, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 49. The method of any one of embodiments 35 to 48, wherein the FAK inhibitor, the topoisomerase inhibitor and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 50. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, and spindle cell carcinoma, undifferentiated large cell carcinoma 50. The method of any one of embodiments 35 to 49, wherein the tumor is follicular lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or a hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML); or wherein the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer. 51. The method of any one of embodiments 35 to 50, wherein the tumor is breast cancer or colon cancer (including colorectal cancer). 52. A FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor for use in a method for treating a tumor by enhancing immunogenic cell death in a subject, wherein the topoisomerase inhibitor is not an anthracycline. 53. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945, or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018 tartrate, and IN10018 is

[0107] [ka]

[0108] 53. The FAK inhibitor, topoisomerase inhibitor, and immune checkpoint inhibitor of embodiment 52, having the structure: 54. The FAK inhibitor, topoisomerase inhibitor, and immune checkpoint inhibitor according to embodiments 52-53, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor. 55. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to embodiment 54, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67 or a pharmaceutically acceptable salt thereof. 56. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to embodiment 55, wherein the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. 57. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 52-53, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor. 58. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to embodiment 57, wherein the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin or a pharmaceutically acceptable salt thereof. 59. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to embodiment 58, wherein the topoisomerase II inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof. 60. The FAK inhibitor, topoisomerase inhibitor, and immune checkpoint inhibitor according to any one of embodiments 52 to 59, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody. 61. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 60, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181. 62. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 60, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001. 63. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 60, wherein the immune checkpoint inhibitor is a TIGIT antibody, optionally wherein the TIGIT antibody is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321. 64. The FAK inhibitor, topoisomerase inhibitor, and immune checkpoint inhibitor according to embodiment 52, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 65. The FAK inhibitor, topoisomerase inhibitor, and immune checkpoint inhibitor according to embodiment 52, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 66. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 65, wherein the FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 67. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-small cell carcinoma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, thyroid cancer ... 67. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 66, wherein the tumor is Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or a hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML); or the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer. 68. The FAK inhibitor, topoisomerase inhibitor and immune checkpoint inhibitor according to any one of embodiments 52 to 67, wherein the tumor is breast cancer or colon cancer (including colorectal cancer). 69. A method for treating a tumor by enhancing immunogenic cell death in a subject, comprising administering to the subject therapeutically effective amounts of a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor, wherein the topoisomerase inhibitor is not an anthracycline. 70. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886, or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945, or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018 tartrate, and IN10018 is

[0109] [ka]

[0110] 70. The method of embodiment 69, having the structure: 71. The method of any one of embodiments 69-70, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor. 72. The method of any one of embodiments 69-71, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67, or a pharmaceutically acceptable salt thereof. 73. The method of embodiment 72, wherein the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. 74. The method of any one of embodiments 69-70, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor. 75. The method of embodiment 74, wherein the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin, or a pharmaceutically acceptable salt thereof. 76. The method of embodiment 75, wherein the topoisomerase II inhibitor is etoposide, teniposide, or a pharmaceutically acceptable salt thereof. 77. The method of any one of embodiments 69 to 76, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody. 78. The method of any one of embodiments 69-77, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 79. The method of any one of embodiments 69-77, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001. 80. The method of any one of embodiments 69 to 77, wherein the immune checkpoint inhibitor is a TIGIT antibody, and optionally the TIGIT antibody is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. 81. The method of embodiment 69, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 82. The method of embodiment 69, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 83. The method of any one of embodiments 69 to 82, wherein the FAK inhibitor, the topoisomerase inhibitor and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 84. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, and spindle cell carcinoma, undifferentiated large cell carcinoma 84. The method of any one of embodiments 69 to 83, wherein the tumor is follicular lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or a hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML); or wherein the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer. 85. The method of any one of embodiments 69-84, wherein the tumor is breast cancer or colon cancer (including colorectal cancer). 86. Use of a FAK inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein a FAK inhibitor, a topoisomerase inhibitor and an immune checkpoint inhibitor are administered to the subject, and the topoisomerase inhibitor is not an anthracycline. 87. Use of a topoisomerase inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor are administered to the subject, and the topoisomerase inhibitor is not an anthracycline. 88. Use of an immune checkpoint inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein a FAK inhibitor, a topoisomerase inhibitor and an immune checkpoint inhibitor are administered to the subject, and the topoisomerase inhibitor is not an anthracycline. 89. Use of a FAK inhibitor, a topoisomerase inhibitor and an immune checkpoint inhibitor in the manufacture of a combination pharmaceutical for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline. 90. Use of a FAK inhibitor in the manufacture of a combination medicament with a topoisomerase inhibitor and an immune checkpoint inhibitor for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline. 91. Use of a topoisomerase inhibitor in the manufacture of a combination medicament with a FAK inhibitor and an immune checkpoint inhibitor for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline. 92. Use of an immune checkpoint inhibitor in the manufacture of a combination medicament with a FAK inhibitor and a topoisomerase inhibitor for treating a tumor, wherein the topoisomerase inhibitor is not an anthracycline. 93. Use of a FAK inhibitor, a topoisomerase inhibitor and an immune checkpoint inhibitor in the manufacture of a medicament for the combined treatment of a tumor, wherein the topoisomerase inhibitor is not an anthracycline. 94. Use of a FAK inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a topoisomerase inhibitor and an immune checkpoint inhibitor, wherein the topoisomerase inhibitor is not an anthracycline. 95. Use of a topoisomerase inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a FAK inhibitor and an immune checkpoint inhibitor, wherein the topoisomerase inhibitor is not an anthracycline. 96. Use of an immune checkpoint inhibitor in the manufacture of a medicament for the combined treatment of a tumor with a FAK inhibitor and a topoisomerase inhibitor, wherein the topoisomerase inhibitor is not an anthracycline. 97. The FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, APG-2449, VS-4718, AMP945, AMP886 or a pharmaceutically acceptable salt thereof, or IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof, and further alternatively IN10018 or a pharmaceutically acceptable salt thereof, or IN10018 tartrate, wherein the structure of IN10018 is

[0111] [ka]

[0112] The use according to any one of embodiments 86 to 96, wherein 98. The use according to any one of embodiments 86 to 97, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor. 99. The use according to embodiment 98, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67 or a pharmaceutically acceptable salt thereof. 100. The use according to embodiment 99, wherein the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof. 101. The use according to any one of embodiments 86 to 97, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor. 102. The use according to embodiment 101, wherein the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin, or a pharmaceutically acceptable salt thereof. 103. The use according to embodiment 102, wherein the topoisomerase II inhibitor is etoposide, teniposide, or a pharmaceutically acceptable salt thereof. 104. The use according to any one of embodiments 86 to 103, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody. 105. The use of any one of embodiments 86 to 104, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181. 106. The use of any one of embodiments 86 to 104, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001. 107. The use of any one of embodiments 86 to 104, wherein the immune checkpoint inhibitor is a TIGIT antibody, and optionally the TIGIT antibody is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321. 108. The use of any one of embodiments 86 to 96, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 109. The use of any one of embodiments 86 to 96, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or an anti-PD-1 / PD-L1 antibody. 110. The use according to any one of embodiments 86 to 109, wherein the FAK inhibitor, the topoisomerase inhibitor and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially. 111. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, and spindle cell carcinoma, undifferentiated large cell carcinoma The use according to any one of embodiments 86 to 110, wherein the tumor is follicular lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or a hematological malignancy, such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML); or the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer. 112. The use according to any one of embodiments 86 to 111, wherein the tumor is breast cancer or colon cancer (including colorectal cancer). [Example]

[0113] The following examples are presented to further illustrate the present disclosure. It should be understood that these examples are used only to illustrate the present disclosure and are not intended to limit the scope of the present disclosure.

[0114] Assay methods without specific conditions in the following examples can be carried out according to conventional conditions for this type of reaction or according to conditions suggested by the manufacturer.

[0115] Unless otherwise specified, assay materials and reagents used in the following examples are obtained from commercial channels.

[0116] The abbreviations used in the examples have the following meanings:

[0117] [Table 1A]

[0118] [Table 1B]

[0119] Example 1 Enhancement of immunogenic cell death in breast cancer cells in response to etoposide by targeting FAK Assay Protocol: 1. FAK silencing in combination with etoposide promotes apoptosis in breast cancer cells MDA-MB-231

[0120] siRNA technology was used in an in vitro assay to reduce the expression level of FAK in combination with etoposide for 48 hours; flow cytometry was used to detect apoptosis in control and FAK-silenced cells.

[0121] 2. FAK silencing in combination with etoposide can efficiently promote the development of ICD in breast cancer cells MDA-MB-231

[0122] Using siRNA technology in an in vitro assay, we reduced the expression level of FAK in combination with etoposide for 48 hours, and used flow cytometry to detect the expression of calreticulin, a primary target of ICD.

[0123] Assay antibodies: recombinant Alexa Fluor® 647 fluorescent anti-calreticulin antibody (Abcam, ab196159), Annexin V Apoptosis Detection Kit (Invitrogen, A35110).

[0124] FAK siRNA was provided by Gene Pharma and the sequence is shown in the table below: F:CCUGUAUGCCUAUCAGCUUTT; R:AAGCUGAUAGGCAUACAGGTT

[0125] Assay equipment: Fluorescence microscope (Olympus U-HGLGPS). Chemiluminescence imager (BIORAD chemidoc touch).

[0126] Assay Results: 1. FAK silencing combined with etoposide significantly enhanced apoptosis in MDA-MB-231 cells. MDA-MB-231 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM. 24 hours after transfection, the cells were treated with 2 μM etoposide for 48 hours. The cells were stained using an Annexin V kit and detected by flow cytometry. Early and late apoptosis values ​​were counted and compared with those of the DMSO control group, and plotted using Graphpad 8.0. The results showed that apoptosis in the FAK-silenced group was significantly enhanced after etoposide treatment compared with the control group, as shown in Figure 1.

[0127] 2. Combining FAK silencing with etoposide significantly enhanced the release and exposure of calreticulin targeted by ICD. MDA-MB-231 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM. 24 hours after transfection, the cells were treated with 2 μM etoposide for 48 hours. The cells were fluorescently stained with calreticulin antibody, and the staining results were analyzed by flow cytometry. Results from FlowJo software showed that after FAK silencing in combination with etoposide, the release and exposure of calreticulin were significantly enhanced, as shown in Figure 2.

[0128] Example 2 Enhancement of immunogenic cell death in breast cancer cells in response to teniposide by targeting FAK Assay Protocol: 1. FAK silencing in combination with teniposide promotes apoptosis in breast cancer cells MDA-MB-231 siRNA technology was used in an in vitro assay to reduce the expression level of FAK in combination with teniposide for 48 hours; flow cytometry was used to detect apoptosis in control and FAK-silenced cells.

[0129] 2. FAK silencing in combination with teniposide can efficiently promote the development of ICD in breast cancer cells MDA-MB-231 They used siRNA technology in an in vitro assay to reduce FAK expression levels and combined it with teniposide for 48 hours, and used flow cytometry to detect the expression of calreticulin, a primary target of ICD.

[0130] Assay antibody: Recombinant Alexa Fluor® 647 fluorescent anti-calreticulin antibody (Abcam, ab196159), Annex V Apoptosis Detection Kit (Invitrogen, A35110).

[0131] FAK siRNA was provided by Gene Pharma and the sequence is shown in the table below: F:CCUGUAUGCCUAUCAGCUUTT; R:AAGCUGAUAGGCAUACAGGTT

[0132] Assay equipment: Fluorescence microscope (Olympus U-HGLGPS) and chemiluminescence imager (BIORAD chemidoc touch).

[0133] Assay Results: 1. FAK silencing combined with teniposide significantly enhanced apoptosis in MDA-MB-231 cells. MDA-MB-231 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM. 24 hours after transfection, the cells were treated with 2 μM teniposide for 48 hours. The cells were stained using an Annexin V kit and detected by flow cytometry. Early and late apoptosis values ​​were counted and compared with those of the DMSO control group, and plotted using Graphpad 8.0. The results showed that apoptosis in the FAK-silenced group was significantly enhanced after teniposide treatment compared with the control group, as shown in Figure 3.

[0134] 2. FAK silencing in combination with teniposide significantly upregulated the release and exposure of the ICD target calreticulin MDA-MB-231 cells were transfected with control siRNA or FAK siRNA at a final concentration of 50 nM. 24 hours after transfection, the cells were treated with 2 μM teniposide for 48 hours. The cells were fluorescently stained with calreticulin antibody, and the staining results were analyzed by flow cytometry. Results from FlowJo software showed that after FAK silencing in combination with teniposide, the release and exposure of calreticulin were significantly enhanced, as shown in Figure 4.

[0135] Example 3 Synergistic effects of IN10018 and etoposide in colon cancer CT26 cells. CT26 cells were cultured in RPMI-1640 (Shanghai Basalmedia, Catalog Number: L210KJ, Batch Number: F210916) + 10% FBS (Gibco, Catalog Number: 10099-141c, Batch Number: 2158737cp) and passaged twice. If the cells were in good condition, they were seeded into a 96-well plate at 3000 cells / well. After the cells were seeded for 24 hours, etoposide-containing medium was added. Ten drug concentrations were established. The first concentration was 30 μM, which was serially diluted five-fold, with the last one serving as a control with zero drug concentration. Each drug concentration was run in triplicate. At the same time, another group of cells was established with the same drug concentrations as in the above method. The difference was that 5 μM IN10018 was added to each well, the drug was mixed, and the plate was cultured at 37°C in a 5% CO2 incubator for 72 hours.

[0136] After 72 hours of drug action, the cells were observed under a microscope. 10 μl of CCK8 detection reagent (Cellorlab, Cat. No. CX001M, Batch No. 2571100) was added to each well, and the plate was incubated at 37°C in a 5% CO2 incubator for 2-4 hours. The plate was then read using a microplate reader (OD450) (chemiluminescence method). The analysis results showed that the IC50 of the etoposide (supplier: MCE, Cat. No. 33419-42-0, Batch No. 113741) group was 24.43 μM, and the IC50 of the etoposide + 5 μM IN10018 group was 4.86 μM. The IC50 of the group containing IN10018 was significantly lower than that of the group without IN10018, indicating that the efficacy of the two-drug combination treatment group was better than that of the single-drug treatment group, as shown in Figure 5.

[0137] Example 4 Studies on IN10018 and etoposide in colon cancer CT26 cells. CT26 cells (Institute of Cell Biology, Chinese Academy of Sciences) were cultured in RPMI-1640 (Shanghai Basalmedia, Catalog No. L210KJ, Batch No. F210916) + 10% FBS (Gibco, Catalog No. 10099-141c, Batch No. 2158737cp) and passaged twice. If the cells were in good condition, they were placed in 24-well plates. 24 hours after cell seeding, four groups were established. Group 1 was the control group, to which medium was added; Group 2 was IN10018 at a concentration of 5 μM; Group 3 was etoposide at a concentration of 20 μM (supplied by MCE Co., Ltd., classification number: 33419-42-0, batch number: 113741); Group 4 was a combination of IN10018 (5 μM) and etoposide (20 μM). The drugs were mixed and cultured at 37°C in a 5% CO incubator for 48 hours.

[0138] After 48 hours of drug action, the cells were observed and photographed under a microscope. Photographs were saved. The cells were then collected for flow cytometry and washed twice with flow buffer (PBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody (Abcam, Catalog No.: ab196159, Batch No.: CR33676773) was added to each well and mixed thoroughly. The cells were incubated in the dark at 4°C for 20 minutes. After 20 minutes, the cells were washed twice with flow buffer (PBS + 2% FBS). A cell apoptosis detection kit (Beyotime, Catalog No.: CL062L, Batch No.: 021921210811) was used. 195 μl of Annexin-V-FITC conjugate solution was added and the cells were gently mixed. 5 μl of Annexin-V-FITC antibody was added and the mixture was gently mixed. 10 μl of PI dye was added and gently mixed. The mixture was incubated in the dark at room temperature for 15 minutes and then analyzed on a flow cytometer.

[0139] The cells were observed under a microscope. The cell condition of the etoposide single drug group and the two-drug combination group was poor, with the two-drug combination group being the worst, with more cell death. The cell condition of the control group and IN10018 group was good. The results showed that the CRT positive rate and Annexin V positive rate of the two-drug combination group were higher than those of the single drug group, as shown in Figures 6 and 7.

[0140] Example 5 In vitro study of the induction of immunogenic cell death targets by irinotecan and IN10018 in murine colon cancer CT26 cells Grouping information is shown in Table 1.

[0141] [Table 2]

[0142] Test compound information is shown in Table 2.

[0143] [Table 3]

[0144] The main reagents used in the assay are shown in Table 3.

[0145] [Table 4]

[0146] Assay Methods and Steps cell culture CT26 cells were maintained and subcultured by InxMed (Nanjing) Co., Ltd. Cells were cultured in vitro in monolayers under the following conditions: RPMI-1640 medium containing 10% fetal bovine serum, 37°C, 5% CO2 incubator. Cells were routinely digested and subcultured using trypsin two to three times a week. When cells were in the exponential growth phase and reached 80% to 90% adherent confluence, they were harvested and plated.

[0147] Cell plating CT26 cells were digested with trypsin, then collected and counted. Based on the counting result, the cells were diluted with the corresponding complete medium to a concentration of 50,000 cells per milliliter. Then, the cells were plated in a 24-well cell culture plate with 1 ml of cell suspension, i.e., 50,000 cells per well. After plating, the cells were cultured in a 37°C, 5% CO2 incubator.

[0148] Addition of test compounds 24 hours after plating, the test compounds irinotecan and IN10018 were added to different wells. The test compounds were homogenously prepared and packaged (before dissolving in DMSO). The packaged volume was 50 μL per vial. They were stored in the dark at −20° C. In this assay, one vial was removed for drug addition and detection. The groups and drug concentrations are shown in Table 4.

[0149] [Table 5]

[0150] Cell collection for flow cytometry: Cells were washed twice with flow buffer (DPBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody was added to each well and mixed thoroughly. Cells were incubated for 20 min at 4°C in the dark. After one wash with flow buffer, 195 μl of Annexin-V-FITC conjugate solution was added and the cells were gently mixed thoroughly. 5 μl of Annexin-V-FITC antibody was added. After further mixing, 10 μl of PI dye was added and mixed thoroughly. Cells were incubated for 15 min at room temperature in the dark. Cells were then subjected to flow cytometry.

[0151] Data analysis After the assay, the cell positive rate was analyzed using Flowjo (V10) software.

[0152] Assay Results After 48 hours of drug action, the results of flow cytometry analysis showed that the CRT positive rate and Annexin V positive rate of the combined drug group were significantly higher than those of the single drug group, as shown in Figure 8 .

[0153] Example 6 Studies on the in vitro growth inhibitory activity of teniposide and IN10018 in mouse colon carcinoma CT26 cells Assay design Grouping information is shown in Table 5.

[0154] [Table 6]

[0155] Test compound information is shown in Table 6.

[0156] [Table 7]

[0157] The main reagent information is shown in Table 7.

[0158] [Table 8]

[0159] Assay Method and Steps: Cell culture: CT26 cells were resuscitated, maintained, and passaged by InxMed (Nanjing) Co., Ltd. Cells were cultured in vitro in monolayers under the following conditions: RPMI-1640 medium with 10% fetal bovine serum, 37°C, 5% CO2. Cells were routinely digested and passaged using trypsin two to three times a week. When cells were in the exponential growth phase and reached 80% to 90% adherent confluence, they were harvested and plated.

[0160] Cell plating CT26 cells were digested with trypsin, then collected and counted. Based on the counting results, the cells were diluted with RPMI 1640 + 10% FBS to a concentration of 30,000 cells per milliliter. The cells were then plated into a 96-well flat-bottom cell culture plate with 0.1 ml of cell suspension, i.e., 30,000 cells per well. After plating, the cells were cultured in a 37°C, 5% CO2 incubator.

[0161] Addition of test compounds 24 hours after plating, the test compound teniposide was added to different wells of the cell plate. The test compounds were homogeneously prepared and packaged before the assay. Briefly, the drug was dissolved in DMSO to 10 mM, the package volume was 50 μL / vial, and the drug was stored in the dark at -20°C. In this assay, one vial was removed for drug addition and treatment. The groups and drug concentrations are shown in Table 8.

[0162] [Table 9]

[0163] Ten drug effect concentrations were designed for teniposide, the last of which was 0, which was set as the negative control group.

[0164] After adding the drug, the drug was mixed gently and the cells were cultured in a 37°C, 5% CO2 incubator.

[0165] Add CCK-8 detection reagent and read plate: After 72 hours of drug action, 10 μL of CCK-8 detection reagent was added to each well of the cell plate using a multichannel pipette, and then the cell plate was incubated for another 4 hours in a 37°C, 5% CO2 incubator. Finally, the absorbance of each well at 450 nm was measured using an ELISA reader.

[0166] Data Analysis: After the assay, the percentage of inhibition of the tested drugs in the cells was analyzed using GraphPad Prism 8 software.

[0167] Calculation of percentage inhibition: Percentage inhibition = {[A(0 drug added) - A(blank)] - [A(drug added) - A(blank)]} / [A(0 drug added) - A(blank)] × 100% A (drug addition): absorbance values ​​of wells containing cells, CCK-8 solution, and drug solution A (blank): absorbance value of wells containing medium and CCK-8 solution but no cells A (0 drug addition): absorbance value of wells containing cells and CCK-8 solution but no drug solution

[0168] Assay Conclusion: This assay evaluated the inhibitory effect of teniposide alone and in combination with IN10018 on the proliferation of CT26 cells in vitro. The relevant test results for each group after 72 hours of drug action are shown in Figure 9. The IC50 value of the teniposide and IN10018 combination group was 0.09799 μM, which was lower than the IC50 value of the single drug group (0.8179 μM), indicating that the combination group had a stronger in vitro inhibitory effect on cancer cell growth.

[0169] Example 7 In vitro study on the induction of immunogenic cell death targets by teniposide and IN10018 in murine colon carcinoma CT26 cells The assay groups are shown in Table 9.

[0170] [Table 10]

[0171] Compound information is shown in Table 10:

[0172] [Table 11]

[0173] Compound information is shown in Table 11.

[0174] [Table 12]

[0175] cell culture CT26 cells were maintained and subcultured by InxMed (Nanjing) Co., Ltd. and cultured in vitro in monolayers under the following conditions: RPMI-1640 medium containing 10% fetal bovine serum, 37°C, 5% CO2 incubator. Cells were routinely digested and passaged using trypsin two to three times a week. When cells were in the exponential growth phase and reached 80%-90% adherent confluence, they were harvested and plated.

[0176] Cell plating CT26 cells were digested with trypsin, then collected and counted. Based on the counting results, the cells were diluted with RPMI1640 + 10% FBS to a concentration of 50,000 cells per milliliter. The cells were then plated into a 12-well cell culture plate with 2 ml of cell suspension, i.e., 100,000 cells per well.

[0177] After plating, the cells were cultured in a 37°C, 5% CO2 incubator.

[0178] Addition of test compounds 24 hours after plating, the test compound teniposide was added to different wells. The test compound was homogenously prepared and packaged before dissolving in DMSO to a concentration of 10 mM, with a package volume of 50 μL per vial. These were stored in the dark at −20°C. In this assay, one vial was removed for drug addition and detection. The groups and drug concentrations are shown in Table 9.

[0179] After 48 hours of drug action, the cells were photographed using a microscope, then trypsinized and collected for flow cytometry staining.

[0180] The cells were washed twice with flow buffer (DPBS + 2% FBS). Each group of cells was divided into two equal portions. In one portion, 0.5 μL of AF647 anti-calreticulin antibody was added to each well and mixed thoroughly. The cells were incubated in the dark at 4°C for 20 min. After one wash with flow buffer, 195 μL of Annexin-V-FITC conjugate solution was added, and the cells were gently mixed thoroughly. 5 μL of Annexin-V-FITC antibody was added. After further mixing, 10 μL of PI dye was added and mixed thoroughly. The cells were incubated in the dark at room temperature for 15 min. The cells were then subjected to flow cytometry.

[0181] Data Analysis: After the assay, the cell positive rate was analyzed using Flowjo (V10) software.

[0182] Assay Results: This assay evaluated the effect of teniposide alone and in combination with IN10018 on inducing the expression of immune cell death targets in CT26 cells in vitro.

[0183] The relevant test results for each group after 48 hours of drug action are shown in Figure 10. Cell status was observed under a microscope. Cell death was evident in the etoposide monotherapy group, and was most pronounced in the combined drug group. Cell viability was better in the negative control group and IN10018 group. Flow cytometry analysis showed that the positive rates of CRT and Annexin V in the combined drug group were significantly higher than those in the single drug group.

[0184] Example 8 In vivo antitumor efficacy study of combination therapy between etoposide, IN10018, and anti-mouse PD-L1 antibody in a subcutaneous allograft tumor model of colon cancer MC38 cells in C57BL / 6 mice Grouping and dosing information is shown in Table 12.

[0185] [Table 13]

[0186] Cell culture: Colorectal cancer cells MC38 (Nanjing Cobioer Biotechnology Co., Ltd., product number: CBP60825) were maintained and passaged by InxMed (Nanjing) Co., Ltd. Cells were cultured in vitro in monolayers under the following conditions: DMEM medium containing 10% fetal bovine serum, in a 37°C, 5% CO2 incubator. Cells were routinely digested and passaged using trypsin-EDTA two to three times a week. When cells were in the exponential growth phase and reached 80%-90% adherent confluence, they were harvested, counted, and then inoculated.

[0187] Cell inoculation and grouping: 2×10 5 0.1 mL of the cell suspension containing the cells was subcutaneously inoculated into the right dorsal surface of each mouse. 3 When tumor volume reached 9 days after cell inoculation, mice were randomly divided into groups according to tumor volume and administered. The preparations of the test substances and control solvents are shown in Table 13.

[0188] [Table 14]

[0189] Daily observation of assay animals Any modifications to the formulation and the assay protocol were reviewed and approved by ArrayBridge's IACUC. The use and welfare of the assay animals was carried out in accordance with AAALAC regulations. Animal health and mortality were monitored daily with routine checks that included tumor growth and the effect of drug treatment on the animals' daily behavior, such as activity, food and water consumption (estimated by visual inspection), changes in body weight, and observation of any physical signs or any other abnormalities. The number of animal deaths and side effects in each group was recorded based on the number of animals in each group.

[0190] Assay Stop If the animal's health condition continues to deteriorate or the tumor volume exceeds 3,000 mm 3 Euthanasia should be performed if the weight of the animal exceeds 3000 mm or if severe disease or pain is observed. The veterinarian was notified and euthanasia was performed in the following cases: obvious weight loss, i.e., weight loss of more than 20%; inability to eat and drink freely; mean tumor volume in the control group exceeding 3,000 mm 3 The assay was terminated when the animal continued to deteriorate, showing the following signs: piloerection, hunched back, pale ears, nose, eyes or paws, rapid breathing, convulsions, persistent diarrhea, dehydration, slow movements, vocalization.

[0191] Tumor Measurements and Assay Parameters The endpoint of the assay was to examine whether tumor growth was inhibited, delayed, or cured. Tumor diameter was measured three times a week using calipers. Tumor volume was calculated using the formula: V = 0.5 × a × b 2 where a and b represent the long and short diameters of the tumor, respectively.

[0192] The antitumor efficacy of compound was evaluated by TGI (%), which reflects tumor growth inhibition rate. Based on the tumor volume on the first day after grouping, the tumor growth inhibition rate TGI (%) was calculated according to the following formula: TGI (%) = [1-(mean tumor volume of treatment group-mean tumor volume of treatment group at the beginning of treatment) / (mean tumor volume of vehicle control group-mean tumor volume of vehicle control group at the beginning of treatment)] × 100%.

[0193] statistical analysis Statistical analysis was performed using Prism Graphpad software and was based on tumor volume at the end of the assay. Comparisons between multiple groups were analyzed using two-way ANOVA and Fisher's LSD test. A P value of less than 0.05 was considered statistically significant.

[0194] Assay Results 1. In vivo efficacy study of combination therapy between test substances etoposide, IN10018, and anti-mouse PD-L1 antibody in a subcutaneous allograft tumor model of mouse colorectal cancer MC38 cells in C57BL / 6 mice After cell inoculation, tumor growth was monitored daily. On day 9 after inoculation, mice were divided into groups based on tumor volume. The mean tumor volume at enrollment was approximately 50 mm. 3 Due to tumor burden, animals in the control group were euthanized on day 26 post-inoculation, i.e., day 17 post-treatment according to group, and the entire assay was terminated.

[0195] On day 17 after group-specific administration, the tumor volume in the control group was 2670.9 ± 1438.9 mm 3 The tumor volumes in the PD-L1 antibody (5 mg / kg) and etoposide (3 mg / kg) monotherapy groups were 2677.7 ± 2029.0 mm, respectively. 3 and 2420.2±1377.3mm 3 The tumor volumes in the etoposide + PD-L1 antibody (3 + 5 mg / kg) and etoposide + IN10018 (3 + 25 mg / kg) combination therapy groups were 1947.6 ± 539.7 mm, respectively. 3 and 1865.0±839.9mm 3 The tumor volume in the etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg) triple therapy group was 1245.6 ± 1064.7 mm 3Compared with the control group, the tumor inhibition rates (TGI) of the PD-L1 antibody (5 mg / kg) and etoposide (3 mg / kg) monotherapy groups were -0.2% (p=0.9827) and 9.5% (p=0.4487), respectively; the tumor inhibition rates (TGI) of the etoposide + PD-L1 antibody (3 + 5 mg / kg) and etoposide + IN10018 (3 + 25 mg / kg) combination therapy groups were 27.6% (p=0.0295) and 30.7% (p=0.0111), respectively; and the tumor inhibition rate (TGI) of the etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg) triple therapy group was 54.4% (p0.0001).

[0196] For statistical analysis, overall tumor volume was compared with the etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg) triple-drug combination group. The P values ​​for the control group, PD-L1 antibody (5 mg / kg), and etoposide (3 mg / kg) monotherapy groups were p<0.0001, p<0.0001, and p=0.0005, respectively; the P values ​​for the etoposide + PD-L1 antibody (3 + 5 mg / kg) and etoposide + IN10018 (3 + 25 mg / kg) two-drug combination therapy groups were p=0.0346 and p=0.0504, respectively, as shown in Table 14. The tumor volumes of each treatment group at different times are shown in Figure 11. Compared with the blank control group, the mean tumor volume of the PD-L1 antibody (5 mg / kg) and etoposide (3 mg / kg) monotherapy group was very close to that of the control group, indicating no inhibitory effect on tumor growth; whereas the etoposide + PD-L1 antibody (3 + 5 mg / kg) and etoposide + IN10018 (3 + 25 mg / kg) combination therapy groups, as well as the etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg) triple therapy group, all showed significant tumor growth inhibitory effects that were statistically different from the control group. Comprehensively considering the entire administration cycle, the tumor volumes in the etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg) triple combination group were consistently smaller than those in the other treatment groups, and were statistically different from the PD-L1 antibody (5 mg / kg) and etoposide (3 mg / kg) monotherapy group and the etoposide + PD-L1 antibody (3 + 5 mg / kg) two-drug combination treatment group. Although there was no statistical difference between the etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg) triple combination group and the etoposide + IN10018 (3 + 25 mg / kg) two-drug combination treatment group, the mean tumor volume of the etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg) triple combination group was always smaller, which also indicated that the etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg) triple combination group showed better efficacy in inhibiting tumor growth.

[0197] [Table 15]

[0198] 2. A study of changes in body weight and clinical status following combination therapy with the test substances etoposide, IN10018, and an anti-mouse PD-L1 antibody in a subcutaneous allograft tumor model of MC38 mouse colorectal cancer cells in C57BL / 6 mice. The assay was performed according to the administration regimen. During the assay, animal activity, such as eating and drinking, was observed daily, and animal weights were recorded three times a week. After 17 days of group administration, the mean body weight of the control group changed from 18.7 g on the day of group administration (day 0) to 23.9 g, representing a weight growth rate of 28.8%; the mean body weights of the PD-L1 antibody (5 mg / kg) and etoposide (3 mg / kg) monotherapy groups changed from 18.8 g and 19.1 g on day 0 to 23.6 g and 22.8 g, respectively, on day 17, representing a weight change rate of 28.8%. The mean body weight in the etoposide + PD-L1 antibody (3 + 5 mg / kg) and etoposide + IN10018 (3 + 25 mg / kg) combination therapy groups changed from 19.1 g and 18.9 g on Day 0 to 22.3 g and 22.5 g, respectively, on Day 17, with weight change rates of 17.2% and 19.0%, respectively; the mean body weight in the etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg) triple drug combination group changed from 19.1 g on Day 0 to 21.6 g on Day 17, with weight change rates of 13.3%. During the entire treatment cycle, one mouse in each of the etoposide (3 mg / kg) monotherapy group and the etoposide + PD-L1 antibody (3 + 5 mg / kg) two-drug combination treatment group died on days 12 and 17 after treatment due to tumor rupture. The animals in the remaining groups did not lose significant weight during the entire treatment cycle and were in good condition, demonstrating that they tolerated the different treatment methods. For details, see Table 15. The weight changes of each treatment group at different times are shown in Figure 12. This indicates that the animals tolerated the three-drug combination etoposide + IN10018 + PD-L1 antibody (3 + 25 + 5 mg / kg).

[0199] [Table 16]

[0200] Example 9 In vitro study of the induction of immunogenic cell death targets in mouse mammary carcinoma 4T1 cells by etoposide and AMP945 Assay materials: 1) Drugs used in this assay Etoposide was provided by MCE, Lot No.: 113741 AMP945 was provided by MCE, Lot No.: 143253.

[0201] 2) Antibodies used in this assay Recombinant Alexa Fluor® 647 fluorescent anti-calreticulin antibody (Abcam, Cat No.: ab196159, Lot No.: CR33676773). Annexin V-Apoptosis Detection Kit (Beyotime, Cat No.: C1062L, Lot No.: 122221220706).

[0202] Assay Method: 4T1 cells (Nanjing Cobioer Biotechnology Co., Ltd., product number: CBP60352) were cultured in RPMI-1640 (Shanghai Basalmedia, Catalog No.: L210KJ, Lot No.: F210916) + 10% FBS (Gibco, Catalog No.: 10099-141c, Lot No.: 2158737cp) at 37°C and 5% CO2. Trypsin was used for routine digestion and passage twice or three times a week. When the cells were in the exponential growth phase and reached 80%-90% adherent confluence, they were harvested and plated. 4T1 cells were digested with trypsin. The cells were then harvested and counted. According to the counting results, the cells were diluted with RPMI-1640 + 10% FBS, and the dilution concentration was 50,000 cells per ml. Then, the cells were plated into a 12-well culture plate, and 2 ml of cell suspension (100,000 cells) was added to each well. After plating, the cells were cultured in a 37 °C and 5% CO2 incubator. After the cells were seeded for 24 hours, six groups were set up: Group 1 was the control group, and medium was added; Group 2 was AMP945 at a concentration of 3 μM; Group 3 was AMP945 at a concentration of 6 μM; Group 4 was etoposide at a concentration of 5 μM; Group 5 was AMP945 (3 μM) combined with etoposide (5 μM); and Group 6 was AMP945 (6 μM) combined with etoposide (5 μM). The drugs were mixed and the mixture was incubated in a 5% CO2 incubator at 37°C for 48 hours.

[0203] Assay Results After 48 hours of drug action, cells were harvested for flow cytometry. Cells were washed twice with flow buffer (PBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody (Abcam) was added to each well and mixed. Cells were incubated in the dark at 4°C. After 20 min of incubation, flow buffer was added. An Annexin V-Apoptosis Detection Kit (Beyotime) was used. 195 μl of Annexin-V-FITC conjugate solution was added and mixed with the cells by pipetting. 5 μl of Annexin-V-FITC antibody was added and mixed gently. Finally, 10 μl of PI dye was added, mixed, and the cells were incubated in the dark at room temperature for 15 min. The samples were then sent to a flow cytometer for signal analysis.

[0204] The results of flow cytometry analysis showed that the CRT positive rate and Annexin-V positive rate in the two-drug combination group were significantly better than those in the single-drug group and the control group, as shown in Figure 13.

[0205] Example 10 In vitro study of the induction of immunogenic cell death targets in mouse breast cancer 4T1 cells by irinotecan and AMP945 Assay materials: 1) Drugs used in this assay Irinotecan provided by Shanghai Chaolan Chemical Technology Center Co., Ltd., Lot No.: 202110 AMP945 was provided by MCE, Lot No.: 143253.

[0206] 2) Antibodies used in this assay Recombinant Alexa Fluor® 647 fluorescent anti-calreticulin antibody (Abcam, Cat No.: ab196159, Lot No.: CR33676773). Annexin V-Apoptosis Detection Kit (Beyotime, Cat No.: C1062L, Lot No.: 122221220706).

[0207] Assay Method: 4T1 cells (Nanjing Cobioer Biotechnology Co., Ltd., product number: CBP60352) were cultured in RPMI 1640 (Shanghai Basalmedia, Catalog No.: L210KJ, Lot No.: F210916) + 10% FBS (Gibco, Catalog No.: 10099-141c, Lot No.: 2158737cp) at 37°C and 5% CO2. Trypsin was used for routine digestion and subculture twice or three times a week. When the cells were in the exponential growth phase and reached 80%-90% adherent confluence, they were harvested and plated. 4T1 cells were digested with trypsin. The cells were then harvested and counted. According to the counting results, the cells were diluted with RPMI-1640 + 10% FBS, and the dilution concentration was 50,000 cells per ml. Then, the cells were plated into a 12-well culture plate, and 2 ml of cell suspension (100,000 cells) was added to each well. After plating, the cells were cultured in a 37 °C and 5% CO2 incubator. After the cells were seeded for 24 hours, six groups were set up: Group 1 was the control group, and medium was added; Group 2 was AMP945 at a concentration of 3 μM; Group 3 was AMP945 at a concentration of 6 μM; Group 4 was irinotecan at a concentration of 120 μM; Group 5 was AMP945 (3 μM) combined with irinotecan (120 μM); and Group 6 was AMP945 (6 μM) combined with irinotecan (120 μM). The drugs were mixed and the mixture was incubated in a 5% CO2 incubator at 37°C for 48 hours.

[0208] Assay Results After 48 hours of drug action, cells were harvested for flow cytometry. Cells were washed twice with flow buffer (PBS + 2% FBS). 0.5 μl of AF647 anti-calreticulin antibody (Abcam) was added to each well and mixed. Cells were incubated in the dark at 4°C. After 20 minutes of incubation, flow buffer was added. An Annexin-V Apoptosis Detection Kit (Beyotime) was used. 195 μl of Annexin-V-FITC conjugate solution was added and mixed with the cells by pipetting. 5 μl of Annexin-V-FITC antibody was added and mixed gently. Finally, 10 μl of PI dye was added, mixed, and the cells were incubated in the dark at room temperature for 15 minutes. The samples were then sent to a flow cytometer for signal analysis.

[0209] The results of flow cytometry analysis showed that the CRT positive rate and Annexin-V positive rate in the two-drug combination group were significantly better than those in the single-drug group and the control group, as shown in Figure 14.

[0210] All references mentioned in this disclosure are incorporated herein by reference in their entirety as if each document were individually listed. After reading this disclosure, those skilled in the art may make various changes or modifications to the disclosure, and it should be understood that equivalents thereof are also within the scope defined by the claims of this application.

Claims

1. 1. Use of a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor in the manufacture of a medicament for treating a tumor in a subject, wherein the topoisomerase inhibitor is not an anthracycline.

2. 1. A pharmaceutical combination product of a FAK inhibitor, a topoisomerase inhibitor and an immune checkpoint inhibitor for use in treating a tumor in a subject, wherein the topoisomerase inhibitor is not an anthracycline.

3. A method for treating a tumor, comprising administering to a subject therapeutically effective amounts of a FAK inhibitor, a topoisomerase inhibitor, and an immune checkpoint inhibitor, wherein the topoisomerase inhibitor is not an anthracycline.

4. 4. The use, pharmaceutical combination product or method of any one of claims 1 to 3, wherein the FAK inhibitor and the topoisomerase inhibitor induce immunogenic cell death (ICD), and the topoisomerase inhibitor is not an anthracycline.

5. the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018 tartrate, wherein IN10018 is 【Chemical 1】 5. The use, pharmaceutical combination product or method according to any one of claims 1 to 4, having the structure:

6. 6. The use, pharmaceutical combination product or method according to any one of claims 1 to 5, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

7. 7. The use, pharmaceutical combination product or method of claim 6, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67 or a pharmaceutically acceptable salt thereof.

8. 8. The use, pharmaceutical combination product or method of claim 7, wherein the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

9. 6. The use, pharmaceutical combination product or method according to any one of claims 1 to 5, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

10. 10. The use, pharmaceutical combination product or method of claim 9, wherein the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin or a pharmaceutically acceptable salt thereof.

11. 11. The use, pharmaceutical combination product or method according to claim 10, wherein the topoisomerase II inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof.

12. 12. The use, pharmaceutical combination product or method according to any one of claims 1 to 11, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor or a TIGIT antibody.

13. 13. The use, pharmaceutical combination product or method of any one of claims 1 to 12, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, optionally wherein the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005 or MX-10181.

14. 13. The use, pharmaceutical combination product or method of any one of claims 1 to 12, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043 or RRx-001.

15. 13. The use, pharmaceutical combination product or method of any one of claims 1 to 12, wherein the immune checkpoint inhibitor is a TIGIT antibody, and optionally the TIGIT antibody is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036 or IBI-321.

16. 6. The use, pharmaceutical combination product or method of any one of claims 1 to 5, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

17. 6. The use, pharmaceutical combination product or method of any one of claims 1 to 5, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

18. 18. The use, pharmaceutical combination product or method according to any one of claims 1 to 17, wherein the FAK inhibitor, the topoisomerase inhibitor and the immune checkpoint inhibitor are administered to the subject simultaneously or sequentially.

19. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, anaplastic large cell lymphoma, 19. The use, pharmaceutical combination product or method of any one of claims 1 to 18, wherein the tumor is anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma or a hematological malignancy such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML); or wherein the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma or pancreatic cancer.

20. 20. The use, pharmaceutical combination product or method according to any one of claims 1 to 19, wherein the tumour is breast cancer or colon cancer (including colorectal cancer).

21. (a) FAK inhibitors, (b) a topoisomerase inhibitor that is not an anthracycline, and (c) A kit or a pharmaceutically acceptable composition comprising an immune checkpoint inhibitor.

22. 22. The kit or composition of claim 21, wherein the FAK inhibitor and the topoisomerase inhibitor induce immunogenic cell death (ICD).

23. the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; alternatively, the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; and further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018 tartrate, wherein IN10018 is 【Chemistry 2】 23. The kit or composition of claim 21 or 22, having the structure:

24. 24. The kit or composition of any one of claims 21 to 23, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

25. 25. The kit or composition of claim 24, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67, or a pharmaceutically acceptable salt thereof.

26. 26. The kit or composition of claim 25, wherein the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

27. 24. The kit or composition of any one of claims 21 to 23, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

28. 28. The kit or composition of claim 27, wherein the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin, or a pharmaceutically acceptable salt thereof.

29. 29. The kit or composition of claim 28, wherein the topoisomerase II inhibitor is etoposide, teniposide, or a pharmaceutically acceptable salt thereof.

30. 30. The kit or composition of any one of claims 21 to 29, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, a PD-1 / PD-L1 small molecule inhibitor, or a TIGIT antibody.

31. 31. The kit or composition of any one of claims 21 to 30, wherein the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody, and optionally the anti-PD-1 / PD-L1 antibody is pembrolizumab, tislelizumab, nivolumab, toripalimab, atezolizumab, durvalumab, avelumab, atezolizumab, camrelizumab, sintilimab, cemiplimab, embafolimab, BMS-936559, JS003, SHR-1316, GS-4224, AN-4005, or MX-10181.

32. 31. The kit or composition of any one of claims 21 to 30, wherein the immune checkpoint inhibitor is a PD-1 / PD-L1 small molecule inhibitor, optionally wherein the PD-1 / PD-L1 small molecule inhibitor is INCB-086550, lazertinib, IMMH-010, CA-170, ABSK043, or RRx-001.

33. 31. The kit or composition of any one of claims 21 to 30, wherein the immune checkpoint inhibitor is a TIGIT antibody, and optionally the TIGIT antibody is osipellimab (BGB-A1217), vibostolimab, domvanalimab (AB154), tiragolumab, berlestog, etigilimab, ONO-4686, JS-006, AZD-2936, HLX-301, SEA-TGT, M-6223, IBI-939, COM-902, AB-308, AGEN-1777, AK-127, BAT-6021, BAT-6005, ASP-8374, PM-1022, BMS-986207, HB0036, or IBI-321.

34. 23. The kit or composition of any one of claims 21 to 22, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is irinotecan or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

35. 23. The kit or composition of any one of claims 21 to 22, wherein the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof, the topoisomerase inhibitor is etoposide, teniposide or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody or a PD-1 / PD-L1 small molecule inhibitor, or the immune checkpoint inhibitor is an anti-PD-1 / PD-L1 antibody.

36. 36. A kit or composition according to any one of claims 21 to 35 for use as a medicament.

37. The medicament is used to treat tumors, and the tumor is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, and metastases caused by spindle cell carcinoma; 37. The kit or composition of any one of claims 21 to 36, wherein the tumor is anaplastic large cell lymphoma, anaplastic thyroid carcinoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, glioma, or a hematological malignancy such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML); or wherein the tumor is breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, or pancreatic cancer.

38. 38. The kit or composition of claim 37, wherein the tumor is breast cancer or colon cancer (including colorectal cancer).

39. 1. A FAK inhibitor for use in enhancing immunogenic cell death induced by a topoisomerase inhibitor in the treatment of tumors, wherein the topoisomerase inhibitor is not an anthracycline.

40. the FAK inhibitor is IN10018, defactinib, GSK2256098, PF-00562271, VS-4718, APG-2449, AMP945, AMP886 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018, defactinib, AMP945 or a pharmaceutically acceptable salt thereof; and, further alternatively, the FAK inhibitor is IN10018 or a pharmaceutically acceptable salt thereof; or the FAK inhibitor is IN10018 tartrate, wherein IN10018 is: 【Chemistry 3】 40. The FAK inhibitor of claim 39, having the structure:

41. 41. The FAK inhibitor according to claim 39 or 40, wherein the topoisomerase inhibitor is a topoisomerase I inhibitor.

42. 42. The FAK inhibitor of claim 41, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, cositecan, exatecan (DX-8951), indenoisoquinoline, indotecan (LMP-400), indimitecan (LMP-776), simmitecan, gimatecan (ST1481), EC-112002, PLX-038 (NK012), AR-67, or a pharmaceutically acceptable salt thereof.

43. 43. The FAK inhibitor of claim 42, wherein the topoisomerase I inhibitor is irinotecan or a pharmaceutically acceptable salt thereof.

44. 41. The FAK inhibitor according to claim 39 or 40, wherein the topoisomerase inhibitor is a topoisomerase II inhibitor.

45. 45. The FAK inhibitor of claim 44, wherein the topoisomerase II inhibitor is etoposide, teniposide, sabalubicin, or a pharmaceutically acceptable salt thereof.

46. 46. ​​The FAK inhibitor of claim 45, wherein the topoisomerase II inhibitor is etoposide, teniposide, or a pharmaceutically acceptable salt thereof.

47. Metastases caused by tumors including bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastoma, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal carcinoma, neuroendocrine carcinoma, ovarian cancer, salivary gland cancer, spindle cell carcinoma, undifferentiated large cell lymphoma, 47. The FAK inhibitor of any one of claims 39 to 46, wherein the tumor is selected from the group consisting of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML); or the tumor is selected from the group consisting of breast cancer, ovarian cancer, colon cancer (including colorectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma and pancreatic cancer.

48. 48. The FAK inhibitor of any one of claims 39 to 47, wherein the tumor is breast cancer or colon cancer (including colorectal cancer).

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