FAK inhibitor and pan-ras inhibitor

Abstract

The present disclosure relates to combining an FAK inhibitor and a Pan-RAS inhibitor to treat tumors.

Description

FAK inhibitors and Pan-RAS inhibitors Technical Field

[0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to the combined use of a focal adhesion kinase (FAK) inhibitor and a Pan-RAS inhibitor to treat tumors. Background Art

[0002] RAS is the most frequently mutated oncogene, comprising three major subtypes: KRAS, NRAS, and HRAS. Approximately 30% of cancers carry RAS mutations, with KRAS having the highest mutation rates in lung, pancreatic, and colorectal cancers. NRAS mutations are primarily found in melanoma and leukemia, while HRAS mutations are less common and primarily found in head and neck cancers. For a long time after the discovery that RAS mutations can cause cancer, both academia and industry considered RAS undruggable until the discovery of the KRAS G12C targetable pocket in 2013. Targeting this pocket can inhibit KRAS activity by keeping it in an inactive state, resulting in anti-tumor effects. Several leading pharmaceutical companies have developed KRAS G12C inhibitors based on this principle, with the leading two, Sotorasib and Adagrasib, now marketed primarily for the treatment of non-small cell lung cancer. Meanwhile, inhibitors targeting other KRAS mutation sites, such as KRAS G12D, are also making rapid progress. MRTX1133 and HRS-4642 have entered clinical trials in humans, and data are gradually maturing. In recent years, the concept of using a single inhibitor to simultaneously target multiple RAS mutations has gained increasing attention. Pan RAS inhibitors, such as Revolution Medicine's RMC6236, have also entered clinical trials for the treatment of tumors harboring different RAS mutations, including KRAS, NRAS, and HRAS. Initial clinical trial results are promising.

[0003] Despite rapid progress, a common problem with targeted inhibitors is the rapid development of drug resistance, which affects the durability of drug efficacy. Therefore, there is still a need to develop new treatment options for tumors with different RAS mutations. Summary of the Invention

[0004] The inventors discovered that combining a FAK inhibitor with a Pan-RAS inhibitor can produce superior results. This approach addresses the limited efficacy and primary resistance of Pan-RAS inhibitors and significantly enhances the response of cancer patients with RAS mutations to these inhibitors.

[0005] In one aspect, the present disclosure provides the use of a FAK inhibitor and a Pan-RAS inhibitor in the preparation of a medicament for treating a tumor in a subject.

[0006] Yet another aspect of the present disclosure provides a pharmaceutical combination product of a FAK inhibitor and a Pan-RAS inhibitor for use in treating a tumor in a subject.

[0007] In another aspect, the present disclosure provides a method for treating tumors, comprising administering a therapeutically effective amount of a FAK inhibitor and a Pan-RAS inhibitor to a subject in need thereof.

[0008] In another aspect, the present disclosure provides a kit or pharmaceutical composition for treating tumors, comprising:

[0009] (a) FAK inhibitors; and

[0010] (b) Pan-RAS inhibitors.

[0011] In another aspect, the present disclosure provides use of a FAK inhibitor and a Pan-RAS inhibitor in preparing a combined drug for treating tumors.

[0012] In another aspect, the present disclosure provides use of a FAK inhibitor in preparing a combined medicament for use with a Pan-RAS inhibitor in treating tumors.

[0013] In another aspect, the present disclosure provides use of a Pan-RAS inhibitor in preparing a combined medicament for use with a FAK inhibitor in treating tumors.

[0014] In another aspect, the present disclosure provides a kit comprising: a FAK inhibitor; and instructions, wherein the instructions indicate that the FAK inhibitor can be used in combination with a Pan-RAS inhibitor to treat tumors.

[0015] In another aspect, the present disclosure provides a kit comprising: a Pan-RAS inhibitor; and instructions, wherein the instructions indicate that the Pan-RAS inhibitor can be used in combination with a FAK inhibitor to treat tumors.

[0016] Optionally, the FAK inhibitor and the Pan-RAS inhibitor are administered to the subject simultaneously or sequentially.

[0017] The FAK inhibitor is, for example, IN10018, Defactinib, AMP945, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof; preferably IN10018, Defactinib, AMP945, deuterated compound 1 of Defactinib (CAS No. 2384121-03-1), deuterated compound 2 of Defactinib (CAS No. 2384120-99-2), or a pharmaceutically acceptable salt thereof; more preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof; even more preferably IN10018 or a pharmaceutically acceptable salt thereof.

[0018] The Pan-RAS inhibitor is, for example, RMC6236, Pan-RAS-IN-1 or ADT-007.

[0019] Optionally, the tumor is a RAS mutant tumor.

[0020] The tumors are, for example, 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 myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, fibrosarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, salivary gland cancer, metastases caused by spindle cell carcinoma, anaplastic large cell lymphoma, undifferentiated thyroid cancer, 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 myeloid leukemia (CML); preferably, the tumor is fibrosarcoma, gastric cancer, lung cancer, breast cancer, glioma esophageal cancer, pancreatic cancer, head and neck cancer, ovarian cancer or colon cancer (including colorectal cancer); more preferably, the tumor is colon cancer (including colorectal cancer), lung cancer, pancreatic cancer or fibrosarcoma; even more preferably, the tumor is colon cancer (including colorectal cancer) or fibrosarcoma.

[0021] The pharmaceutically acceptable salt of IN10018 is, for example, tartrate.

[0022] The pharmaceutically acceptable salt of AMP945 is, for example, tartrate.

[0023] The pharmaceutically acceptable salt of Defactinib is, for example, hydrochloride.

[0024] The use, pharmaceutical combination product, method, kit or pharmaceutical composition includes a therapeutic agent.

[0025] The therapeutic agent is an immune checkpoint inhibitor.

[0026] The immune checkpoint inhibitor is a PD-1 or PD-L1 inhibitor, especially a PD-1 or PD-L1 antibody inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the technical solutions of the embodiments of the present disclosure, the drawings of the embodiments will be briefly introduced below. Obviously, the drawings in the following description only relate to some embodiments of the present disclosure, and are not intended to limit the present invention.

[0028] FIG1 shows the effect of the combined use of RMC6236 and IN10018 on the proliferation of HT1080 cells in Example 1.

[0029] FIG2 shows the effect of the combination of RMC6236 and AMP945 on the proliferation of HT1080 cells in Example 1.

[0030] FIG3 shows the effect of the combination of RMC6236 and Defactinib on the proliferation of HT1080 cells in Example 1.

[0031] FIG4 shows the effect of the combined use of RMC6236 and IN10018 on the proliferation of CT26 cells in Example 2.

[0032] FIG5 shows the effect of the combination of RMC6236 and AMP945 on the proliferation of CT26 cells in Example 2.

[0033] FIG6 shows the effect of the combination of RMC6236 and Defactinib on the proliferation of CT26 cells in Example 2.

[0034] FIG7 shows the effect of RMC6236 on the proliferation of CT26 cells when the FAK target site is silenced in Example 3.

[0035] Figures 8-1 and 8-2 show the in vitro proliferation inhibitory effect of IN10018 alone on RAS mutant cell lines described in Example 4. Figure 8-1 shows the in vitro proliferation inhibitory effect on Capan1 cells; Figure 8-2 shows the in vitro proliferation inhibitory effect on NCI-H358 cells. Data are presented as mean ± SEM.

[0036] Figures 9-1 and 9-2 show the in vitro proliferation inhibitory effects of RMC6236 alone and in combination with IN10018 on RAS mutant cell lines as described in Example 4. Figure 9-1 shows the in vitro proliferation inhibitory effect on Capan1 cells; Figure 9-2 shows the in vitro proliferation inhibitory effect on NCI-H358 cells. Data are presented as mean ± SEM.

[0037] Figures 10-1 and 10-2 show the in vitro proliferation inhibitory effects of Pan-RAS-IN-1 alone and in combination with IN10018 on RAS mutant cell lines as described in Example 4. Figure 10-1 shows the in vitro proliferation inhibitory effects on Capan1 cells; Figure 10-2 shows the in vitro proliferation inhibitory effects on NCI-H358 cells. Data are presented as mean ± SEM.

[0038] Figures 11-1 and 11-2 show the in vitro proliferation inhibitory effects of ADT-007 alone and in combination with IN10018 on RAS mutant cell lines as described in Example 4. Figure 11-1 shows the in vitro proliferation inhibitory effects on Capan1 cells; Figure 11-2 shows the in vitro proliferation inhibitory effects on NCI-H358 cells. Data are presented as mean ± SEM.

[0039] Figure 12 shows the tumor growth curve of the CT26 cell subcutaneous transplant tumor model after administration in Example 5. The data are presented as mean ± SEM.

[0040] Figure 13 shows the tumor growth curve of the Capan1 cell subcutaneous transplant tumor model after administration in Example 6. The data are expressed as mean ± SEM. DETAILED DESCRIPTION

[0041] To make the purpose, technical solutions, and advantages of the embodiments of the present disclosure more clear, the technical solutions of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the drawings of the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, not all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0042] The present invention may be implemented in other specific forms without departing from the essential attributes of the present invention. It should be understood that, without conflict, any and all embodiments of the present invention may be combined with the technical features of any other embodiment or multiple other embodiments to produce additional embodiments. The present invention includes additional embodiments resulting from such combinations.

[0043] All publications and patents mentioned in this disclosure are hereby incorporated into the present disclosure in their entirety by reference. If the purposes or terms used in any publications and patents incorporated by reference conflict with the purposes or terms used in this disclosure, then the purposes and terms of this disclosure shall prevail.

[0044] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0045] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those commonly used in the art to which the claimed subject matter belongs. If there are multiple definitions for a term, the definition herein shall prevail.

[0046] The following terms and symbols used in this application have the meanings described below, unless the context indicates otherwise.

[0047] Except in the working examples or otherwise indicated, all numbers stating quantitative properties such as dosage in the specification and claims should be understood to be modified by the term "about" in all cases. It should also be understood that any numerical range recited herein is intended to include all subranges within the range and any combination of the various endpoints of the range or subrange.

[0048] As used in this disclosure, words such as "include," "comprising," or "including" mean that the elements preceding the word include the elements listed after the word and their equivalents, without excluding unlisted elements. The terms "comprising" or "including" as used herein may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0049] As used herein, "FAK inhibitor" refers to an effective inhibitor of FAK, which can be suitable for mammals, particularly humans. In some embodiments, the FAK inhibitor is IN10018 (CAS No.: 1227948-82-4), Defactinib (CAS No.: 1073154-85-4), AMP945 (CAS No.: 1393653-34-3), deuterated compounds thereof, or pharmaceutically acceptable salts thereof. In some embodiments, the FAK inhibitor is IN10018, Defactinib, AMP945, deuterated compound 1 of Defactinib (CAS No.: 2384121-03-1), deuterated compound 2 of Defactinib (CAS No.: 2384120-99-2), or a pharmaceutically acceptable salt thereof, for example, the pharmaceutically acceptable salt of IN10018 may be tartrate, the pharmaceutically acceptable salt of AMP945 may be tartrate, and the pharmaceutically acceptable salt of Defactinib may be hydrochloride.

[0050] The term "Pan-RAS inhibitor" as described herein refers to an inhibitor that targets all RAS mutations. In some embodiments, the Pan-RAS inhibitor is RMC6236 (CAS No.: 2765081-21-6), Pan-RAS-IN-1 (CAS No.: 1835283-94-7), or ADT-007 (CAS No.: 1945941-09-2).

[0051] As used herein, "drug combination" or "drug combination product" may refer to a fixed combination in the form of one dosage unit (for example, all active pharmaceutical ingredients are present in one dosage form) or a kit of parts for combined administration, or it may refer to a combination of one drug and instructions indicating that the drug can be used in combination with one or more other drugs.

[0052] As used herein, "combination therapy" or "combination drug" refers to the use of a drug in combination with one or more other drugs to treat a disease, including both the combination of a drug with one or more other drugs and the combination of a drug with instructions indicating that the drug can be used in combination with one or more other drugs.

[0053] "Simultaneous or sequential administration" in this application refers to the simultaneous or sequential administration of two or more drugs within a dosing cycle (e.g., within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours) or at certain time intervals. The modes of drug administration (e.g., oral, intravenous, intramuscular, or subcutaneous administration, etc.) may be the same or different, and the dosing frequency / cycle of the two or more drugs may be the same or different. When the treatment method, product, or use of the present disclosure involves two drugs, the two drugs may be administered simultaneously or separately at certain time intervals.

[0054] As used herein, the term "treat" refers to administering one or more pharmaceutical substances to a subject suffering from a disease or symptoms of a disease in order to cure, alleviate, relieve, alter, cure, ameliorate, improve, or affect the disease or symptoms of the disease. In some embodiments, the disease is a tumor or cancer.

[0055] The term "tumor" as used herein refers to an abnormal lesion formed when the cells of local tissues lose the normal regulation of their growth at the genetic level under the action of various tumorigenic factors, thereby causing abnormal proliferation of their clonal types. The tumors include, but are not limited to: 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 myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, fibrosarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, salivary gland cancer, metastatic tumors caused by spindle cell carcinoma, anaplastic large cell lymphoma, undifferentiated thyroid cancer, non Hodgkin's lymphoma, Hodgkin's lymphoma, glioma and 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), chronic myeloid leukemia (CML); preferably, the tumor is fibrosarcoma, lung cancer, breast cancer, glioma, esophageal cancer, pancreatic cancer, head and neck cancer, ovarian cancer or colon cancer (including colorectal cancer); more preferably, the tumor is colon cancer (including colorectal cancer), lung cancer, pancreatic cancer or fibrosarcoma; more preferably, the tumor is colon cancer (including colorectal cancer) or fibrosarcoma.

[0056] As used herein, the term "subject" or "subject" refers to both mammals and non-mammals. Mammals refer to any member of the class mammalia, including but not limited to humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; laboratory animals, including rodents such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds. The term "subject" does not limit the subject to a particular age or sex. In some embodiments, the subject is a human.

[0057] As used herein, the term "pharmaceutically acceptable" means non-toxic, biologically tolerable, and suitable for administration to a subject.

[0058] As used herein, the term "pharmaceutically acceptable salt" refers to non-toxic, biologically tolerable acid addition salts suitable for administration to a subject, including, but not limited to, acid addition salts formed with inorganic acids, such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, and the like; and acid addition salts formed with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts with the formula HOOC-(CH2) n -COOH (wherein n is 0-4) and the like.

[0059] In addition, pharmaceutically acceptable acid addition salts can be prepared by dissolving the free base in a suitable solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art can determine various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable acid addition salts without undue experimentation. In some embodiments, the pharmaceutically acceptable salt of IN10018 is a tartrate salt. In some embodiments, the pharmaceutically acceptable salt of AMP945 is a tartrate salt. In some embodiments, the pharmaceutically acceptable salt of Defactinib is a hydrochloride salt.

[0060] As used herein, the term "pharmaceutically acceptable" means that it must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation, and / or compatible with the subject being treated therewith. As used herein, the term "therapeutically effective amount" refers to an amount that is generally sufficient to produce a beneficial therapeutic effect on the subject. The therapeutically effective amount of the present invention can be determined by conventional methods (e.g., modeling, dose escalation studies, or clinical trials) in combination with conventional influencing factors (e.g., route 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 drug, etc.).

[0061] As used herein, the term "inhibit" refers to a decrease in the baseline activity of a biological activity or process.

[0062] The term "kit" as used herein refers to a box for containing chemical reagents for detecting chemical components, drug residues, virus species, etc. The kit of the present invention may include (i) a FAK inhibitor and / or a Pan-RAS inhibitor; and (ii) instructions, wherein the instructions indicate that the FAK inhibitor and the Pan-RAS inhibitor can be used to treat tumors in a subject. In one embodiment, the kit includes (i) a FAK inhibitor; and (ii) instructions, wherein the instructions indicate that the FAK inhibitor and the Pan-RAS inhibitor can be used to treat tumors in a subject. In one embodiment, the kit includes (i) a Pan-RAS inhibitor; and (ii) instructions, wherein the instructions indicate that the Pan-RAS inhibitor and the FAK inhibitor can be used to treat tumors in a subject. In one embodiment, the kit includes (i) a FAK inhibitor and a Pan-RAS inhibitor; and (ii) instructions, wherein the instructions indicate that the FAK inhibitor and the Pan-RAS inhibitor can be used to treat tumors in a subject.

[0063] The compound of the test kit can be contained in a separate container. Alternatively, two or more compounds are contained in the same container. For example, the test kit can include a first container, a second container and a package insert, wherein the first container includes at least one dose of a FAK inhibitor, the second container includes at least one dose of a Pan-RAS inhibitor, and the package insert includes instructions for using the drug to treat the tumor of the subject. The first container and the second container can include the same or different shapes (for example, vials, syringes and bottles) and / or materials (for example, plastic or glass). The test kit can also include other materials that can help administer the drug, such as diluents, filters, IV bags and pipelines, needles and syringes.

[0064] The precise amount of FAK inhibitor and Pan-RAS inhibitor administered to a subject will depend on various factors, such as the given drug or compound, the drug formulation, the route of administration, the type of disease, the condition, the identity of the subject or host being treated, etc., but can still be routinely determined by one skilled in the art. For example, determining an effective amount also depends on the extent, severity, and type of cell proliferation. A skilled person will be able to determine an appropriate dosage based on these and other factors.

[0065] The FAK inhibitor and Pan-RAS inhibitor can be administered by a suitable route such as oral, intravenous, intramuscular or subcutaneous administration.

[0066] For example, when administered orally, the drug can be administered orally with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. They can be encapsulated in hard-shell or soft-shell gelatin capsules, compressed into tablets, or mixed directly with the patient's food. For example, the drug can be combined with one or more excipients and used in the form of an ingestible tablet, buccal tablet, lozenge, capsule, elixir, suspension, syrup, or wafer. Tablets, lozenges, pills, capsules, etc. may further include: a binder, such as gum tragacanth, 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.

[0067] For example, when administered intravenously or intraperitoneally by infusion or injection, solutions of the drug can be prepared in water, optionally mixed with a nontoxic surfactant.

[0068] Exemplary pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient, which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In any case, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.

[0069] Sterile injectable solutions can be prepared by incorporating the required amount of the drug into an appropriate solvent with the various other ingredients listed above as required, followed by filtered sterilization. For sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods may be vacuum drying and freeze drying techniques, which can produce a powder of the active ingredient plus any other desired ingredients that have been previously sterile filtered.

[0070] The amount of FAK inhibitor and PAN-RAS inhibitor required for treatment may vary not only with the specific agent selected, but also with the route of administration, the nature of the disease being treated, and the age and condition of the patient, and may ultimately be determined at the discretion of the attending physician or clinician. However, in general, dosages may be in the range of about 0.1 to about 50 mg / kg body weight per day.

[0071] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0072] Example

[0073] The following examples are provided to further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0074] The experimental methods in the following examples without specifying specific conditions can be carried out according to conventional conditions of such reactions or according to conditions recommended by the manufacturers.

[0075] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0076] The abbreviations used in the examples have the following meanings:

[0077] Example 1: Study on the inhibitory activity of RMC6236 combined with FAK inhibitor on the proliferation of HT1080 fibrosarcoma cells in vitro

[0078] Experimental design:

[0079] The grouping is shown in Table 1.

[0080] Table 1: Grouping scheme for HT1080 cell proliferation inhibition assay

[0081] The test sample information is shown in Table 2.

[0082] Table 2:

[0083] Experimental methods and steps:

[0084] HT1080 cells were revived and maintained for passage. Cells were cultured as adherent monolayers in RPMI1640 medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2. Cells were trypsinized and passaged two to three times weekly. When cells reached the exponential growth phase and confluency reached 80%-90%, cells were digested and plated.

[0085] HT1080 cells were trypsinized and counted. Based on the count, the cells were diluted to 30,000 cells / mL in RPMI1640 + 10% FBS. The cells were then plated into 96-well flat-bottom culture plates, with 0.1 mL of cell suspension added to each well, representing 3,000 cells. After plating, the plates were placed in a 37°C, 5% CO2 incubator for continued culture.

[0086] 24 hours after plating the cells, test compounds were added to different wells of the cell plate. Test compounds were uniformly prepared and aliquoted prior to the experiment. Briefly, each drug was dissolved to 10 mM using the corresponding solvent, aliquoted into 50 μL vials, and stored at -20°C in the dark. For this experiment, one vial was removed for drug administration and treatment of the cells.

[0087] After drug addition, the drugs were gently mixed, and the cells were cultured in a 37°C, 5% CO2 incubator.

[0088] After 120 hours of drug treatment, 10 μL of CCK-8 detection reagent was added to each well of the cell plate using a multichannel pipette, and the cell plate was then incubated for another 4 hours in a 37°C, 5% CO2 incubator. Finally, the absorbance of each well was measured at 450 nm using a microplate reader.

[0089] Data Analysis:

[0090] After the experiment, GraphPad Prism 8 software was used to analyze the inhibition percentage of the test drugs on the cells.

[0091] Calculation of inhibition percentage: Inhibition percentage = {[A(0 drug addition) - A(blank)] - [A(drug addition) - A(blank)]} / [A(0 drug addition) - A(blank)] × 100%

[0092] A (drug added): absorbance value of the wells with cells, CCK-8 solution and drug solution

[0093] A (blank): absorbance value of the well with culture medium and CCK-8 solution but no cells

[0094] A(0 drug addition): absorbance value of the well with cells and CCK-8 solution but no drug solution

[0095] This study evaluated the inhibitory effect of RMC6236 alone and in combination with different FAK inhibitors on HT1080 cell proliferation in vitro.

[0096] The relevant test results of each group of cells 120 hours after drug treatment are shown in Figures 1 to 3 and Tables 3 to 5.

[0097] Table 3: HT 1080 cell viability percentage (%) (RMC6236 + different concentrations of IN10018)

[0098] Table 4: HT 1080 cell viability percentage (%) (RMC6236 + different concentrations of AMP945)

[0099] Table 5: HT 1080 cell viability percentage (%) (RMC6236 + different concentrations of Defactinib)

[0100] The effects of different concentrations of RMC6236 combined with different FAK inhibitors on cell proliferation showed that the combination group showed a stronger cell killing effect than the single-drug group, and as the drug concentration increased, the cell viability decreased. Therefore, the combination group has a stronger inhibitory effect on cancer cell growth in vitro.

[0101] Example 2: Study on the inhibitory activity of RMC6236 combined with FAK inhibitor on the proliferation of CT26 colon cancer cells in vitro

[0102] Experimental design:

[0103] The grouping is shown in Table 6.

[0104] Table 6: Grouping scheme for CT26 cell proliferation inhibition assay

[0105] The test sample information is shown in Table 2.

[0106] Experimental methods and steps:

[0107] CT26 cells were revived and maintained for passage. Cells were cultured as adherent monolayers in RPMI1640 medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2. Cells were trypsinized and passaged two to three times weekly. When cells reached 80%-90% confluency and were in the exponential growth phase, cells were digested and plated.

[0108] CT26 cells were trypsinized and counted. Based on the count, the cells were diluted to 30,000 cells / mL in RPMI1640 + 10% FBS. The cells were then plated into 96-well flat-bottom culture plates, with 0.1 mL of cell suspension added to each well, equating to 3,000 cells. After plating, the plates were placed in a 37°C, 5% CO2 incubator for continued culture.

[0109] 24 hours after plating the cells, test compounds were added to different wells of the cell plate. Test compounds were uniformly prepared and aliquoted prior to the experiment. Briefly, each drug was dissolved to 10 mM using the corresponding solvent, aliquoted into 50 μL vials, and stored at -20°C in the dark. For this experiment, one vial was removed for drug administration and treatment of the cells.

[0110] After drug addition, the drugs were gently mixed, and the cells were cultured in a 37°C, 5% CO2 incubator.

[0111] After 120 hours of drug treatment, 10 μL of CCK-8 detection reagent was added to each well of the cell plate using a multichannel pipette, and the cell plate was then incubated for another 4 hours in a 37°C, 5% CO2 incubator. Finally, the absorbance of each well at 450 nm was measured using a microplate reader.

[0112] Data Analysis:

[0113] After the experiment, GraphPad Prism 8 software was used to analyze the inhibition percentage of the test drugs on the cells.

[0114] Calculation of inhibition percentage: Inhibition percentage = {[A(0 drug addition) - A(blank)] - [A(drug addition) - A(blank)]} / [A(0 drug addition) - A(blank)] × 100%

[0115] A (drug added): absorbance value of the wells with cells, CCK-8 solution and drug solution

[0116] A (blank): absorbance value of the well with culture medium and CCK-8 solution but no cells

[0117] A(0 drug addition): absorbance value of the well with cells and CCK-8 solution but no drug solution

[0118] This study evaluated the inhibitory effect of RMC6236 alone and in combination with different FAK inhibitors on CT26 cell proliferation in vitro.

[0119] The relevant test results of each group of cells 120 hours after drug treatment are shown in Figures 4 to 6 and Tables 7 to 9.

[0120] Table 7: CT26 cell viability percentage (%) (RMC6236 + different concentrations of IN10018)

[0121] Table 8: CT26 cell viability percentage (%) (RMC6236 + different concentrations of AMP945)

[0122] Table 9: CT26 cell viability percentage (%) (RMC6236 + different concentrations of Defactinib)

[0123] The effects of different concentrations of RMC6236 combined with different FAK inhibitors on cell proliferation showed that the combination group showed better cell killing effect than the single-drug group, and as the drug concentration increased, the cell survival rate in the combination group decreased; therefore, the combination group had a stronger in vitro inhibitory effect on tumor cell growth.

[0124] Example 3: Study on the inhibitory activity of RMC6236 and FAK siRNA on the proliferation of CT26 colon cancer cells in vitro

[0125] Experimental design:

[0126] The grouping is shown in Table 10.

[0127] Table 10: Grouping scheme for CT26 cell proliferation inhibition test

[0128] The test sample information is shown in Table 11.

[0129] Table 11:

[0130] Reagent information is shown in Table 12. Table 12:

[0131] Experimental methods and steps:

[0132] CT26 cells were revived and maintained for passage. Cells were cultured as adherent monolayers in RPMI1640 medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2. Cells were trypsinized and passaged two to three times weekly. When cells reached 80%-90% confluency and were in the exponential growth phase, cells were digested and plated.

[0133] CT26 cells were trypsinized and counted. Based on the count, the cells were diluted to 50,000 cells / mL in RPMI1640 + 10% FBS. Then, 0.1 mL of the cell suspension (5,000 cells) was added to each well. After plating, the plates were placed in a 37°C, 5% CO2 incubator for further culture.

[0134] CT26 cells were transfected with siRNA using Lipofectamine 3000. siRNA was diluted to 100 nM in 125 μL of Opti-MEM (Solution A). 6 μL of Lipofectamine 3000 was added to 125 μL of Opti-MEM and mixed thoroughly to create Solution B. Gently mix Solution A and Solution B to prepare the transfection complex and incubate at room temperature for 15 minutes. Add 10 μL of the transfection complex to each well of the 96-well plate containing the cells.

[0135] 24 hours after plating the cells, test compounds were added to different wells of the cell plate. Test compounds were uniformly prepared and aliquoted prior to the experiment. Briefly, each drug was dissolved to 10 mM in the corresponding solvent, aliquoted into 50 μL vials, and stored at -20°C in the dark. For this experiment, one vial was removed for drug administration and treatment of the cells. After drug administration, the drug was gently mixed, and the cells were then incubated at 37°C in a 5% CO2 incubator.

[0136] After 120 hours of drug treatment, 10 μL of CCK-8 detection reagent was added to each well of the cell plate using a multichannel pipette, and the cell plate was then incubated for another 4 hours in a 37°C, 5% CO2 incubator. Finally, the absorbance of each well at 450 nm was measured using a microplate reader.

[0137] Data Analysis:

[0138] After the experiment, GraphPad Prism 8 software was used to analyze the inhibition percentage of the test drugs on the cells.

[0139] Calculation of inhibition percentage: Inhibition percentage = {[A(0 drug addition) - A(blank)] - [A(drug addition) - A(blank)]} / [A(0 drug addition) - A(blank)] × 100%

[0140] A (drug added): absorbance value of the wells with cells, CCK-8 solution and drug solution

[0141] A (blank): absorbance value of the well with culture medium and CCK-8 solution but no cells

[0142] A(0 drug addition): absorbance value of the well with cells and CCK-8 solution but no drug solution

[0143] This study evaluated the killing effect of RMC6236 alone and after FAK target silencing on CT26 cells in vitro.

[0144] After FAK target silencing, the cell killing results of CT26 cells after drug treatment for 120 hours are shown in FIG7 and Table 13.

[0145] Table 13: CT26 cell viability percentage (%)

[0146] Compared with the control siRNA group, FAK silencing significantly increased the sensitivity of CT26 cells to RMC6236. Therefore, under the condition of FAK target silencing, RMC6236 has a stronger in vitro tumor cell killing effect.

[0147] Example 4: Study on the in vitro proliferation inhibitory activity of different Pan-RAS inhibitors combined with IN10018 on RAS mutant cell lines.

[0148] Experimental design:

[0149] The grouping is shown in Table 14.

[0150] Table 14: Grouping scheme for HT1080 cell proliferation inhibition assay

[0151] The information of test samples IN10018 and RMC6236 is shown in Table 2, and the information of other test samples is shown in Table 15.

[0152] Table 15:

[0153] Experimental methods and steps:

[0154] Capan1 cells (Nanjing Kebai Biotechnology Co., Ltd., product number CBP60543, human pancreatic cancer cells) and NCI-H358 cells (Nanjing Kebai Biotechnology Co., Ltd., product number CBP60136, human non-small cell lung cancer cells) were revived and maintained for passage. Cells were cultured as monolayer adherent cells in vitro. The culture conditions for Capan1 cells were DMEM medium supplemented with 10% fetal bovine serum, and the culture conditions for NCI-H358 cells were RPMI1640 medium supplemented with 10% fetal bovine serum. Both cells were cultured at 37°C and 5% CO2. The cells were digested and passaged using trypsin two to three times a week. When the cells were in the exponential growth phase and adhered to the wall to a confluence of 80%-90%, the cells were harvested and plated.

[0155] Capan1 and NCI-H358 cells were trypsinized, harvested, and counted. Based on the counts, the cells were diluted to 30,000 cells / mL in culture medium. The cells were then plated into 96-well flat-bottom culture plates, with 0.1 mL of cell suspension (approximately 3,000 cells) added to each well. After plating, the plates were placed in a 37°C, 5% CO2 incubator for continued culture.

[0156] 24 hours after cell plating, test compounds were added to different wells of the cell plate. Test compounds were uniformly prepared and aliquoted prior to the experiment. Briefly, the drug was dissolved in DMSO to 10 mM, aliquoted into 50 μL vials, and stored at -20°C in the dark. For this experiment, one vial was removed for drug administration and treatment of the cells.

[0157] After drug addition, the drugs were gently mixed, and the cells were cultured in a 37°C, 5% CO2 incubator.

[0158] After 120 hours of drug treatment, 10 μL of CCK-8 detection reagent was added to each well of the cell plate using a multichannel pipette, and the cell plate was then incubated for another 4 hours in a 37°C, 5% CO2 incubator. Finally, the absorbance of each well was measured at 450 nm using a microplate reader.

[0159] Data analysis is the same as in Example 1.

[0160] This study evaluated the in vitro proliferation inhibitory effects of three Pan-RAS inhibitors, RMC6236, Pan-RAS-IN-1, and ADT-007, alone or in combination with IN10018, on RAS mutant cell lines under in vitro conditions.

[0161] The relevant test results of each group of cells 120 hours after drug treatment are shown in Figures 8 to 11 and Tables 16 to 19.

[0162] Table 16: Percentage of IN10018 single-drug viability in different cell types (%)

[0163] Table 17: Cell viability percentage (%)

[0164] Table 18: Cell viability percentage (%)

[0165] Table 19: Cell viability percentage (%)

[0166] IC of IN10018 monotherapy on Capan1 cells 50 The IC value for NCI-H358 cells was 18.38 μM. 50 The combination of a Pan-RAS inhibitor and IN10018 showed lower cell viability compared to the Pan-RAS inhibitor alone. These results demonstrate that IN10018 effectively enhances the cell-killing effect of Pan-RAS inhibitors in RAS-mutant cell lines, resulting in a stronger in vitro inhibitory effect on cancer cell growth.

[0167] Example 5: In vivo evaluation of the anti-tumor efficacy of the test article in the CT26 colorectal cancer subcutaneous transplantation model.

[0168] CT26 cells (Nanjing Kebai Biotechnology Co., Ltd., Cat. No. CBP60043) were cultured in a 37°C, 5% CO2 incubator using RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum. Cells were harvested during the exponential growth phase, resuspended in DPBS, and quantified using a cell counter before tumor inoculation.

[0169] Each mouse (BALB / c mouse, 6-7 weeks old, Shanghai Lingchang Biotechnology Co., Ltd.) was subcutaneously inoculated with 3*10 5 CT26 cells were seeded in 0.1 mL of DPBS. When the average tumor volume reached approximately 94 mm 3 At 12 days post-inoculation, mice with moderate tumor volume were enrolled and treatment began. Group and regimen information is shown in Table 20.

[0170] Table 20: Note: 1. N: Number of animals per group

[0171] The information of the test samples IN10018 and RMC6236 is shown in Table 2, anti-mPD-1 (KYINNO Biotechnology, Lots: 20230919, concentration 5 mg / mL, solvent: DPBS, stored at 4°C).

[0172] After cell inoculation, the animals were routinely observed for activity, food and water intake, weight gain or loss, and abnormalities of the eyes, coat, and other conditions. Clinical symptoms observed during the experiment were recorded in the original data. After cell inoculation, the animals' weight and tumor size were measured every two days. Tumor size calculation formula: Tumor volume (mm 3 ) = 0.5 × (long diameter of tumor × short diameter of tumor 2 ).

[0173] Tumor volume inhibition rate TGI TV (%): TGI%=(1-ΔT / ΔC)×100%; where ΔC is the tumor volume C of the control group t -C0, C0 is the average tumor volume of the control group when grouped, C t is the average tumor volume of the control group after treatment, and ΔT is the tumor volume T of the treatment group t -T0, T0 is the average tumor volume of the control group at the time of grouping, T t is the average tumor volume of the control group after treatment.

[0174] According to the tumor inhibition rate (TGI TV %) for pharmacodynamic activity evaluation, and tolerance evaluation was performed based on changes in animal body weight and mortality.

[0175] Tumor volume and animal body weight are expressed as mean ± SEM. All data were analyzed using GraphPad Prism 8.0. Differences in tumor volume between groups throughout the experiment were statistically analyzed using two-way analysis of variance and Fisher's LSD test. A p < 0.05 was considered significant.

[0176] Tumor growth was observed daily. Due to excessive tumor volume, mice in the blank control group, RMC6236 10 mg / kg group, and anti-mPD-1 10 mg / kg group were euthanized on day 12, and mice in the IN10018 25 mg / kg group were euthanized on day 14. Mice in the other groups were observed until the end of the experiment (day 19). The tumor volume, TGI value, and statistical analysis of each group are shown in Table 21. The tumor volume of each group at different time periods is shown in Figure 12.

[0177] Table 21: Notes: 1. Mean ± SEM; 2. Calculated based on data from day 12; 3. Calculated based on data from day 12, ****: p < 0.0001, vs. blank control group, two-way ANOVA; 4. Calculated based on data from day 19, **: p < 0.01, ***: p < 0.001, vs. RMC6236 + anti-mPD-1 + IN10018 10 + 10 + 25 mg / kg group, two-way ANOVA.

[0178] All experimental animals showed no abnormal body weight changes. The body weight change trend of the treatment group was consistent with that of the vehicle control group, as shown in Table 22. These results indicate that the animals tolerated the treatment well.

[0179] Table 22: Note: 1. Number of animals surviving on day 12 / number of animals surviving on day 0; 2. Mean ± SEM; 3. Body weight change rate = (W 12 -W0) / W0*100%.

[0180] Compared with the blank control group, the IN10018 group, the RMC6236 + IN10018 group, and the RMC6236 + anti-mPD-1 + IN10018 group showed significant differences, indicating that these monotherapy and combination therapies have significant anti-tumor effects. Furthermore, the tumor volume in the RMC6236 + anti-mPD-1 + IN10018 triple-drug group was consistently the smallest, statistically different from the RMC6236 + IN10018 dual-drug group. These results suggest that IN10018 synergizes with RMC6236 and anti-mPD-1 in the treatment of cancer.

[0181] Example 6: In vivo evaluation of the anti-tumor efficacy of the test article in the Capan 1 human pancreatic cancer subcutaneous transplantation model.

[0182] Capan1 cells (COBIOER, Cat. No. CBP60543) were cultured in a 37°C, 5% CO2 incubator using DMEM medium supplemented with 10% heat-inactivated fetal bovine serum. Cells were harvested during the exponential growth phase, resuspended in a 1:1 ratio of DPBS to Matrigel, and quantified using a cell counter before tumor inoculation.

[0183] Each mouse (BALB / c mouse, 6-7 weeks old, Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.) was subcutaneously inoculated with 10*10 6 Capan1 cells were inoculated in a volume of 0.2 mL DPBS:Matrigel = 1:1. When the average tumor volume reached approximately 260 mm 3At 12 days post-inoculation, mice with moderate tumor volume were enrolled and treatment began. Group and regimen information is shown in Table 23.

[0184] Table 23:

[0185] The information of test samples IN10018 and RMC6236 is shown in Table 2.

[0186] After cell inoculation, the animals were routinely observed for activity, food and water intake, weight gain or loss, and abnormalities of the eyes, coat, and other conditions. Clinical symptoms observed during the experiment were recorded in the original data. After cell inoculation, the animals' weight and tumor size were measured every two days. Tumor size calculation formula: Tumor volume (mm 3 ) = 0.5 × (long diameter of tumor × short diameter of tumor 2 ).

[0187] Tumor volume inhibition rate TGI TV (%): TGI%=(1-ΔT / ΔC)×100%; where ΔC is the tumor volume C of the control group t -C0, C0 is the average tumor volume of the control group when grouped, C t is the average tumor volume of the control group after treatment, and ΔT is the tumor volume T of the treatment group t -T0, T0 is the average tumor volume of the control group at the time of grouping, T t is the average tumor volume of the control group after treatment.

[0188] According to the tumor inhibition rate (TGI TV %) for pharmacodynamic activity evaluation, and tolerance evaluation was performed based on changes in animal body weight and mortality.

[0189] Tumor volume and animal body weight are expressed as mean ± SEM. All data were analyzed using GraphPad Prism 8.0. Differences in tumor volume between groups throughout the experiment were statistically analyzed using two-way analysis of variance and Fisher's LSD test. A p < 0.05 was considered significant.

[0190] Tumor growth was observed daily, and the tumor volume, TGI value, and statistical analysis of each group are shown in Table 24. The tumor volume of each group at different time periods is shown in Figure 13.

[0191] Table 24: Note: 1. Mean ± SEM; 2. ****: p < 0.0001, vs. blank control group, Two-way ANOVA; 3. ***: p < 0.001, ****: p < 0.0001, vs. RMC6236 + IN10018 group, Two-way ANOVA.

[0192] No abnormalities were observed in the body weights of the experimental animals. The trends in body weight changes in the treatment groups were consistent with those in the vehicle control group. See Table 25 for details. These results indicate that the animals tolerated the treatment well.

[0193] Table 25: Note: 4. Number of animals surviving on day 12 / number of animals surviving on day 0; 5. Mean ± SEM; 6. Body weight change rate = (W 20 -W0) / W0*100%.

[0194] Compared with the blank control group, the IN10018 group, the RMC6236 group, and the RMC6236 + IN10018 group showed significant differences, indicating that the above monotherapy and combination therapy have significant anti-tumor effects. The RMC6236 + IN10018 group has better anti-tumor activity.

[0195] All references mentioned in this application are incorporated herein by reference in their entirety, just as if each reference were listed separately. It should be understood that after reading the disclosure of this application, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope of the claims appended hereto.

Claims

1. Use of a FAK inhibitor and a Pan-RAS inhibitor in the preparation of a medicament for treating tumors in a subject.

2. Use of a FAK inhibitor in the preparation of a medicament for use in combination with a Pan-RAS inhibitor for treating tumors in a subject.

3. Use of a Pan-RAS inhibitor in the preparation of a medicament for use in combination with a FAK inhibitor for treating tumors in a subject.

4. A pharmaceutical combination product of a FAK inhibitor and a Pan-RAS inhibitor for treating tumors in a subject.

5. A method for treating tumors, the method comprising administering a therapeutically effective amount of a FAK inhibitor and a Pan-RAS inhibitor to a subject in need thereof.

6. A kit or pharmaceutical composition for treating tumors, comprising: (a) a FAK inhibitor; and (b) a Pan-RAS inhibitor.

7. The use, pharmaceutical combination product, method, kit or pharmaceutical composition according to any one of claims 1-6, wherein the FAK inhibitor and the Pan-RAS inhibitor are administered simultaneously or sequentially.

8. The use, pharmaceutical combination product, method, kit or pharmaceutical composition according to any one of claims 1-7, wherein the FAK inhibitor is IN10018, Defactinib, AMP945, or a deuterated compound or pharmaceutically acceptable salt thereof; preferably IN10018, Defactinib, AMP945, deuterated compound 1 of Defactinib, deuterated compound 2 of Defactinib, or a pharmaceutically acceptable salt thereof; preferably IN10018, Defactinib, AMP945, or a pharmaceutically acceptable salt thereof; more preferably IN10018 or a pharmaceutically acceptable salt thereof.

9. The use, pharmaceutical combination product, method, kit or pharmaceutical composition according to any one of claims 1-8, wherein the Pan-RAS inhibitor is RMC6236, Pan-RAS-IN-1 or ADT-007, or a pharmaceutically acceptable salt thereof; preferably RMC6236.

10. The use, pharmaceutical combination product, method, kit or pharmaceutical composition according to any one of claims 1-9, wherein the tumor is a RAS-mutated tumor; preferably, wherein the RAS mutation is KRAS G12V, KRAS G12C or KRAS G12D, preferably KRAS G12V or KRAS G12C.

11. The use, pharmaceutical combination product, method, kit or pharmaceutical composition according to any one of claims 1-9, wherein the tumor is 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 myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma, fibrosarcoma (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, metastatic tumor caused by spindle cell carcinoma, anaplastic large cell lymphoma, undifferentiated thyroid cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, glioma or malignant hematological disease, such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or chronic myeloid leukemia (CML); preferably, the tumor is fibrosarcoma, gastric cancer, lung cancer, breast cancer, glioma, esophageal cancer, pancreatic cancer, head and neck cancer, ovarian cancer or colon cancer (including colorectal cancer); more preferably, the tumor is colon cancer (including colorectal cancer), lung cancer, pancreatic cancer or fibrosarcoma; still more preferably, the tumor is colon cancer (including colorectal cancer) or fibrosarcoma.

12. The use, pharmaceutical combination product, method, kit or pharmaceutical composition according to any one of claims 1-11, further comprising other therapeutic agents.

13. The use, pharmaceutical combination product, method, kit or pharmaceutical composition according to claim 12, wherein the other therapeutic agent is an immune checkpoint inhibitor.

14. The use, pharmaceutical combination product, method, kit or pharmaceutical composition according to claim 13, wherein the immune checkpoint inhibitor is a PD-1 or PD-L1 inhibitor, especially a PD-1 or PD-L1 antibody inhibitor.

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