Use of anti-PD-1 antibodies in combination with famitinib in the preparation of drugs for treating tumors

Abstract

The present disclosure provides the use of an anti-PD-1 antibody in combination with famitinib in the preparation of a drug for treating tumors. This technical solution has controllable and tolerable toxicity. Additionally, the described drug combination effectively reduces the side effects of anti-PD-1 antibodies, such as the occurrence of reactive capillary endothelial proliferation.

Description

Technical Field

[0001] The present disclosure relates to the use of an anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of tumors.

Background Art

[0002] Cancer has various genetic and epigenetic changes, leading to new antigens that can be recognized by the immune system. The adaptive immune system, including T lymphocytes and B lymphocytes, has strong anti-cancer potential, a wide range of capabilities, and excellent specificity for responding to various tumor antigens. Furthermore, the immune system exhibits a significant element of plasticity and memory. By making good use of all these characteristics of the adaptive immune system, immunotherapy becomes unique among all treatment means for cancer.

[0003] Cancer immunotherapy has focused on methods to enhance the immune response against tumors through adoptive transfer of activated effector cells, immunity against related antigens, or provision of non-specific immune stimulants such as cytokines. In recent years, the development of inhibitors specific to the immune checkpoint pathway, such as ipilimumab (YERVOY (registered trademark)) (Hodi et al., 2010), a CTLA antibody for the treatment of advanced melanoma, nivolumab or pembrolizumab that specifically binds to programmed death receptor (PD-1), has become a new immunotherapy for the treatment of cancer.

[0004] The PD-1 antibody specifically recognizes and binds to PD-1 present on the surface of lymphocytes, blocks the PD-1 / PD-L1 signaling pathway, thereby activating the effect of immune T cells to kill tumors and mobilizing the body's immune system to eliminate tumor cells in the body. WO2015085847 discloses a novel anti-PD-1 antibody. The PD-1 antibody is currently in the clinical trial stage and shows a certain anti-tumor effect.

[0005] In a multicenter, randomized, double-blind, placebo-controlled phase II trial of advanced / metastatic colorectal adenocarcinoma in patients who had failed second-line or higher standard chemotherapy with famitinib, famitinib (25 mg once daily for 42 days) improved progression-free survival (PFS) by 1.3 months compared to placebo (HR 0.596, P 0.0053). The objective remission rate (ORR) was 2.2%, the disease control rate (DCR) was 59.8%, the median overall survival (mOS) was 7.5 months, and the median overall survival in the placebo group was 7.6 months. Adverse events were controlled. The structure of the study is as follows: [ka]

[0006] Currently, several combination therapies of PD-1 antibodies and VEGFR inhibitors (such as sunitinib and sorafenib) are in Phase II / III clinical trials, and are suitable for malignant liver cancer (sorafenib and PD-1 antibody combination) and metastatic renal cell carcinoma (sunitinib and PD-1 antibody combination), respectively. Preliminary results have shown that the combination of the two drugs is more effective than the single drug. However, there are no reports on the combination of famitinib and PD-1 antibody. [Overview of the Initiative]

[0007] This disclosure provides the use of an anti-PD-1 antibody or its antigen-binding fragment in combination with famitinib or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of tumors.

[0008] The PD-1 antibody is known, and preferably, the light chain variable region of the PD-1 antibody includes LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.

[0009] The heavy chain variable region of the PD-1 antibody includes HCDR1, HCDR2, and HCDR3, as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively.

[0010] Among them, the above CDR sequences are shown in the following table:

[0011] [Table 1]

[0012] Preferably, the PD-1 antibody is a humanized antibody.

[0013] In some embodiments, the humanized antibody comprises a light chain variable region or a variant thereof shown in SEQ ID NO: 10, wherein the variant preferably has 0 to 10 amino acid changes, more preferably an A43S amino acid change, in the light chain variable region of SEQ ID NO: 10; and the humanized antibody comprises a heavy chain variable region or a variant thereof shown in SEQ ID NO: 9, wherein the variant preferably has 0 to 10 amino acid changes, more preferably a G44R amino acid change, in the heavy chain variable region of SEQ ID NO: 9.

[0014] The sequences of the heavy chain variable region and light chain variable region of the aforementioned humanized antibody are as follows:

[0015] [ka]

[0016] In other embodiments, the humanized antibody comprises a light chain or a variant thereof shown in SEQ ID NO: 8, wherein the variant preferably has 0 to 10 amino acid changes, more preferably an A43S amino acid change, in the variable region of the light chain; and the humanized antibody comprises a heavy chain or a variant thereof shown in SEQ ID NO: 7, wherein the variant preferably has 0 to 10 amino acid changes, more preferably a G44R amino acid change, in the variable region of the heavy chain.

[0017] In another embodiment, the humanized antibody comprises a light chain shown in SEQ ID NO: 8 and a heavy chain shown in SEQ ID NO: 7.

[0018] The sequences of the heavy and light chains of the humanized antibody are as follows:

Chemical formula

[0019] The anti-PD-1 antibody or antigen-binding fragment thereof in combination with the sunitinib or pharmaceutically acceptable salt thereof disclosed herein has a synergistic effect.

[0020] According to the present disclosure, for the use, based on the patient's body weight, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 0.1 mg / kg to 10.0 mg / kg, and the 0.1 mg / kg to 10.0 mg / kg can be 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.2 mg / kg, 3.4 mg / kg, 3.6 mg / kg, 3.8 mg / kg, 4.0 mg / kg, 4.2 mg / kg, 4.4 mg / kg, 4.6 mg / kg, 4.8 mg / kg, 5.0 mg / kg, 5.2 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 5.8 mg / kg, 6.0 mg / kg, 6.2 mg / kg, 6.4 mg / kg, 6.6 mg / kg, 6.8 mg / kg, 7.0 mg / kg, 7.2 mg / kg, 7.4 mg / kg, 7.6 mg / kg, 7.8 mg / kg, 8.0 mg / kg, 8.2 mg / kg, 8.4 mg / kg, 8.6 mg / kg, 8.8 mg / kg, 9.0 mg / kg, 9.2 mg / kg, 9.4 mg / kg, 9.6 mg / kg, 9.8 mg / kg, 10.0 mg / kg, or any value between any two of these values.

[0021] In an alternative embodiment, the PD-1 antibody or its antigen-binding fragment is administered to a human subject at a dose of 10 mg to 300 mg, and the 10 mg to 300 mg can be 10.0 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, or any value between any two of these values, preferably can be 50 mg to 300 mg, and most preferably can be 200 mg.

[0022] The anti-PD-1 antibody or its antigen-binding fragment of the present disclosure is administered once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, preferably at a frequency of once every three weeks.

[0023] In an alternative embodiment, the anti-PD-1 antibody or its antigen-binding fragment of the present disclosure is administered once every 2 to 3 weeks at a dose of 50 mg to 300 mg, more preferably once every 2 to 3 weeks at a dose of 200 mg.

[0024] The use described herein involves administering famitinib or a pharmaceutically acceptable salt thereof to a human subject in doses of 0.1 mg / kg to 10.0 mg / kg based on the patient's body weight, where 0.1 mg / kg to 10.0 mg / kg is 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.2 mg / kg, 3.4 mg / kg, 3.6 mg / kg, 3.8 mg / kg, 4.0 mg / kg, 4.2 mg / kg, 4.4 mg / kg, 4.6 mg / kg, 4.8 mg / kg, 5.0 mg / kg, 5.2 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 5.8 mg / kg, 6.0 mg / kg, 6.2 mg / kg, 6.4 mg / kg, 6.6 mg / kg, 6.8 mg / kg, 7.0 mg / kg, 7.2 mg / kg, 7.4 mg / kg, 7.6 mg / kg, 7.8 mg / kg, 8.0 mg / kg, 8.2 mg / kg, 8.4 mg / kg, 8.6 mg / kg, 8.8 mg / kg, 9.0 mg / kg, 9.2 mg / kg, 9.4 mg / kg, 9.6 mg / kg, 9.8 mg / kg, 10.0 mg / kg, or any value between any two of these values.

[0025] In an alternative embodiment, the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects in doses of 0.1 mg to 100 mg, where 0.1 mg to 100 mg corresponds to 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, The amount may be 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, or any value between any two of these values, preferably between 1mg and 20mg.

[0026] In use of the present disclosure, the famitinib or a pharmaceutically acceptable salt thereof is administered at the following frequencies: once daily; once every two days; once every three days; once every four days; once every five days; once every six days; once a week; once daily for three days a week; once daily for four days a week; and once daily for five days a week.

[0027] In alternative embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered to human subjects in doses of 10 mg to 300 mg, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects in doses of 0.1 mg to 100 mg.

[0028] In alternative embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered to human subjects at doses of 10 mg to 300 mg once every 2 to 3 weeks, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects at doses of 0.1 mg to 100 mg once daily.

[0029] In alternative embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered to human subjects in doses of 50 mg to 300 mg, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects in doses of 1 mg to 20 mg.

[0030] In alternative embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered to human subjects at a dose of 50 mg to 300 mg once every 2 to 3 weeks, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects at a dose of 1 mg to 20 mg once daily.

[0031] In alternative embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered to human subjects at a dose of 200 mg, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects at a dose of 1 mg to 20 mg.

[0032] In an alternative embodiment, the anti-PD-1 antibody or its antigen-binding fragment is administered to human subjects at a dose of 200 mg once every 2-3 weeks, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects at a dose of 1 mg to 20 mg once daily.

[0033] In an alternative embodiment, the anti-PD-1 antibody or its antigen-binding fragment is administered to human subjects at a dose of 200 mg once every three weeks, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects at a dose of 1 mg to 20 mg once daily.

[0034] In a different embodiment, in an alternative embodiment, the AUC of famitinib or a pharmaceutically acceptable salt thereof is increased by at least 15% (including 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, and 30% or more), preferably at least 20%, and most preferably at least 25%, compared to the AUC of the same dose of famitinib or a pharmaceutically acceptable salt thereof administered alone.

[0035] In alternative embodiments, in use of the present disclosure, C of famitinib or a pharmaceutically acceptable salt thereof max This refers to the same dose of famitinib or a pharmaceutically acceptable salt administered alone. maxCompared to that, it increases by at least 15% (including 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, and 30% or more), preferably by at least 20%.

[0036] In preferred embodiments of the present disclosure, the PD-1 antibody is administered by injection, such as subcutaneous or intravenous injection, and the PD-1 antibody is formulated into an injectable form before injection. Particularly preferred injectable forms of the PD-1 antibody are an injection solution or a lyophilized powder injection, which comprises the PD-1 antibody, a buffer, a stabilizer, and optionally a surfactant. The buffer may be one or more selected from the group consisting of acetate buffer, citrate buffer, succinate buffer, and phosphate buffer. The stabilizer may be selected from sugars or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, and maltose. The surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, glycerol fatty acid esters, and polyoxyethylene sorbitan fatty acid esters, preferably the polyoxyethylene sorbitan fatty acid ester being polysorbate 20, 40, 60, or 80, most preferably polysorbate 20. The most preferred injectable form of the PD-1 antibody comprises the PD-1 antibody, acetate buffer, trehalose, and polysorbate 20.

[0037] This disclosure provides the above-mentioned anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof for use in the preparation of agents for the treatment of tumors.

[0038] This disclosure provides the above-mentioned anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing side effects. Preferably, the side effects are caused by the anti-PD-1 antibody or by famitinib or a pharmaceutically acceptable salt thereof.

[0039] In alternative embodiments, the side effects described in the Use of the Disclosure are side effects caused by the anti-PD-1 antibody, most preferably reactive capillary hyperplasia.

[0040] In some embodiments, the incidence of reactive capillary hyperplasia is 15% or less (including 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, and 1%), preferably 2.5% or less, compared to the same dose of the anti-PD-1 antibody administered alone (for example, its heavy chain sequence and light chain sequence are shown in SEQ ID NO: 7 and SEQ ID NO: 8, respectively).

[0041] This disclosure provides the above-mentioned anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof, as an agent for reducing the dose of an anti-PD-1 antibody administered alone and / or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone.

[0042] This disclosure provides a method for treating a tumor, comprising administering to a patient the above-mentioned anti-PD-1 antibody and famitinib or a pharmaceutically acceptable salt thereof.

[0043] This disclosure provides a method for reducing the dose of an anti-PD-1 antibody administered alone and / or famitinib or a pharmaceutically acceptable salt thereof administered alone, the method comprising administering the anti-PD-1 antibody to a patient in combination with famitinib or a pharmaceutically acceptable salt thereof.

[0044] In other embodiments, when used in combination with PD-1, the famitinib or a pharmaceutically acceptable salt thereof is administered in amounts ranging from 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, and 95%) of the dose administered alone, preferably 10% to 75%, and more preferably 75%, 50%, 25%, and 12.5%.

[0045] In other embodiments, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, the anti-PD-1 antibody is administered at 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, and 95%) of the dose administered alone, preferably at 10% to 50%.

[0046] The disclosure also provides a method for mitigating adverse events caused by the anti-PD-1 antibody or its antigen-binding fragment, or famitinib or a pharmaceutically acceptable salt thereof, the method comprising administering famitinib or a pharmaceutically acceptable salt thereof to a patient in combination with the anti-PD-1 antibody, wherein the adverse event is preferably an adverse event caused by the anti-PD-1 antibody, most preferably reactive capillary hyperplasia.

[0047] In alternative embodiments, the side effects described herein are preferably side effects caused by the anti-PD-1 antibody, most preferably reactive capillary hyperplasia.

[0048] In some embodiments, the incidence of reactive capillary hyperplasia is 15% or less (including 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11%, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, and 1% or less), preferably 2.5% or less, compared to the same dose of the anti-PD-1 antibody administered alone (for example, the heavy chain sequence and light chain sequence are shown in SEQ ID NO: 7 and SEQ ID NO: 8, respectively).

[0049] This disclosure also provides a pharmaceutical kit, pharmaceutical package, or pharmaceutical combination comprising famitinib or a pharmaceutically acceptable salt thereof and a PD-1 antibody.

[0050] This disclosure provides the use of an anti-PD-L1 antibody or an anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of tumors.

[0051] In an alternative embodiment, based on the patient's body weight, the anti-PD-L1 antibody or its antigen-binding fragment or the anti-CTAL-4 antibody or its antigen-binding fragment is administered to a human subject in doses of 0.1 mg / kg to 10.0 mg / kg, where 0.1 mg / kg to 10.0 mg / kg corresponds to 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.2 mg The possible values ​​are g / kg, 3.4mg / kg, 3.6mg / kg, 3.8mg / kg, 4.0mg / kg, 4.2mg / kg, 4.4mg / kg, 4.6mg / kg, 4.8mg / kg, 5.0mg / kg, 5.2mg / kg, 5.4mg / kg, 5.6mg / kg, 5.8mg / kg, 6.0mg / kg, 6.2mg / kg, 6.4mg / kg, 6.6mg / kg, 6.8mg / kg, 7.0mg / kg, 7.2mg / kg, 7.4mg / kg, 7.6mg / kg, 7.8mg / kg, 8.0mg / kg, 8.2mg / kg, 8.4mg / kg, 8.6mg / kg, 8.8mg / kg, 9.0mg / kg, 9.2mg / kg, 9.4mg / kg, 9.6mg / kg, 9.8mg / kg, and 10.0mg / kg.

[0052] In another alternative embodiment, the anti-PD-L1 antibody or its antigen-binding fragment or the anti-CTAL-4 antibody or its antigen-binding fragment is administered to human subjects in doses of 50 mg to 700 mg, where the doses are 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 1 60mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255 mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg , 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg, 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg, 540mg, 54 The dosage may be 5 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, or 700 mg, preferably between 50 mg and 600 mg, and most preferably 200 mg.

[0053] The anti-PD-L1 antibody or its antigen-binding fragment, or the anti-CTAL-4 antibody or its antigen-binding fragment, described herein are administered at a frequency of once daily, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

[0054] In alternative embodiments, the anti-PD-L1 antibody or its antigen-binding fragment or the anti-CTAL-4 antibody or its antigen-binding fragment described herein is administered to human subjects at a dose of 50 mg to 600 mg, more preferably at a dose of 200 mg, once every 2 to 3 weeks.

[0055] In alternative embodiments, the anti-PD-L1 antibody or its antigen-binding fragment or the anti-CTAL-4 antibody or its antigen-binding fragment is administered to human subjects at a dose of 50 mg to 700 mg once every 2 to 3 weeks, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects at a dose of 0.1 mg to 100 mg once daily.

[0056] In alternative embodiments, the anti-PD-L1 antibody or its antigen-binding fragment or the anti-CTAL-4 antibody or its antigen-binding fragment is administered to human subjects in doses of 50 mg to 600 mg, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects in doses of 1 mg to 20 mg.

[0057] In alternative embodiments, the anti-PD-L1 antibody or its antigen-binding fragment or the anti-CTAL-4 antibody or its antigen-binding fragment is administered to human subjects at a dose of 50 mg to 600 mg once every 2 to 3 weeks, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects at a dose of 1 mg to 20 mg once daily.

[0058] In alternative embodiments, the anti-PD-L1 antibody or its antigen-binding fragment or the anti-CTAL-4 antibody or its antigen-binding fragment is administered to human subjects at a dose of 200 mg, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects at a dose of 1 mg to 20 mg.

[0059] In alternative embodiments, the anti-PD-L1 antibody or its antigen-binding fragment or the anti-CTAL-4 antibody or its antigen-binding fragment is administered to human subjects at a dose of 200 mg once every 2-3 weeks, and the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects at a dose of 1 mg to 20 mg once daily.

[0060] In preferred embodiments of the present disclosure, the PD-L1 antibody or the anti-CTAL-4 antibody is administered by injection, such as subcutaneous or intravenous injection, and the PD-L1 antibody or the anti-CTAL-4 antibody is formulated in an injectable form before injection.

[0061] This disclosure provides the above-mentioned anti-PD-L1 antibody or anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof, as a drug for reducing side effects. Preferably, the side effects are caused by the anti-PD-L1 antibody or the anti-CTAL-4 antibody, or by famitinib or a pharmaceutically acceptable salt thereof.

[0062] This disclosure provides the above-mentioned anti-PD-L1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof, as an agent for reducing the dose of an anti-PD-L1 antibody administered alone and / or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone.

[0063] This disclosure provides the above-mentioned anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof, as an agent for reducing the dose of the anti-CTAL-4 antibody administered alone and / or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone.

[0064] This disclosure provides a method for treating a tumor, comprising administering to a patient the above-mentioned anti-PD-L1 antibody or anti-CTAL-4 antibody and famitinib or a pharmaceutically acceptable salt thereof.

[0065] This disclosure provides a method for reducing the dose of an anti-PD-L1 antibody administered alone and / or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone, the method comprising administering the anti-PD-L1 antibody to a patient in combination with famitinib or a pharmaceutically acceptable salt thereof.

[0066] This disclosure provides a method for reducing the dose of an anti-CTAL-4 antibody administered alone and / or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone, the method comprising administering the anti-CTAL-4 antibody to a patient in combination with famitinib or a pharmaceutically acceptable salt thereof.

[0067] In alternative embodiments, when used in combination with PD-L1, famitinib or a pharmaceutically acceptable salt thereof is administered at 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, and 95%) of the dose administered alone, preferably 10% to 75%, more preferably 75%, 50%, 25%, and 12.5%.

[0068] In alternative embodiments, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, the dose of the anti-PD-L1 antibody is 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, and 95%) of the dose administered alone, preferably 10% to 50%.

[0069] In alternative embodiments, when used in combination with an anti-CTAL-4 antibody, the dose of famitinib or a pharmaceutically acceptable salt thereof is 10% to 100%, preferably 10% to 75%, more preferably 75%, 50%, 25%, or 12.5% ​​of the dose administered alone.

[0070] In alternative embodiments, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, the dose of the anti-CTAL-4 antibody is 10% to 100%, preferably 10% to 50%, of the dose administered alone.

[0071] This disclosure also provides a pharmaceutical kit or pharmaceutical package comprising famitinib or a pharmaceutically acceptable salt thereof and a PD-L1 antibody or an anti-CTAL-4 antibody.

[0072] In use of this disclosure, examples of tumors are selected from, but are not limited to, the following: breast cancer (including triple-negative breast cancer), lung cancer, gastric cancer, intestinal cancer (including rectal cancer, colorectal cancer), kidney cancer (including renal cell carcinoma), liver cancer (including primary liver cancer, hepatocellular carcinoma, cholangiocarcinoma, metastatic liver cancer, secondary liver cancer), melanoma (including metastatic melanoma), non-small cell lung cancer, urothelial carcinoma (including bladder cancer, ureteral cancer, urethral cancer), cervical cancer, ovarian cancer (including recurrent ovarian cancer), endometrial cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, and A. Adenocarcinoma, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (AML), chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryocyte leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, multiple myeloma, plasmacytoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, myelodysplastic syndrome (MDS).

[0073] In alternative embodiments, tumors treated by the use of the present disclosure include non-small cell lung cancer, thyroid cancer, breast cancer (such as triple-negative breast cancer), melanoma (e.g., metastatic melanoma), kidney cancer, urothelial carcinoma (such as bladder cancer, ureteral cancer, urethral cancer), cervical cancer, thyroid cancer, ovarian cancer (e.g., recurrent ovarian cancer), endometrial cancer, colon cancer, or liver cancer.

[0074] In a preferred embodiment, tumor patients have been treated with platinum-based drugs. For example, patients who have experienced treatment failure with platinum-based drugs or are intolerant to platinum-based drugs, or whose disease has progressed or relapsed during or within 6 months after treatment with platinum therapy.

[0075] In some embodiments, the tumor in use of the present disclosure is renal cancer (renal cell carcinoma). Preferably, the tumor is advanced clear cell carcinoma (a mixed tumor such as clear cell carcinoma) diagnosed by histology or cytology.

[0076] In a preferred embodiment, the patient with renal cell carcinoma in use of the present disclosure has previously been treated with interleukin-2 and / or anti-angiogenic targeted agents, and such treatment has failed.

[0077] In some embodiments, the tumor described in the Use of the Disclosure is urothelial carcinoma (such as bladder cancer, ureteral cancer, and urethral cancer). Preferably, the tumor is an incurable urothelial carcinoma diagnosed by histology or cytology (such as renal pelvis cancer, ureteral cancer, bladder cancer, urethral cancer, and mixed-type cancers such as transitional cell carcinoma subtypes by histology).

[0078] In preferred embodiments, patients with urothelial carcinoma in use of this disclosure have been treated with platinum-based drugs. For example, patients who have experienced failure with platinum-based drugs or are intolerant to platinum-based drugs, or whose disease has progressed or relapsed during or after treatment with platinum therapy.

[0079] In some embodiments, the tumor in use of the present disclosure is cervical cancer. Preferably, the tumor is advanced cervical squamous cell carcinoma diagnosed by histology or cytology.

[0080] In a preferred embodiment, treatment of cervical cancer in a patient using one or more previous systems has failed.

[0081] In other embodiments, the tumor in use of the present disclosure is ovarian cancer, preferably recurrent ovarian cancer, and moreover, recurrent ovarian epithelial carcinoma, fallopian tube cancer, or primary peritoneal cancer diagnosed by histopathology.

[0082] In a preferred embodiment, patients with recurrent ovarian cancer have been treated with platinum-based drugs. For example, patients who have experienced failure with platinum-based drugs or are intolerant to platinum-based drugs, or whose disease has progressed or relapsed during or within 6 months after platinum-based therapy (after completing 4 or more courses of treatment).

[0083] In some other embodiments, the tumor in use of the present disclosure is endometrial cancer, preferably endometrial cancer diagnosed by histopathology. In preferred embodiments, endometrial cancer patients have been treated with platinum-based drugs. For example, patients who have experienced failure or intolerance to platinum-based drugs, or patients whose disease has progressed or recurred during or within 6 months after treatment with platinum therapy (after completing 4 or more courses of treatment).

[0084] This disclosure also provides the use of famitinib or a pharmaceutically acceptable salt thereof in the preparation of agents for the treatment of disorders that benefit from inhibition of TYRO3 and / or AXL and / or MER.

[0085] This disclosure also provides a method for treating a disorder that benefits from inhibition of TYRO3 and / or AXL and / or MER with famitinib or a pharmaceutically acceptable salt thereof, the method comprising administering the famitinib or a pharmaceutically acceptable salt thereof to a patient. Furthermore, in alternative embodiments, famitinib or a pharmaceutically acceptable salt thereof may be used alone or in combination.

[0086] Furthermore, in alternative embodiments, famitinib or a pharmaceutically acceptable salt thereof may be administered alone or in combination.

[0087] Examples of disorders that would benefit from inhibition of TYRO3 (Tyro3 tyrosine kinase receptor inhibitor) and / or AXL (Axl tyrosine kinase receptor inhibitor) and / or MER (Mer tyrosine kinase receptor inhibitor) as described in this disclosure include, but are not limited to, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (AML), chronic neutrophil leukemia Lymphoblastic leukemia, acute lymphoblastic T-cell leukemia, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryocyte leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, multiple myeloma, plasmacytoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, myelodysplastic syndrome (MDS), thrombotic disorders (myocardial infarction, ischemic stroke, peripheral vascular disease, venous thromboembolism, etc.).

[0088] The pharmaceutically acceptable salts of famitinib in this disclosure are, but are not limited to, selected from methanesulfonate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate, with malate being preferred.

[0089] In some embodiments of this disclosure, a pharmaceutically acceptable salt of famitinib is administered to a human subject in a dose calculated based on the form of its free base.

[0090] Unless otherwise stated, the terms used in this disclosure are defined as follows:

[0091] In this disclosure, “AUC” refers to the area enclosed by the curve of pharmacokinetic blood drug concentration over time. This parameter reflects the in vivo exposure profile of a drug and is an important indicator for evaluating the degree of drug absorption. Since blood drug concentration in pharmacokinetic studies can only be observed up to a specific time t, AUC can be expressed in two ways: AUC(0-t) and AUC(0-∞). Here, AUC(0-t) is derived from the trapezoidal area, and AUC(0-∞) is calculated by the following equation: AUC(0-∞) = AUC(0-t) + endpoint concentration / endpoint removal rate. The AUC referred to in this application refers to the mean AUC0-24 of patients who reach steady state after a single or multiple doses, preferably the mean AUC0-24 of patients who reach steady state after multiple doses (i.e., AUC ss ).

[0092] In this disclosure, “combination” refers to a mode of administration; this means that at least one dose of famitinib or a pharmaceutically acceptable salt and at least one dose of an anti-PD-1 antibody or its antigen-binding fragment are administered within a period of time in which both substances exhibit pharmacological effects. This period may be within a single administration cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or 24 hours. Famitinib or a pharmaceutically acceptable salt thereof may be administered concurrently or consecutively with the anti-PD-1 antibody or its antigen-binding fragment. This period may include treatments in which famitinib or a pharmaceutically acceptable salt is administered with the anti-PD-1 antibody or its antigen-binding fragment via the same or different route of administration. The combination modes of administration in this disclosure are selected from the group consisting of concurrent administration, concurrent administration of separate formulations, and consecutive administration of separate formulations. Overall survival (OS) refers to the period from a random time to death from any cause. For subjects still alive at the last follow-up, the time of the last follow-up is recorded as censored data for OS. For subjects that fail to be followed up on, the last time the subject was confirmed to be alive is recorded as censored data for the OS. The OS with censored data is defined as the period from the time of random grouping to the time the data is censored.

[0093] Objective response rate (ORR) refers to the percentage of patients whose tumors have shrunk to a specific level and been maintained for a specific period, including cases of complete response (CR) and partial response (PR). Objective tumor remission was assessed using the Solid Tumor Response Assessment Criteria (RECIST 1.1 criteria). Subjects must have measurable tumor lesions at baseline. In the efficacy assessment criteria, efficacy can be classified into complete remission (CR), partial remission (PR), stable disease (SD), and disease progression (PD) according to the RECIST 1.1 criteria.

[0094] Disease control rate (DCR) refers to the proportion of patients who achieved complete remission, partial remission, or stable disease (8 weeks or more) out of the total number of patients for whom treatment effectiveness can be evaluated.

[0095] Complete remission (CR): All target lesions must disappear, and the shorter diameter of all pathological lymph nodes (including target and non-target nodules) must be reduced to less than 10 mm (<10 mm).

[0096] Partial remission (PR): The total diameter of the target lesions decreases by at least 30% from the baseline level.

[0097] Disease progression (PD): The sum of the diameters of all target lesions increases by at least 20% compared to the minimum sum of diameters measured throughout the entire experimental study (as the baseline value) (if the sum of the diameters of all target lesions measured at baseline is the minimum value, that value is used as the baseline value); in addition, the absolute value of the sum of diameters must increase by at least 5 mm (the occurrence of one or more new lesions is also considered disease progression).

[0098] Stable disease (SD): A state between PR and PD, where the degree of reduction of target lesions does not reach PR, but the degree of increase does not reach PD levels. The minimum sum of diameters can be used as a reference value during the investigation.

[0099] "mpk": mg / kg.

[0100] The reagents, biological samples, or activators used in this disclosure are commercially available. For example, 4-5 week old human PD-1 transgenic mice were purchased from Cephrim Biosciences, Inc. UK. Detailed description of the invention

[0101] The following examples are provided to further illustrate this disclosure, but are not intended to limit the scope of the disclosure. [Examples]

[0102] Example 1: Using human PD-1 transgenic mice as test animals, the efficiency of co-administration of PD-1 antibody and famitinib was evaluated in human PD-1 transgenic mice transplanted with tumor C57 of mouse colon cancer cells MC-38 (PD-L1).

[0103] Compound A: A PD-1 antibody having the heavy chain and light chain sequences shown in SEQ ID NOs: 7 and 8 of this disclosure. Formulated at 20 mg / ml for use, 200 mg / vial.

[0104] Compound B: Famitinib malate prepared according to the method of patent application WO2007085188.

[0105] Test protocol:

[0106] On the 7th day, MC38 cells (5 × 10 5 The drug was subcutaneously inoculated into the right flank of 40 human PD-1 transgenic mice (including males and females). The average tumor volume of the mice was approximately 100 mm². 3 When the target was reached, 32 mice were selected and randomly divided into 4 groups, with 8 mice in each group. After grouping, the mice were given vehicle control, intraperitoneal injection of compound A, forced oral administration of the compound, and simultaneous administration of both, according to the protocol. Tumor volume was measured twice a week, mouse body weight was measured, and data were recorded.

[0107] [Table 2]

[0108] The results of this experiment demonstrate that the combination of PD-1 antibody (3mpk) and famitinib malate (10mpk) is more effective than PD-1 antibody or famitinib malate alone. The mice in each group had normal body weight, indicating that the drugs did not cause any apparent side effects.

[0109] Example 2: Effect of famitinib malate on the in vitro activity of TYRO3, AXL, and MER kinases.

[0110] (1) Experimental procedure for IC50Profile (trademark)

[0111] [Table 3]

[0112] Appropriate amounts of kinase and peptide substrates were separately mixed with different concentrations of famitinib malate (1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1 μM, 3 μM, 10 μM) and incubated at room temperature for 60 minutes. Magnesium acetate and [γ-33P]-ATP were added to initiate the kinase catalytic reaction, which was carried out at room temperature for 40 minutes. After the reaction was complete, a 3% phosphoric acid solution was added to stop the reaction. 10 μL of the reaction mixture was taken and added to a P30 filter membrane for filtration. The membrane was washed three times with 75 mM phosphate buffer and once with methanol to remove free [γ-33P]-ATP. The proteins were immobilized and the membrane was dried. The amount of peptide substrate was determined by counting the amount of 33P using a liquid scintillation analyzer.

[0113] (2) Test results

[0114] Table 1 shows the IC50 values ​​obtained from fitting using concentration-inhibition curves.

[0115] [Table 4]

[0116] Example 3: 1. Antibodies and compounds to be tested Compound A: Its heavy and light chain sequences are as shown in Sequence ID No. 7 and Sequence ID No. 8 of this disclosure. Formulated at 20 mg / ml for use, 200 mg / vial; Compound B: Famitinib malate prepared according to the method of patent application WO2007085188.

[0117] 2. Inclusion criteria: Patients with advanced renal cancer, urothelial carcinoma, cervical cancer, recurrent ovarian cancer, and endometrial cancer.

[0118] In the case of renal cell carcinoma: Advanced clear cell carcinoma of the renal cell line diagnosed by histology or cytology (mixed tumors, e.g., clear cell carcinoma of the renal cell line as the primary component, can be included in the group); the primary tumor was surgically resected and treated with interleukin-2 and / or anti-angiogenic targeted drugs, but treatment was unsuccessful.

[0119] (2) In the case of urothelial carcinoma: Incurable urothelial carcinoma diagnosed by histology or cytology, including renal pelvis cancer, urinary tract cancer, bladder cancer, and urethral cancer. In the case of mixed-type cancer, the dominant histological type must be a subtype of transitional cell carcinoma; the disease has progressed or recurred after treatment with a previous platinum-based regimen, and there have been two or fewer previous systemic treatment regimens.

[0120] (3) In the case of cervical cancer: Advanced squamous cell carcinoma of the cervix diagnosed by histology or cytology; previously treated with one or more lines of systemic therapy but unsuccessful.

[0121] (4) In the case of recurrent ovarian cancer: Recurrent ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer diagnosed by histopathology and previously treated with a platinum-based regimen, in which the disease progressed or recurred during treatment or within 6 months after treatment with platinum-based therapy (completion of 4 or more courses of treatment).

[0122] (5) In the case of endometrial cancer: Endometrial cancer diagnosed by histopathology and previously treated with at least a platinum-based regimen, wherein the disease has progressed or recurred after or during treatment.

[0123] 3. Dosage regimen: Compound A: Intravenous injection, 200 mg, once every 3 weeks, 1 cycle every 3 weeks; Compound B: 20 ​​mg or 15 mg, orally, once daily.

[0124] 4. Safety Data No drug-related deaths were observed when compound A was administered in combination with compound B. The incidence of grade 3 or higher adverse events was 60%, but all were controllable. Toxic reactions were mainly associated with the administration of compound B, which were effectively controlled by adjusting the regimen or discontinuing the administration of compound B. The incidence of immune-related adverse events determined by the researchers was low (13.8%) and consisted of virtually low-grade adverse events. Only one case was grade 3 acute enteritis, and the others were grade 2 or lower adverse events. Furthermore, when the two drugs were administered concurrently, only two subjects (2.5%) developed reactive cutaneous capillary hyperplasia, and in the treatment of solid tumors, the incidence was significantly lower than that of compound A alone (54.3%), suggesting that the side effects of compound A can be mitigated by concurrent administration with compound B. The overall incidence of serious adverse events was not high, and only two subjects (2.5%) discontinued treatment due to serious adverse events (SAEs). Therefore, simultaneous administration of compound A and compound B for the treatment of urinary tract and gynecological tumors is safe.

[0125] 5. Effectiveness Of the 80 participants, 75 underwent at least one efficacy assessment, while 5 participants could not be assessed because they withdrew or died before the first assessment.

[0126] Of the 25 patients in the renal cancer cohort, efficacy was evaluated in 23 patients. Twelve patients showed partial remission (PR), nine showed stable disease (SD), and two showed disease progression (PD). The objective remission rate (ORR) was 52.2%, and the disease control rate (DCR) was 91.3%. The ORR was superior to that of compound B 25 mg alone (four times daily) for the treatment of renal cancer (36%).

[0127] Of the 10 patients in the urothelial carcinoma cohort, efficacy was evaluated in 9 patients. Three patients showed partial remission (PR), three showed stable disease (SD), and three showed disease progression (PD). The objective remission rate (ORR) was 33.3%, and the disease control rate (DCR) was 66.7%.

[0128] The efficacy of the treatment was evaluated in 24 patients from an ovarian cancer cohort. Eight patients showed partial remission (PR), 10 showed stable disease (SD), and 7 showed disease progression (PD). The objective remission rate (ORR) was 33.3%, and the disease control rate (DCR) was 75%.

[0129] Of the five subjects in the endometrial cancer cohort, efficacy was evaluated in four. Two subjects showed partial remission (PR), one showed stable disease (SD), and one showed disease progression (PD). The objective remission rate (ORR) was 50%, and the disease control rate (DCR) was 75%.

[0130] Of the 16 patients in the cervical cancer cohort, 15 were evaluated for efficacy. Eight patients showed partial remission (PR), five showed stable disease (SD), and two showed disease progression (PD). The objective remission rate (ORR) was 53.3%, and the disease control rate (DCR) was 86.7%.

[0131] Overall, of the 80 subjects, 75 underwent at least one efficacy evaluation. 33 subjects showed partial remission (PR), 27 showed stable disease (SD), and 15 showed disease progression (PD). The objective remission rate (ORR) was 44.0%, and the disease control rate (DCR) was 80.0%.

[0132] 6. Pharmacokinetics Of the 12 subjects who participated in the pharmacokinetic study, PK blood samples were collected from 9 subjects.

[0133] The results showed that the exposure to compound B (when administered simultaneously with compound A) increased compared to the exposure to compound B when administered alone, and the PK parameter (C) of compound B increased. ss ,min,C ss , max, AUC ss (including) showed better PK parameters than when administered alone.

[0134] [Table 5]

[0135] 7. Summary When compound A and compound B are administered simultaneously, tolerance is good, and toxicity is controllable and tolerable. In addition, simultaneous administration can effectively reduce the occurrence of reactive capillary hyperplasia (a common side effect caused by compound A) and lead to favorable therapeutic effects.

Claims

1. The use of an anti-PD-1 antibody or its antigen-binding fragment in combination with famitinib or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of tumors, The light chain variable region of the PD-1 antibody includes LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively, and the heavy chain variable region of the PD-1 antibody includes HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively. The tumors used are selected from the group consisting of lung cancer, kidney cancer, urothelial carcinoma, cervical cancer, ovarian cancer, endometrial cancer, and non-small cell lung cancer.

2. The use according to claim 1, wherein the PD-1 antibody is a humanized antibody.

3. The use according to claim 2, wherein the humanized antibody comprises the light chain variable region shown in SEQ ID NO: 10 or a variant thereof, wherein the variant has an A43S amino acid change in the light chain variable region of SEQ ID NO: 10; and the humanized antibody comprises the heavy chain variable region shown in SEQ ID NO: 9 or a variant thereof, wherein the variant has a G44R amino acid change in the heavy chain variable region of SEQ ID NO:

9.

4. The use according to claim 2, wherein the humanized antibody comprises a light chain or a variant thereof shown in SEQ ID NO: 8, the variant having an A43S amino acid change in the variable region of the light chain; and the humanized antibody comprises a heavy chain or a variant thereof shown in SEQ ID NO: 7, the variant having a G44R amino acid change in the variable region of the heavy chain.

5. The use according to claim 4, wherein the humanized antibody comprises the light chain shown in SEQ ID NO: 8 and the heavy chain shown in SEQ ID NO:

7.

6. The use according to any one of claims 1 to 5, wherein the AUC of famitinib or a pharmaceutically acceptable salt thereof is increased by at least 15% compared to the AUC of the same dose of famitinib or a pharmaceutically acceptable salt thereof administered alone.

7. The use according to any one of claims 1 to 5, wherein the AUC of famitinib or a pharmaceutically acceptable salt thereof is increased by at least 20% compared to the AUC of the same dose of famitinib or a pharmaceutically acceptable salt thereof administered alone.

8. The use according to any one of claims 1 to 5, wherein the AUC of famitinib or a pharmaceutically acceptable salt thereof is increased by at least 25% compared to the AUC of the same dose of famitinib or a pharmaceutically acceptable salt thereof administered alone.

9. The C of the famitinib or a pharmaceutically acceptable salt thereof ｍａｘ This refers to the same dose of famitinib or a pharmaceutically acceptable salt administered alone. ｍａｘ The use according to any one of claims 1 to 5, which increases by at least 15% compared to the use according to any one of claims 1 to 5.

10. The C of the famitinib or a pharmaceutically acceptable salt thereof ｍａｘ This refers to the same dose of famitinib or a pharmaceutically acceptable salt administered alone. ｍａｘ The use according to any one of claims 1 to 5, which increases by at least 20% compared to the use according to any one of claims 1 to 5.

11. The use according to claim 1, wherein the PD-1 antibody or its antigen-binding fragment is administered to a human subject in a dose of 10 mg to 300 mg once every two to three weeks.

12. The use according to claim 1, wherein the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects once daily in a dose of 0.1 mg to 100 mg.

13. The use according to claim 1, wherein the famitinib or a pharmaceutically acceptable salt thereof is administered to human subjects once daily in a dose of 1 mg to 20 mg.

14. The use according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt of famitinib is malate.

15. The use according to claim 1, wherein the incidence of reactive capillary hyperplasia is 15% or less compared to the incidence of reactive capillary hyperplasia caused by the same dose of the anti-PD-1 antibody according to any one of claims 1 to 5 administered alone.

16. A pharmaceutical package comprising famitinib or a pharmaceutically acceptable salt thereof and a PD-1 antibody or an antigen-binding fragment thereof according to any one of claims 1 to 5.

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