Combination of proteasome inhibitors and anti-PD-1 antibodies

Abstract

This application relates to the field of pharmaceutical technology and relates to drug combinations of proteasome inhibitors and anti-PD-1 antibodies. Specifically, it relates to drug combinations of the disclosed Formula I' compound, its prodrug, or pharmaceutically acceptable salt, and an anti-PD-1 antibody or antigen-binding fragment thereof, and their use in preventing or treating solid tumors. #imgabs0#

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority and benefits of the following Chinese patent application filed with the State Intellectual Property Office of China, the contents of which are incorporated herein by reference in their entirety: Chinese Patent Application No. 202210378911.2 filed on April 12, 2022. Technical Field

[0003] The present disclosure belongs to the field of pharmaceutical technology and relates to a pharmaceutical combination of a proteasome inhibitor and an anti-PD-1 antibody. Specifically, the present disclosure relates to a pharmaceutical combination of a compound of Formula I', a prodrug thereof, or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody or an antigen-binding fragment thereof, and their use in preventing or treating solid tumors. Background Art

[0004] The ubiquitin-proteasome pathway is a key pathway for intracellular protein degradation. Proteins are ubiquitinated through interactions with ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases. Ubiquitinated proteins are then recognized and degraded by the 26S proteasome. The 26S proteasome consists of two parts: the 20S core particle and the 19S regulatory particle. Tumor cells, due to their proliferation needs, are more sensitive to protein homeostasis. Proteasome inhibitors inhibit the ubiquitin-proteasome pathway, leading to the accumulation of polyubiquitinated proteins and affecting related signaling pathways, ultimately inducing tumor cell apoptosis.

[0005] Compounds such as the compound of formula I disclosed in WO2018157820A1 and compounds such as the compound of formula II disclosed in WO2020025037A1 are proteasome inhibitors.

[0006] PD-1 (programmed death-1) is a key immune checkpoint receptor expressed by activated T lymphocytes and B lymphocytes, and its ligands include at least PD-L1 and PD-L2. PD-L1 (Programmed death-ligand 1), also known as CD274 or B7-H1, is a ligand of PD-1. The binding of PD-1 and PD-L1 mediates co-inhibitory signals of T cell activation, inhibits the killing function of T cells, and negatively regulates the human immune response. Chinese patent document CN106977602A discloses an anti-PD-1 monoclonal antibody 14C12H1L1, which can very effectively block the binding of PD1 and PDL1 and show good anti-tumor activity.

[0007] The biggest challenge encountered in the process of tumor immunotherapy is the poor efficacy caused by tumor immune tolerance and escape. The combined use of small molecule anti-tumor compounds and anti-PD-1 / PD-L1 antibodies to try to break the body's established immune tolerance to tumor cells has important theoretical significance and application value. Summary of the Invention

[0008] In one aspect, the present disclosure provides a pharmaceutical combination comprising a compound of formula I', an ester thereof, or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0009] in,

[0010] Ring A is selected from phenyl or 5-10 membered heteroaryl;

[0011] Every R 1 Independently selected from halogen, CN, OH, NH2, C 1-6 Alkyl or C 1-6 heteroalkyl, wherein the C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with one or more groups selected from halogen, OH or NH2;

[0012] n is selected from 0, 1, 2, 3, 4 or 5;

[0013] R 2 and R 3 are independently selected from H or C 1-6 alkyl.

[0014] In some embodiments, Ring A is selected from phenyl or 5-6 membered heteroaryl. In some embodiments, Ring A is selected from phenyl or pyridinyl.

[0015] In some embodiments, each R 1 Independently selected from halogen, CN, OH, NH2, C 1-3 Alkyl or C 1-3 In some embodiments, each R 1 are independently selected from fluorine or CN.

[0016] In some embodiments, n is selected from 1 or 2.

[0017] In some embodiments, R 2 and R 3 are independently selected from H.

[0018] In some embodiments, the compound of formula I', its ester or pharmaceutically acceptable salt thereof is selected from the compound of formula I, formula I-1, formula I-2 or formula I-3, its ester or pharmaceutically acceptable salt thereof

[0019]

[0020] In another aspect, the present disclosure provides a kit comprising a drug combination, specifically comprising 1) a compound of formula I', an ester thereof, or a pharmaceutically acceptable salt thereof; 2) an anti-PD-1 antibody or an antigen-binding fragment thereof,

[0021] Also included are instructions for use of the compound of formula I', its ester or pharmaceutically acceptable salt and the anti-PD-1 antibody or antigen-binding fragment thereof.

[0022] In some embodiments, the ester of the compound of Formula I' is a prodrug form of the compound of Formula I'.

[0023] In some embodiments, the ester of the compound of formula I' is a malate of the compound of formula I'. In some embodiments, the ratio of the number of molecules of the compound of formula I' to malic acid in the malate of the compound of formula I' is selected from 1:1.

[0024] In some embodiments, the malate ester of the compound of Formula I' is a prodrug form of the compound of Formula I'.

[0025] In some embodiments, the ester structure of the compound of formula I' or the malate structure of the compound of formula I' is selected from the compounds of formula II, formula II-1, formula II-2 or formula II-3

[0026]

[0027] In one aspect, the present disclosure provides a pharmaceutical combination comprising a compound of Formula I (or Formulas I-1 to I-3), an ester thereof, or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0028]

[0029] In another aspect, the present disclosure provides a kit comprising a drug combination, specifically comprising 1) a compound of Formula I (or Formulas I-1 to I-3), an ester thereof, or a pharmaceutically acceptable salt thereof; 2) an anti-PD-1 antibody or an antigen-binding fragment thereof,

[0030] It also includes: instructions for use of the compound of formula I (or formulas I-1 to I-3), its ester or pharmaceutically acceptable salt and the anti-PD-1 antibody or its antigen-binding fragment,

[0031]

[0032] In some embodiments, the ester of the compound of Formula I (or Formula I-1 to I-3) is a prodrug form of the compound of Formula I (or Formula I-1 to I-3).

[0033] In some embodiments, the ester of the compound of Formula I (or Formulas I-1 to I-3) is a malic acid ester of the compound of Formula I (or Formulas I-1 to I-3). In some embodiments, the ratio of the number of molecules of the compound of Formula I (or Formulas I-1 to I-3) to malic acid in the ester of the compound of Formula I (or Formulas I-1 to I-3) is selected from 1:1.

[0034] In some embodiments, the malate ester of the compound of Formula I (or Formula I-1 to I-3) is a prodrug form of the compound of Formula I (or Formula I-1 to I-3).

[0035] In some embodiments, the ester of the compound of formula I is a compound of formula II

[0036]

[0037] In some embodiments, the ester of the compound of formula I-1 is a compound of formula II-1

[0038]

[0039] In some embodiments, the ester of the compound of formula I-2 is a compound of formula II-2

[0040]

[0041] In some embodiments, the ester of the compound of formula I-3 is a compound of formula II-3

[0042]

[0043] In another aspect, the present disclosure provides a pharmaceutical combination comprising a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0044] On the other hand, the present disclosure provides a kit comprising 1) a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof; 2) an anti-PD-1 antibody or an antigen-binding fragment thereof, and 3) instructions for use of the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof.

[0045] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises light chain complementary determining regions LCDR1, LCDR2 and LCDR3 and heavy chain complementary determining regions HCDR1, HCDR2 and HCDR3, wherein the LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, and the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6.

[0046] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises light chain complementary determining regions LCDR1, LCDR2 and LCDR3 and heavy chain complementary determining regions HCDR1, HCDR2 and HCDR3, wherein the light chain complementary determining regions LCDR1, LCDR2 and LCDR3 consist of the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the heavy chain complementary determining regions HCDR1, HCDR2 and HCDR3 consist of the amino acid sequences shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

[0047] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence that is 85% or more (including 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region having an amino acid sequence that is 85% or more (including 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 8.

[0048] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 7 and a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 8.

[0049] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence that is 85% or more (including 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 9 and a heavy chain having an amino acid sequence that is 85% or more (including 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence of SEQ ID NO: 10.

[0050] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain with an amino acid sequence as shown in SEQ ID NO: 9 and a heavy chain with an amino acid sequence as shown in SEQ ID NO: 10.

[0051] In some embodiments, the anti-PD-1 antibody is 14C12H1L1.

[0052] In other embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, toripalimab (JS-001), sintilimab (IBI308), camrelizumab, tislelizumab (BGB-A317), balstilimab, genoluzumab (GB226), LZM009, HLX10, AK103 (HX008), CS1003, SCT-I10A, F520, SG001 or sepalizumab (GLS-010).

[0053] In some embodiments, the drug combination comprises: a compound of formula I (or formulas I-1 to I-3), an ester thereof (e.g., a compound of formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.

[0054] In some embodiments, the drug combination comprises: a compound of Formula I (or Formulas I-1 to I-3) or a malate thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.

[0055] In some embodiments, the pharmaceutical combination comprises: a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.

[0056] In some embodiments, the pharmaceutical combination comprises: a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.

[0057] In some embodiments, the pharmaceutical combination comprises 0.5 mg to 8.5 mg of a compound of formula I (or formulas I-1 to I-3), an ester thereof (eg, a compound of formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof.

[0058] In some embodiments, the drug combination comprises 0.5 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg or a range formed by any of the above values ​​of a compound of formula I (or formula I-1 to I-3), an ester thereof (e.g., a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the pharmaceutical combination comprises 0.8 mg-8.0 mg of a compound of formula I (or formulas I-1 to I-3), an ester thereof (eg, a compound of formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the drug combination comprises 0.8 mg, 1.2 mg, 1.6 mg, 2.0 mg, 2.4 mg, 2.8 mg, 3.2 mg, 3.6 mg, 4.0 mg, 4.4 mg, 4.8 mg, 5.2 mg, 5.6 mg, 6.0 mg, 6.4 mg, 6.8 mg, 7.2 mg, 7.6 mg, 8.0 mg or a range formed by any of the above values ​​of a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, the pharmaceutical combination comprises a compound of Formula I (or Formula I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 4.0 mg to 8 mg. In some embodiments, the pharmaceutical combination comprises a compound of Formula I (or Formula I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg to 6 mg. In some embodiments, the pharmaceutical combination comprises a compound of Formula I (or Formula I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 4.0 mg to 5.6 mg. In some embodiments, the pharmaceutical combination comprises a compound of Formula I (or Formula I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 4.0 mg, 4.8 mg or 5.6 mg.

[0062] In some embodiments, the pharmaceutical combination comprises 1.0 mg to 10 mg of the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II (or II-1 to II-3)).

[0063] In some embodiments, the drug combination comprises 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg or a range formed by any of the above values ​​of a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II (or II-1 to II-3)).

[0064] In some embodiments, the pharmaceutical combination comprises 5.0 mg to 7.0 mg of a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 5.0 mg, 6.0 mg, or 7.0 mg of a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical combination comprises 6.0 mg of a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the pharmaceutical combination comprises 1.0 mg to 10 mg of the compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II).

[0066] In some embodiments, the pharmaceutical composition comprises about 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.1 mg, 6.2 mg, 6.3 mg, 6.4 mg, 6.5 mg, 7.0 mg, 7.1 mg, 7.2 mg, 7.3 mg, 7.4 mg, 7.5 mg, 8.0 mg, 8.5 mg, 8.6 mg, 8.7 mg, 8.8 mg, 8.9 mg, 9.0 mg, 9.5 mg, 10 mg or a range formed by any of the above values ​​(based on the weight of the compound of Formula II) or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the pharmaceutical combination comprises an amount of about 5.5 mg to 9.5 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II). In some embodiments, the pharmaceutical combination comprises an amount of about 6.0 mg to 9.0 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II). In some embodiments, the pharmaceutical combination comprises an amount of about 6.3 mg, 7.5 mg, or 8.8 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II). In some embodiments, the pharmaceutical combination comprises an amount of about 7.5 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II).

[0068] In some embodiments, the pharmaceutical composition comprises about 10 mg to about 1000 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

[0069] In some embodiments, the pharmaceutical composition comprises about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or a range of any of the foregoing values ​​of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0070] In some embodiments, the pharmaceutical composition comprises approximately 50-350 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0071] In some embodiments, the pharmaceutical composition comprises approximately 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0072] In some embodiments, the drug combination disclosed herein comprises: 4.0 mg-5.6 mg of a compound of Formula I (or Formulas I-1 to I-3) or a malate thereof, or a pharmaceutically acceptable salt thereof; and 50-350 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0073] In some embodiments, the drug combination disclosed herein comprises: 5.0 mg-7.0 mg (e.g., 6 mg) of a compound of formula II (or II-1 to II-3); and 50 mg-350 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0074] In some embodiments, the pharmaceutical combination disclosed herein comprises: 5.0 mg, 6.0 mg, or 7.0 mg of a compound of Formula II (or II-1 to II-3); and 100 mg or 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0075] In some embodiments, the drug combination described in the present disclosure comprises a compound of formula I (or formulas I-1 to I-3), an ester thereof (e.g., a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof in a weight ratio selected from 4 mg:100 mg, 4.4 mg:100 mg, 4.8 mg:100 mg, 5.2 mg:100 mg, 5.6 mg:100 mg, 6.0 mg:100 mg, 4 mg:200 mg, 4.4 mg:200 mg, 4.8 mg:200 mg, 5.2 mg:200 mg, 5.6 mg:200 mg, 6.0 mg:200 mg or a range formed by any of the above values.

[0076] In some embodiments, the pharmaceutical combination of the present disclosure comprises a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II (or II-1 to II-3)) and an anti-PD-1 antibody or an antigen-binding fragment thereof in an (approximate) weight ratio selected from 5 mg: 100 mg, 5.5 mg: 100 mg, 6 mg: 100 mg, 6.1 mg: 100 mg, 6.2 mg: 100 mg, 6.3 mg: 100 mg, 6.4 mg: 100 mg, 6.5 mg: 100 mg, 7 mg: 100 mg, 7.1 mg: 100 mg, 7.2 mg: 100 mg, 7.3 mg: 100 mg, 7.4 mg: 100 mg, 7.5 mg: 100 mg, 7.6 mg: 100 mg, 7.7 mg: 100 mg, 7.8 mg: 100 mg, 7.9 mg: 100 mg, 7.1 mg: 100 mg, 7. g: 100mg, 7.2mg: 100mg, 7.3mg: 100mg, 7.4mg: 100mg, 7.5mg: 100mg, 7.6mg: 100mg, 7.7mg: 100mg, 7.8mg: 100mg, 7.9mg: 100m g, 8.0mg: 100mg, 8.5mg: 100mg, 8.6mg: 100mg, 8.7mg: 100mg, 8.8mg: 100mg, 8.9mg: 100mg, 9.0mg: 100mg, 9.1mg: 100mg, 9.2m g: 100mg, 9.3mg: 100mg, 9.4mg: 100mg, 9.5mg: 100mg, 5mg: 200mg, 5.5mg: 200mg, 6mg: 200mg, 6.1mg: 200mg, 6.2mg: 200mg, 6. 3mg: 200mg, 6.4mg: 200mg, 6.5mg: 200mg, 7mg: 200mg, 7.1mg: 200mg, 7.2mg: 200mg, 7.3mg: 200mg, 7.4mg: 200mg, 7.5mg: 200m g, 7.6 mg: 200 mg, 7.7 mg: 200 mg, 7.8 mg: 200 mg, 7.9 mg: 200 mg, 8.0 mg: 200 mg, 8.5 mg: 200 mg, 8.6 mg: 200 mg, 8.7 mg: 200 mg, 8.8 mg: 200 mg, 8.9 mg: 200 mg, 9.0 mg: 200 mg, 9.1 mg: 200 mg, 9.2 mg: 200 mg, 9.3 mg: 200 mg, 9.4 mg: 200 mg, 9.5 mg: 200 mg, or a range formed by any of these values.

[0077] In some embodiments, the pharmaceutical combination is a fixed combination or a non-fixed combination.

[0078] In some embodiments, the pharmaceutical combination is a fixed combination.In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

[0079] In some embodiments, the compound of Formula I (or Formulas I-1 to I-3), its ester (e.g., a compound of Formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof and the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) in the fixed combination are present in the same pharmaceutical composition.

[0080] In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) in the fixed combination are present in the same pharmaceutical composition.

[0081] In some embodiments, the pharmaceutical combination is a non-fixed combination.

[0082] In some embodiments, the compound of Formula I (or Formulas I-1 to I-3), its ester (e.g., a compound of Formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof and the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) in the non-fixed combination are each in the form of a pharmaceutical composition.

[0083] In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) in the non-fixed combination are each in the form of a pharmaceutical composition.

[0084] In some embodiments, the compound of Formula I (or Formulas I-1 to I-3), its ester (e.g., compound of Formula II (or II-1 to II-3)) or pharmaceutically acceptable salt thereof, and the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) in the non-fixed combination are each in the form of a pharmaceutical composition, and the pharmaceutical composition of the compound of Formula I (or Formulas I-1 to I-3), its ester (e.g., compound of Formula II (or II-1 to II-3)) or pharmaceutically acceptable salt thereof and the pharmaceutical composition of the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) are present or not in the same medicine bag.

[0085] The present disclosure also aims to provide at least one pharmaceutical pack comprising individually packaged pharmaceutical compositions in separate containers, wherein one container comprises a pharmaceutical composition of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof, and a second container comprises a pharmaceutical composition of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof).

[0086] In some embodiments, the pharmaceutical composition of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is selected from a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition of a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is selected from a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is selected from a tablet or a capsule.

[0087] In some embodiments, the pharmaceutical composition of an anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is selected from a liquid pharmaceutical composition. In some embodiments, the liquid pharmaceutical composition is selected from an injectable solution.

[0088] In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof can be administered once a day, twice 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, twice every three weeks, or three times every three weeks.

[0089] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) can be administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, or once every three weeks.

[0090] In some embodiments, the drug combination is administered every 14 days (2 weeks), 21 days (3 weeks) or 28 days (4 weeks) as a treatment cycle. In some embodiments, the drug combination is administered every 21 days (3 weeks) as a treatment cycle.

[0091] In some embodiments, the drug combination is administered once, twice, three times, or four times per treatment cycle with a compound of Formula I (or Formula I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I (or Formula I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is administered two or three times per treatment cycle. In some embodiments, the compound of Formula I (or Formula I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is administered twice per treatment cycle. In some embodiments, the compound of Formula I (or Formula I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is administered once on day 1 and once on day 8 of each treatment cycle.

[0092] In some embodiments, the drug combination is administered once, twice, three times, or four times per treatment cycle of a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered two or three times per treatment cycle. In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered twice per treatment cycle. In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8 of each treatment cycle.

[0093] In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt can be taken orally in the morning on an empty stomach; alternatively, at least 1 hour before a meal or at least 2 hours after a meal.

[0094] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) is administered once, twice, or three times per treatment cycle. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) is administered once per treatment cycle. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) is administered intravenously on day 1 (D1) of each treatment cycle. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) is administered once per treatment cycle, and the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) is administered intravenously on day 1 (D1) of each treatment cycle, with an intravenous infusion time of 60±10 min. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) is administered intravenously once per treatment cycle on day 1 (D1) of each treatment cycle, with an intravenous infusion time of 60±10 minutes, and the maximum duration of medication is no more than 24 months.

[0095] In some embodiments, the compound of Formula I (or Formula I-1 to I-3), its ester (e.g., compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is administered once on Day 1 and Day 8 for a treatment cycle of 3 weeks (21 days). In some embodiments, the compound of Formula II (or II-1 to II-3), or a pharmaceutically acceptable salt thereof, is administered once on Day 1 and Day 8 for a treatment cycle of 3 weeks (21 days).

[0096] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is administered in a 3-week (21-day) treatment cycle, and the anti-PD-1 antibody or antigen-binding fragment thereof is administered intravenously on Day 1 (D1) of each treatment cycle. That is, the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is administered once every 3 weeks (q3w).

[0097] In some embodiments, the drug combination is suitable for administration within a single treatment cycle, and the drugs administered within a single treatment cycle include: 10 mg-16 mg of a compound of Formula I or Formula I', an ester thereof, or a pharmaceutically acceptable salt thereof; and 10-1000 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0098] In some embodiments, the drug combination is suitable for administration within a single treatment cycle, which (the drug administered within a single treatment cycle) comprises approximately: 10-20 mg of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II (or Formulas II-1 to II-3)); and 10-1000 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof).

[0099] In some embodiments, the drug combination is suitable for administration in a single treatment cycle and comprises approximately 10 mg, 10.6 mg, 11.6 mg, 12.3 mg, 12.4 mg, 12.5 mg, 12.6 mg, 13.6 mg, 14.6 mg, 14.7 mg, 14.8 mg, 14.9 mg, 15.0 mg, 15.1 mg, 15.2 mg, 15.3 mg, 15.4 mg, 15.5 mg, 16.6 mg, 16.8 mg, 17.0 mg, 17.2 mg, 17.4 mg, 17.5 mg, 17.6 mg, 17.8 mg, or 18 mg of Formula I ( or Formula I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II (or Formula II-1 to II-3)); and an anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or a range formed by any of the above values.

[0100] In some embodiments, the drug combination is suitable for administration within a single treatment cycle, which (the drug administered within a single treatment cycle) comprises approximately: 12.0 mg-18.0 mg of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II (or Formulas II-1 to II-3)); and 50-350 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof).

[0101] In some embodiments, the drug combination is suitable for administration within a single treatment cycle, which (the drug administered within a single treatment cycle) contains approximately: 12.6 mg, 15 mg or 17.6 mg of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II (or Formulas II-1 to II-3)); and 100 mg or 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof).

[0102] In some embodiments, the drug combination is administered in an amount of 6.0 mg to 9 mg (e.g., 7.5 mg) of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II (or Formulas II-1 to II-3)), and an amount of 100 mg to 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) is administered each time.

[0103] In some embodiments, the drug combination is suitable for administration within a single treatment cycle, which (the drug administered within a single treatment cycle) comprises: 10 mg-16 mg of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof; and 10-1000 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof).

[0104] In some embodiments, the drug combination is suitable for administration within a single treatment cycle, which (the drug administered within a single treatment cycle) comprises: 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg or 16 mg of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof; and about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, or a range formed by any of the above values ​​of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof).

[0105] In some embodiments, the drug combination is suitable for administration within a single treatment cycle, which (the drug administered within a single treatment cycle) comprises: 10 mg-14 mg of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof; and 50-350 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof).

[0106] In some embodiments, the drug combination is suitable for administration within a single treatment cycle, which (drugs administered within a single treatment cycle) comprises: 10 mg, 11 mg, 12 mg, 13 mg or 14 mg of a compound of Formula I (or Formula I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof; and 100 mg or 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof). In some embodiments, the drug combination is administered at each administration of a compound of Formula I (or Formula I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or The dosage of the compound of Formula I (or Formula I-1 to I-3), its ester (e.g., the compound of Formula II (or II-1 to II-3) or its pharmaceutically acceptable salt is 5 mg-8 mg, and the dosage of the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) is 100 mg-200 mg per administration. In some embodiments, the drug combination, the compound of Formula I (or Formula I-1 to I-3), its ester (e.g., the compound of Formula II (or II-1 to II-3) or its pharmaceutically acceptable salt is 5 mg-7 mg (e.g., 6 mg) per administration, and the dosage of the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) is 200 mg per administration.

[0107] In some embodiments, the drug combination is administered in the following manner, with each 21-day treatment cycle: 5 mg, 5.5 mg, 6 mg, 6.5 mg or 7 mg of a compound of Formula I, an ester thereof (e.g., a compound of Formula II) or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) is administered once on day 1.

[0108] In some embodiments, the drug combination is administered in a treatment cycle of 21 days as follows: a compound of Formula I or an ester thereof (e.g., a compound of Formula II or a pharmaceutically acceptable salt thereof) is administered once on day 1 and day 8, 5 mg, 6 mg, or 7 mg / time; and an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) is administered once on day 1, 200 mg / time.

[0109] In some embodiments, the dosage of the compound of Formula II for each administration of the drug combination is 5 mg-8 mg, and the dosage of 14C12H1L1 for each administration is 100 mg-200 mg.

[0110] In some embodiments, the dosage of the compound of Formula II is 5 mg to 7 mg per administration, and the dosage of 14C12H1L1 is 200 mg per administration.

[0111] In some embodiments, the drug combination is administered in the following manner, with each 21-day treatment cycle: the compound of Formula II or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8, with a dose of 5 mg to 8 mg for each administration of the compound of Formula II; the anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) is administered once on day 1, with a dose of 14C12H1L1 of 100 mg to 200 mg for each administration.

[0112] In some embodiments, the drug combination is administered in the following manner, with each 21-day treatment cycle: the compound of Formula II or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8, with a dose of 5 mg to 7 mg of the compound of Formula II each time; 14C12H1L1 or an antigen-binding fragment thereof is administered once on day 1, with a dose of 200 mg of 14C12H1L1 each time.

[0113] In some embodiments, the drug combination is administered in the following manner, with each 21-day treatment cycle: the compound of Formula II is administered once on day 1 and day 8, with a dose of 5 mg, 5.5 mg, 6 mg, 6.5 mg or 7 mg of the compound of Formula II each time; 14C12H1L1 is administered once on day 1, with a dose of 200 mg of 14C12H1L1 each time.

[0114] In some embodiments, the drug combination is administered in a 21-day treatment cycle as follows: the compound of Formula II is administered once on day 1 and once on day 8, with a dose of 5 mg, 6 mg, or 7 mg of the compound of Formula II each time; 14C12H1L1 is administered once on day 1, with a dose of 200 mg of 14C12H1L1 each time. In some embodiments, the compound of Formula II or a pharmaceutically acceptable salt thereof in the drug combination is administered at a dose of 0.5 mg or 2 mg each time.

[0115] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10 mL:100 mg per administration.

[0116] In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt and the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) in the pharmaceutical combination are administered separately in a single dose or multiple doses. In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt and the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) in the pharmaceutical combination are administered separately in a single dose. In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt and the anti-PD-1 antibody or its antigen-binding fragment (e.g., 14C12H1L1 or its antigen-binding fragment) in the pharmaceutical combination are administered separately in multiple doses.

[0117] In another aspect, the present disclosure further provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for treating tumors. The present disclosure further provides a method for treating tumors, comprising administering an effective amount of the pharmaceutical combination of the present disclosure to a subject in need thereof. The present disclosure further provides a pharmaceutical combination for treating tumors. The present disclosure further provides the use of the pharmaceutical combination of the present disclosure for treating tumors.

[0118] The present disclosure also provides a method for treating a subject suffering from a tumor, comprising administering to the subject a therapeutically effective amount of a compound of Formula I (or Formulas I-1 to I-3) described herein, an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof, in combination with an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0119] On the other hand, the present disclosure provides a kit comprising 1) a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof; 2) an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof); and 3) instructions for use of the compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof, and the anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen-binding fragment thereof) for treating tumors.

[0120] In another aspect, the present disclosure provides the use of a compound of formula I (or formula I-1 to I-3), an ester thereof (e.g., a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating solid tumors. The present disclosure also provides a method for treating solid tumors, comprising administering an effective amount of a compound of formula I (or formula I-1 to I-3), an ester thereof (e.g., a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to an individual in need thereof. The present disclosure also provides a compound of formula I (or formula I-1 to I-3), an ester thereof (e.g., a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating solid tumors. The present disclosure also provides the use of a compound of formula I (or formula I-1 to I-3), an ester thereof (e.g., a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating solid tumors.

[0121] In some embodiments, the ester of the compound of Formula I (or Formula I-1 to I-3) is a prodrug form of the compound of Formula I (or Formula I-1 to I-3).

[0122] In some embodiments, the ester of the compound of Formula I (or Formulas I-1 to I-3) is a malic acid ester of the compound of Formula I (or Formulas I-1 to I-3). In some embodiments, the ratio of the number of molecules of the compound of Formula I (or Formulas I-1 to I-3) to malic acid in the ester of the compound of Formula I is selected from 1:1.

[0123] In some embodiments, the malate ester of the compound of Formula I (or Formula I-1 to I-3) is a prodrug form of the compound of Formula I (or Formula I-1 to I-3).

[0124] In some embodiments, the ester of the compound of formula I (or formula I-1 to I-3) is a compound of formula II (or II-1 to II-3)

[0125]

[0126] In some embodiments, the dose of each administration of the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt or its pharmaceutical composition is selected from 0.5 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg or a range formed by any of the above values.

[0127] In some embodiments, the dose of each administration of the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt or its pharmaceutical composition is selected from 0.8 mg, 1.2 mg, 1.6 mg, 2.0 mg, 2.4 mg, 2.8 mg, 3.2 mg, 3.6 mg, 4.0 mg, 4.4 mg, 4.8 mg, 5.2 mg, 5.6 mg, 6.0 mg, 6.4 mg, 6.8 mg, 7.2 mg, 7.6 mg, 8.0 mg or a range formed by any of the above values.

[0128] In some embodiments, the dose of each administration of the compound of formula II (or II-1 to II-3), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10 mg or a range formed by any of the above values.

[0129] In some embodiments, the dosage of the compound of Formula II (or II-1 to II-3), or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 5 mg to 7 mg per administration. In some embodiments, the drug combination, wherein the compound of Formula II (or II-1 to II-3), or its pharmaceutically acceptable salt, or its pharmaceutical composition is selected from 5 mg, 6 mg, or 7 mg per administration.

[0130] In some embodiments, the pharmaceutical composition of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is selected from a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition of a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is selected from a solid pharmaceutical composition. In some embodiments, the solid pharmaceutical composition is selected from a tablet or a capsule.

[0131] In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof can be administered once a day, twice 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, twice every three weeks, or three times every three weeks.

[0132] In some embodiments, one treatment cycle is every 21 days (3 weeks) or 28 days (4 weeks).

[0133] In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is administered once on day 1 and once on day 8 of a 3-week (21-day) treatment cycle. Alternatively, in some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (e.g., compound of formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is administered once on day 1, once on day 8, and once on day 15 of a 3-week (21-day) treatment cycle.

[0134] In some embodiments, the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.5 mg or 2 mg (based on the weight of the compound of Formula II) each time.

[0135] In some embodiments, the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt in the pharmaceutical combination is administered in a single dose or multiple doses.

[0136] In some embodiments, the tumor is selected from solid tumors. In some embodiments, the tumor is selected from advanced solid tumors. In some embodiments, the tumor or advanced solid tumor is selected from advanced malignant solid tumors. In some embodiments, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from lung cancer. In some embodiments, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from advanced or locally advanced lung cancer. In some embodiments, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from metastatic, recurrent and / or refractory lung cancer. In some embodiments, the tumor, advanced solid tumor, advanced malignant solid tumor or lung cancer is selected from lung cancer with EGFR cancer driver gene mutations. In some embodiments, the tumor, advanced solid tumor, advanced malignant solid tumor or lung cancer is selected from lung cancer in situ tumors. In some embodiments, the tumor, advanced solid tumor, advanced malignant solid tumor or lung cancer is selected from lung cancer in situ tumors with CC10RTTA-EGFR-DEL cancer driver gene mutations.

[0137] In some embodiments, the tumor is selected from lung adenocarcinoma. In some embodiments, the tumor is selected from EGFR-driven lung adenocarcinoma.

[0138] In some embodiments, the tumor is selected from a histopathologically and / or cytologically confirmed late progressive / metastatic solid tumor.

[0139] In some embodiments, the patient / individual with the tumor has no standard treatment options, or has previously received standard treatment for disease progression or intolerance. In some embodiments, the patient / individual with the tumor is confirmed to have at least one measurable lesion according to RECIST 1.1 standards.

[0140] In some embodiments, the patient / subject whose tumor has previously received targeted therapy has had disease progression or intolerance.

[0141] In some embodiments, the patient / subject has a tumor that has progressed on or is intolerant to ALK inhibitor therapy.

[0142] In some embodiments, the patient / subject has a tumor with an ECOG score of 0 to 2. In some embodiments, the patient / subject has a tumor with an expected survival of more than 3 months.

[0143] In some embodiments, the patient / subject in which the tumor has good major organ function meets the following criteria:

[0144] (1) Routine blood test standards (no blood transfusion, hematopoietic stimulating factor medication or other medical support treatment within 14 days before the test):

[0145] a) Hemoglobin (HGB) ≥ 90 g / L;

[0146] b) neutrophil absolute count (NEUT) ≥1.5×109 / L;

[0147] c) Platelet count (PLT) ≥100×109 / L;

[0148] (2) Blood biochemistry examination must meet the following standards:

[0149] a) Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);

[0150] b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If there is liver metastasis, ALT and AST < 5 × ULN;

[0151] c) creatinine clearance (CCR) ≥50 ml / min (estimated according to the Cockcroft-Gault formula);

[0152] (3) Urinalysis: urine protein <2+ (if the baseline urine protein is ≥2+, a 24-hour urine protein quantitative test is performed within 7 days, and only patients with urine protein <1g can be selected);

[0153] (4) Coagulation function tests must meet the following requirements: prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ≤ 1.5 × ULN;

[0154] (5) Thyroid function test: thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be examined; if T3 and T4 levels are normal, the patient can be selected;

[0155] (6) Cardiac ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%.

[0156] Compound of formula I, its ester or pharmaceutically acceptable salt thereof (Formula I-1 to I-3 and similar thereof)

[0157] As used in the present disclosure, the compound of formula I has the following structural formula and is prepared by referring to the method disclosed in WO2018157820A1:

[0158]

[0159] As used in the present disclosure, the ester of the compound of formula I is a compound of formula II, which is a prodrug form of the compound of formula I and is prepared according to the method disclosed in WO2020025037A1:

[0160]

[0161] As used in the present disclosure, the compound of formula I includes its free compound, its ester form, and its pharmaceutically acceptable salt. Both the non-salt form and the salt are included in the protection scope of the present disclosure.

[0162] In some embodiments, the compound of formula I, its ester (e.g., compound of formula II), or pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, wherein a single dose of the pharmaceutical composition is 0.5 mg to 50 mg, preferably a single dose of 0.5 mg to 10 mg.

[0163] In some embodiments, the compound of formula II or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, wherein a single dose of the pharmaceutical composition is 0.5 mg to 50 mg, preferably a single dose of 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, The present invention relates to a pharmaceutical composition having a single dose of 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg or a range formed by any of the above values; preferably, a pharmaceutical composition having a single dose of 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg or a range formed by any of the above values; more preferably, a pharmaceutical composition having a single dose of 0.5 mg and 2 mg or a range formed by any of the above values.

[0164] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0165] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula I, its ester (e.g., compound of formula II) or its pharmaceutically acceptable salt further contains a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, adhesives, disintegrants, lubricants, etc. In some embodiments of the present disclosure, the pharmaceutical composition includes but is not limited to preparations suitable for oral, parenteral, and topical administration. In some embodiments, the pharmaceutical composition is a preparation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid preparation suitable for oral administration. In some embodiments, the pharmaceutical composition includes but is not limited to tablets and capsules.

[0166] In some embodiments of the present disclosure, the pharmaceutical composition is a solid pharmaceutical composition.

[0167] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula I, its ester (e.g., compound of formula II) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition of the compound of formula I, its ester (e.g., compound of formula II) or a pharmaceutically acceptable salt thereof.

[0168] In some embodiments of the present disclosure, the pharmaceutical composition of the compound of formula I, its ester (e.g., compound of formula II) or a pharmaceutically acceptable salt thereof is a capsule of the compound of formula I, its ester (e.g., compound of formula II) or a pharmaceutically acceptable salt thereof.

[0169] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0170] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0171] 14C12H1L1

[0172] As used in this disclosure, 14C12H1L1 is an anti-PD-1 monoclonal antibody, the sequence and structure of which can be found in the literature (CN106977602A). In the 14C12H1L1, LCDR1 comprises the sequence QDINTY (SEQ ID NO: 1), LCDR2 comprises the sequence RAN (SEQ ID NO: 2), LCDR3 comprises the sequence LQYDEFPLT (SEQ ID NO: 3), HCDR1 comprises the sequence GFAFSSYD (SEQ ID NO: 4), HCDR2 comprises the sequence ISGGGRYT (SEQ ID NO: 5), and HCDR3 comprises the sequence ANRYGEAWFAY (SEQ ID NO: 6).

[0173] It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although the present disclosure has shown the CDR sequence of 14C12H1L1, when referring to antibodies defined by specific CDR sequences, the scope of the antibodies encompasses antibodies defined by CDR sequences defined by any numbering system (e.g., a combination of one or more of the definitions known in the art, such as AbM, Kabat, Chothia, IMGT, or Contact).

[0174] The amino acid sequence of the light chain variable region of 14C12H1L1 is:

[0175] DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELK (SEQ ID NO: 7).

[0176] The amino acid sequence of the heavy chain variable region of 14C12H1L1 is:

[0177] EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKG RFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS (SEQ ID NO: 8).

[0178] The amino acid sequence of the light chain of 14C12H1L1 is:

[0179] DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:9)

[0180] The amino acid sequence of the heavy chain of 14C12H1L1 is:

[0181] EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:10)

[0182] In some embodiments, the 14C12H1L1 is in the form of a pharmaceutical composition, wherein a single dose of the pharmaceutical composition is 50 mg to 500 mg, preferably a single dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, or a range formed by any of the foregoing values. In some embodiments, the 14C12H1L1 is in the form of a pharmaceutical composition, wherein a single dose of the pharmaceutical composition is 100 mg.

[0183] In some embodiments, the 14C12H1L1 is in the form of a pharmaceutical composition comprising 14C12H1L1, a buffer, an isotonicity regulator / stabilizer, and a surfactant. In a specific embodiment, the 14C12H1L1 is in the form of a pharmaceutical composition comprising 14C12H1L1, sodium acetate trihydrate, glacial acetic acid, sorbitol, and polysorbate 80.

[0184] In some embodiments, the pharmaceutical composition of 14C12H1L1 is a water-soluble injection, including but not limited to a water-soluble formulation that has not been lyophilized or a water-soluble formulation reconstituted from a lyophilized powder. In other embodiments, the pharmaceutical composition of 14C12H1L1 is a lyophilized preparation. The lyophilized preparation refers to an aqueous solution that undergoes a lyophilization process to prepare a preparation. Lyophilization is a stabilization process in which a substance is first frozen, and then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent is a value that no longer supports biological activity or chemical reaction.

[0185] It should be understood that for the above-mentioned technical solutions and implementation plans, the present disclosure also includes a technical solution in which the “compound of formula I (or formula I-1 to I-3)” is replaced by a “compound of formula I'”, and also includes a technical solution in which the “compound of formula II (or II-1 to II-3)” is replaced by an “ester of the compound of formula I'”.

[0186] definition

[0187] Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this disclosure, it is intended to refer to the corresponding commercial product, composition, or active ingredient thereof.

[0188] In the present disclosure, unless otherwise specified, the weight of the corresponding compound is based on the weight of the free acid compound, for example, based on the weight of the compound of formula I (or formula I-1 to I-3), further for example, the compound of formula I (or formula I-1 to I-3), its ester (for example, the compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt or its pharmaceutical composition, each administration dose is selected from 0.5 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 ... .5mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg or a range formed by any of the above values, wherein the dosage is based on the weight of the compound of Formula I (or Formulas I-1 to I-3); for example, in some embodiments, the drug combination, the dosage of the compound of Formula II is 5mg-8mg per administration, and the dosage of 14C12H1L1 per administration is 100mg-200mg, and the dosage of the compound of Formula II per administration is also based on the weight of the free acid form of the compound of Formula II, i.e., the compound of Formula I.

[0189] As used herein, the term "antibody" refers to an antigen-binding protein having at least one antigen-binding domain. The antibodies and fragments thereof disclosed herein may be whole antibodies or any fragment thereof. Therefore, the antibodies and fragments thereof disclosed herein include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof. Examples of antibodies and antigen-binding fragments thereof include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)'2 fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv) and other antibody fragments known in the art. The anti-PD-1 antibodies or antigen-binding fragments thereof disclosed herein may be of the IgG1, IgG2, IgG3 or IgG4 isotype. The term "isotype" refers to the class of antibodies encoded by the heavy chain constant region gene. In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof disclosed herein are of the IgG1 or IgG4 isotype. The anti-PD-1 antibodies or antigen-binding fragments thereof disclosed herein may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans. The anti-PD-1 antibody or antigen-binding fragment thereof disclosed herein may be a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody. Unless otherwise indicated, the “antibody” disclosed herein includes a whole antibody and any antigen-binding fragment (or “antigen-binding portion”) or single chain thereof. A conventional “whole antibody” is a glycoprotein comprising two heavy (H) chains and two light (L) chains, with the heavy and light chains linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains, namely CH1, CH2 and CH3. Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain, CL. VH and VL can also be divided into hypervariable regions, namely complementarity determining regions (CDRs), and framework regions (FRs) whose sequences are relatively conserved. Each VH and VL is composed of three CDRs and four FRs, respectively, from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. At the same time, as will be appreciated by those skilled in the art, special "whole antibodies," such as nanobodies, have only heavy (H) chains and no light (L) chains.

[0190] An "antigen-binding fragment" or "antibody binding portion" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., PD-1). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody. Examples encompassed by the term "antigen-binding portion / fragment" of an antibody include: (i) Fab fragment: composed of VL 、V H The invention relates to a monovalent fragment consisting of a single variable domain (VL), a monovalent fragment consisting of a CL and a CH1 domain; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of a VH domain (see Ward et al., Nature. 341:544-546 (1989)); (vi) an isolated complementarity determining region (CDR); and (vii) a nanobody, a heavy chain variable region comprising a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, VH and VL can be connected into a single protein chain by a recombinant method through a synthetic linker, wherein VL and VH pair to form a monovalent molecule (called single-chain Fv (scFv); see, for example, Bird et al., Science. 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85: 5879-5883 (1988)). These single-chain antibodies are also encompassed by the term antigen-binding portion / fragment. In addition, recombinant polypeptides, fusion proteins, and immunoconjugates comprising the antigen-binding portion / fragment are also encompassed by the term antigen-binding portion / fragment.

[0191] The term "humanized antibody" refers to an antibody in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from a human immunoglobulin sequence. Humanized antibodies may contain substitutions in the framework region so that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.

[0192] An "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds PD-1 / PD-L1 is substantially free of antibodies that specifically bind antigens other than PD-1 / PD-L1). However, an isolated antibody that specifically binds PD-1 / PD-L1 may have cross-reactivity with other antigens (such as PD-1 / PD-L1 molecules from different species). In addition, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0193] As used herein, the terms "sequence identity" or "percent identity" in the comparison of two nucleic acids or polypeptides refer to a specified percentage of sequences that are similar or identical when compared and aligned for maximum correspondence using a nucleotide or amino acid residue sequence comparison algorithm or as measured by visual inspection. That is, nucleotide or amino acid sequence identity can be defined as the ratio of the number of identical nucleotides or amino acids to the total number of nucleotides or amino acids in the aligned portions when two or more nucleotide or amino acid sequences are aligned in a manner that maximizes the number of identical nucleotides or amino acids, adding gaps as needed.

[0194] As used herein, the sequence identity between two or more polynucleotides or polypeptides can be measured by the following method: the nucleotide or amino acid sequence of a polynucleotide or polypeptide is aligned and the number of positions containing the same nucleotide or amino acid residue in the aligned polynucleotide or polypeptide is scored, and compared with the number of positions containing different nucleotides or amino acid residues in the aligned polynucleotide or polypeptide. Polynucleotides can be different at a position, for example, by containing different nucleotides or missing nucleotides. Polypeptide can be different at a position, for example, by containing different amino acids or missing amino acids. Sequence identity can be calculated by dividing the number of positions containing the same nucleotide or amino acid residue by the sum of amino acid residues in the polynucleotide or polypeptide. For example, the number of positions containing the same nucleotide or amino acid residue by the sum of nucleotides or amino acid residues in the polynucleotide or polypeptide and multiplied by 100 to calculate the identity percentage.

[0195] Exemplary, herein, two or more sequences or subsequences have "sequence identity" or "percent identity" of at least 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% nucleotide or amino acid residues when compared and aligned using a sequence comparison algorithm or as measured by visual inspection for maximum correspondence. "Sequence identity" or "percent identity" can be determined / calculated over any suitable region of the sequence. For example, a region of at least about 10 residues in length, a region of at least about 20 residues in length, a region of at least about 50 residues in length, a region of at least about 100 residues in length, a region of at least about 200 residues in length, or a region of at least about 400 residues in length. In certain embodiments, the sequences are substantially identical over the entire length of any one or both of the compared biopolymers (i.e., nucleic acids or polypeptides).

[0196] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0197] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0198] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0199] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0200] As used herein, the term "systemic therapy" refers to treatment in which a drug substance is delivered through the bloodstream, reaching and affecting cells throughout the body.

[0201] As used herein, the term "subject" includes mammals, such as rodents, felines, canines, and primates. Preferably, the subject according to the present disclosure is a human.

[0202] The term "administering" or "giving" or "administering" means physically introducing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0203] As used herein, " adverse event " (AE) is any unfavorable and usually unintentional or undesirable sign (including abnormal laboratory findings), symptom or disease relevant to the application of medical treatment.For example, adverse event can be relevant to the activation of the immune system or the amplification of immune system cells (for example, T cells) in response to treatment.Medical treatment can have one or more related AEs, and each AE can have the same or different severity levels.Reference to the method that can " modify adverse event " refers to the treatment embodiment that reduces the incidence and / or severity of one or more AEs relevant to the application of different treatment embodiments.

[0204] As used herein, "dosing interval" refers to the amount of time that elapses between each administration (which may be two adjacent administrations or two administrations spaced apart) of a formulation disclosed herein administered to a subject. Thus, the dosing interval can be indicated as a range.

[0205] The application of the term "fixed dose" with respect to compositions of the present disclosure refers to that two or more different antibodies in a single composition are present in the composition at a specific (fixed) ratio to each other. In certain embodiments, the fixed dose is based on the weight (e.g., mg) of the antibody. In certain embodiments, the fixed dose is based on the concentration (e.g., mg / ml) of the antibody. In certain embodiments, the ratio of mg first antibody:mg second antibody is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:15 1, about 1:1, about 1:160, about 1:180, about 1:200, about 200: 1, about 180: 1, about 160: 1, about 140: 1, about 120: 1, about 100: 1, about 90: 1, about 80: 1, about 70: 1, about 60: 1, about 50: 1, about 40: 1, about 30: 1, about 20: 1, about 15: 1, about 10: 1, about 9: 1, about 8: 1, about 7: 1, about 6: 1, about 5: 1, about 4: 1, about 3: 1, or about 2: 1. For example, a 3: 1 ratio of the first antibody to the second antibody can mean that the vial can contain about 240 mg of the first antibody and 80 mg of the second antibody, or about 3 mg / ml of the first antibody and 1 mg / ml of the second antibody.

[0206] "Programmed death receptor-1 (PD-1)" refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is primarily expressed on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. The term "PD-1" as used herein includes human PD-1 (hPD-1), variants, isotypes, and species homologs of hPD-1, as well as analogs that share at least one common epitope with hPD-1.

[0207] Programmed death ligand-1 (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2), which downregulates T cell activation and cytokine secretion after binding to PD-1.

[0208] "Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. The terms "subject," "subject," and "patient" are used interchangeably in certain contexts herein.

[0209] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of disease or promotes disease regression, as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of impairment or disability resulting from disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays.

[0210] As an example for treating tumors, a therapeutically effective amount of an anticancer drug can inhibit cell growth or tumor growth by at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80%, relative to an untreated subject, or, in certain embodiments, relative to a patient treated with a standard of care therapy. In other embodiments of the present disclosure, tumor regression can be observed and persists for a period of at least about 7 days, at least about 10 days, at least about 14 days, at least about 20 days, at least about 40 days, or at least about 60 days. Despite these ultimate measures of therapeutic effectiveness, the evaluation of immunotherapeutic drugs must also consider "immune-related" response patterns.

[0211] An "immune-related" response pattern refers to a clinical response pattern frequently observed in cancer patients treated with immunotherapeutics, which produce anti-tumor effects by inducing a cancer-specific immune response or by altering innate immune processes. This response pattern is characterized by a beneficial therapeutic effect following an initial increase in tumor burden or the appearance of new lesions, which would be classified as disease progression and synonymous with drug failure in the evaluation of traditional chemotherapeutics. Therefore, appropriate evaluation of immunotherapeutics may require long-term monitoring of the effects of these agents on the target disease.

[0212] A therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of a drug that, when administered alone or in combination with an anti-tumor agent to a subject at risk of developing cancer (e.g., a subject with a pre-malignant condition) or a subject at risk of cancer recurrence, inhibits the development or recurrence of cancer. In certain embodiments, a prophylactically effective amount completely prevents the development or recurrence of cancer. "Inhibiting" the development or recurrence of cancer means reducing the likelihood of the development or recurrence of cancer, or completely preventing the development or recurrence of cancer.

[0213] A "recurrent" cancer is one that grows back in the original site or at a distant site after responding to initial treatment (such as surgery). A "locally recurrent" cancer is one that appears after treatment in the same location as a previously treated cancer.

[0214] "Metastatic" cancer is cancer that has spread from one part of the body (such as the lungs) to another part of the body.

[0215] The use of alternative embodiments (e.g., "or") should be understood to refer to any one, two, or any combination of the alternative embodiments. The indefinite articles "a" or "an" used herein should be understood to mean "one or more" of any listed or enumerated components.

[0216] The terms "about," "approximately," or "substantially encompass" refer to values ​​or compositions that are within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about," "approximately," or "substantially encompass" can mean within 1 or more than 1 standard deviation, as practiced in the art. Alternatively, "about" or "substantially encompass" can mean a range that differs by up to 10% or 20% (i.e., ±10% or ±20%) from the parameter or value modified by it. For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). In addition, particularly with respect to biological systems or processes, the term can mean up to an order of magnitude or up to 5 times the value. When a particular value or composition is provided in the specification and claims of the present disclosure, unless otherwise indicated, the meaning of "about" or "substantially encompass" should be assumed to be within an acceptable error range for that particular value or composition.

[0217] The terms "about once a week", "about once every two weeks" or any other similar dosing interval terms used herein refer to approximate values. "About once a week" can include every 7 days ± 1 day, that is, every 6 days to every 8 days. "About once every two weeks" can include every 14 days ± 3 days, that is, every 11 days to every 17 days. Similar approximate values ​​are applicable to, for example, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In certain embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to the first dose being administered on any day of the first week, and then the second dose can be administered on any day of the sixth or twelfth week, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to administering the first dose on a specific day (e.g., Monday) of the first week, and then administering the second dose on the same day (i.e., Monday) of the sixth or twelfth week, respectively. Similar principles apply to phrases including, but not limited to, "about once every 2 weeks," "about once a month," etc.

[0218] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0219] The term "pharmaceutically acceptable salts" includes salts formed between a basic ion and a free acid or between an acid ion and a free base.

[0220] The term "prodrug" is intended to include any covalently bonded carriers which release the active parent drug of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the invention are prepared by modifying functional groups present in the compound in such a manner that the modifications are cleaved to the parent compound in routine manipulation or in vivo.

[0221] The term "fixed combination" means that the active ingredients (eg, anti-PD-1 antibody or compound of Formula I) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

[0222] The term "non-fixed combination" refers to two or more active ingredients that are administered to a subject as independent entities (e.g., pharmaceutical compositions, formulations) simultaneously, concurrently or sequentially and without specific time limits, wherein the active ingredients administered to the subject reach a therapeutically effective level. An example of a non-fixed combination is cocktail therapy, e.g., administration of three or more active ingredients. In a non-fixed combination, the individual active ingredients may be packaged, sold or administered as completely independent pharmaceutical compositions. The "non-fixed combination" also includes the combined use of "fixed combinations" or "fixed combinations" with any one or more independent entities of the active ingredients.

[0223] As used herein, "combination" or "combined use" means that two or more active substances may be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially in any order as a single formulation.

[0224] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure (e.g., an anti-PD-1 antibody or a compound of Formula I) or a pharmaceutical combination thereof, and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure or a pharmaceutical combination thereof to a subject.

[0225] The term "synergistic effect" refers to an effect (e.g., inhibition or alleviation of lung cancer or colon cancer (symptoms), specifically, inhibition of colon cancer growth, or alleviation of colon cancer symptoms, inhibition of lung cancer growth, or alleviation of lung cancer symptoms) produced by two or more components (e.g., anti-PD-1 antibodies or compounds of Formula I) that is greater than the simple addition of the effects of administering the components alone.

[0226] Unless otherwise specifically stated, singular terms encompass plural terms and plural terms encompass the singular. Unless otherwise specifically stated, the words "a" or "an" mean "at least one" or "at least one." Unless otherwise specified, the use of "or" means "and / or."

[0227] Herein, unless otherwise specified, the terms "comprise, include and contain" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0228] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.

[0229] The term "multiple doses" consists of a plurality of single doses.

[0230] Administration

[0231] The following does not limit the mode of administration of the disclosed pharmaceutical combination.

[0232] The components of the pharmaceutical combination of the present disclosure can be formulated separately, or some or all of them can be formulated together. In one embodiment, the pharmaceutical combination of the present disclosure can be formulated into a pharmaceutical composition suitable for single or multiple administrations.

[0233] The components of the pharmaceutical combination of the present disclosure may be administered separately, or some or all of them may be administered together. The components of the pharmaceutical combination of the present disclosure may be administered substantially at different times, or some or all of them may be administered substantially at the same time.

[0234] The components of the pharmaceutical combination of the present disclosure can be administered individually or in part or in whole in various suitable ways, including but not limited to, orally or parenterally (by intravenous, intramuscular, topical or subcutaneous route). In some embodiments, the components of the pharmaceutical combination of the present disclosure can be administered individually or in part or in whole or in whole or in oral administration or by injection, such as intravenous or intraperitoneal injection.

[0235] The components of the pharmaceutical combination of the present invention can be in the form of suitable dosage forms, either independently or in combination, including but not limited to tablets, buccal tablets, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.

[0236] The components in the pharmaceutical combination of the present disclosure may each independently, or some or all of them may contain a pharmaceutically acceptable carrier and / or excipient.

[0237] The pharmaceutical combination of the present disclosure may further comprise an additional therapeutic agent. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art.

[0238] Technical Effects

[0239] The compounds of formula I' (specifically formula I, etc.) disclosed herein, their esters (such as compounds of formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof can exert therapeutic effects on solid tumors such as lung cancer, have good pharmacokinetic properties, few adverse reactions, good tolerability, and good pharmaceutical value.

[0240] The drug combination disclosed herein can exert therapeutic effects on solid tumors such as lung cancer; and compared with single drugs, the drug combination disclosed herein exhibits an enhanced effect, has a synergistic effect, has good pharmacokinetic properties, has few adverse reactions, is well tolerated, and has good medicinal value.

[0241] The "clinical benefits" of the drug combination disclosed herein include, but are not limited to: prolonged progression-free survival (PFS) of clinical patients, prolonged overall survival (OS), improved objective response rate (ORR), improved disease control rate (DCR), reduced number and / or severity of adverse reactions, decreased distant metastasis rate and local control rate, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0242] Figure 1 Relative tumor burden of mice;

[0243] Figure 2 Relative tumor area of ​​mice. DETAILED DESCRIPTION

[0244] The present disclosure is further described below in conjunction with specific examples. However, these examples are intended to illustrate and not to limit the scope of the present disclosure. Similarly, the present disclosure is not limited to any specific preferred embodiment described herein. Those skilled in the art will appreciate that equivalent replacements or corresponding improvements made to the technical features of the present disclosure still fall within the scope of protection of the present disclosure. Unless otherwise specified, the reagents used in the following examples are all commercially available products, and the preparation of the solutions can be performed using conventional techniques in the art.

[0245] Table 1 Abbreviations

[0246]

[0247]

[0248] "14C12H1L1 injection" refers to an injectable medical formulation containing the monoclonal antibody 14C12H1L1, which is typically administered to patients via intravenous infusion. In specific embodiments, the phrase "14C12H1L1 injection, 200 mg / dose" can be understood, as is common practice in the art, to mean a water-soluble injectable medical formulation containing 200 mg of 14C12H1L1 administered to a patient each time.

[0249] Example 1

[0250] Inducing Orthotopic Lung Tumor Formation in Transgenic Mice Carrying the CC10RTTA-EGFR-DEL Cancer Driver Gene Mutation: Treatment was performed using CC10RTTA-EGFR-DEL transgenic mice (hereinafter referred to as EGFR-DEL mice). The mice were fed a doxycycline (DOX)-containing diet at 6 weeks of age, and tumors developed in the lungs approximately 1-2 months later.

[0251] Before treatment, computed tomography (CT) was used to assess the size and severity of EGFR-DEL mouse tumors. Mice with lung tumors were then divided into four groups: a saline control group (vehicle), a group treated with the compound of Formula II, a group treated with 14C12H1L1, and a group treated with a combination of the compound of Formula II and 4C12H1L1.

[0252] Dosage:

[0253] Formula II compound, oral, once every two days, 7 mg / kg / time;

[0254] 14C12H1L1, intraperitoneal injection, once every two days, 10 mg / kg / time.

[0255] The drug was administered for two weeks according to the aforementioned administration method and dosage, and the changes in the mouse lung tumors were recorded by computed tomography on the 7th and 14th days of treatment.

[0256] After treatment, the mice were euthanized and their lung tissues were removed to prepare paraffin sections. The paraffin sections were stained with HE and the changes in the pathological sections of the mouse lung cancer tissues after drug treatment were observed under a microscope.

[0257] Results and analysis:

[0258] From the results of CT scans, it can be found that after two weeks of treatment (including the control group and the treatment group), the infiltration area of ​​the lung tumors in the mice in the control group increased to varying degrees; compared with the control group, 14C12H1L1 monotherapy can slightly reduce the infiltration of the mouse lung tumors; monotherapy with the compound of formula II can significantly reduce the infiltration of the mouse lung tumors, which is reduced by about 50-80% compared with before treatment; and the inhibition of tumor infiltration by the compound of formula II combined with 14C12H1L1 is more obvious, which is reduced by about 80-90% compared with before treatment; especially for mice with lighter lung tumor burden, whether it is the compound of formula II alone or combined with 14C12H1L1 treatment, the lung tumors can almost completely disappear after two weeks of administration. This shows that the compound of formula II has a significant therapeutic effect on in situ lung cancer tumors in mice with EGFR-DEL driver gene mutations (EGFR gene exon 19 deletion), and the combination with 14C12H1L1 can further enhance the therapeutic effect (see for details). Figure 1 ).

[0259] After 2 weeks of treatment (including the control group and the treatment group), part of the lung was taken for formalin fixation, paraffin embedding, sectioning, H&E staining, and microscopic observation and photography. Pathological analysis showed that the lungs of the control group mice had highly heterogeneous nuclear morphology, an increased ratio of nuclear to cytoplasm, and highly disordered arrangement of tumor cells along the alveoli, all of which showed the malignant nature of lung cancer. In sharp contrast, a high degree of intratumoral space and thickened alveolar walls were detected in the lungs of mice treated with the compound of formula II and the compound of formula II combined with 14C12H1L1, indicating that the area originally occupied by the tumor had undergone drastic remodeling. In addition, in the lungs of mice treated with the compound of formula II combined with 14C12H1L1, the heterogeneity of nuclear morphology and the ratio of nuclear to cytoplasm were significantly milder. These results pathologically confirmed the anti-tumor effects of the compound of formula II and the compound of formula II combined with 14C12H1L1 (see for details). Figure 2 ).

[0260] Example 2

[0261] 2.1 Inclusion Criteria:

[0262] 1. The subjects voluntarily participated in this study and signed the informed consent form;

[0263] 2. Age: ≥18 years old (at the time of signing the informed consent form); gender is not limited;

[0264] 3. Subjects with advanced progressive / metastatic solid tumors confirmed by histopathology and / or cytology;

[0265] 4. Patients with no standard treatment implementation plan, or with disease progression or intolerance after previous standard treatment;

[0266] 5. According to RECIST 1.1 criteria, at least one measurable lesion was confirmed;

[0267] 6.ECOG score: 0-2 points;

[0268] 7. The expected survival period is more than 3 months;

[0269] 8. Major organ functions are good and meet the following criteria:

[0270] (1) Routine blood test standards (no blood transfusion, hematopoietic stimulating factor medication or other medical support treatment within 14 days before the test):

[0271] a) Hemoglobin (HGB) ≥ 90 g / L;

[0272] b) neutrophil absolute count (NEUT) ≥1.5×109 / L;

[0273] c) Platelet count (PLT) ≥100×109 / L;

[0274] (2) Blood biochemistry examination must meet the following standards:

[0275] a) Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);

[0276] b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If there is liver metastasis, ALT and AST < 5 × ULN;

[0277] c) creatinine clearance (CCR) ≥50 ml / min (estimated according to the Cockcroft-Gault formula);

[0278] (3) Urinalysis: urine protein <2+ (if the baseline urine protein is ≥2+, a 24-hour urine protein quantitative test is performed within 7 days, and only patients with urine protein <1g can be selected);

[0279] (4) Coagulation function tests must meet the following requirements: prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ≤ 1.5 × ULN;

[0280] (5) Thyroid function test: thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be examined; if T3 and T4 levels are normal, the patient can be selected;

[0281] (6) Echocardiography assessment: left ventricular ejection fraction (LVEF) ≥ 50%;

[0282] 9. Female subjects of childbearing age must agree to use contraceptive measures (such as intrauterine devices, birth control pills, or condoms) during the study and for 6 months after the study. They must have a negative serum pregnancy test within 7 days before study enrollment and must not be breastfeeding. Women of childbearing age include premenopausal women and women within 2 years of menopause. Male subjects must agree to use contraceptive measures during the study and for 6 months after the study.

[0283] 2.2 Treatment drugs:

[0284] Capsules of compound of formula II: specifications 0.5 mg and 2 mg, provided by Zhengda Tianqing Pharmaceutical Group Co., Ltd.

[0285] 14C12H1L1 injection: Specification: 10ml: 100mg, provided by Zhengda Tianqing Pharmaceutical Group Co., Ltd.

[0286] 2.3 Dosage regimen

[0287] Option 1:

[0288] Formula II compound capsules: Administer once on the 1st and 8th days of each treatment cycle, 5 mg each time (based on the weight of the Formula I compound). Each 3-week treatment cycle is oral administration in the morning on an empty stomach (at least 1 hour before or at least 2 hours after a meal);

[0289] 14C12H1L1 injection: Administer once every 3 weeks (i.e., once on day 1 of each cycle), with each 3-week treatment cycle consisting of 200 mg / time, via intravenous infusion. The infusion time is 60 ± 10 minutes.

[0290] Option 2:

[0291] Formula II compound capsules: Administer once on the 1st and 8th days of each treatment cycle, 6 mg (based on the weight of Formula I compound) each time. Each 3-week treatment cycle should be taken orally in the morning on an empty stomach (at least 1 hour before or at least 2 hours after a meal).

[0292] 14C12H1L1 injection: Administer once every 3 weeks (i.e., once on day 1 of each cycle), with each 3-week treatment cycle consisting of 200 mg / time, via intravenous infusion. The infusion time is 60 ± 10 minutes.

[0293] Option 3:

[0294] Formula II compound capsules: Administer once on days 1 and 8 of each treatment cycle, 7 mg (based on the weight of Formula I compound) each time. Each 3-week treatment cycle should be taken orally in the morning on an empty stomach (at least 1 hour before or at least 2 hours after a meal).

[0295] 14C12H1L1 injection: Administer once every 3 weeks (i.e., once on day 1 of each cycle), with each 3-week treatment cycle consisting of 200 mg / time, via intravenous infusion. The infusion time is 60 ± 10 minutes.

[0296] 2.3 Efficacy evaluation

[0297] The efficacy evaluation criteria for patients were based on RECIST1.1 (Effectiveness Evaluation Criteria for Solid Tumors).

[0298] Efficacy evaluation metrics include, but are not limited to, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Descriptive statistics were used to describe the ORR and DCR for each group, along with their corresponding 95% confidence intervals (CIs). CIs were calculated using the Clopper-Pearson method. For PFS, OS, and DOR, the Kaplan-Meier method was used to calculate median progression-free survival, median overall survival, and median duration of response, with 95% confidence intervals provided. Survival curves were then plotted.

[0299] The incidence and severity of adverse events (AEs) were also assessed.

[0300] 2.4 Treatment outcomes

[0301] The compound of Formula II combined with 14C12H1L1 can safely and effectively treat solid tumors (especially lung cancer), improve the clinical benefits of patients, alleviate and control their condition, and slow the progression of the disease. Specific exemplary results are described below:

[0302] Patient serial number Disease Dosage Efficacy evaluation In group time 1 Lung adenocarcinoma 6 mg of compound of formula II + 200 mg of 14C12H1L1 SD C9 (9 treatment cycles) .

Claims

1. Use of a drug combination in the preparation of a medicament for treating lung cancer, wherein the drug combination comprises a compound of formula II or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, ， The anti-PD-1 antibody or antigen-binding fragment thereof comprises light chain complementary determining regions LCDR1, LCDR2 and LCDR3 and heavy chain complementary determining regions HCDR1, HCDR2 and HCDR3, the amino acid sequences of LCDR1, LCDR2 and LCDR3 are shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the amino acid sequences of HCDR1, HCDR2 and HCDR3 are shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; the lung cancer is lung cancer with EGFR-DEL cancer driver gene mutation.

2. The use according to claim 1, wherein the compound of formula II or a pharmaceutically acceptable salt thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof are each in the form of a pharmaceutical composition.

3. The use according to claim 1 or 2, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 7 and a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:

8.

4. The use according to claim 1 or 2, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain with an amino acid sequence as shown in SEQ ID NO: 9 and a heavy chain with an amino acid sequence as shown in SEQ ID NO:

10.

5. The use according to claim 1 or 2, wherein the pharmaceutical combination comprises 1.0 mg to 10 mg of the compound of formula II or a pharmaceutically acceptable salt thereof.

6. The use according to claim 5, wherein the pharmaceutical combination comprises 5.0 mg to 7.0 mg of the compound of formula II or a pharmaceutically acceptable salt thereof.

7. The use according to claim 6, wherein the pharmaceutical combination comprises 5.0 mg, 6.0 mg or 7.0 mg of the compound of formula II or a pharmaceutically acceptable salt thereof.

8. The use according to claim 1 or 2, wherein the pharmaceutical combination comprises 50-350 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

9. The use according to claim 8, wherein the pharmaceutical combination comprises 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

10. The use according to claim 1 or 2, wherein the weight ratio of the compound of formula II or a pharmaceutically acceptable salt thereof to the anti-PD-1 antibody or an antigen-binding fragment thereof is selected from 5 mg:100 mg, 5.5 mg:100 mg, 6 mg:100 mg, 6.5 mg:100 mg, 7 mg:100 mg, 5 mg:200 mg, 5.5 mg:200 mg, 6 mg:200 mg, 6.5 mg:200 mg or 7 mg:200 mg.

11. The use according to claim 1 or 2, wherein the pharmaceutical combination is a non-fixed combination.

12. The use according to claim 2, wherein the pharmaceutical composition of the compound of formula II or a pharmaceutically acceptable salt thereof is selected from tablets or capsules, and / or the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is selected from injection.

13. The use according to claim 2, wherein a single dose of the pharmaceutical composition of the compound of Formula II or a pharmaceutically acceptable salt thereof is 0.5 mg and 2 mg, and / or a single dose of the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is 100 mg.

14. Use of a compound of formula II or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating lung cancer, ， The anti-PD-1 antibody or antigen-binding fragment thereof comprises light chain complementary determining regions LCDR1, LCDR2 and LCDR3 and heavy chain complementary determining regions HCDR1, HCDR2 and HCDR3, the amino acid sequences of LCDR1, LCDR2 and LCDR3 are shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the amino acid sequences of HCDR1, HCDR2 and HCDR3 are shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; the lung cancer is lung cancer with EGFR-DEL cancer driver gene mutation.

15. The use according to claim 14, wherein the compound of formula II or a pharmaceutically acceptable salt thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof are each in the form of a pharmaceutical composition.

16. The use according to claim 14 or 15, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 7 and a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO:

8.

17. The use according to claim 14 or 15, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain with an amino acid sequence as shown in SEQ ID NO: 9 and a heavy chain with an amino acid sequence as shown in SEQ ID NO:

10.

18. The use according to claim 15, wherein the pharmaceutical composition of the compound of formula II or a pharmaceutically acceptable salt thereof is selected from tablets or capsules, and / or the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is selected from injection.

19. The use according to claim 15, wherein a single dose of the pharmaceutical composition of the compound of Formula II or a pharmaceutically acceptable salt thereof is 0.5 mg and 2 mg, and / or a single dose of the pharmaceutical composition of the anti-PD-1 antibody or an antigen-binding fragment thereof is 100 mg.

20. The use according to claim 14 or 15, wherein the dose of the compound of formula II or a pharmaceutically acceptable salt thereof is selected from 5.0 mg, 6.0 mg or 7.0 mg per administration, and / or the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is selected from 200 mg per administration.

21. The method of claim 14 or 15, wherein every 21 days is a treatment cycle.

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