TW202128171A - Pharmaceutical combination of anti-pd-1 antibody and quinazoline derivaticves and use thereof, and methods using the same - Google Patents

Abstract

The present invention is related to a pharmaceutical combination of an anti-PD-1 antibody and quinazoline derivatives, and their use in rophylatic or treatment of cancers and methods using the same.

Description

Drug combination of anti-PD-1 antibody and quinazoline derivative, its use and method of using it

The invention relates to the field of medicine. Specifically, the present invention relates to a pharmaceutical combination comprising an anti-PD-1 antibody or antigen-binding fragment thereof targeting programmed death-1 (programmed death-1 (PD-1)) and a quinazoline derivative for use Prevent or treat cancer. The present invention also relates to the use and method of using the combination to prevent or treat cancer.

PD-1 is a key immune checkpoint receptor expressed by activated T and B cells and mediates immune suppression (Yao S, Zhu Y and Chen L., Advances in targeting cell surface signaling molecules for immune modulation. Nat Rev Drug Discov, 2013, 12(2): 130-146). Two cell surface glycoprotein ligands of PD-1 have been identified, namely programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2), which are expressed in antigen-presenting cells and In many human cancers, it has been shown that their binding to PD-1 can lead to T cell apoptosis, immune non-response, T cell "exhaustion" and IL-10 secretion. Blocking the binding of PD-1 to its ligand can restore T cell function in cancer patients (Sheridan C., Cautious optimism surrounds early clinical data for PD-1 blocker, Nature Biotechnology, 2012, 30: 729-730). Monoclonal antibodies against PD-1 have been documented, for example, Bristol-Myers Squibb (BMS) Nivolumab (Nivolumab), Merck (Merck & Co., Inc.) Pembrolizumab (Pembrolizumab) ), the anti-PD-1 antibody disclosed in WO2017133540A1, the anti-PD-1 antibody disclosed in WO2017025016A1, etc. The anti-PD-1 monoclonal antibody can inhibit the binding of PD-1 to its ligand after binding to PD-1 on T lymphocytes, thereby promoting the activation and proliferation of T lymphocytes and the production of immune-activated cytokines such as IL-2 , And relieve the inhibition of PD-1 on the immune surveillance of T lymphocytes with anti-tumor activity.

Although anti-PD-1 antibodies have therapeutic effects on tumors, their average therapeutic efficiency is only about 20%, and the five-year survival rate for lung cancer is only 16%. Therefore, how to improve the effectiveness of tumor therapy is still an urgent problem in the field of tumor therapy.

On the other hand, tumor angiogenesis is also an important reason for rapid tumor growth (Ferrara N and Alitalo K, Clinical applications of angiogenic growth factors and their inhibitors, Nat Med., 1999; 5(12): 1359-64) . On the surface and deep of the tumor, blood vessels of varying thickness can be seen everywhere. The nutrients and oxygen of life are transported to the tumor tissue through these blood vessels. Tumor angiogenesis is a very complicated process, which is regulated by a variety of factors. Among these factors, the vascular endothelial growth factor (VEGF) family is one of the most powerful positive regulators. By combining with its receptor VEGFR, it greatly promotes the division, proliferation and migration of vascular endothelial cells. Improve vascular permeability, inhibit tumor cell apoptosis, and provide a good microenvironment for tumor growth and metastasis.

A variety of VEGFR inhibitors are disclosed in the prior art, such as sorafenib, sunitinib, vatalanib, axitinib (axitinib), apatinib, tivozanib, etc. They are small molecule VEGFR inhibitors with different mechanisms of action.

The biological behavior of most tumors is not dominated by a single signal transduction pathway, but multiple signal transduction pathways work together. In some cases, drugs with different mechanisms of action can be used in combination. However, any combination form of drugs that have different mechanisms of action but work in similar fields does not necessarily produce a combination form with beneficial effects. Therefore, although there is indeed a demand for combination medication schemes and products for different signal transduction pathways in the prior art, in view of the complexity of tumorigenesis and the unpredictability of the interaction between different drugs, it is found that it is feasible and can bring about relevant factors. Compared with a single drug, a combination drug plan and Products are still a major challenge in the medical field.

The inventors surprisingly found that the drug combination of the present application can prevent and treat cancer, especially advanced solid cancer, in a way of synergistic effect and/or improving the incidence and/or severity of adverse events (AE) during treatment. / Or the effect of treatment.

The present invention provides a pharmaceutical combination comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and a quinazoline derivative or a pharmaceutically acceptable salt thereof, and the use and method of the combination for preventing or treating cancer.

Specifically, the present invention provides the following embodiments:

1. A pharmaceutical combination comprising (i) an anti-PD-1 antibody and/or an antigen-binding fragment thereof and (ii) a quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof,

The anti-PD-1 antibody contains 6 CDRs, among which HCDR1, HCDR2 and HCDR3 are composed of amino acid sequences KASGGTFSSYAIS (SEQ ID NO: 11), LIIPMFDTAGYAQKFQG (SEQ ID NO: 12) and ARAEHSSTGTFDY (SEQ ID NO: 13), respectively And LCDR1, LCDR2 and LCDR3 are respectively composed of amino acid sequences RASQGISSWLA (SEQ ID NO: 14), SAASSLQS (SEQ ID NO: 15) and QQANHLPFT (SEQ ID NO: 16); or

The anti-PD-1 antibody contains 6 CDRs, of which HCDR1, HCDR2 and HCDR3 are respectively composed of amino acid sequences KASGYTFTAQYMH (SEQ ID NO: 1), IINPSGGETGYAQKFQG (SEQ ID NO: 2) and AKEGVADGYGLVDV (SEQ ID NO: 3), And LCDR1, LCDR2 and LCDR3 are respectively composed of amino acid sequences RASQSVSSYLA (SEQ ID NO: 4), YDASKRAT (SEQ ID NO: 5) and DQRNNWPLT (SEQ ID NO: 6);

The quinazoline derivative of formula (I) has the following structure:

Wherein R ₁ , R ₂ , R ₅ , R ₈ , R ₉ and R ₁₀ are each independently H, halogen, nitro, amino, cyano, hydroxyl, alkyl containing 1-10 carbon atoms, containing 2 Alkenyl with -10 carbon atoms, alkynyl with 2-10 carbon atoms, 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aryl, cycloalkyl with 3-12 carbon atoms, 3- 8-membered monocyclic, 8-12-membered bicyclic or 11-14-membered tricyclic heterocycloalkyl, 5-8-membered monocyclic, 8-12-membered bicyclic or 11-14-membered tricyclic heteroaryl, alkoxy, alkane Thio group, alkylcarbonyl group, carboxyl group, alkoxycarbonyl group, aminocarbonyl group or aminosulfonyl group;

Wherein R ₃ and R ₄ are each alkoxy;

R ₆ is an alkyl group;

R ₇ is _{-C (O) NR a R b} , R a and R _{b are} each independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, or R _a and R _b , together with the N atom to which they are connected, form a 3-8 membered ring containing 1-3 heteroatoms;

X is O; and

Z is N;

Among them, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and alkoxy may or may not contain substituents, and the substituents are selected from halogen, hydroxyl, Hydroxyl group, amino group, cyano group, nitro group, amino group, alkoxycarbonyl group, amide group, carboxyl group, alkylsulfonyl group, alkylcarbonyl group, ureido group, aminomethyl group, carboxyl group, thiourea group, cyano group Thio, sulfonamido, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

2. The pharmaceutical combination according to embodiment 1, wherein

The anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 17 or is at least 90%, 95%, 98% or 99% identical to it Sexual sequence, and the variable region of the light chain comprises the sequence of SEQ ID NO: 18 or a sequence that is at least 90%, 95%, 98% or 99% identical to it;

Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 19 or a heavy chain sequence that is at least 90%, 95%, 98% or 99% identical to SEQ ID NO: 19 or a heavy chain sequence that is at least 90% identical to SEQ ID NO: 20. %, 95%, 98% or 99% identical light chain sequence;

or

The anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL , wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or is at least 90%, 95%, 98% or 99% identical to it Sexual sequence, and the variable region of the light chain comprises the sequence of SEQ ID NO: 8 or a sequence that is at least 90%, 95%, 98% or 99% identical to it;

Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 9 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and SEQ ID NO: 10 or at least 90% therewith , 95%, 98% or 99% identity of the light chain sequence.

3. The pharmaceutical combination according to embodiment 1 or 2, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group and The alkoxy group is unsubstituted.

4. The pharmaceutical combination according to embodiment 1 or 2, wherein R ₆ in the quinazoline derivative of formula (I) is a methyl group.

5. The pharmaceutical combination according to embodiment 1 or 2, wherein R _a and R _b in the quinazoline derivative of formula (I) are each independently H, alkyl or cycloalkyl.

6. The pharmaceutical combination according to embodiment 5, wherein in the quinazoline derivative of formula (I), _Ra is H and _Rb is methyl.

7. The pharmaceutical combination according to embodiment 5, wherein R ₃ and R ₄ in the quinazoline derivative of formula (I) are each a methoxy group.

8. The pharmaceutical combination according to embodiment 1 or 2, wherein the quinazoline derivative of formula (I) is selected from:

9. The pharmaceutical combination according to any one of the preceding embodiments, wherein the quinazoline derivative of formula (I) is fruquintinib.

10. The pharmaceutical combination according to any one of the preceding embodiments, wherein

(i) It is in the form of a dosage unit of 100-300 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, more preferably 200 mg, preferably a parenteral, more preferably intravenous administration form; and

(ii) It is in the form of a dosage unit of 1-8 mg, preferably 2 mg, 3 mg, 4 mg, 5 mg or 6 mg, preferably an oral administration dosage form.

11. The pharmaceutical combination according to any one of the preceding embodiments, wherein:

The single dose of (i) is selected from 100-300 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, which is preferably administered parenterally, preferably intravenously, more preferably by infusion; more preferably 200 mg ;with

The daily dose of (ii) is selected from 1-8 mg, preferably 2 mg, 3 mg, 4 mg, 5 mg, 6 mg or 7 mg, which is preferably administered orally.

12. The pharmaceutical combination according to any one of the preceding embodiments, which is administered in cycles, each cycle being 14 to 30 days, preferably 14 days, 21 days or 28 days, wherein

Administer once in each cycle (i), and

Continuous administration (ii) at least on days 1 to 7 of each cycle, preferably on days 1 to 14 or continuous administration (ii) on days 1 to 21, and then discontinued until the end of the cycle, preferably discontinuation 7 Days, or preferably continuously in each cycle (ii).

13. The drug combination according to any one of the preceding embodiments, which is administered in cycles, each cycle being three to four weeks, wherein

Administer once in each cycle (i), and

Continuous administration in each cycle (ii); or first continuous administration in each cycle (ii), and then stop administration in the last week of each cycle (ii).

14. The pharmaceutical combination according to any one of the preceding embodiments, which is administered in cycles, each cycle being three weeks.

15. The drug combination according to any one of the preceding embodiments, which is administered in cycles, each cycle being four weeks.

16. The pharmaceutical combination according to any one of the preceding embodiments, wherein

The drug combination is administered in a cycle every four weeks, wherein the dose of (i) is 200 mg, once per cycle, preferably intravenously, and the daily dose of (ii) is 2 to 6 mg, preferably 2, 3, 4 , 5 or 6 mg, administered continuously in each cycle, or continuously administered for three weeks, and then stopped for one week, preferably oral administration; or

The drug combination is administered in a cycle every three weeks, wherein the dosage of (i) is 200 mg, which is administered once per cycle, preferably intravenously, and the daily dosage of (ii) is 2 to 6 mg, preferably 2, 3. , 4, 5 or 6 mg, administered continuously in each cycle, or continuously administered for two weeks and then stopped for one week, preferably oral administration.

17. The pharmaceutical combination according to any one of the preceding embodiments, wherein

Administer once in each cycle (i),

Continuous use in each cycle (ii), and

Each cycle is three or four weeks.

18. The pharmaceutical combination according to any one of the preceding embodiments, wherein

Administer once in each cycle (i),

Administer (ii) continuously for two weeks in each cycle, then stop the drug for one week, and

Each cycle is three weeks.

19. The pharmaceutical combination according to any one of the preceding embodiments, wherein

Administer once in each cycle (i),

(Ii) Three weeks of continuous administration in each cycle, followed by a week of discontinuation of the drug, and

Each cycle is four weeks.

20. The pharmaceutical combination according to any one of the preceding embodiments, wherein

(i) The single administration dose is 200 mg; and

The daily dose of (ii) is 3 mg, preferably the dose is a single administration dose.

21. The pharmaceutical combination according to any one of the preceding embodiments, wherein

The intravenous dose of (i) is 200 mg, preferably the dose is a single dose; and

(ii) The oral daily dose is 3 mg, preferably the dose is a single administration dose.

22. The pharmaceutical combination according to any one of the preceding embodiments, wherein

(i) The single administration dose is 200 mg; and

The daily dose of (ii) is 4 mg, preferably the dose is a single administration dose.

23. The pharmaceutical combination according to any one of the preceding embodiments, wherein

The intravenous dose of (i) is 200 mg, preferably the dose is a single dose; and

(ii) The oral daily dose is 4 mg, preferably the dose is a single administration dose.

24. The pharmaceutical combination according to any one of the preceding embodiments, wherein

(i) The single administration dose is 200 mg; and

The daily dose of (ii) is 5 mg, preferably the dose is a single-use dose.

25. The pharmaceutical combination according to any one of the preceding embodiments, wherein

The intravenous dose of (i) is 200 mg, preferably the dose is a single dose; and

(ii) The oral daily dose is 5 mg, preferably the dose is a single-use dose.

26. The pharmaceutical combination according to any one of the preceding embodiments, wherein

(i) The single administration dose is 200 mg; and

The daily dose of (ii) is 6 mg, preferably the dose is a single-use dose.

27. The pharmaceutical combination according to any one of the preceding embodiments, wherein

The intravenous dose of (i) is 200 mg, preferably the dose is a single dose; and

(ii) The oral daily dose is 6 mg, preferably the dose is a single-use dose.

28. The pharmaceutical combination according to any one of the preceding embodiments, wherein

The drug combination is administered in a cycle every three weeks, wherein the dosage of (i) is 200 mg, which is administered once per cycle, preferably intravenously, and the daily dosage of (ii) is 3 mg, which is continuously administered in each cycle , Preferably oral administration.

29. The pharmaceutical combination according to any one of the preceding embodiments, wherein

The drug combination is administered in a cycle every three weeks, wherein the dosage of (i) is 200 mg' to be administered once per cycle, preferably intravenously, and the daily dosage of (ii) is 5 mg, which is administered continuously in each cycle Two weeks, then stop the drug for one week, preferably oral administration.

30. The pharmaceutical combination according to any one of the preceding embodiments, wherein (i) and (ii) are administered separately, simultaneously or sequentially; preferably on the day of intravenous administration (i), oral administration (ii) first.

31. The drug combination as defined in any one of the preceding embodiments, which is used to prevent or treat cancer, wherein the cancer is preferably a solid tumor, which is preferably selected from cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, ovarian cancer, Endometrial cancer, lung cancer (such as non-small cell lung cancer), thymic cancer, kidney cancer, melanoma, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors (such as gastric cancer, gastric adenocarcinoma, gastroesophageal junction gland) Cancer, colon cancer, colorectal cancer, colorectal adenocarcinoma), brain cancer and bone cancer, or hematological cancer, which are preferably selected from leukemia and Hodgkin's lymphoma.

32. The drug combination as defined in any one of the preceding claims, which is used to treat cancer patients with an objective response rate ORR greater than 15% and a median PFS greater than 4 months.

33. The use of the drug combination as defined in any one of the preceding embodiments in the preparation of a drug for the prevention or treatment of cancer, the cancer is preferably a solid tumor, which is preferably selected from cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma , Ovarian cancer, endometrial cancer, lung cancer (such as non-small cell lung cancer), thymic cancer, kidney cancer, melanoma, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors, such as stomach cancer, gastric adenocarcinoma, stomach Esophageal junction adenocarcinoma, colon cancer, colorectal cancer, colorectal adenocarcinoma, brain cancer and bone cancer, or hematological cancer, which are preferably selected from leukemia and Hodgkin's lymphoma.

34. A method for preventing or treating cancer, the method comprising administering to a patient in need an effective amount of the drug combination as defined in any one of the preceding embodiments, the cancer is preferably a solid tumor, which is preferably selected from Hepatocellular carcinoma, ovarian cancer, endometrial cancer, lung cancer, such as cholangiocarcinoma, gallbladder cancer, non-small cell lung cancer, thymic cancer, kidney cancer, melanoma, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors (Such as gastric cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, colon cancer, colorectal cancer, colorectal adenocarcinoma), brain cancer and bone cancer, or hematological cancer, which is preferably selected from leukemia and Hodgkin’s lymphoma .

35. A kit of medicines, which comprises a drug combination as defined in any one of the preceding embodiments, preferably the kit is in the form of a drug dosage unit.

Other embodiments of the present invention will be made clear by referring to the detailed description hereinafter.

When read in conjunction with the following drawings, the preferred embodiments of the present invention described in detail below will be better understood. For the purpose of illustrating the present invention, the figure shows the presently preferred embodiment. However, it should be understood that the present invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

Figure 1 shows the effect of 0.1 mg/kg or 1 mg/kg PD-1 antibody IBI308 and 0.3 mg/kg fruquintinib on the tumor volume of tumor-bearing mice.

Figure 2 shows the effect of the combination of PD-1 antibody 11430 and Fruquintinib on the survival time of MC38 tumor-bearing mice.

Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions in this specification, because the methods and conditions can be changed. In addition, the terms used herein are only for describing specific embodiments, and are not intended to be limiting.

I. Definition

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. For the purpose of the present invention, the following terms are defined below.

The term "about" when used in conjunction with a numerical value means to cover a numerical value within a range having a lower limit 10% smaller than the specified numerical value and an upper limit 10% larger than the specified numerical value.

When the term "and/or" is used to connect two or more alternatives, it should be understood to mean any one of the alternatives or any two or more of the alternatives.

As used herein, the term "comprising" or "including" means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps. In this document, when the term "comprises" or "includes" is used, unless otherwise specified, it also encompasses the situation consisting of the stated elements, integers or steps. For example, when referring to an antibody variable region that "comprises" a specific sequence, it is also intended to encompass the antibody variable region composed of the specific sequence.

The term "antibody" is used in the broadest sense and refers to a protein containing an antigen-binding site, encompassing natural antibodies and artificial antibodies of various structures, including but not limited to whole antibodies and antigen-binding fragments of antibodies.

The terms "whole antibody", "full-length antibody", "full antibody" and "whole antibody" are used interchangeably herein to refer to at least two heavy chains (H) and two light chains interconnected by disulfide bonds. (L) Glycoprotein. Each heavy chain is composed of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region. The heavy chain constant region is composed of three structural domains CH1, CH2 and CH3. Each light chain is composed of a light chain variable region (abbreviated as VL herein) and a light chain constant region. The light chain constant region consists of a domain CL. The VH and VL regions can be further subdivided into hypervariable regions (complementarity determining regions (CDR), with a more conservative region (FR)) interposed between them. Each VH and VL consists of three CDRs and four The FR composition is arranged in the following order from the amino end to the carboxyl end: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The constant region does not directly participate in the binding of the antibody to the antigen, but displays a variety of effector functions. In one In a given VH or VL amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any one or a combination of many well-known schemes, including, for example, the Chothia numbering scheme (Chothia et al., Canonical structures). for the hypervariable regions of immunoglobulins", Joumal of Molecular Biology, 196, 901-917 (1987)); Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, USDepartment of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath) and Contact (University College London); North numbering scheme (North et al., A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, 406, 228-256 (2011) ). The CDR of the anti-PD-1 antibody of the present invention can be defined according to any scheme in the art or its combination and artificial evaluation. In one embodiment, the CDR of the anti-PD-1 antibody of the present invention is based on North numbering The CDR sequence defined by the protocol.

Although the CDR is different from antibody to antibody, there are only a limited number of amino acid positions within the CDR that directly participate in antigen binding. Using at least two of the Kabat, Chothia, AbM and Contact methods, the minimum overlap area can be determined, thereby providing the "minimum binding unit" for antigen binding. The minimum binding unit can be a sub-portion of the CDR. As those skilled in the art know, the structure of the antibody and protein folding can determine the residues of the rest of the CDR sequence. Therefore, the present invention also considers any CDR variants given herein. For example, in a CDR variant, the amino acid residue of the smallest binding unit can remain unchanged, while the remaining CDR residues defined by Kabat or Chothia can be replaced by conserved amino acid residues.

The term "antigen-binding fragment" refers to a part or segment of a complete or complete antibody that has fewer amino acid residues than a complete or complete antibody, which can bind to an antigen or a complete antibody (ie, the complete antibody from which the antigen-binding fragment is derived) Competition for antigen binding. The antigen-binding fragment can be prepared by recombinant DNA technology, or by enzymatic or chemical cleavage of the intact antibody. Antigen-binding fragments include but are not limited to Fab, Fab', F(ab') ₂ , Fv, single chain Fv, diabody, single domain antibody (sdAb). The Fab fragment is a monovalent fragment composed of VL, VH, CL and CH1 domains. For example, the Fab fragment can be obtained by digesting a complete antibody with papain. In addition, pepsin digests the complete antibody under the disulfide bond in the hinge region to produce F(ab') ₂ , which is a dimer of Fab' and a bivalent antibody fragment. F(ab') ₂ can be reduced by breaking the disulfide bond in the hinge region under neutral conditions, thereby converting the F(ab') ₂ dimer into Fab' monomer. The Fab' monomer is basically a Fab fragment with a hinge region (for a more detailed description of other antibody fragments, please refer to: Fundamental Immunology, edited by WEPaul, Raven Press, NY (1993)). The Fv fragment is composed of the VL and VH domains of one arm of the antibody. In addition, although the two domains VL and VH of the Fv fragment are encoded by independent genes, using recombination methods, they can be connected by a synthetic linking peptide that can produce these two domains as a single protein chain. The VL and VH regions in a single protein chain are paired to form a single chain Fv. The antibody fragment can be obtained by chemical methods, recombinant DNA methods, or protease digestion methods.

The term "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human CDRs and amino acid residues from human FRs. In some embodiments, the humanized antibody comprises all or substantially all of the CDRs corresponding to those of the non-human antibody and all or substantially all of the FR regions corresponding to those of the human antibody. The humanized antibody optionally can comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody (e.g., a non-human antibody) refers to an antibody that has undergone humanization.

The term "specifically binds" and the like means that the antibody forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, surface plasmon resonance assays, MSD assays (Estep, P. et al., High throughput solution-based measurement of antibody-antigen affinity and epitope binning, MAbs, 2013.5(2): p.270-278) etc. For example, in the present invention, an antibody that "specifically binds" PD-1 includes measuring at least about 10 ⁶ M ^-1 , for example, at least about 10 ⁷ M ^-1 , preferably about 10 ^{8, as measured in the MSD assay.} An affinity constant of M ^-1 and more preferably about 10 ⁹ M ^-1 or stronger binds to PD-1 expressed on the surface of T lymphocytes. In one embodiment, the anti-PD-1 antibody in the pharmaceutical combination of the present invention has a K _{D of} less than about 150 pM, as determined by the MSD assay, inhibits the binding of PD-1 on T cells to PD-L1 on the surface of tumor cells , Induces T cell activation and exerts anti-tumor effects.

The term "pharmaceutical combination" refers to non-fixed combination products or fixed combination products, including but not limited to kits and pharmaceutical compositions. The term "non-fixed combination" means that the active ingredients (for example, (i) anti-PD-1 antibody or antigen-binding fragment thereof, and (ii) quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof) are separated The entities of are administered to the patient simultaneously, without a specific time limit, or at the same or different time intervals, sequentially, wherein such administration provides a preventive or therapeutically effective level of the two active agents in the patient. In some real In the embodiment, the anti-PD-1 antibody or its antigen-binding fragment and the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof used in the drug combination are administered at a level not exceeding the level when they are used alone. The term "fixed combination" means that the two active agents are simultaneously administered to the patient in the form of a single entity. It is preferable to select the dosage and/or time interval of the two active agents, so that the combined use of each part can produce an effect greater than that achieved by using either component alone in the treatment of diseases or conditions. Each component may be in the form of a separate preparation, and the preparation form may be the same or different.

The term "period" refers to a specific period of time expressed in days or weeks that repeats on a regular schedule. For example, each treatment cycle (or prevention cycle) for administering the drug combination of the present invention is 14 to 30 days, such as 14 to 28 days, preferably each cycle is two weeks (ie, 14 days), three weeks (ie, 21 Days) or four weeks (ie, 28 days). The components of the pharmaceutical combination of the present invention can be administered on the same day or on different days of the cycle, that is to say, (i) and (ii) of the pharmaceutical combination of the present invention are administered separately, simultaneously or sequentially during the cycle.

The term "administration" refers to the physical introduction of each active ingredient of the pharmaceutical combination of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art. The administration route of each active ingredient in the pharmaceutical combination of the present invention includes oral, intravenous (for example, infusion (also called drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local or other parenteral administration routes. The phrase "parenteral administration" as used herein refers to methods of administration other than gastrointestinal and topical administration, usually by intravenous, and without limitation includes intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrasaccular , Intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injection and infusion, and in vivo electroporation. Correspondingly, each active ingredient in the pharmaceutical combination of the present invention can be formulated into capsules, tablets, injections (including infusions or injections), syrups, sprays, lozenges, liposomes or suppositories, etc.

The term "continuous administration" refers to daily administration. In the case of continuous administration, the drug may be administered one or more times a day, for example, the drug may be administered at a frequency of once a day, twice a day, or three times a day, preferably at a frequency of once a day.

The term "dose" is the amount of a drug that induces a therapeutic effect. Unless otherwise stated, the dosage is related to the amount of the free form of the drug. If the drug is in the form of a pharmaceutically acceptable salt, the amount of the drug is increased in proportion to the amount of the drug in the free form. For example, the dosage will be stated on the product packaging or product information sheet.

The term "pharmaceutically acceptable salts" includes, but is not limited to, acid addition salts or salt addition salts, for example: acid addition salts formed by compounds of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, and carbonate , Bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acid addition salts formed by compounds of formula (I) with organic acids, such as formate, acetate, malate, and maleic acid Salt, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, Stearates and salts formed with alkane dicarboxylic acids of the formula HOOC-(CH ₂ ) _n -COOH (where n is 0-4), etc. "Pharmaceutically acceptable salts" also include the addition salts of compounds of formula (I) with acidic groups and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

The term "pharmaceutically acceptable" refers to those compounds, materials, materials that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and commensurate with a reasonable benefit/risk ratio. Composition and/or dosage form.

The term "cancer" refers to a disease characterized by rapid and uncontrolled growth of abnormal cell proliferation. Cancer cells can spread to other parts of the body locally or through the bloodstream and lymphatic system. Cancer includes but is not limited to solid tumors and hematological malignancies, preferably solid tumors. Examples of various cancers include, but are not limited to, cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, ovarian cancer, endometrial cancer, lung cancer (e.g., non- Small cell lung cancer), thymic cancer, kidney cancer, melanoma, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors (e.g. gastric cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, colon cancer, colorectal cancer, Colorectal adenocarcinoma), brain and bone cancer, leukemia and Hodgkin’s lymphoma. The cancer is preferably advanced cancer, recurrent and/or refractory cancer, or cancer resistant to chemotherapy, more preferably advanced solid tumor, such as (diagnosed by histology or cytology) that cannot be surgically removed or metastatic Advanced solid tumors.

The term "inhibition" means that a given molecule (for example (i) an anti-PD-1 antibody or antigen-binding fragment thereof and/or (ii) a quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof) makes certain Decrease in parameters such as PD-1 activity and/or VEGFR activity. For example, the term includes inhibition of at least 5%, 10%, 20%, 30%, 40% or more of activity. Therefore, the suppression does not have to be 100%.

The term "treatment" includes administering the drug combination of the present invention to an individual in need to achieve the purpose of curing the disease or having an effect on the regression of the disease or delaying the progression of the disease. When referring to a disease, the term "treatment" refers to alleviating the disease (ie, slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof), preventing or delaying the onset or development or progression of the disease.

The term "prevention" includes the suppression or delay of the occurrence or frequency of the occurrence or occurrence of a disease or disorder or its symptoms, and it generally refers to the administration of drugs before the occurrence or occurrence of the symptoms or symptoms, especially before the occurrence of the symptoms or symptoms in individuals at risk.

The term "individual" or "patient" refers to mammals and non-mammals. Mammal refers to any member of the mammalian class, including but not limited to: humans; non-human primates, cows, horses, sheep, pigs, rabbits, dogs, cats, etc. The term "individual" does not limit a specific age or gender. In some embodiments, the individual or patient is a human.

The term "adverse event" (AE) is any unfavorable and often unexpected or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of medical treatment. For example, adverse events It may be related to the activation of the immune system in response to the treatment or the expansion of immune system cells (such as T cells) in response to the treatment. Medical treatments can have one or more related AEs, and each AE can have the same or different levels of severity.

The term "overall survival" or "OS" is the time from the first use of the study drug to death from any cause.

The term "progression-free survival" or "PFS" refers to the time from the first use of the drug under study to the onset of disease progression or death from any cause.

As used herein, the "quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof" includes the quinazoline derivative or pharmaceutically acceptable salt thereof described in US7829574B2, EP2297115B1, WO2009/137797 and other patent applications/patents of the same family Salt, the entire content of the patent or patent application (including definitions of terms) is incorporated herein. It is preferably fruquintinib or a pharmaceutically acceptable salt thereof. The chemical name of furquintinib is: 6-(6,7-dimethoxyquinazolin-4-yloxy)-N,2-dimethylbenzofuran-3-carbamide which has the following Structural formula

The "anti-PD-1 antibody" as used herein includes the anti-PD-1 antibody described in WO2017025016, CN108473977B and WO2017133540 and other patent applications/patents of the same family. The entire content of the patent or patent application (including the definition of terms) is incorporated herein . Among them, preferably, the anti-PD-1 antibody is the anti-PD-1 antibody D-S228P IgG4 disclosed in WO2017025016A1, which is also referred to as the PD-1 antibody IBI308 in this application, or the anti-PD-1 antibody disclosed in WO2017133540A1 Antibody C-S228P IgG4, also referred to as PD-1 antibody 11430 in this application.

All numerical ranges herein should be understood as disclosing every value and a subset of values within the range, regardless of whether it is specifically disclosed otherwise. For example, when referring to any numerical range, it should be regarded as referring to every numerical value in the numerical range, for example, every integer in the numerical range. The present invention relates to all values falling within these ranges, all smaller ranges, and the upper or lower limit of the range of values.

The technical and scientific terms used herein that are not specifically defined have the meanings commonly understood by those skilled in the art to which the present invention belongs.

II. The drug combination of the present invention

The anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination of the present invention is at least about 10 ⁶ M ^-1 , for example, at least about 10 ⁷ M ^-1 , preferably about 10 ⁸ M ^-1 and more preferably about 10 8 M -1. The affinity constant of 10 ⁹ M ^-1 or stronger binds to PD-1 expressed on the surface of T lymphocytes, thereby blocking the binding of PD-1 to its ligand, and promoting T lymphocyte activation, proliferation and production of immune-activated cells Factors such as IL-2. For example, the anti-PD-1 antibody or its antigen-binding fragment in the drug combination has a K _{D of} less than about 150 pM, such as by MSD assay (Estep, P. et al., High throughput solution-based measurement of antibody-antigen affinity and epitope binning, MAbs, 2013, 5(2): p.270-278)), inhibit the binding of PD-1 on T cells to PD-L1 on the surface of tumor cells, induce T cell activation and exert anti-tumor effects.

In one embodiment, the anti-PD-1 antibody in the pharmaceutical combination of the present invention contains 6 CDRs, wherein HCDR1, HCDR2 and HCDR3 are respectively composed of amino acid sequences KASGGTFSSYAIS (SEQ ID NO: 11), LIIPMFDTAGYAQKFQG (SEQ ID NO: 12). ) And ARAEHSSTGTFDY (SEQ ID NO: 13), and LCDR1, LCDR2 and LCDR3 are respectively composed of amino acid sequences RASQGISSWLA (SEQ ID NO: 14), SAASSLQS (SEQ ID NO: 15) and QQANHLPFT (SEQ ID NO: 16). The CDR sequence is a CDR sequence defined according to the North numbering scheme.

Preferably, the anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL , wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 17 or at least 90%, 95%, 98% thereof. % Or 99% identical sequence, and the light chain variable region comprises the sequence of SEQ ID NO: 18 or a sequence that is at least 90%, 95%, 98% or 99% identical to it.

Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 19 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and SEQ ID NO: 20 or at least 90% therewith , 95%, 98% or 99% identity of the light chain sequence.

Preferably, the anti-PD-1 antibody is the anti-PD-1 antibody D-S228P IgG4 disclosed in WO2017025016A1, which is also referred to as the PD-1 antibody IBI308 in this application.

In another embodiment, the anti-PD-1 antibody in the pharmaceutical combination of the present invention comprises 6 CDRs, wherein HCDR1, HCDR2 and HCDR3 are respectively determined by the amino acid sequence KASGYTFTAQYMH (SEQ ID NO: 1), IINPSGGETGYAQKFQG (SEQ ID NO: 2) and AKEGVADGYGLVDV (SEQ ID NO: 3), and LCDR1, LCDR2 and LCDR3 are respectively composed of amino acid sequences RASQSVSSYLA (SEQ ID NO: 4), YDASKRAT (SEQ ID NO: 5) and DQRNNWPLT (SEQ ID NO: 6) Composition. The CDR sequence is a CDR sequence defined according to the North numbering scheme.

Preferably, the anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL , wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or at least 90%, 95%, 98% thereof. % Or 99% identical sequence, and the light chain variable region comprises the sequence of SEQ ID NO: 8 or a sequence that is at least 90%, 95%, 98% or 99% identical to it.

Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 9 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and SEQ ID NO: 10 or at least 90% therewith , 95%, 98% or 99% identity of the light chain sequence.

Preferably, the anti-PD-1 antibody is the anti-PD-1 antibody C-S228P IgG4 disclosed in WO2017133540A1, which is also referred to as PD-1 antibody 11430 in this application.

The quinazoline derivative of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical combination of the present invention has a potent and highly selective inhibitory effect on VEGFR.

The quinazoline derivative of formula (I) has the following structure:

Wherein R ₁ , R ₂ , R ₅ , R ₈ , R ₉ and R ₁₀ are each independently H, halogen, nitro, amino, cyano, hydroxyl, alkyl containing 1-10 carbon atoms, containing 2 Alkenyl with -10 carbon atoms, alkynyl with 2-10 carbon atoms, 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aryl, cycloalkyl with 3-12 carbon atoms, 3- 8-membered monocyclic, 8-12-membered bicyclic or 11-14-membered tricyclic heterocycloalkyl, 5-8-membered monocyclic, 8-12-membered bicyclic or 11-14-membered tricyclic heteroaryl, alkoxy, alkane Thio group, alkylcarbonyl group, carboxyl group, alkoxycarbonyl group, aminocarbonyl group or aminosulfonyl group;

Wherein R ₃ and R ₄ are each alkoxy;

R ₆ is an alkyl group;

R ₇ is _{-C (O) NR a R b} , R a and R _{b are} each independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, or R _a and R _b , together with the N atom to which they are connected, form a 3-8 membered ring containing 1-3 heteroatoms;

X is O; and

Z is N;

Among them, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and alkoxy may or may not contain substituents, and the substituents are selected from halogen, hydroxyl, Hydroxyl, amino, cyano, nitro, sulfhydryl, alkoxycarbonyl, amide, carboxy, alkylsulfonyl, alkylcarbonyl, ureido, carbamate, carboxyl, thiourea, thiocyanate Group, sulfonamido, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

Preferably, the quinazoline derivative of formula (I) in the pharmaceutical combination of the present invention is fruquintinib.

Fruquintinib is a potent small molecule VEGFR inhibitor with extremely high kinase selectivity. It only has inhibitory activity on the VEGFR kinase family (VEGFR1, 2 and 3). The half inhibitory concentrations (IC ₅₀ ) of the aforementioned three kinases are respectively 35nM, 33nM and 0.5nM. Fruquintinib affects 12 other kinases, including cyclin-dependent kinases (CDK1, 2, 5), epidermal growth factor receptor (EGFR), and mesenchymal cell transformation factor (c-Met). Cycle or cell proliferation-related kinases have no obvious inhibitory activity (IC ₅₀ >3μM). In addition, in a further 264 kinase selectivity experiments, Fruquintinib also only showed strong inhibition of VEGFR kinase, while inhibiting other kinases, including platelet-derived growth factor receptor β (PDGFR β). The activity is very weak or weak. Thus, Fruquintinib is a very selective VEGFR inhibitor.

Although a variety of anti-VEGFR inhibitors are disclosed in the prior art, such as sorafenib, sunitinib, vatalanib, cabozantinib, brinib ( brivanib), cediranib, linifanib, regorafenib and famitinib, but they inhibit VEGFR and other signals related to angiogenesis with similar efficacy Relevant receptors. Because they inhibit many targets, they are different from the mechanism of Fruquintinib's highly selective inhibition of VEGFR kinase.

III. Use of the drug combination of the present invention and treatment method using the drug combination of the present invention

The present invention provides the aforementioned pharmaceutical combination of the present invention for preventing and/or treating the severity of at least one symptom or indication of cancer in an individual or inhibiting the growth of cancer cells.

The present invention provides a method of preventing or treating cancer, which comprises administering an effective amount of the pharmaceutical combination of the present invention to an individual in need. The effective amount includes a preventive effective amount and a therapeutically effective amount.

The present invention provides the use of the aforementioned pharmaceutical combination of the present invention in the preparation of drugs for the prevention or treatment of cancer.

The cancer of the present invention includes solid tumors and hematological malignancies, such as cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, ovarian cancer, endometrial cancer, lung cancer (such as non-small cell lung cancer), thymic cancer, kidney cancer, melanoma, Head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors (such as gastric cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, colon cancer, colorectal cancer, colorectal adenocarcinoma), brain cancer, bone cancer, leukemia, Hodgkin's lymphoma. The cancer is preferably advanced cancer, refractory cancer and/or cancer resistant to chemotherapy, more preferably advanced solid tumor, (diagnosed by histology or cytology) unresectable or metastatic advanced solid tumor. The cancer is preferably bowel cancer (including colorectal cancer), lung cancer (including non-small cell lung cancer). The cancer is preferably an advanced recurrent or metastatic cancer (advanced malignant tumor).

The drug combination of the present invention can be administered to individuals who have been treated with one or more previous therapies but subsequently relapsed or metastasized.

After the drug combination of the present invention is used to treat cancer patients, its objective remission rate ORR is greater than 15%, and the median PFS is greater than 4 months.

The drug combination of the present invention is administered to display one or more cancer-related biomarkers [e.g., programmed death ligand 1 (PD-L1), CA125, CA19-9, prostate specific antigen (PSA), lactate dehydrogenase Individuals with elevated levels of, KIT, carcinoembryonic antigen, vascular endothelial growth factor (VEGF)]. For example, a prophylactically effective amount or a therapeutically effective amount of the pharmaceutical combination of the present invention is administered to an individual with an elevated PD-L1 level and/or an elevated VEGF level.

The anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination of the present invention can be administered to an individual in need in one or more doses, wherein in the case of administering multiple doses, after the previous dose 1, 2, 3 , 4, 5, 6, 7, 8, 9 or 10 weeks to administer the next dose. A dose of the anti-PD-1 antibody or antigen-binding fragment thereof may be selected from 0.1-10 mg/kg of the individual's body weight (for example, 0.3 mg/kg, 1 mg/kg, 3 mg/kg or 10 mg/kg). In some other embodiments, each dose contains 50-500 mg of anti-PD-1 antibody or antigen-binding fragment thereof, such as 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg of anti-PD-1 Antibodies or antigen-binding fragments thereof.

The quinazoline derivative of formula (I) (for example, furquintinib) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination of the present invention is administered about once a day, once every two days, once every three days, or once every four days , Or use it once a day for three weeks and stop for one week every three weeks, or once a day for two weeks and stop for one week every two weeks. The dosage of the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is 1-8 mg/day, for example, 1 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5 mg/day, 6 mg/day, 7mg/day, 8mg/day.

The pharmaceutical combination of the present invention can be any dosage form known to those skilled in the art, such as tablets, capsules, granules, syrups, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions , Solutions, syrups, aerosols, ointments, creams and injections, etc. Wherein, the anti-PD-1 antibody or its antigen-binding fragment and the quinazoline derivative of formula (I) or its pharmaceutically acceptable salt may each be in a separate dosage form, and their dosage forms may be different or the same. The anti-PD-1 antibody The antigen-binding fragment thereof is preferably an intravenous dosage form, such as an injection, and the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is preferably an oral dosage form, such as a capsule.

The drug combination of the present invention may be a drug dosage unit, such as a single drug dosage unit.

The anti-PD-1 antibody or antigen-binding fragment thereof and the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination of the present invention can be administered separately, simultaneously or sequentially.

Each administration cycle of the drug combination of the present invention is at least 14-35 days, for example, 2, 3, 4, or 5 weeks, preferably 3 or 4 weeks.

The pharmaceutical combination of the present invention can be administered for at least one cycle, for example, 2-12 or more treatment cycles.

Preferably, one or two anti-PD-1 antibodies or antigen-binding fragments thereof are administered in each cycle, or 1-2 doses of anti-PD-1 antibody or antigen-binding fragments thereof are administered in each cycle; and

The quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is administered at least on days 1 to 7 of each cycle, preferably on days 1 to 14 or on days 1 to 21 or on days 1 to 28. The quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is administered daily, and then the drug is stopped to the end of the cycle, preferably for 7 days, or preferably continuously administered in each cycle, preferably on every day of administration. Administer once a day, preferably each cycle is at least 14 to 35 days, to At least 14 to 30 days, preferably 21 days or 28 days; or continuously administer the quinazoline derivative of formula (I) or its pharmaceutically acceptable salt in each cycle for 1, 2, 3, or 4 weeks and then stop the drug 1 Weekly or continuously during the use cycle.

Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in each cycle, and

Continuously administer the quinazoline derivative of formula (I) or its pharmaceutically acceptable salt or its pharmaceutically acceptable salt in each cycle; or continuously administer fruquintinib or its pharmaceutically acceptable salt in each cycle, and then The administration of Fruquintinib or its pharmaceutically acceptable salt was stopped in the last week of each cycle.

The pharmaceutical combination of the present invention can be administered in a cycle every 3 or 4 weeks, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-300 mg, for example 200 mg, once per cycle, preferably intravenously, for example Intravenous drip, and the daily dose of the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is 2 to 6 mg, preferably 2, 3, 4, 5 or 6 mg, administered continuously in each cycle, or Stop the administration of the quinazoline derivative of formula (I) or its pharmaceutically acceptable salt in the last week of each cycle, and continuously administer the quinazoline derivative of formula (I) or its pharmaceutically acceptable salt on the other days of each cycle With salt, oral administration is preferred.

Preferably, the drug combination is administered in a cycle every four weeks, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, which is administered once per cycle, preferably intravenous drip, and the quinazole of formula (I) The daily dose of the morpholine derivative or its pharmaceutically acceptable salt is 3, 4, 5 or 6 mg, which is continuously administered in each cycle, or continuously administered for three weeks, and then the drug is discontinued for one week, preferably orally administered, for example, once a day .

Preferably, the drug combination is administered in a cycle every three weeks, wherein the dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, which is administered once per cycle, preferably intravenous drip, and the quinine of formula (I) The daily dose of the oxazoline derivative or its pharmaceutically acceptable salt is 3, 4, 5 or 6 mg, continuously in each cycle Administration, or continuous administration for two weeks and then discontinuation of the drug for one week, preferably oral administration, for example, oral administration once a day.

Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination of the present invention can be administered before, at the same time, or after the start of administration of the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof. When the anti-PD-1 antibody or its antigen-binding fragment is administered "before" the quinazoline derivative of formula (I) or its pharmaceutically acceptable salt is administered, the anti-PD-1 antibody or its antigen-binding fragment may be administered at the beginning The quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is greater than 150 hours, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about It is administered for 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, or about 30 minutes, about 15 minutes, or about 10 minutes. When administered after the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is administered, the anti-PD-1 antibody or antigen-binding fragment thereof can be administered at the beginning of the quinazoline derivative of formula (I) or its pharmaceutically acceptable salt. About 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 10 minutes after the pharmaceutically acceptable salt It is administered for 36 hours, about 48 hours, about 60 hours, about 72 hours, or more than 72 hours. Administration "simultaneously" with the start of administration of the quinazoline derivative of formula (I) or its pharmaceutically acceptable salt means that the anti-PD-1 antibody or antigen-binding fragment thereof is administered at the beginning of the administration of the quinazoline derivative of formula (I) or its The pharmaceutically acceptable salt is administered to the individual in less than 10 minutes (before, after, or simultaneously). Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination of the present invention is administered after the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is administered, for example, an anti-PD-1 antibody The antigen-binding fragment thereof is administered about 1 hour, about 3 hours, about 6 hours, about 12 hours, about 15 hours after the start of administration of the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof.

Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination of the present invention is an injection, and if it is administered by intravenous drip, the administration time can be about 15-60 minutes.

Preferably, the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination of the present invention is a capsule. Preferably, on the day of intravenous administration of the anti-PD-1 antibody or antigen-binding fragment thereof, the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is administered first.

In some embodiments, compared with patients who are administered anti-PD-1 antibodies or antigen-binding fragments of monotherapy or quinazoline derivatives of formula (I) or pharmaceutically acceptable salts thereof, the administration of at least one The cyclical drug combination of the invention results in an increase, preferably synergistically, in the patient's progression-free survival (PFS) or overall survival (OS). In some embodiments, compared with patients who are administered anti-PD-1 antibodies or antigen-binding fragments of monotherapy or quinazoline derivatives of formula (I) or pharmaceutically acceptable salts thereof, the administration of at least one The cycle of the drug combination of the present invention causes the patient's PFS to increase at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months. Months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years or more. In some embodiments, compared with patients who are administered anti-PD-1 antibodies or antigen-binding fragments of monotherapy or quinazoline derivatives of formula (I) or pharmaceutically acceptable salts thereof, the administration of at least one The cycle of the drug combination of the present invention causes the patient's OS to increase at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months. Months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years or more.

Compared with the monotherapy of administration of anti-PD-1 antibody or its antigen-binding fragment or the monotherapy of administration of the quinazoline derivative of formula (I) or its pharmaceutically acceptable salt, the drug combination of the present invention results in increased, better synergy Increase the inhibitory effect on tumor growth. In some embodiments, the drug combination of the present invention is compared with monotherapy of administration of anti-PD-1 antibody or antigen-binding fragment thereof or monotherapy of administration of quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof This results in tumor growth being inhibited by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%. In some embodiments, the present invention The administration of the drug combination indicated results in increased tumor regression, tumor shrinkage and/or disappearance. In some embodiments, compared with an untreated individual or with a monotherapy using an anti-PD-1 antibody or antigen-binding fragment thereof or a monotherapy using a quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof The drug combination of the present invention prevents tumor recurrence in an individual and/or increases the duration of survival, for example, the duration of survival is increased by more than 15 days, more than 1 month, more than 3 months, more than 6 months, and more. Within 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months. In some embodiments, the drug combination of the present invention can increase progression-free survival or overall survival.

In some embodiments, administration of the drug combination of the invention to an individual suffering from cancer results in the complete disappearance of the tumor ("complete response"). In some embodiments, administration of the drug combination of the invention to an individual suffering from cancer results in a reduction in tumor cells or tumor size by at least 30% or more ("partial response"). The tumor reduction can be measured by any method known in the art, such as X-ray, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetics analyze.

In some embodiments, the pharmaceutical combination of the present invention can reduce adverse events caused by the administration of an anti-PD-1 antibody or an antigen-binding fragment thereof and/or a quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof, such as Hematological toxic reactions, non-hematological toxic reactions or other toxic reactions, such as pneumonia, diarrhea, enterocolitis, renal insufficiency, rash, hepatitis, endocrine diseases, peripheral or central neuritis, abnormal liver function, etc.

IV. The kit of the present invention

Another object of the present invention is to provide a kit of medicines comprising the drug combination of the present invention, preferably the kit is in the form of a drug dosage unit. Thereby, dosage units can be provided according to the dosing schedule or drug administration interval.

In one embodiment, the kit of the present invention contains in the same package:

-A first container containing a pharmaceutical composition for parenteral administration, the pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof;

-A second container containing a pharmaceutical composition for oral administration, the pharmaceutical composition comprising the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof.

The various embodiments/technical solutions described in the present invention and the features in the various embodiments/technical solutions should be understood to be arbitrarily combined with each other, and the various solutions obtained by these mutual combinations are all included in the scope of the present invention, just like in This article specifically and one by one lists the solutions obtained by combining these mutually, unless the context clearly shows otherwise.

The following examples are described to assist the understanding of the present invention. It is not intended and should not be construed in any way to limit the scope of protection of the present invention.

Example

The following examples provide those of ordinary skill in the art with a complete disclosure and description of how to prepare and use the methods and compositions of the present invention, and are not intended to limit the scope of the present invention as the inventors think.

Example 1. One of the effects of PD-1 antibody IBI308 and furquintinib in combination on H292 tumor-bearing mice

1. Laboratory animals and sources

SPF (Specific Pathogen Free, no specific pathogen) grade NOG female mice (15-18g, 35-41 days) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. The quantity is 40, The certificate number is 1100111911026280. After arriving at the experimental center, the mice were domesticated and reared for 3 days and then used for experiments.

2. Experimental operation process:

NOG mouse is a kind of mouse that lacks T cells, B cells and NK cells. Human peripheral blood mononuclear cells (PBMC) were purchased from AllCells, lot number 3010492, and 2 million human PBMC cells per mouse were inoculated with NOG mice through the ocular vein, thereby enabling the human PBMC to directly use NOG cells. The blood circulation of mice was reconstructed in a short period of time to successfully simulate the NOG mouse model of human immune environment. The research using the NOG mouse model that mimics the human immune environment is closer to clinical research.

After 5 days of intravenous inoculation of human PBMC into NOG mice, NOG mice were subcutaneously inoculated with H292 cells, which are human lung cancer cell lines (purchased from ATCC, catalog number CRL-1848, lot number 61020695). The inoculation amount of H292 cells is 5 million cells per mouse. On the 8th day after subcutaneous inoculation of H292 cells, the NOG mice were grouped into serpentine groups according to the tumor volume. Divided into 6 groups, 6 NOG mice in each group.

3. The dosage and mode of administration are shown in Table 1 below

Table 1. The amount and method of administration of each experimental animal group

h-IgG control group: h-IgG was purchased from Equitech-Bio, batch number 1612066-0656, at a concentration of 10 mg/ml. Dilute with PBS to the administration concentration. The intraperitoneal administration was once every 3 days for a total of 4 administrations.

PD-1 antibody IBI308 group: The PD-1 antibody IBI308 was obtained from Zida Biopharmaceutical (Suzhou) Co., Ltd., the batch number is DP1901007, and the concentration is 10mg/ml. Dilute with PBS to the administration concentration. The intraperitoneal administration was once every 3 days for a total of 4 administrations.

Fruquintinib group: Fruquintinib was obtained from Hutchison Whampoa Pharmaceutical (Suzhou) Co., Ltd., batch number 181001-01, with a specification of 1.086 g. Dilute with 0.5% CMC-Na (sodium carboxymethyl cellulose) to the administration concentration. Gavage is administered every day for 16 consecutive days.

Fruquintinib + PD-1 antibody IBI308 combination group: The source and preparation of Fruquintinib and PD-1 antibody IBI308 are the same as those of the single administration group. Fruquintinib was administered by gavage every day for 16 consecutive days. PD-1 antibody IBI308 was administered intraperitoneally every 3 days for a total of 4 times.

4. Experimental results and conclusions

(i) Effect on tumor volume of tumor-bearing mice:

A vernier caliper (purchased from China Baogong, model PD-051) was used to determine the maximum long axis (L) and maximum wide axis (W) of the tumor in tumor-bearing mice. The tumor volume was calculated as follows: V=L×W ² / 2.

The tumor inhibition rate is calculated as follows:

Tumor suppression rate TGI(%)=100%×(Tvolcontrol-Tvoltreated)/(Tvolcontrol-Tvolpredose)

Tvolcontrol-Tvoltreated: Terminal tumor volume after administration in the control group-Terminal tumor volume in the administration group after administration;

Tvolcontrol-Tvolpredose: Terminal tumor volume after administration of control group-tumor volume before administration of control group.

Table 2. Tumor inhibition rate of NOG mice on the 26th day after inoculation with H292 cells

From the TGI results in Table 2 and Figure 1, it can be seen that the combined effect of PD-1 antibody IBI308 and fruquintinib is not only better than that of PD-1 antibody IBI308 alone or fruquintinib alone, the combination also shows synergy The anti-tumor effect of the anti-tumor effect has unexpected anti-tumor effect.

Example 2. The effect of PD-1 antibody 11430 and furquintinib in combination on MC38 tumor-bearing mice

1. Laboratory animals and sources

SPF C57BL/6N mice, female, 6-8 weeks old when they arrived at the experimental center, purchased from Zhejiang Weitong Lihua Laboratory Animal Technology Co., Ltd.

2. Experimental drugs and sources

mIgG (Mouse immunoglobulin G, mouse immunoglobulin G) was purchased from Equitech Bio, the product number is SLM56-1000, and the batch number is SLM66-912.

PD-1 antibody 11430 was acquired by Sunshine Biopharmaceutical (Suzhou) Co., Ltd.

Fruquintinib was obtained from Hutchison Whampoa Pharmaceutical (Suzhou) Co., Ltd.

CMC-Na (Sodium carboxymethyl cellulose, sodium carboxymethyl cellulose) was purchased from Sinopharm Chemical Reagent Co., Ltd., batch number 20170830. When in use, use sterile deionized water to prepare a solution with a concentration of 0.5%.

Normal saline for injection: 0.9% sodium chloride injection, purchased from Huayu (Wuxi) Pharmaceutical Co., Ltd., batch number 18022701.

3. Experimental operation process:

MC38 mouse intestinal cancer cells were purchased from ATCC, and routinely subcultured in strict accordance with ATCC requirements for subsequent in vivo experiments. After culturing MC38 mouse intestinal cancer cells to a sufficient number in vitro, SPF grade C57BL/6N mice were subcutaneously inoculated with ^{2×10 6 cells per animal to establish an animal model of MC38 subcutaneous transplantation tumor.} When the average tumor volume reached about 90 mm ³ , mice were randomly grouped according to tumor volume, with 10 mice in each group. On the day of grouping, Fruquintinib was intragastrically administered, and anti-mouse PD-1 antibody 11430 and its isotype control mIgG were injected intraperitoneally, with a volume of 10 mL/kg. The specific experimental program is shown in Table 3.

Table 3. Anti-tumor experimental protocol of PD-1 antibody 11430 and/or Fruquintinib

4. Observation indicators and statistical analysis of data

The Kaplan-Meier survival curve was used as an indicator of anti-tumor efficacy. When the animal died and the tumor volume reached or exceeded 3500 mm ^{3, the} experimental endpoint was considered to be reached. The tumor volume calculation formula is the same as in Example 1.

Use GraphPad Prism 8 software to calculate the median survival time (MST, Median survival time) of each group, and calculate the survival time extension rate (ILS%, increased life span)=〔(MST _{treatment group-} MST _{control group} )/MST _{control group} ]×100%. The Log-rank test method was used to compare and analyze the survival curves. Calculate the p value of each drug treatment group compared with the mIgG control group. When p<0.05, it is considered that there is a significant difference between the survival curve of the survival curve and the mIgG control group. At the same time, when the survival time extension rate (ILS%)>25%, it can be considered as having biological significance.

5. Experimental results and conclusions

During the experiment, the animals were in good condition and no abnormal performance related to administration toxicity was seen. Animals that reached the end of the experiment were all due to the tumor volume reaching or exceeding the standard, and no deaths caused by other causes were found. Figure 2 shows the survival rate of each group of animals over time, Table 4 shows the median survival time of each treatment group and the statistical difference with the mIgG control group; for the combination group, it is also compared with each single The statistical difference of the drug group. In the mIgG control group, 50% of the animals reached the experimental end point 25 days after administration (ie MST=25 days), and the median survival of the anti-mouse PD-1 antibody 11430, furquintinib single-drug group and combination drug group The time was 26.5, 34 and 44 days, respectively; compared with the control group, the prolonged survival rate reached 6%, 36%, and 76%, respectively. Compared with the anti-PD-1 antibody 11430 and fruquintinib single-agent groups, the combined drug group had a 66% and 29% longer survival time, and there was a statistically significant difference.

The data of this experiment show that the combination of furquintinib and anti-mouse PD-1 antibody 11430 can significantly prolong the survival time of MC38 tumor-bearing mice, and the percentage increase in survival time (ILS) of the combined drug group is much greater than that of the two separate drug groups, showing that the combination The medication has a synergistic anti-tumor effect.

Table 4. Fruquintinib combined with anti-mouse PD-1 antibody 11430 on the survival of MC38 mouse tumor model

Example 3. Evaluation of Fruquintinib combined with PD-1 antibody IBI308 in the treatment of advanced solid tumors in a phase Ib/II clinical study

1. Research design:

This study includes a dose escalation study phase and a dose expansion study phase.

˙The dose escalation phase includes 6 study cohorts (cohort A, cohort B, cohort C, cohort D, cohort E, and cohort F). It is planned to enroll about 26 to 39 patients with advanced solid tumors until September 15, 2020 Twenty-three patients with advanced solid tumors have been enrolled and received Fruquintinib combined with PD-1 antibody IBI308 to evaluate the tolerability, safety, pharmacokinetic (PK) PK characteristics and effectiveness.

After the dose escalation study, the best dose and administration method of Fruquintinib combined with PD-1 antibody IBI308 can be determined according to the obtained combination drug safety, tolerability, PK and efficacy information, or explore new Dosage and mode of administration of combination medication (such as Fruquintinib 5mg QD, oral, continuous taking for 2 weeks, stop for 1 week, once every 3 weeks; or Fruquintinib 6mg QD, oral, continuous taking for 2 weeks, stop 1 Weeks, a cycle every 3 weeks; or Fruquintinib 3mg QD orally continuously; or Fruquintinib 4mg QD orally continuously. Combined with PD-1 antibody IBI308 200mg, Q3W). At least 6 patients are needed in the Maximum Tolerated Dose (MTD) group or the Recommended Phase 2 Dose (RP2D) group.

˙Dose expansion stage, it is planned to enroll about 126~169 patients to receive the phase II recommended dose (RP2D) treatment determined in the dose escalation stage, including about 22-40 patients with advanced hepatocellular carcinoma and about 19-29 patients with advanced renal cell carcinoma Patients, about 25-40 patients with advanced endometrial cancer, about 60 patients with advanced gastrointestinal tumors, etc. To further collect the safety and preliminary efficacy data of the combination therapy. As of September 15, 2020, 37 patients with advanced colorectal cancer (Colorectal Cancer, CRC) were enrolled for safety and tolerability assessment; as of November 18, 2020, 44 patients with advanced colorectal cancer (Colorectal Cancer) were enrolled. Cancer, CRC) patients were evaluated for effectiveness.

2. Indications (types of tumors included):

Dose escalation stage: patients with unresectable or metastatic advanced solid tumors confirmed by histology or cytology (including but not limited to hepatocellular carcinoma, ovarian cancer, endometrial cancer, thymic cancer, non-small cell lung cancer, kidney cancer, Colorectal cancer);

Dose expansion stage: unresectable or metastatic advanced hepatocellular carcinoma confirmed by histology or cytology (Barcelona clinical liver cancer staging (BCLC staging) stage B or C), or containing Advanced renal cell carcinoma with clear cell components, or advanced endometrial cancer, or advanced gastrointestinal tumors (gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, and colorectal adenocarcinoma).

3. Requirements for previous anti-tumor system therapy:

Dose escalation stage: patients who have failed standard treatment (disease progression after treatment or intolerable side effects of treatment), no standard treatment method or unable to receive standard treatment (such as economic constraints or patient willingness, etc.);

Patients enrolled in the dose expansion phase are required to receive a standard treatment after disease progression, or toxicity is intolerable, or unable to receive standard treatment. Among them, the standard treatment requirements for patients with hepatocellular carcinoma, renal cell carcinoma, endometrial cancer and gastrointestinal tumors (gastric adenocarcinoma, gastroesophageal junction adenocarcinoma and colorectal adenocarcinoma) are as follows:

-Patients with hepatocellular carcinoma have received a molecular targeted therapy (sorafenib or lenvatinib) or/and systemic chemotherapy (arsenite monotherapy or oxaliplatin-based combination drugs);

-Patients with renal cell carcinoma have received a standard systemic anti-tumor treatment (sunitinib, sorafenib, pezopanib, axitinib, cabotinib, bevacizumab combined with IFN-α, Tesirolimus, interleukin-2 or IFN-α);

-Patients with endometrial cancer have received a systemic anti-tumor therapy (except hormone therapy)

-Patients with gastric adenocarcinoma and gastroesophageal junction adenocarcinoma have previously failed standard chemotherapy;

-Patients with colorectal adenocarcinoma have previously received combined treatment with fluorouracil + leucovorin + platinum or irinotecan ± cetuximab or bevacizumab.

ECOG physical status score is 0 or 1;

It is clear that there are measurable lesions that meet the requirements of the solid tumor efficacy evaluation criteria (RECIST v1.1).

4. Main exclusion criteria:

˙Histological diagnosis is fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma or a mixed component of the above pathological types (Hepatocellular Carcinoma, HCC); or gastric squamous cell carcinoma or gastric adenosquamous carcinoma;

˙Central Nervous System (CNS) metastasis in the past or during screening;

˙Have received any anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody or anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibody in the past (or act on T cell co-stimulation or checkpoint Any other antibodies of the pathway) or Fruquintinib treatment;

˙Use corticosteroids (dose>10mg/day prednisone or other curative hormones) or other immunosuppressive agents for systemic therapy within 4 weeks before the first medication;

˙Have any active autoimmune disease or history of autoimmune disease;

˙Any live vaccine or live attenuated vaccine will be vaccinated within 4 weeks before the first medication or during the study period;

˙Have undergone major surgery within 60 days before the first medication;

˙Have received any surgery or invasive treatment (except puncture biopsy, venous catheterization) within 4 weeks before the first medication; or unhealed wounds, ulcers, fractures;

˙Uncontrollable malignant pleural effusion, ascites or pericardial effusion (defined as the researcher's judgment that cannot be effectively controlled by diuretics or puncture);

140mmHg和/或舒張壓

90mmHg； ˙Patients have high blood pressure that is not controlled by drugs, stipulated as: systolic blood pressure

140mmHg and/or diastolic blood pressure

90mmHg;

˙Patients have gastrointestinal diseases such as active gastric and duodenal ulcers, ulcerative colitis, or unresected tumors have active bleeding, or other conditions determined by the investigator that may cause gastrointestinal bleeding or perforation; or previous gastrointestinal perforation or gastrointestinal perforation Tract fistula, who has not healed after surgical treatment;

˙Patients with obvious evidence of bleeding tendency or medical history within 2 months before the first medication (such as melena, hematemesis, hemoptysis, bloody stools, etc.);

˙It was found that the tumor invaded large blood vessel structures during screening, such as the pulmonary artery, superior vena cava, or inferior vena cava. The researchers judged that there is a greater risk of bleeding;

˙Have a history of arterial thrombosis or deep vein thrombosis within 6 months before the first medication; or have a stroke and/or transient ischemic attack within 12 months;

˙ Cardiovascular diseases with significant clinical significance.

5. Dosing regimen:

The test drug is Fruquintinib and PD-1 antibody IBI308, and the treatment plan is combination therapy.

Fruquintinib

˙Continuous use for 3 weeks and stop for 1 week plan:

Cohort A: The initial dose of Fruquintinib is 3 mg, once a day (QD), orally, the drug is taken continuously for 3 weeks and the drug is stopped for 1 week, with a treatment cycle every 4 weeks;

Cohort B: Fruquintinib 4 mg, QD, orally, taking the drug for 3 weeks and stopping the drug for 1 week, with a treatment cycle every 4 weeks;

˙Continuous use for 2 weeks and stop for 1 week plan:

Cohort C: Fruquintinib 5mg QD, orally, taking the drug continuously for 2 weeks and stopping for 1 week, a cycle every 3 weeks;

Cohort D: Fruquintinib 6mg QD, orally, taking the drug continuously for 2 weeks and stopping for 1 week, a cycle every 3 weeks;

˙Continuous medication plan:

Cohort E: Fruquintinib 3 mg QD orally;

Cohort F: Fruquintinib 4 mg QD orally;

˙Others: If necessary, some of the above-mentioned dosing schedules can be adjusted or deleted, or new dosing schedules can be added.

PD-1 antibody IBI308:

˙In the combined Fruquintinib for 3 consecutive weeks, stop for 1 week regimen group (ie, cohort A and B groups) : PD-1 antibody IBI308 200mg, intravenous drip, once every 4 weeks (Q4W), the infusion time is controlled at 30- Complete within 60 minutes, with a treatment cycle every 4 weeks.

˙In the combined Fruquintinib other medication regimen group: PD-1 antibody IBI308 200mg, intravenous drip, Q3W, the infusion time is controlled within 30-60 minutes, and a treatment cycle every 3 weeks.

During the study period, on the day of the combined administration of Fruquintinib and PD-1 antibody IBI308, it is recommended to take fruquintinib orally first, and then intravenously instill the PD-1 antibody IBI308.

1/6患者出現DLT)時，才能進行劑量遞增至下一隊列研究。 The starting dose group of the study was cohort A, and each cohort had at least 3 patients enrolled. Only when the DLT observation period of a certain cohort study is completed and the safety of patients in the cohort is determined to be tolerable (0/3 or

Only when 1/6 patients have DLT) can the dose be escalated to the next cohort study.

6. Evaluation criteria:

1) Safety evaluation:

˙According to NCI CTCAE version 5.0 to determine and classify all adverse events (Adverse Event, AE), by the incidence of DLT (dose-limiting toxicity), AE/SAE (serious adverse event)/TEAE (during treatment) The incidence, severity, and nature of adverse events are critical to safety Comprehensive evaluation of resistance and tolerance.

˙Other safety indicators also include: vital signs evaluation, physical status score and physical examination, laboratory evaluation (blood routine, coagulation function, blood biochemistry, urine routine, stool occult blood test, electrocardiogram (ECG) and echocardiogram, etc. ).

2) Efficacy evaluation:

According to the RECIST 1.1 standard, it includes objective response rate (Overall Response Rate, ORR, which is defined as the proportion of patients with complete or partial response that is the best overall assessment), and duration of response (Duration of Response, DOR, which is defined as Among patients with objective remission, the time from the initial appearance of complete or partial remission to the appearance of disease progression or death due to any cause (whichever occurs earlier), disease control rate (Disease Control Rate, DCR, defined as The best overall assessment is confirmed complete remission and partial remission, as well as the proportion of patients with stable disease), Progression Free Survival (PFS, defined as the period from the first use of the study drug to the appearance of disease progression or death from any cause) Time), Overall Survival (OS, defined as the time from the first use of the study drug to death from any cause).

3) Pharmacokinetic evaluation:

Describe the PK characteristics of the drug in the human body. The main pharmacokinetic parameters include: peak concentration (C _max ), peak time (T _max ), terminal elimination half-life (t _1/2 ), area under the plasma concentration-time curve ( AUC _0-t , AUC _0-∞ ), apparent clearance (CL/F), apparent volume of distribution of terminal phase (V _z /F), etc.

4) Evaluation of immunogenicity:

Evaluation indicators include anti-drug antibody (ADA) and neutralizing antibody (NAb).

5) Evaluation of biomarkers:

Explore potential biomarkers related to the anti-tumor effect of PD-1 antibody IBI308 in combination with Fruquintinib.

7. Statistics and analysis methods:

statistical methods:

Descriptive statistical methods are mainly used for the research results. The measurement data lists the number of people, mean, standard deviation, median, maximum, and minimum. Count data and grade data list frequency and percentage.

˙Security analysis:

All patients who have used the study drug at least once, that is, the Intention-to-Treat (ITT) set (all people receiving treatment) will be included in the safety analysis. Safety evaluation includes adverse events, DLT, serious adverse events, changes in laboratory test results, changes in vital signs, electrocardiogram, left ventricular ejection fraction and ECOG score. Adverse events will be classified according to NCI CTCAE5.0. Adverse events were compiled with the International Dictionary of Medical Terms (MedDRA).

˙Validity analysis:

The tumor efficacy analysis will be based on the evaluable population of tumor efficacy, which is defined as all patients who have used study drugs, have measurable lesions according to the RECIST v1.1 standard baseline, and have at least one post-baseline tumor imaging evaluation. Calculate ORR and DCR respectively, and use the Clopper-pearson method to calculate the 95% exact confidence interval (CI). The analysis of PFS and OS will be based on the ITT set. For the event Interrelated variables include DoR, TTR, PFS, and OS. If the data allows, the Kaplan-Meier method will be used to estimate the median value and its 95% CI, as well as the PFS rate and OS rate at the time of interest.

˙Pharmacokinetic analysis:

All patients who have used the study drug, have at least one PK sampling and analysis, and have not had an important protocol deviation that affects the PK data will be included in the PK analysis (i.e., PK analysis set). If the data is sufficient, the non-compartmental model will be used to analyze the blood drug concentration data with Winnolin software to calculate the relevant PK parameters, including: t _1/2 , T _max , C _max , AUC _0-∞ , AUC _0-t , CL/F, V _Z /F, etc. When necessary, the population PK method will be used to characterize the PK characteristics of the drug. The blood drug concentration data and PK parameters will be described using appropriate statistical tables and graphs.

˙Immunogenicity analysis:

Calculate the positive rate of PD-1 antibody IBI308 anti-drug antibody (ADA) and neutralizing antibody (NAb), and use descriptive statistical analysis for summary. The list describes the antibody levels of positive patients.

˙Biomarker analysis:

It is used to provide the results of descriptive statistical analysis that the biomarkers may be related to the prognosis of the disease.

8. Results

8.1 Dose escalation study phase

˙Demography and other baseline characteristics

In the dose-escalation study phase, 23 subjects received treatment, and the average age (± standard deviation) of the subjects was 54.23 (±12.351) years, of which 13 were male subjects (56.5%); All of them were Han nationality; the median of Body Mass Index (BMI) was 23.72kg/m ² (range: 19.0-28.7kg/m ² ); 22 subjects (accounting for 95.7%) had an ECOG score of 1 point, 1 case (4.3%) has a score of 0. The research phase includes four research cohorts (cohort A, cohort B, cohort C, and cohort E).

All subjects were patients with unresectable or metastatic advanced solid tumors, including 1 case of cholangiocarcinoma (4.3%), 1 case of gallbladder cancer (4.3%), 11 cases of colon cancer (47.8%), and 1 case of rectal cancer ( 4.3%), 1 case of ovarian cancer (4.3%), 1 case of gastric cancer (4.3%), and 7 cases (30.4%) of other tumors. The median time from the initial diagnosis of the disease to the first administration of the study was 26.71 months (range: 2.0-125.4 months); 22 (95.7%) subjects had a history of tumor-related surgery, and 22 (95.7%) subjects Previously received chemotherapy and targeted therapy, and 9 patients (39.1%) had previously received radiotherapy.

˙Safety analysis results:

3級的TEAE；有9例(39.1%)受試者發生CTCAE

3級的治療相關的TEAE(TRAE)；有7例(30.4%)受試者發生治療期間嚴重不良反應(TESAE)；有4例(17.4%)受試者發生治療相關TESAE；無導致死亡的治療相關TESAEs發生(見表5)。最大耐受劑量(MTD)未達到。CTCAE

3級的TEAE中最常見的為：天冬胺酸胺基轉移酶升高、掌蹠紅腫綜合征、高血壓、結合膽紅素升高、γ-穀胺醯轉移酶升高、丙胺酸胺基轉移酶升高、肌鈣蛋白T升高、血膽紅素升高、總膽汁酸增加、甘膽酸升高、降鈣素原增高、高血糖症、食欲下降、高胺血症、呼吸衰竭、口腔潰瘍、肝功能異常。 As of September 15, 2020, 12 cases (52.2%) of the subjects had CTCAE during the dose escalation phase

Grade 3 TEAE; CTCAE occurred in 9 subjects (39.1%)

Grade 3 treatment-related TEAE (TRAE); 7 cases (30.4%) of subjects had serious adverse reactions (TESAE) during treatment; 4 cases (17.4%) of subjects had treatment-related TESAEs; no deaths Treatment-related TESAEs occurred (see Table 5). The maximum tolerated dose (MTD) has not been reached. CTCAE

The most common grade 3 TEAEs are: elevated aspartate aminotransferase, palmoplantar swelling syndrome, hypertension, elevated conjugated bilirubin, elevated gamma-glutamine transferase, alanine Elevated base transferase, increased troponin T, increased blood bilirubin, increased total bile acid, increased glycocholic acid, increased procalcitonin, hyperglycemia, decreased appetite, hyperamineemia, respiration Failure, oral ulcers, abnormal liver function.

Table 5. Summary of adverse events in the dose-escalation phase (ITT population)

˙Results of effectiveness analysis:

In the ITT population, 23 subjects received efficacy evaluation. According to the RECIST v1.1 standard, the overall efficacy of the confirmed tumors evaluated by the investigator is shown in Table 6. Three subjects (13.0%) achieved partial remission. The best curative effect for 16 subjects (69.6%) was stable disease (SD). ORR and its 95% CI were 13.0% (2.8-33.6). The DCR and its 95% CI are 82.6% (61.2-95.0).

Table 6. Overall best efficacy evaluation in the dose-escalation phase (ITT population) ^a

According to the results of the safety analysis and effectiveness analysis of the dose escalation study phase, the dose extension study phase was selected to be carried out at the two dose levels of cohort C and cohort E.

8.2 Dose extension research phase:

˙Demography and other baseline characteristics

In the dose extension study phase, as of September 15, 2020, 37 patients with advanced colorectal cancer (CRC) were enrolled and received treatment evaluation; as of November 18, 2020, 44 patients with advanced colorectal cancer had been enrolled. Colorectal cancer (Colorectal Cancer, CRC) subjects received treatment evaluation, the average age (± standard deviation) of the subjects was 55.02 (±10.353) years; 30 male subjects (81.1%); all The subjects were all Han nationality; the average BMI (± standard deviation) was 24.71 (±3.328) kg/m ² ; the ECOG score of 20 subjects (54.1%) was 1 point, and 17 subjects (45.9%) The score is 0 points.

The research phase includes the following dosing regimens:

Dosing regimen 1: Fruquintinib 5mg, once a day (QD), orally, continuous medication for 2 weeks, withdrawal for 1 week; PD-1 antibody IBI308 200mg, intravenous drip (IV), once every 3 weeks (Q3W ).

Dosing regimen 2: Fruquintinib 3 mg, once a day (QD), oral, continuous medication; PD-1 antibody IBI308 200 mg, intravenous drip (IV), once every 3 weeks (Q3W).

˙Safety analysis results:

3級的TEAE；有14例(37.8%)受試者發生CTCAE

3級的治療相關TEAE(TRAE)；有11例(29.7%)受試者發生治療期間嚴重不良反應(TESAE)；有5例(13.5%)受試者發生治療相關TESAEs；無導致死亡的治療相關TESAEs發生(見表7)；聯合用藥整體安全性可控。對兩個給藥方案進行了安全性比較，其中給藥方案1有31.6%的受試者發生了

3級的TEAE，26.3%的受試者發生了

3級的TRAE，15.8%的受試者發生了SAE；而在給藥方案2中，有66.7%的受 試者發生了

3級的TEAE，50%的受試者發生了

3級的TRAE，44.4%的受試者發生了SAE。這提示給藥方案1具有更好的安全性。CTCAE

3級的TEAE中最常見的為：高血壓、天冬胺酸胺基轉移酶升高、γ-穀胺醯轉移酶升高、血鹼性磷酸酶升高、高甘油三酯血症、貧血各有2例(5.4%)、血小板計數降低和血膽紅素升高。 As of September 15, 2020, 18 subjects (48.6%) had CTCAE

Grade 3 TEAE; CTCAE occurred in 14 subjects (37.8%)

Grade 3 treatment-related TEAE (TRAE); 11 cases (29.7%) of subjects experienced serious adverse reactions (TESAE) during treatment; 5 cases (13.5%) of subjects experienced treatment-related TESAEs; no treatment leading to death Related TESAEs occurred (see Table 7); the overall safety of the combination is controllable. The safety of the two dosing regimens was compared. Among them, 31.6% of the subjects in dosing regimen 1 had

Grade 3 TEAE occurred in 26.3% of subjects

For grade 3 TRAE, SAE occurred in 15.8% of subjects; while in Dosing Plan 2, 66.7% of subjects experienced

Grade 3 TEAE occurred in 50% of subjects

For grade 3 TRAE, SAE occurred in 44.4% of subjects. This suggests that dosing regimen 1 has better safety. CTCAE

The most common of grade 3 TEAEs are: hypertension, elevated aspartate aminotransferase, elevated γ-glutamine transferase, elevated blood alkaline phosphatase, hypertriglyceridemia, anemia In each of 2 cases (5.4%), the platelet count was decreased and the blood bilirubin was increased.

Table 7. Summary of adverse events during the dose extension phase (CRC ITT population)

˙Results of effectiveness analysis:

In the ITT population, as of November 18, 2020, 44 subjects have undergone efficacy evaluation. According to the RECIST v1.1 standard, the overall efficacy of the confirmed tumors evaluated by the investigator is shown in Table 8. 10 cases (22.7%) of the subjects achieved partial remission (PR), and a total of 25 cases (56.8%) of the subjects had the best efficacy For stable disease (SD), the overall objective response rate ORR was 9.1% (95%CI: 11.5-37.8), the overall disease control rate DCR was 79.5% (95%CI: 64.7-90.2), and the overall median PFS (Median PFS) ) Was 5.6 months, while the standard treatment (fruquintinib single agent) median PFS was only 3.7 months. Comparing plan 1 and plan 2, 6 cases of PR (27.3%) in plan 1 and 4 cases of PR (18.2%) in plan 2; 15 subjects in plan 1 reached stable disease (SD), and 10 cases in plan 2 The subjects reached stable disease (SD); the objective response rate ORR in plan 1 was 27.3%, and the objective response rate ORR in plan 2 was 13.6%; the disease control rate DCR in plan 1 was 95.5%, and the disease control in plan 2 The DCR rate was 63.6%; the median PFS in Plan 1 was 6.8 months, and the median PFS in Plan 2 was 5.6 months. The above comparison shows that the treatment effectiveness of Option 1 is better than that of Option 2.

Table 8. Overall Best Efficacy Evaluation in the Dose Expansion Phase (CRC ITT Population) ^a

^a Remission is confirmed according to RECIST v1.1, see SAP for details.

^b 95% CI calculated by the accurate (Clopper-Pearson) method.

8.3 Results of immunogenicity analysis:

As of September 15, 2020, 60 subjects (including 23 in the dose escalation stage and 37 in the dose expansion stage) 178 ADA test samples have been evaluated. Among them, there were 23 subjects and 92 biological samples in the dose-escalation phase; 37 subjects and 86 biological samples were in the research expansion phase. All samples were tested in Shanghai Covance using a validated electrochemiluminescence method. The main indicators for assessing the incidence of immunogenicity include: baseline anti-drug antibody (ADA) positive rate, ADA positive rate during treatment, ADA titer, Neutralizing antibody (NAb) positive rate during the treatment period. The results of immunogenicity testing and the incidence of immunogenicity are as follows.

All 60 enrolled subjects underwent baseline immunogenicity testing, of which 53 were ADA-negative and 7 were ADA-positive (including 3 NAb-positive), and the baseline ADA-positive rate was 11.7% (Table 9).

53 subjects underwent immunogenicity testing during the treatment period, so they were included in the immunogenic treatment period to evaluate subjects. During the treatment period, 47 subjects with negative ADA at baseline were not detected to be ADA positive after administration; there were 6 subjects with positive ADA at baseline (including 3 NAb positive) subjects, and 4 of them were after administration ADA turned negative, and ADA was still positive after administration in 2 cases (NAb test results were all positive), but the titer was less than 4 times the baseline titer. Of the 3 subjects who were NAb-positive at baseline, 2 cases remained NAb-positive after administration, and 1 case was NAb-negative after administration. Subjects can be evaluated based on the treatment period. The ADA positive rate (including treatment-induced ADA positive and treatment-induced ADA titer enhancement) during the treatment period is 0%, and the NAb positive rate during the treatment period is 0% (Table 10).

Seven subjects were not included in the immunogenicity assessment during the treatment period due to no treatment period samples, including 6 baseline ADA-negative subjects and 1 baseline ADA-positive subject. This ADA-positive subject had a negative NAb (Table 10).

Table 9. Summary of baseline immunogenicity test results

Table 10. Summary of immunogenicity test results during the treatment period

Therefore, the combination of PD-1 antibody and Fruquintinib prolongs disease-free period (PFS), prolongs overall survival (OS), improves objective response rate (ORR), prolongs duration of remission (DOR), and improves disease control Rate (DCR) and the overall safety of the combination medication is controllable; the patients are well tolerated.

Although certain representative embodiments and details have been shown for the purpose of illustrating the present invention, it will be obvious to those skilled in the art that various changes and modifications can be made to them without departing from the scope of the subject invention. In this respect, the scope of the present invention is limited only by the scope of the following patent applications.

<110> INNOVENT BIOLOGICS (SUZHOU) CO., LTD. Hutchison Whampoa Pharmaceutical (Shanghai) Co., Ltd. (HUTCHISON MEDIPHARMA LIMITED)

<120> The drug combination of anti-PD-1 antibody and quinazoline derivative, its use, and the method of using it (PHARMACEUTICAL COMBINATION OF ANTI-PD-1 ANTIBODY AND QUINAZOL INE DERIVATICVES AND USE THEREOE, AND METHODS USING THE SAME)

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<220>

<223> LCDR1 of anti-PD-1 antibody 11430

<400> 6

<210> 7

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> VH of anti-PD-1 antibody 11430

<400> 7

<210> 8

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> VL of anti-PD-1 antibody 11430

<400> 8

<210> 9

<211> 448

<212> PRT

<213> Artificial sequence

<220>

<223> Heavy chain sequence of anti-PD-1 antibody 11430

<400> 9

<210> 10

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<223> Light chain sequence of anti-PD-1 antibody 11430

<400> 10

<210> 11

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> HCDR1 of anti-PD-1 antibody IBI308

<400> 11

<210> 12

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> HCDR2 of anti-PD-1 antibody IBI308

<400> 12

<210> 13

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<223> HCDR3 of anti-PD-1 antibody IBI308

<400> 13

<210> 14

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> LCDR1 of anti-PD-1 antibody IBI308

<400> 14

<210> 15

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> LCDR2 of anti-PD-1 antibody IBI308

<400> 15

<210> 16

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> LCDR3 of anti-PD-1 antibody IBI308

<400> 16

<210> 17

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> VH of anti-PD-1 antibody IBI308

<400> 17

<210> 18

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> VL of anti-PD-1 antibody IBI308

<400> 18

<210> 19

<211> 447

<212> PRT

<213> Artificial sequence

<220>

<223> Heavy chain sequence of anti-PD-1 antibody IBI308

<400> 19

<210> 20

<211> 214

<212> PRT

<213> Artificial sequence

<220>

<223> Light chain sequence of anti-PD-1 antibody IBI308

<400> 20

Claims (18)

A pharmaceutical combination comprising (i) an anti-PD-1 antibody and/or an antigen-binding fragment thereof and (ii) a quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof, The anti-PD-1 antibody contains 6 CDRs, among which HCDR1, HCDR2 and HCDR3 are composed of amino acid sequences KASGGTFSSYAIS (SEQ ID NO: 11), LIIPMFDTAGYAQKFQG (SEQ ID NO: 12) and ARAEHSSTGTFDY (SEQ ID NO: 13), respectively And LCDR1, LCDR2 and LCDR3 are respectively composed of amino acid sequences RASQGISSWLA (SEQ ID NO: 14), SAASSLQS (SEQ ID NO: 15) and QQANHLPFT (SEQ ID NO: 16); or The anti-PD-1 antibody contains 6 CDRs, of which HCDR1, HCDR2 and HCDR3 are respectively composed of amino acid sequences KASGYTFTAQYMH (SEQ ID NO: 1), IINPSGGETGYAQKFQG (SEQ ID NO: 2) and AKEGVADGYGLVDV (SEQ ID NO: 3), And LCDR1, LCDR2 and LCDR3 are respectively composed of amino acid sequences RASQSVSSYLA (SEQ ID NO: 4), YDASKRAT (SEQ ID NO: 5) and DQRNNWPLT (SEQ ID NO: 6); The quinazoline derivative of formula (I) has the following structure:

Wherein R ₁ , R ₂ , R ₅ , R ₈ , R ₉ and R ₁₀ are each independently H, halogen, nitro, amino, cyano, hydroxyl, alkyl containing 1-10 carbon atoms, containing 2 Alkenyl with -10 carbon atoms, alkynyl with 2-10 carbon atoms, 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aryl, cycloalkyl with 3-12 carbon atoms, 3- 8-membered monocyclic, 8-12-membered bicyclic or 11-14-membered tricyclic heterocycloalkyl, 5-8-membered monocyclic, 8-12-membered bicyclic or 11-14-membered tricyclic heteroaryl, alkoxy, alkane Thio group, alkylcarbonyl group, carboxyl group, alkoxycarbonyl group, aminocarbonyl group or aminosulfonyl group; Wherein R ₃ and R ₄ are each alkoxy; R ₆ is an alkyl group; R ₇ is _{-C (O) NR a R b} , R a and R _{b are} each independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, or R _a and R _b , together with the N atom to which they are connected, form a 3-8 membered ring containing 1-3 heteroatoms; X is O; and Z is N; Among them, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and alkoxy may or may not contain substituents, and the substituents are selected from halogen, hydroxyl, Hydroxyl, amino, cyano, nitro, sulfhydryl, alkoxycarbonyl, amide, carboxy, alkylsulfonyl, alkylcarbonyl, ureido, carbamate, carboxyl, thiourea, thiocyanate Group, sulfonamido, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. The drug combination according to claim 1, wherein The anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 17 or is at least 90%, 95%, 98% or 99% identical to it Sexual sequence, and the variable region of the light chain comprises the sequence of SEQ ID NO: 18 or a sequence that is at least 90%, 95%, 98% or 99% identical to it; Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 19 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and SEQ ID NO: 20 or a heavy chain sequence with at least 90% identity. %, 95%, 98% or 99% identical light chain sequence; or The anti-PD-1 antibody comprises a heavy chain variable region VH and a light chain variable region VL , wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or is at least 90%, 95%, 98% or 99% identical to it Sexual sequence, and the light chain variable region comprises the sequence of SEQ ID NO: 8 or a sequence that is at least 90%, 95%, 98% or 99% identical to it; Preferably, the anti-PD-1 antibody comprises SEQ ID NO: 9 or a heavy chain sequence with at least 90%, 95%, 98% or 99% identity and SEQ ID NO: 10 or at least 90% therewith , 95%, 98% or 99% identity of the light chain sequence. The pharmaceutical combination according to claim 1 or 2, wherein the quinazoline derivative of formula (I) is fruquintinib. The drug combination according to any one of claims 1 to 3, wherein (i) It is in the form of a dosage unit of 100-300 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg or 300 mg, more preferably 200 mg, preferably a parenteral, more preferably intravenous administration form; and (ii) It is in the form of a dosage unit of 1-8 mg, preferably 2 mg, 3 mg, 4 mg, 5 mg or 6 mg, preferably an oral administration dosage form. The drug combination according to any one of claims 1 to 4, wherein: The single dose of (i) is selected from 100-300 mg, preferably 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg, which is preferably administered parenterally, preferably intravenously, more preferably by infusion; more preferably 200 mg ;with The daily dose of (ii) is selected from 1-8 mg, preferably 2 mg, 3 mg, 4 mg, 5 mg, 6 mg or 7 mg, which is preferably administered orally. The drug combination according to any one of claims 1 to 5, which is administered in cycles, and each cycle is 14 to 30 days, preferably 14 days, 21 days or 28 days, wherein Administer once in each cycle (i), and Continuously administer (ii) at least on the 1st to 7th day of each cycle, preferably on the 1st to 14th day or on the 1st to 21st day (ii) and then discontinue the drug until the end of the cycle, preferably discontinue 7 Days, or preferably continuously in each cycle (ii). The drug combination according to any one of claims 1 to 6, which is administered in cycles, and each cycle is three to four weeks, wherein Administer once in each cycle (i), and Continuous administration in each cycle (ii); or first continuous administration in each cycle (ii), and then stop administration in the last week of each cycle (ii). The drug combination according to any one of claims 1 to 7, wherein The drug combination is administered in a cycle every four weeks, wherein the dose of (i) is 200 mg, which is administered once per cycle, preferably intravenously, and the daily dose of (ii) is 2 mg to 6 mg, preferably 2 mg, 3 mg, 4 mg , 5mg or 6mg, administered continuously in each cycle, or continuously administered for three weeks, and then stopped for one week, preferably oral administration; or The drug combination is administered in a cycle every three weeks, wherein the dosage of (i) is 200 mg, once per cycle, preferably intravenously, and the daily dosage of (ii) is 2 mg to 6 mg, preferably 2 mg, 3 mg , 4mg, 5mg or 6mg, administered continuously in each cycle, or continuously administered for two weeks, and then stopped for one week, preferably oral administration. The drug combination according to any one of claims 1 to 8, wherein Administer once in each cycle (i), Continuous administration (ii) in each cycle, and Each cycle is three or four weeks. The drug combination according to any one of claims 1 to 9, wherein The intravenous dose of (i) is 200 mg, preferably the dose is a single dose; and (ii) The oral daily dose is 3 mg or 4 mg; preferably, the dose is a single administration dose. The drug combination according to any one of claims 1 to 10, wherein The intravenous dose of (i) is 200 mg, preferably the dose is a single dose; and (ii) The oral daily dose is 5 mg or 6 mg, preferably the dose is a single-use dose. The drug combination according to any one of claims 1 to 11, wherein Administer once in each cycle (i), Administer (ii) continuously for two weeks in each cycle, then stop the drug for one week, and Each cycle is three weeks. The drug combination according to any one of claims 1 to 12, wherein (i) and (ii) are administered separately, simultaneously or sequentially; preferably on the day of intravenous administration (i), oral administration (ii) . The drug combination according to any one of claims 1 to 13, which is used for the prevention or treatment of cancer, wherein the cancer is preferably a solid tumor, which is preferably selected from cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, ovarian cancer, Endometrial cancer, lung cancer (such as non-small cell lung cancer), thymus cancer, kidney cancer, melanoma, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors (such as gastric cancer, gastric adenocarcinoma, gastroesophageal junction gland) Cancer, colon cancer, colorectal cancer, colorectal adenocarcinoma), brain cancer and bone cancer, or hematological cancer, which are preferably selected from leukemia and Hodgkin's lymphoma. The drug combination according to any one of claims 1 to 14, which is used for the treatment of cancer patients with an objective response rate ORR greater than 15% and a median PFS greater than 4 months. A use of the drug combination according to any one of claims 1 to 15 in the preparation of a drug for the prevention or treatment of cancer, the cancer is preferably a solid tumor, which is preferably selected from cholangiocarcinoma, gallbladder cancer, liver cancer Cell cancer, ovarian cancer, endometrial cancer, lung cancer (e.g. non-small cell lung cancer), thymic cancer, kidney cancer, melanoma, head and neck cancer, bladder cancer, prostate cancer, breast cancer, gastrointestinal tumors (e.g. stomach cancer, gastric adenocarcinoma) , Gastroesophageal junction adenocarcinoma, colon cancer, colorectal cancer, colorectal adenocarcinoma), brain cancer and bone cancer, or hematological cancer, which is preferably selected from leukemia and Hodgkin's lymphoma. A method for preventing or treating cancer, the method comprising administering an effective amount of the drug combination according to any one of claims 1 to 15 to a patient in need, and the cancer is preferably a solid tumor, which is preferably From cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, ovarian cancer, endometrial cancer, lung cancer (e.g. non-small cell lung cancer), thymic cancer, kidney cancer, melanoma, head and neck cancer, bladder cancer, prostate cancer, breast Cancer, gastrointestinal tumors (such as gastric cancer, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, colon cancer, colorectal cancer, colorectal adenocarcinoma), brain cancer and bone cancer, or hematological cancer, which are preferably selected from leukemia and Hodgkin's lymphoma. A kit of medicines comprising the drug combination according to any one of claims 1 to 15, preferably the kit is in the form of a medicine dosage unit.

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