WO2021143671A1 - Composition pharmaceutique d'anticorps anti-pd-1 et de dérivé de quinazoline, utilisations de la composition et son procédé d'utilisation - Google Patents

Composition pharmaceutique d'anticorps anti-pd-1 et de dérivé de quinazoline, utilisations de la composition et son procédé d'utilisation Download PDF

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WO2021143671A1
WO2021143671A1 PCT/CN2021/071254 CN2021071254W WO2021143671A1 WO 2021143671 A1 WO2021143671 A1 WO 2021143671A1 CN 2021071254 W CN2021071254 W CN 2021071254W WO 2021143671 A1 WO2021143671 A1 WO 2021143671A1
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cancer
cycle
seq
antibody
dose
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PCT/CN2021/071254
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Chinese (zh)
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陈炳良
刘扬
谭攀峰
尹红燕
范士明
任永欣
王岩
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信达生物制药(苏州)有限公司
和记黄埔医药（上海）有限公司
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Publication of WO2021143671A1 publication Critical patent/WO2021143671A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the invention relates to the field of medicine. Specifically, the present invention relates to a pharmaceutical combination comprising an anti-PD-1 antibody or an antigen-binding fragment thereof targeting programmed death-1 (programmed death-1 (PD-1)) and a quinazoline derivative, which is used for Prevent or treat cancer.
  • PD-1 programmed death-1
  • the present invention also relates to uses and methods 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 immunosuppression (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, and the like.
  • 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.
  • anti-PD-1 antibodies 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.
  • tumor angiogenesis is also an important reason for the rapid growth of tumors (Ferrara N and Alitalo K, Clinical applications of angiogenic growth factors and their inhibitors, Nat Med., 1999; 5(12): 1359-64) .
  • Tumor angiogenesis is a very complicated process, which is regulated by a variety of factors.
  • vascular endothelial growth factor vascular endothelial growth factor, VEGF
  • VEGF vascular endothelial growth factor family
  • VEGF vascular endothelial growth factor family
  • Migrate improve vascular permeability, inhibit tumor cell apoptosis, and provide a good microenvironment for tumor growth and metastasis.
  • VEGFR inhibitors are disclosed in the prior art, such as sorafenib, sunitinib, vatalanib, axitinib, apatinib ( apatinib), tivozanib, etc. They are small molecule VEGFR inhibitors with different mechanisms of action.
  • AE adverse events
  • 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.
  • the present invention provides the following embodiments:
  • 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 Wherein LCDR1, LCDR2 and LCDR3 are respectively composed of the amino acid sequence 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 among them LCDR1, LCDR2 and LCDR3 respectively consist of the amino acid sequence 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:
  • 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 Member monocyclic, 8-12 member bicyclic or 11-14 member tricyclic heterocycloalkyl, 5-8 member monocyclic, 8-12 member bicyclic or 11-14 member tricyclic heteroaryl, alkoxy, alkylsulfide Group, alkylcarbonyl group, carboxyl group, alkoxycarbonyl group, aminocarbonyl group or aminosulfonyl group;
  • 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
  • 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, mercapto, alkoxycarbonyl, amide, carboxy, alkylsulfonyl, alkylcarbonyl, ureido, carbamoyl, carboxy, thiourea, thiocyano, sulfonyl Amino, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.
  • 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 light chain variable region includes the sequence of SEQ ID NO: 18 or a sequence that is at least 90%, 95%, 98% or 99% identical to it;
  • 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: 20 or has at least 90% identity therewith. %, 95%, 98% or 99% identity of the light chain sequence;
  • 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 includes the sequence of SEQ ID NO: 8 or a sequence that is at least 90%, 95%, 98% or 99% identical to it;
  • the anti-PD-1 antibody comprises SEQ ID NO: 9 or a heavy chain sequence having at least 90%, 95%, 98% or 99% identity with SEQ ID NO: 10 or at least 90% therewith, 95%, 98% or 99% identity of the light chain sequence.
  • R a and R b in the quinazoline derivative of formula (I) are each independently H, alkyl or cycloalkyl.
  • the single administration 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; and
  • 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.
  • Continuous administration 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 subsequent withdrawal to the end of the cycle, preferably for 7 days, Or it is preferably administered continuously in each cycle (ii).
  • 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, 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.
  • Each cycle is three or four weeks.
  • Each cycle is three weeks.
  • Each cycle is four weeks.
  • the single administration dose is 200 mg.
  • the daily dose of (ii) is 3 mg, preferably the dose is a single administration dose.
  • the intravenous administration dose is 200 mg, preferably the dose is a single administration dose;
  • the oral daily dose of (ii) is 3 mg, preferably the dose is a single administration dose.
  • the single administration dose is 200 mg.
  • the daily dose of (ii) is 4 mg, preferably the dose is a single administration dose.
  • the intravenous administration dose is 200 mg, preferably the dose is a single administration dose;
  • the oral daily dose of (ii) is 4 mg, preferably the dose is a single administration dose.
  • the single administration dose is 200 mg.
  • the daily dose of (ii) is 5 mg, preferably the dose is a single-use dose.
  • the intravenous administration dose is 200 mg, preferably the dose is a single administration dose;
  • the oral daily dose is 5 mg, preferably the dose is a single-use dose.
  • the single administration dose is 200 mg.
  • the daily dose of (ii) is 6 mg, preferably the dose is a single-use dose.
  • the intravenous administration dose is 200 mg, preferably the dose is a single administration dose;
  • the oral daily dose is 6 mg, preferably the dose is a single-use dose.
  • 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.
  • 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 5 mg, which is continuously administered in each cycle Two weeks, and then stop the drug for one week, preferably oral administration.
  • the cancer is preferably a solid tumor, which is preferably selected from cholangiocarcinoma, gallbladder cancer, hepatocellular carcinoma, ovarian cancer, intrauterine cancer Membrane 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.
  • lung cancer such as non-small cell lung cancer
  • thymus cancer kidney cancer
  • melanoma head and neck cancer
  • bladder cancer prostate cancer
  • breast cancer breast cancer
  • gastrointestinal tumors such as gastric cancer, gastric adenocarcinoma, gastroesophageal
  • 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, 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.
  • 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 cancer Tract 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 lymph tumor.
  • 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, breast cancer, gastrointestinal cancer Tract tumors (such as
  • kits 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.
  • 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 furquintinib on the survival time of MC38 tumor-bearing mice.
  • the term “comprising” or “including” means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps.
  • the term “comprises” or “includes” when used, unless otherwise specified, it also encompasses the situation consisting of the stated elements, integers or steps.
  • an antibody variable region that "comprises” a specific sequence 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.
  • antibody is used in the broadest sense and refers to a protein containing an antigen-binding site, covering natural and artificial antibodies of various structures, including but not limited to intact 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 chain (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 divided into hypervariable regions (complementarity determining regions (CDR)), with more conservative regions (framework regions (FR)) interposed between them.
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL consists of three CDRs and four FR composition, arranged in the following order from the amino terminus to the carboxy terminus: 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.
  • the precise amino acid sequence boundary 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", Journal of Molecular Biology, 196,901-917 (1987)); Kabat numbering plan (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, USDepartment of Health and Human Services of National Institutes (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 defined according to the North
  • CDRs are 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.
  • 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 residues 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.
  • antigen-binding fragment is a part or section of a complete or complete antibody that has fewer amino acid residues than a complete or complete antibody, which can bind to the antigen or compete with the complete antibody (ie, the complete antibody from which the antigen-binding fragment is derived) Binding antigen.
  • 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.
  • the Fab fragment can be obtained by papain digestion of a complete antibody.
  • 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.
  • 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 fragments can be obtained by chemical methods, recombinant DNA methods or protease digestion methods.
  • humanized antibody refers to a chimeric antibody comprising amino acid residues from non-human CDRs and amino acid residues from human FRs.
  • 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.
  • 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 M, as measured in the MSD assay.
  • an affinity constant of -1 and more preferably about 10 9 M -1 or stronger binds to PD-1 expressed on the surface of T lymphocytes.
  • 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.
  • 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.
  • the anti-PD-1 antibody or antigen-binding fragment thereof used in the pharmaceutical combination and the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof are administered at a level not exceeding 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.
  • the dosage and/or time interval of the two active agents are selected, 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.
  • 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 within the cycle.
  • 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 route of administration of each active ingredient in the pharmaceutical combination of the present invention includes oral, intravenous (e.g., infusion (also known as drip) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, local or other parenteral routes of administration .
  • parenteral administration refers to methods of administration other than gastrointestinal and topical administration, usually via 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.
  • 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.
  • continuous administration refers to daily 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.
  • 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.
  • salts includes, but is not limited to, acid addition salts or base addition salts, for example: acid addition salts formed by compounds of formula (I) with inorganic acids, such as hydrochloride, hydrobromide, and carbonic acid Salts, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed by compounds of formula (I) with organic acids, such as formates, acetates, malates, and Lysoate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate Salts, stearates, and salts formed with alkane dicarboxylic acids of the formula HOOC-(CH 2 ) n -COOH (where n is 0-4), etc.
  • inorganic acids such as hydrochloride, hydrobromide, and
  • pharmaceutically acceptable refers to those compounds and 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.
  • 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 cancer and bone cancer, leukemia, and Hodgkin Lymphoma.
  • the cancer is preferably advanced cancer, recurrent and/or refractory cancer, or cancer resistant to chemotherapy, more preferably advanced solid tumor, such as (confirmed by histology or cytology) that cannot be surgically removed or metastatic Advanced solid tumors.
  • inhibitor means that a given molecule (e.g. (i) 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.
  • a given molecule e.g. (i) anti-PD-1 antibody or antigen-binding fragment thereof and/or (ii) a quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof
  • the term includes inhibition of activity of at least 5%, 10%, 20%, 30%, 40% or more. Therefore, the suppression does not have to be 100%.
  • 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.
  • 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.
  • 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.
  • AE adverse event
  • an adverse event may be related to the activation of the immune system in response to treatment or the expansion of immune system cells (e.g., T cells) in response to treatment.
  • Medical treatments can have one or more related AEs, and each AE can have the same or different levels of severity.
  • progression-free survival refers to the time from the first use of the drug under study to the onset of disease progression or death from any cause.
  • 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-carboxamide, which has the following structural formula
  • anti-PD-1 antibody 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 introduced This article.
  • 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
  • the antibody C-S228P IgG4 is also referred to as PD-1 antibody 11430 in this application.
  • 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 6 M -1.
  • the affinity constant of 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 cytokines Such as IL-2.
  • the anti-PD-1 antibody or antigen-binding fragment thereof in the drug combination has a K D of less than about 150 pM, such as by MSD assay (Estep, P.
  • the anti-PD-1 antibody in the drug 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 composed of amino acid sequences RASQGISSWLA (SEQ ID NO: 14), SAASSLQS (SEQ ID NO: 15) and QQANHLPFT (SEQ ID NO: 16), respectively.
  • the CDR sequence is a CDR sequence defined according to the North numbering scheme.
  • 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 includes the sequence of SEQ ID NO: 17 or has at least 90%, 95%, 98% thereof. % Or 99% identity sequence, and the light chain variable region includes the sequence of SEQ ID NO: 18 or a sequence that has at least 90%, 95%, 98% or 99% identity therewith.
  • the anti-PD-1 antibody comprises SEQ ID NO: 19 or a heavy chain sequence having at least 90%, 95%, 98% or 99% identity thereto, and SEQ ID NO: 20 or a heavy chain sequence having at least 90% identity therewith. %, 95%, 98% or 99% identity of the light chain sequence.
  • 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.
  • the anti-PD-1 antibody in the drug combination of the present invention contains 6 CDRs, wherein HCDR1, HCDR2 and HCDR3 are respectively composed of 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).
  • the CDR sequence is a CDR sequence defined according to the North numbering scheme.
  • 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% identity sequence, and the light chain variable region includes the sequence of SEQ ID NO: 8 or a sequence with at least 90%, 95%, 98%, or 99% identity.
  • the anti-PD-1 antibody comprises SEQ ID NO: 9 or a heavy chain sequence that is at least 90%, 95%, 98% or 99% identical to SEQ ID NO: 9 and SEQ ID NO: 10 or has at least 90% identity therewith. %, 95%, 98% or 99% identity of the light chain sequence.
  • 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:
  • 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 Member monocyclic, 8-12 member bicyclic or 11-14 member tricyclic heterocycloalkyl, 5-8 member monocyclic, 8-12 member bicyclic or 11-14 member tricyclic heteroaryl, alkoxy, alkylsulfide Group, alkylcarbonyl group, carboxyl group, alkoxycarbonyl group, aminocarbonyl group or aminosulfonyl group;
  • 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
  • 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, mercapto, alkoxycarbonyl, amide, carboxy, alkylsulfonyl, alkylcarbonyl, ureido, carbamoyl, carboxy, thiourea, thiocyano, sulfonyl Amino, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.
  • 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), and the half inhibitory concentration (IC 50 ) of the aforementioned three kinases They are 35nM, 33nM and 0.5nM respectively.
  • 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 >3 ⁇ M).
  • Fruquintinib also only showed strong inhibition of VEGFR kinase, while inhibiting other kinases, including platelet-derived growth factor receptor ⁇ (PDGFR ⁇ ). The activity is very weak or weak. Thus, Fruquintinib is a very selective VEGFR inhibitor.
  • anti-VEGFR inhibitors such as sorafenib, sunitinib, vatalanib, cabozantinib, briny Brivanib, cediranib, linifanib, regorafenib and famitinib, but they inhibit VEGFR and other angiogenesis with similar efficacy Receptors related to signal transduction. Because they inhibit many targets, they are different from the mechanism of Fruquintinib's highly selective inhibition of VEGFR kinase.
  • 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 Tumor, 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 cancer, bone cancer , Leukemia, Hodgkin’s lymphoma.
  • cholangiocarcinoma gallbladder cancer
  • hepatocellular carcinoma ovarian cancer
  • endometrial cancer lung cancer (such as non-small cell lung cancer), thymic cancer, kidney cancer, melanoma Tumor, head and neck cancer, bladder cancer, prostate cancer
  • the cancer is preferably advanced cancer, refractory cancer and/or cancer resistant to chemotherapy, more preferably advanced solid tumor, unresectable or metastatic advanced solid tumor (confirmed by histology or cytology).
  • 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 malignancy).
  • 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.
  • 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 Individuals with elevated levels of hydrogenase, KIT, carcinoembryonic antigen, vascular endothelial growth factor (VEGF)].
  • PD-L1 programmed death ligand 1
  • PSA prostate specific antigen
  • lactate Individuals with elevated levels of hydrogenase KIT
  • carcinoembryonic antigen vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • 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).
  • 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.
  • 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 antigen-binding fragment thereof is preferably an intravenous dosage form, such as an injection
  • 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 pharmaceutical 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.
  • 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 Administration of the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof, followed by withdrawal to the end of the cycle, preferably for 7 days, or preferably continuous administration in each cycle, preferably once a day on the day of administration, Preferably, each cycle is at least 14 to 35 days, at least 14 to 30 days, preferably 21 days or 28 days; or the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is continuously administered in each cycle. 2, 3 or 4 weeks and then stop the drug for 1 week or continue to be administered during the use cycle.
  • the anti-PD-1 antibody or antigen-binding fragment thereof is administered once in each cycle, and
  • 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, such as 200 mg, once per cycle, preferably intravenously, such as intravenous Instillation, 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, continuously administered in each cycle, or in each cycle 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 , Preferably oral administration.
  • 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 quinazoline of formula (I)
  • the daily dose of the 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.
  • 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, and 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 two weeks and then the drug is stopped for one week, preferably orally administered, for example, once a day.
  • the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination of the present invention may 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.
  • 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.
  • 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.
  • Administration 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).
  • 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 or The antigen-binding fragment thereof is administered about 1 hour, about 3 hours, about 6 hours, about 12 hours, or about 15 hours after the start of administration of the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof.
  • 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 may be about 15-60 minutes.
  • the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof in the pharmaceutical combination of the present invention is a capsule.
  • the quinazoline derivative of formula (I) or a pharmaceutically acceptable salt thereof is administered first.
  • 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).
  • PFS progression-free survival
  • OS overall survival
  • the administration of at least one The cycle of the drug combination of the present invention results in an increase in the PFS of the patient by 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.
  • 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.
  • the drug combination of the present invention results in an increase, preferably synergistically Increase the inhibitory effect on tumor growth.
  • 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%.
  • administration of the drug combination of the invention results in increased tumor regression, tumor shrinkage and/or disappearance.
  • administration of the drug combination of the invention results in increased tumor regression, tumor shrinkage and/or disappearance.
  • 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.
  • the drug combination of the present invention can increase progression-free survival or overall survival.
  • 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), computer tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetics analyze.
  • 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.
  • 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.
  • Another object of the present invention is to provide a kit of medicines, which contains the drug combination of the present invention, preferably the kit is in the form of a drug dosage unit.
  • dosage units can be provided according to the dosing schedule or drug administration interval.
  • 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.
  • Example 1 One of the effects of PD-1 antibody IBI308 and furquintinib in combination on H292 tumor-bearing mice
  • SPF Specific Pathogen Free, no specific pathogen
  • NOG female mice (15-18g, 35-41 days) were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. The quantity is 40, and 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.
  • 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 NOG mice were inoculated through the eye vein at the amount of 2 million human PBMC cells per mouse, thereby enabling the human PBMC to pass directly through NOG mice In a short period of time, the blood circulation is reconstructed successfully to simulate the NOG mouse model of the human immune environment. The research using the NOG mouse model that mimics the human immune environment is closer to clinical research.
  • 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.
  • the NOG mice were grouped into serpentine groups according to the tumor volume. Divided into 6 groups, 6 NOG mice in each 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 by 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.
  • CMC-Na sodium carboxymethyl cellulose
  • 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.
  • 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 inhibition rate is calculated as follows:
  • Tumor inhibition 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 End-of-tumor volume of the control group after administration-the volume of the tumor before administration of the control group.
  • Example 2 The effect of PD-1 antibody 11430 and furquintinib in combination on MC38 tumor-bearing mice
  • mIgG Mouse immunoglobulin G, mouse immunoglobulin G
  • SLM56-1000 the product number is SLM56-1000
  • batch number the batch number is SLM66-912.
  • PD-1 antibody 11430 was acquired by Sunshine Biopharmaceutical (Suzhou) Co., Ltd.
  • CMC-Na Sodium carboxymethyl cellulose
  • 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.
  • 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.
  • administering dose drug concentration ⁇ administration volume.
  • the drug concentration is generally formulated as 0.2mg/mL
  • Fruquintinib is 0.5% CMC-Na (sodium carboxymethyl cellulose), and the diluent of the anti-mouse PD-1 antibody 11430 and the mIgG control group is normal saline for injection.
  • 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.
  • 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.
  • 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 (Pharmacokinetic, PK) PK characteristics and effectiveness.
  • 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 the combined 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 Weekly, one cycle every 3 weeks; or Fruquintinib 3mg QD continuous oral; or Fruquintinib 4mg QD continuous oral.
  • PD-1 antibody IBI308 200mg, Q3W. At least 6 patients are required in the Maximum Tolerated Dose (MTD) group or the Recommended Phase 2Dose (RP2D) group.
  • MTD Maximum Tolerated Dose
  • R2D Recommended Phase 2Dose
  • the dose expansion phase it is planned to enroll about 126 to 169 patients to receive the phase II recommended dose (RP2D) treatment determined in the dose escalation phase, 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.
  • R2D phase II recommended dose
  • R2D phase II recommended dose
  • 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 advanced renal cell carcinoma containing clear cell components, Or advanced endometrial cancer, or advanced gastrointestinal tumors (gastric adenocarcinoma, gastroesophageal junction adenocarcinoma and colorectal adenocarcinoma) and so on.
  • 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.
  • the standard treatment requirements for patients with hepatocellular carcinoma, renal cell carcinoma, endometrial cancer and gastrointestinal tumors 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);
  • ECOG physical status score is 0 or 1;
  • the 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;
  • CNS Central Nervous System
  • ⁇ Use corticosteroids dose>10mg/day prednisone or other curative hormones
  • other immunosuppressive agents for systemic therapy within 4 weeks before the first medication
  • Any live vaccine or live attenuated vaccine will be vaccinated within 4 weeks before the first medication or during the study period;
  • ⁇ Have received any surgery or invasive treatment (except puncture biopsy, venous catheterization) within 4 weeks before the first medication; or unhealed wounds, ulcers, fractures;
  • ⁇ Patients have hypertension that is not controlled by drugs, which is defined as: systolic blood pressure ⁇ 140mmHg and/or diastolic blood pressure ⁇ 90mmHg;
  • ⁇ Patients with gastrointestinal diseases such as active ulcers of the stomach and duodenum, ulcerative colitis, or active bleeding from unresected tumors, or other conditions determined by the researcher that may cause gastrointestinal bleeding or perforation; or previous stomach Intestinal perforation or gastrointestinal fistula, which has not recovered after surgical treatment;
  • the tumor invades the structure of large blood vessels, such as the pulmonary artery, superior vena cava, or inferior vena cava.
  • the investigator judges 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;
  • test drug is Fruquintinib and PD-1 antibody IBI308, and the treatment plan is combination therapy.
  • 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;
  • 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 6 mg QD, orally, taking the drug continuously for 2 weeks and stopping for 1 week, with a cycle every 3 weeks;
  • Cohort F Fruquintinib 4mg QD orally;
  • ⁇ In combination with Fruquintinib for 3 consecutive weeks and stop for 1 week regimen group ie, cohort A and B groups: PD-1 antibody IBI308200mg, 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.
  • 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 ⁇ 1/6 patients with DLT), the dose escalation can be carried out to the next cohort study.
  • ⁇ Other safety indicators 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. ).
  • the RECIST 1.1 standard includes the objective response rate (Overall Response Rate, ORR, which is defined as the proportion of patients with complete or partial response in the best overall assessment), and the duration of response (DOR, which is defined as the Among patients with objective remission, the time from the first complete or partial remission to the disease progression or death due to any cause (whichever occurs earlier), the disease control rate (Disease Control Rate, DCR, is 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 development of disease 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).
  • ORR Average Response Rate
  • DOR Disease Control Rate
  • 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.
  • Evaluation indicators include anti-drug antibody (ADA) and neutralizing antibody (NAb).
  • the measurement data lists the number of people, mean, standard deviation, median, maximum, and minimum.
  • Count data and grade data list frequency and percentage.
  • 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).
  • 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 separately, and use the Clopper-pearson method to calculate the 95% accurate confidence interval (CI).
  • the analysis of PFS and OS will be based on the ITT set. For time-dependent variables including DoR, TTR, PFS, and OS, 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, if the data permits.
  • PK analysis set 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 through 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.
  • biomarkers may be related to the prognosis of the disease.
  • the research phase includes four research cohorts (cohort A, cohort B, cohort C, and cohort E).
  • the most common TEAEs with CTCAE ⁇ grade 3 are: elevated aspartate aminotransferase, palmoplantar swelling syndrome, hypertension, elevated conjugated bilirubin, elevated ⁇ -glutamyltransferase, alanine Increased acid aminotransferase, increased troponin T, increased blood bilirubin, increased total bile acid, increased glycocholic acid, increased procalcitonin, hyperglycemia, decreased appetite, hyperammonemia, Respiratory failure, oral ulcers, abnormal liver function.
  • Adverse events during treatment are defined as those occurring on or after the first administration of the study drug to 90 days after the last administration of the study drug or before the start of a new anti-tumor treatment (whichever occurs first).
  • the subject At each summary level, if the subject reports one or more events, the subject only counts once.
  • the dose extension study phase was selected to be carried out at the two dose levels of cohort C and cohort E.
  • Dosing regimen 1 Fruquintinib 5mg, once a day (QD), oral, continuous medication for 2 weeks, withdrawal for 1 week; PD-1 antibody IBI308 200mg, intravenous drip (IV), once every 3 weeks (Q3W ).
  • Dosage regimen 2 Fruquintinib 3mg, once a day (QD), oral, continuous medication; PD-1 antibody IBI308200mg, intravenous drip (IV), once every 3 weeks (Q3W).
  • Adverse events during treatment are defined as those occurring on or after the first administration of the study drug to 90 days after the last administration of the study drug or before the start of a new anti-tumor treatment (whichever occurs first).
  • the subject At each summary level, if the subject reports one or more events, the subject only counts once.
  • ADA test samples 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.
  • ADA baseline anti-drug antibody
  • NAb Neutralizing antibody
  • the numerator is the subjects whose treatment-induced ADA is positive and the treatment-induced ADA titer is increased ⁇ 4 times; the denominator is the subjects who can be evaluated during the treatment period.
  • the numerator is a subject who is NAb-negative at baseline and NAb-positive after treatment; the denominator is the subject that can be evaluated during the treatment period.
  • 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.
  • PFS disease-free period
  • OS overall survival
  • ORR objective response rate
  • DOR duration of remission
  • DCR disease control Rate

Abstract

L'invention concerne une composition pharmaceutique d'un anticorps anti-PD-1 et d'un dérivé de quinazoline, et des utilisations de la composition dans la prévention ou le traitement du cancer.
PCT/CN2021/071254 2020-01-13 2021-01-12 Composition pharmaceutique d'anticorps anti-pd-1 et de dérivé de quinazoline, utilisations de la composition et son procédé d'utilisation WO2021143671A1 (fr)

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