WO2023001283A1 - 用于治疗胃癌和/或食管胃结合部癌的联用药物 - Google Patents

用于治疗胃癌和/或食管胃结合部癌的联用药物 Download PDF

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WO2023001283A1
WO2023001283A1 PCT/CN2022/107363 CN2022107363W WO2023001283A1 WO 2023001283 A1 WO2023001283 A1 WO 2023001283A1 CN 2022107363 W CN2022107363 W CN 2022107363W WO 2023001283 A1 WO2023001283 A1 WO 2023001283A1
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Prior art keywords
antibody
seq
anlotinib
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/107363
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English (en)
French (fr)
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WO2023001283A9 (zh
Inventor
罗素霞
李宁
马一杰
别良玉
李佳君
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正大天晴药业集团股份有限公司
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Priority to CN202280046125.0A priority Critical patent/CN117597146A/zh
Priority to EP22845446.8A priority patent/EP4374875A1/en
Publication of WO2023001283A1 publication Critical patent/WO2023001283A1/zh
Publication of WO2023001283A9 publication Critical patent/WO2023001283A9/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the application belongs to the field of biomedicine, and specifically relates to a combined drug for treating gastric cancer and/or esophagogastric junction cancer.
  • Gastric cancer is a malignant tumor originating from the gastric mucosal epithelium. It is the most common malignant tumor of the digestive tract and one of the leading causes of cancer death worldwide. It is estimated that more than half of gastric cancer cases and deaths occur in my country. In 2015, there were approximately 679,000 new cases of gastric cancer and 498,000 deaths in China. It is the second most common cancer after lung cancer.
  • the first-line treatment of advanced gastric cancer is based on fluorouracil antineoplastic drugs (5-FU, capecitabine, S-1), combined with platinum (oxalidomide).
  • Platinum, cisplatin) and/or paclitaxel antineoplastic drugs constitute the main two-drug or three-drug chemotherapy regimen, but the median overall survival (mOS) does not exceed 1 year.
  • mOS median overall survival
  • most gastric cancer patients cannot tolerate follow-up treatment due to the deterioration of their condition.
  • First-line treatment is the best chance for gastric cancer patients to achieve curative effect. Therefore, it is necessary to actively explore and study new therapeutic drugs or methods.
  • the esophagogastric junction refers to a virtual anatomical junction between the esophagus and the stomach, specifically a region, which can be located by the following methods: In the barium meal examination of the digestive tract, it is the narrowest part of the lower esophagus area; endoscopically, it is the longitudinal palisade vessel in the lower esophagus or the upper edge of the proximal gastric fold; pathologically, it is the junction area between squamous epithelium and columnar epithelium; on gross specimen, it is the change in diameter of esophagus and gastric lumen Area.
  • esophagogastric junction cancer esophagogastric junction cancer
  • AEG adenocarcinoma of esophagogastric junction
  • the present application provides a drug combination for treating gastric cancer and/or esophagogastric junction cancer, which includes: an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the drug combination further includes at least one third therapeutic agent, and the third therapeutic agent is one or more of fluorouracil antineoplastic drugs, platinum antineoplastic drugs and paclitaxel antineoplastic drugs kind.
  • the fluorouracil antineoplastic drugs include but are not limited to those selected from capecitabine, 5-fluorouracil, bisfururacil, doxifluridine, trifluridine, tegafur, and carmofur One or more of , S-1, Ufdine;
  • the platinum antineoplastic drugs include but are not limited to selected from miplatin, cisplatin, carboplatin, bicycloplatin, nedaplatin, oxaliplatin, One or more of Lobaplatin, triplatin tetranitrate, phenanthroplatin, picoplatin, and satraplatin; One or more of paclitaxel and docetaxel.
  • the third therapeutic agent includes a fluorouracil antineoplastic drug and/or a platinum antineoplastic drug. In some embodiments, the third therapeutic agent includes capecitabine and/or a platinum-based antineoplastic drug. In some embodiments, the third therapeutic agent includes fluorouracil antineoplastic drugs and/or oxaliplatin. In some embodiments, the third therapeutic agent comprises capecitabine and/or oxaliplatin. In some embodiments, the third therapeutic agent comprises capecitabine and/or cisplatin. In some embodiments, the third therapeutic agent includes 5-fluorouracil and/or oxaliplatin.
  • the anti-PD-L1 antibody is a humanized anti-PD-L1 monoclonal antibody.
  • the third therapeutic agent includes: selected from capecitabine, 5-fluorouracil, bisfururacil, doxifluridine, trifluridine, tegafur, carmofur, tige One or more of Oral and Youfudine; and at least one selected from cisplatin, carboplatin, nedaplatin and oxaliplatin.
  • the third therapeutic agent includes: capecitabine, and at least one selected from cisplatin, carboplatin, nedaplatin, and oxaliplatin.
  • the present application provides a drug combination for treating non-HER2-positive gastric cancer and/or esophagogastric junction cancer, which includes: anti-PD-L1 antibody, and anlotinib or its pharmaceutically acceptable Accepted salt.
  • the pharmaceutical combination further includes at least one third therapeutic agent as described above.
  • the pharmaceutical combination further includes a pharmaceutically acceptable carrier.
  • the present application also provides a drug combination for treating gastric cancer and/or esophagogastric junction cancer, which includes the first drug combination administered to patients in need during initial treatment, and optionally, A second drug combination administered to patients in need during maintenance therapy, the first drug combination comprising an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, and at least one third therapeutic agent , the third therapeutic agent is one or more of fluorouracil antineoplastic drugs, platinum antineoplastic drugs and paclitaxel antineoplastic drugs; the second drug combination includes anti-PD-L1 antibody, and anrotinib Nephrine or a pharmaceutically acceptable salt thereof.
  • the third therapeutic agent includes a fluorouracil antineoplastic drug and/or a platinum antineoplastic drug. In some embodiments, the third therapeutic agent includes capecitabine and/or a platinum-based antineoplastic drug. In some embodiments, the third therapeutic agent includes fluorouracil antineoplastic drugs and/or oxaliplatin. In some embodiments, the third therapeutic agent comprises capecitabine and/or oxaliplatin. In some embodiments, the third therapeutic agent comprises capecitabine and/or cisplatin. In some embodiments, the third therapeutic agent includes 5-fluorouracil and/or oxaliplatin.
  • the initial treatment includes 0 to 10 treatment cycles, preferably 1 to 10 treatment cycles, more preferably 1 to 6 treatment cycles, most preferably 6 treatment cycles. In some embodiments, the initial treatment includes 0 to 10 continuous treatment cycles from the first administration, preferably 1 to 10 continuous treatment cycles, further preferably 1 to 6 continuous treatment cycles, most preferably continuous 6 treatment cycles.
  • the maintenance treatment is the treatment carried out after the initial treatment.
  • the application provides a drug combination for treating non-HER2-positive gastric cancer and/or EGJ cancer, comprising a first drug combination administered to a patient in need thereof during initial treatment, and optionally, the second drug combination administered to patients in need during maintenance treatment, the first drug combination includes anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, and at least one A third therapeutic agent, the third therapeutic agent is one or more of fluorouracil antineoplastic drugs, platinum antineoplastic drugs and paclitaxel antineoplastic drugs; the second drug combination includes anti-PD-L1 antibody , and anlotinib or a pharmaceutically acceptable salt thereof.
  • the initial treatment includes 0 to 10 treatment cycles, preferably 1 to 10 treatment cycles, more preferably 1 to 6 treatment cycles, most preferably 6 treatment cycles. In some embodiments, the initial treatment includes 0 to 10 continuous treatment cycles from the first administration, preferably 1 to 10 continuous treatment cycles, further preferably 1 to 6 continuous treatment cycles, most preferably continuous 6 treatment cycles.
  • the pharmaceutical combination further includes a pharmaceutically acceptable carrier.
  • the present application provides the use of a drug combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating gastric cancer and/or esophagogastric junction cancer.
  • the present application provides a pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for use in the treatment of non-HER2-positive gastric cancer and/or esophagogastric junction cancer use in medicines.
  • the drug combination further includes at least one third therapeutic agent, and the third therapeutic agent is one or more of fluorouracil antineoplastic drugs, platinum antineoplastic drugs, and paclitaxel antineoplastic drugs kind.
  • the present application provides the use of a drug combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for treating gastric cancer and/or esophagogastric junction cancer.
  • the present application provides the use of a pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for the treatment of non-HER2-positive gastric cancer and/or esophagogastric junction cancer .
  • the drug combination further includes at least one third therapeutic agent, and the third therapeutic agent is one or more of fluorouracil antineoplastic drugs, platinum antineoplastic drugs, and paclitaxel antineoplastic drugs kind.
  • the present application also provides a method for treating gastric cancer and/or esophagogastric junction cancer, which includes administering a therapeutically effective amount of anti-PD-L1 antibody and anlotinib or its pharmaceutically effective dose to patients in need. acceptable salt.
  • the method of treatment further comprises administering to the patient in need thereof a therapeutically effective amount of at least one third therapeutic agent.
  • the treatment method includes, administering an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, and a third therapeutic agent for initial treatment; then, optionally administering an anti-PD -L1 antibody and anlotinib or its pharmaceutically acceptable salt for maintenance treatment.
  • the third therapeutic agent is one or more of fluorouracil anti-tumor drugs, platinum-based anti-tumor drugs and paclitaxel anti-tumor drugs.
  • the third therapeutic agent includes a fluorouracil antineoplastic drug and/or a platinum antineoplastic drug.
  • the third therapeutic agent includes capecitabine and/or a platinum-based antineoplastic drug.
  • the third therapeutic agent includes fluorouracil antineoplastic drugs and/or oxaliplatin.
  • the third therapeutic agent comprises capecitabine and/or oxaliplatin.
  • the application also provides a method for treating non-HER2-positive gastric cancer and/or esophagogastric junction cancer, which includes administering a therapeutically effective amount of anti-PD-L1 antibody and anlotinib to patients in need or a pharmaceutically acceptable salt thereof.
  • the method of treatment further comprises administering to the patient in need thereof a therapeutically effective amount of at least one third therapeutic agent.
  • the treatment method includes, administering an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, and a third therapeutic agent for initial treatment; then, optionally administering an anti-PD -L1 antibody and anlotinib or its pharmaceutically acceptable salt for maintenance treatment.
  • the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof can be administered simultaneously, sequentially or sequentially.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof and the third therapeutic agent may be administered simultaneously, sequentially or sequentially.
  • the present application also provides a method for treating gastric cancer and/or esophagogastric junction cancer, which comprises administering to patients in need a therapeutically effective amount of an anti-PD-L1 antibody and anlotinib or Pharmaceutical combinations of pharmaceutically acceptable salts thereof.
  • the application also provides a method for treating non-HER2-positive gastric cancer and/or esophagogastric junction cancer, which comprises administering a therapeutically effective amount of an anti-PD-L1 antibody and anrotinib to a patient in need.
  • the pharmaceutical combination further includes at least one third therapeutic agent.
  • the third therapeutic agent is one or more of fluorouracil anti-tumor drugs, platinum-based anti-tumor drugs and paclitaxel anti-tumor drugs.
  • the present application provides a kit for treating gastric cancer and/or esophagogastric junction cancer, or a kit for treating non-HER2-positive gastric cancer and/or esophagogastric junction cancer, comprising: an anti-PD-L1 antibody; and anlotinib or a pharmaceutically acceptable salt thereof.
  • the anti-PD-L1 antibody is contained in the first compartment
  • anlotinib or a pharmaceutically acceptable salt thereof is contained in the second compartment, and can be administered simultaneously, sequentially or sequentially as needed. of patients.
  • the kit further comprises instructions for the combined use of the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.
  • the kit includes: a pharmaceutical composition of an anti-PD-L1 antibody; and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof.
  • the present application provides a kit for treating gastric cancer and/or esophagogastric junction cancer, or provides a kit for treating non-HER2-positive gastric cancer and/or esophagogastric junction cancer, which Comprising: an anti-PD-L1 antibody; and anlotinib or a pharmaceutically acceptable salt thereof; and at least one third therapeutic agent.
  • the anti-PD-L1 antibody is contained in the first compartment, anlotinib or a pharmaceutically acceptable salt thereof is contained in the second compartment, and the third therapeutic agent is contained in the other compartment,
  • the number of compartments in the kit may be increased according to the type of the third therapeutic agent, anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof; and at least one third therapeutic agent may be Simultaneously, sequentially or sequentially administered to patients in need.
  • the kit further comprises instructions for combined use of the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a third therapeutic agent.
  • the kit includes: a pharmaceutical composition of an anti-PD-L1 antibody; and a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition of a third therapeutic agent.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described herein includes: a pharmaceutical composition of an anti-PD-L1 antibody, and anlotinib or a pharmaceutical composition of a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination further comprises a pharmaceutical composition of at least one third therapeutic agent.
  • the third therapeutic agent comprises capecitabine and/or oxaliplatin.
  • the pharmaceutical combination containing anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in this application includes: a pharmaceutical composition of anti-PD-L1 antibody, and anlotinib A pharmaceutical composition of Fantasylin or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of capecitabine, and a pharmaceutical composition of oxaliplatin.
  • the pharmaceutical composition further contains a pharmaceutically acceptable carrier.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in this application includes: a pharmaceutical composition of 600-2400 mg of an anti-PD-L1 antibody.
  • the pharmaceutical composition of the anti-PD-L1 antibody is a unit dose or multiple doses.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in this application includes: 6 mg to 12 mg of anlotinib or a pharmaceutically acceptable salt thereof pharmaceutical composition.
  • the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof is administered in the form of a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg.
  • the pharmaceutical combination containing anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in this application includes: 600-2400 mg of pharmaceutical composition and unit of anti-PD-L1 antibody The dosage is 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition of the anti-PD-L1 antibody is a unit dose or multiple doses.
  • the pharmaceutical combination includes: 600-2400 mg of anti-PD-L1 antibody in a pharmaceutical composition provided in multiple doses and a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or its pharmaceutical composition A pharmaceutical composition of an acceptable salt.
  • the pharmaceutical combination is a preparation suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days), including: a pharmaceutical composition containing 600-2400 mg of an anti-PD-L1 antibody and a pharmaceutical composition containing 84 A pharmaceutical composition of ⁇ 168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the preparation suitable for administration in a single treatment cycle further comprises: a pharmaceutical composition containing 65-780 mg of oxaliplatin, and/or a pharmaceutical composition containing 14000-168000 mg Pharmaceutical compositions of capecitabine.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in the present application includes: the weight ratio is (0.35 ⁇ 29):1, (3.5 ⁇ 29):1, (3.5 ⁇ 14.5):1, or (7 ⁇ 14.5):1 anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.
  • the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof can be packaged separately or together.
  • anlotinib can be packaged in multiple equal parts (for example, 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts or more equal parts); the anti-PD-L1 antibody can be packaged in single or multiple equal parts.
  • Equal portions are packaged.
  • the drug combination further comprises oxaliplatin and/or capecitabine, wherein, anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, oxaliplatin and The weight ratio of capecitabine is (600-2400):(84-168):(65-780):(14000-168000).
  • oxaliplatin and capecitabine can be packaged in single or multiple equal parts (for example, 2 equal parts, 4 equal parts or more equal parts).
  • the pharmaceutical combination containing anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in this application wherein the anti-PD-L1 antibody and anlotinib or its
  • the pharmaceutically acceptable salts are each in the form of a pharmaceutical composition which can be administered simultaneously, sequentially or sequentially.
  • the amount of anti-PD-L1 antibody administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
  • the daily dose of anti-PD-L1 antibody administered may be 600-2400 mg.
  • the daily dose of anti-PD-L1 antibody administered may be 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, or 2400 mg.
  • the anti-PD-L1 antibody is administered parenterally.
  • the anti-PD-L1 antibody is administered intravenously.
  • the concentration of the pharmaceutical composition of anti-PD-L1 antibody is 10-60 mg/mL. In some embodiments, the concentration of the pharmaceutical composition of anti-PD-L1 antibody is 10, 20, 30, 40, 50 or 60 mg/mL.
  • the dosing regimen of the anti-PD-L1 antibody can be comprehensively determined according to the activity, toxicity, and tolerance of the patient.
  • the anti-PD-L1 antibody is used as a treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the anti-PD-L1 antibody is administered weekly, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the dose of anti-PD-L1 antibody is 600-2400 mg per treatment cycle.
  • the dose of anti-PD-L1 antibody is 1200 mg per treatment cycle.
  • the anti-PD-L1 antibody is administered once every 3 weeks, with a dose of 600-2400 mg each time.
  • the anlotinib or a pharmaceutically acceptable salt thereof is administered in a daily dose of 6 mg, 8 mg, 10 mg or 12 mg, administered continuously for 2 weeks and rested for 1 week.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described herein includes a pharmaceutical composition of an anti-PD-L1 antibody and anlotinib or its pharmaceutical composition.
  • the pharmaceutical composition of said anlotinib or its pharmaceutically acceptable salt is prepared to be suitable for giving 6mg, 8mg, 10mg and/or 12mg of anlotinib or its pharmaceutically acceptable salt to patients every day for 14 consecutive days. Unit dose of salt.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in this application includes: a pharmaceutical combination with an anti-PD-L1 antibody concentration of 10-60 mg/mL Composition, and a pharmaceutical composition with a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in this application includes: a pharmaceutical composition with an anti-PD-L1 antibody concentration of 30 mg/mL, And a pharmaceutical composition with a unit dose of 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described in this application includes: a pharmaceutical composition with an anti-PD-L1 antibody concentration of 10 mg/mL, And a pharmaceutical composition with a unit dose of 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described herein includes: a pharmaceutical combination in which 1200 mg of an anti-PD-L1 antibody is provided in multiple doses and a pharmaceutical composition with a unit dose of 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof described herein further includes at least one third therapeutic agent, wherein the anti-PD-L1 The antibody, anlotinib or a pharmaceutically acceptable salt thereof and the third therapeutic agent are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or sequentially.
  • the third therapeutic agent is one or more of fluorouracil anti-tumor drugs, platinum-based anti-tumor drugs and paclitaxel anti-tumor drugs.
  • the third therapeutic agent includes capecitabine and/or a platinum-based antineoplastic drug.
  • the third therapeutic agent includes fluorouracil antineoplastic drugs and/or oxaliplatin.
  • the third therapeutic agent comprises capecitabine and/or oxaliplatin.
  • the pharmaceutical combination containing anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof further includes a pharmaceutical composition of capecitabine and a pharmaceutical composition of oxaliplatin .
  • the oxaliplatin is administered every 3 weeks by intravenous infusion.
  • the capecitabine is administered orally, and is administered in a regimen of continuous administration for 2 weeks and rest for 1 week.
  • the oxaliplatin is administered once every 3 weeks, each time at a dose of 130 mg/m 2 , administered by intravenous infusion.
  • the capecitabine is administered orally in a single dose of 1000 mg/m 2 , twice a day, and administered in a regimen of continuous administration for 2 weeks and rest for 1 week.
  • the kit is a kit suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days), comprising a pharmaceutical composition containing 600-2400 mg of an anti-PD-L1 antibody and containing A pharmaceutical composition of 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the kit further includes a pharmaceutical composition of capecitabine and a pharmaceutical composition of oxaliplatin.
  • a method of treating gastric cancer and/or esophagogastric junction cancer comprising: administering a therapeutically effective amount of an anti-PD-L1 antibody and anlotinib or its pharmaceutically effective amount to a patient in need thereof. acceptable salt.
  • the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or sequentially.
  • the anti-PD-L1 antibody is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
  • the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time.
  • the anti-PD-L1 antibody is administered at a single dose of 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200, or 2400 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 6 mg to 12 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 8 mg to 12 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 6 mg, 8 mg, 10 mg or 12 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered in a regimen of continuous administration for 2 weeks and rest for 1 week. In some embodiments, every 3 weeks is a treatment cycle. In some embodiments, 21 days is a treatment cycle, and the anti-PD-L1 antibody is administered to the patient on the first day of each treatment cycle. In some embodiments, every 3 weeks is a treatment cycle, the anti-PD-L1 antibody is administered on the first day of each cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered on the first to first day of each cycle. 14 days of dosing. In some embodiments, the anti-PD-L1 antibody is administered parenterally.
  • the concentration of the pharmaceutical composition of anti-PD-L1 antibody is 10-60 mg/mL. In some embodiments, the concentration of the pharmaceutical composition of anti-PD-L1 antibody is 10, 20, 30, 40, 50 or 60 mg/mL. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered orally.
  • the method of treating gastric cancer and/or esophagogastric junction cancer further comprises administering to a patient in need thereof a therapeutically effective amount of at least one third therapeutic agent.
  • the third therapeutic agent is one or more of fluorouracil anti-tumor drugs, platinum-based anti-tumor drugs and paclitaxel anti-tumor drugs.
  • the third therapeutic agent includes capecitabine and/or a platinum-based antineoplastic drug.
  • the third therapeutic agent includes fluorouracil antineoplastic drugs and/or oxaliplatin.
  • the third therapeutic agent comprises capecitabine and/or oxaliplatin.
  • the method comprises administering said oxaliplatin at a dose of 130 mg/m 2 each; and administering said capecitabine at a dose of 1000 mg/m 2 each.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, oxaliplatin and capecitabine are administered simultaneously, sequentially and sequentially.
  • the anti-PD-L1 antibody, anlotinib, oxaliplatin, and capecitabine have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. treatment cycle.
  • every 3 weeks is a treatment cycle
  • the anti-PD-L1 antibody and oxaliplatin are administered on the first day of each cycle
  • anlotinib or a pharmaceutically acceptable salt thereof and capec Tabine was administered on days 1 to 14 of each cycle.
  • the method includes administering an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, and a third therapeutic agent for initial treatment; then, optionally administering an anti-PD-L1 L1 antibody and anlotinib or its pharmaceutically acceptable salt for maintenance treatment.
  • the method includes, every 3 weeks as a treatment cycle, administering the anti-PD-L1 antibody and oxaliplatin on the first day of each cycle, and administering the drug on days 1 to 14 of each cycle.
  • Anlotinib or its pharmaceutically acceptable salt and capecitabine for initial treatment then, optionally, every 3 weeks as a treatment cycle, anti-PD-L1 antibody and Anlotinib or a pharmaceutically acceptable salt thereof was administered on days 1 to 14 of each cycle for maintenance treatment.
  • the initial treatment includes 0 to 10 treatment cycles, preferably 1 to 10 treatment cycles, more preferably 1 to 6 treatment cycles, most preferably 6 treatment cycles.
  • the initial treatment includes 0 to 10 continuous treatment cycles from the first administration, preferably 1 to 10 continuous treatment cycles, further preferably 1 to 6 continuous treatment cycles, most preferably continuous 6 treatment cycles.
  • the present application provides a method for treating gastric cancer and/or esophagogastric junction cancer, which includes: (1) obtaining or having obtained a biological sample of a patient; (2) detecting the biological sample or having obtained the biological sample The sample was tested; (3) Determine whether the sample is HER2/neu negative (or HER2/neu status cannot be determined), if the test result is HER2/neu negative (or HER2/neu status cannot be determined), then give treatment to the patient An effective amount of an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof; preferably, in some embodiments, further administering a therapeutically effective amount of a third therapeutic agent to the patient; or (3') determining Whether the sample is HER2/neu negative (or the HER2/neu status cannot be determined), if the test result is HER2/neu negative (or the HER2/neu status cannot be determined), the patient will be given a therapeutically effective amount of anti-PD-L1 antibody and Anlotinib or a pharmaceutically acceptable salt thereof and
  • the initial treatment includes 0 to 10 treatment cycles, preferably 1 to 10 treatment cycles, more preferably 1 to 6 treatment cycles, most preferably 6 treatment cycles. In some embodiments, the initial treatment includes 0 to 10 continuous treatment cycles from the first administration, preferably 1 to 10 continuous treatment cycles, further preferably 1 to 6 continuous treatment cycles, most preferably continuous 6 treatment cycles.
  • the third therapeutic agent is one or more of fluorouracil anti-tumor drugs and/or platinum-based anti-tumor drugs and/or paclitaxel anti-tumor drugs. In some embodiments, the third therapeutic agent includes a fluorouracil antineoplastic drug and/or a platinum antineoplastic drug.
  • the third therapeutic agent includes capecitabine and/or a platinum-based antineoplastic drug. In some embodiments, the third therapeutic agent includes fluorouracil antineoplastic drugs and/or oxaliplatin. In some embodiments, the third therapeutic agent comprises capecitabine and/or oxaliplatin.
  • Anlotinib 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy Base] methyl] cyclopropylamine, which has the following structural formula:
  • the pharmaceutically acceptable salts include, but are not limited to, salts formed by anlotinib and acids selected from the following: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid , heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, Methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid
  • anlotinib or a pharmaceutically acceptable salt thereof involved in this application is based on the molecular weight of anlotinib free base.
  • Anlotinib or a pharmaceutically acceptable salt thereof can be administered by various routes, including gastrointestinal administration and parenteral administration, including but not limited to oral, intravenous, intraarterial, transdermal , sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal. In some specific embodiments, the administration is orally.
  • the amount of anlotinib or a pharmaceutically acceptable salt thereof to be administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient.
  • the daily dose of anlotinib or a pharmaceutically acceptable salt thereof may be 2 mg to 20 mg, and in some embodiments, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof may be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16 mg.
  • Anlotinib or a pharmaceutically acceptable salt thereof can be administered once or more than once a day. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered as an oral solid formulation once a day.
  • the dosing regimen of anlotinib or its pharmaceutically acceptable salt can be comprehensively determined according to the activity, toxicity and tolerance of the drug, etc.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at intervals.
  • the interval dosing includes a dosing period and a dosing period, and during the dosing period, anlotinib or a pharmaceutically acceptable salt thereof can be given once or more than once a day.
  • the ratio in days between the administration period and the withdrawal period is 2:(0.5-5), 2:(0.5-3), 2:(0.5-2), or 2:(0.5-1).
  • the administration is continued for 2 weeks and the administration is off for 2 weeks.
  • the administration is continued for 2 weeks with 1 week rest.
  • anlotinib or a pharmaceutically acceptable salt thereof can be administered orally at a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day, continuously for 2 weeks, and administered in a manner of resting for 1 week.
  • composition of anlotinib or pharmaceutically acceptable salt thereof is provided.
  • the unit dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof includes 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib.
  • the total dose of the pharmaceutical composition of anlotinib or its pharmaceutically acceptable salt administered in each cycle includes 84-168mg .
  • the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof includes a range selected from 84 mg, 112 mg, 140 mg, 168 mg or any of the above values.
  • the total dose of the pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof includes 112 mg to 168 mg.
  • the pharmaceutical composition includes, but is not limited to, formulations suitable for oral, parenteral, or topical administration. In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid preparation suitable for oral administration. In some embodiments, the pharmaceutical composition includes, but is not limited to, tablets, capsules.
  • oxaliplatin (1R-trans)-(1,2-cyclohexanediamine-N,N')[oxalic acid (2-)-O,O']platinum, which has the following Structural formula:
  • Oxaliplatin can be administered by a variety of routes, including gastrointestinal and parenteral routes, including but not limited to oral, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transdermal Buccal, intranasal, inhalation, vaginal, intraocular, subcutaneous, intrafat, intraarticular, intraperitoneal, and intrathecal. In some specific embodiments, administration is by injection.
  • the single dose of oxaliplatin in this application may be 65-130 mg/m 2 ; in some embodiments, the single dose may be 85-130 mg/m 2 .
  • oxaliplatin is administered as an injection every 2 weeks.
  • oxaliplatin is administered as an injection every 3 weeks, for example, oxaliplatin is administered as an injection of 130 mg/m 2 on the first day of each cycle.
  • mg/ m2 refers to the dose of the drug used per square meter of body surface area of the subject.
  • the pharmaceutical composition of oxaliplatin includes but not limited to formulations suitable for intravenous, oral, parenteral, and topical administration; in some embodiments, the pharmaceutical composition is suitable for Injectable formulations; In some embodiments, the pharmaceutical composition includes but not limited to lyophilized powder injection.
  • capecitabine amyl [1-(5-deoxy- ⁇ -D-ribofuranosyl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl]carbamate , which has the following structural formula:
  • Capecitabine can be administered by a variety of routes including gastrointestinal as well as parenteral routes including, but not limited to, oral, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal , buccal, intranasal, inhalation, vaginal, intraocular, subcutaneous, intrafat, intraarticular, intraperitoneal and intrathecal. In some specific embodiments, the administration is orally.
  • the single dose of capecitabine in this application may be 1000-1250 mg/m 2 ; in some embodiments, the single dose may be 1000 mg/m 2 .
  • capecitabine is administered as a single dose of 1000 mg/m 2 twice a day in a regimen of continuous administration for 2 weeks and rest for 1 week.
  • mg/ m2 refers to the dose of the drug used per square meter of body surface area of the subject.
  • the pharmaceutical composition of capecitabine includes but not limited to formulations suitable for intravenous, oral, parenteral, and topical administration; in some embodiments, the pharmaceutical composition is suitable for Formulations for oral administration; In some embodiments, the pharmaceutical compositions include, but are not limited to, tablets.
  • the anti-PD-L1 antibody is the antibody in WO2016022630 or CN107001463A.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: at least 80% (such as 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous heavy chain CDR1 region; at least 80% (e.g., 81%, 82%, 83%, 84%, 85%) to the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 5 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous Heavy chain CDR2 region; at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%) of the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6 %
  • the anti-PD-L1 antibody comprises the following amino acid sequence: selected from the heavy chain CDR1 region of SEQ ID NO: 1 or SEQ ID NO: 4; selected from SEQ ID NO: 2 or SEQ ID The heavy chain CDR2 region of NO:5; the heavy chain CDR3 region selected from SEQ ID NO:3 or SEQ ID NO:6; the light chain CDR1 region selected from SEQ ID NO:7 or SEQ ID NO:10; selected from SEQ ID NO:7 or the light chain CDR1 region of SEQ ID NO:10; The light chain CDR2 region of ID NO:8 or SEQ ID NO:11; the light chain CDR3 region selected from SEQ ID NO:9 or SEQ ID NO:12.
  • the isolated anti-PD-L1 antibody described herein comprises: a heavy chain CDR1 region having the amino acid sequence set forth in SEQ ID NO:1, having a heavy chain CDR1 region set forth in SEQ ID NO:2
  • the heavy chain CDR2 region of the amino acid sequence has the heavy chain CDR3 region of the amino acid sequence shown in SEQ ID NO:3
  • the light chain CDR1 region having the amino acid sequence shown in SEQ ID NO:7 has the amino acid sequence shown in SEQ ID NO
  • the light chain CDR2 region with the amino acid sequence shown in SEQ ID NO:8 has the light chain CDR3 region with the amino acid sequence shown in SEQ ID NO:9.
  • Each of the CDR regions described herein and the above-mentioned variants can specifically recognize and bind to PD-L1, thereby effectively blocking the signal transduction between PD-L1 and PD-1.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: at least 80% (such as 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous heavy chain variable region; at least 80% (eg, 81%, 82%, 83%, 84%, 85%) to the amino acid sequence shown in SEQ ID NO: 15 or SEQ ID NO: 16 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology light chain variable region.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region as shown in SEQ ID NO:13; a light chain variable region as shown in SEQ ID NO:15 .
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region as shown in SEQ ID NO:14; a light chain variable region as shown in SEQ ID NO:16 .
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO:17; a light chain amino acid sequence as shown in SEQ ID NO:18.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO:19; a light chain amino acid sequence as shown in SEQ ID NO:20.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO:21; a light chain amino acid sequence as shown in SEQ ID NO:18.
  • the anti-PD-L1 humanized monoclonal antibody provided by the application comprises SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO :5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, One of SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21 or multiple conservative substitution variants.
  • the anti-PD-L1 humanized monoclonal antibody comprising the conservative substitution variant retains the ability to specifically recognize and bind to PD-L1.
  • the anti-PD-L1 antibody can be an IgG1 or IgG4 antibody.
  • the anti-PD-L1 antibody is an IgG1 antibody. In some embodiments, the anti-PD-L1 antibody is a glycosylated IgG1 antibody.
  • the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) selected from 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from 13C5 or 5G11 antibody.
  • CDR heavy chain complementarity determining region
  • the anti-PD-L1 antibody described in the present application comprises a variable heavy chain selected from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and selected from ch5G11- Variable light chains of hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies.
  • the anti-PD-L1 antibody described in the present application comprises a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody, and a variable heavy chain selected from hu13C5 - the variable light chain of a hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody.
  • the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), and the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID ), the HCDR3 sequence is GYDSGFAY (SEQ ID NO:6), the LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO:10), the LCDR2 sequence is YASNLES (SEQ ID NO:11), and the LCDR3 sequence is QHSWEIPYT (SEQ ID NO:12);
  • the anti-PD-L1 antibody in the drug combination can be selected from one or more.
  • the term "plurality" may be more than one, eg, two, three, four, five or more.
  • the anti-PD-L1 antibody is selected from the group comprising a heavy chain variable region as shown in SEQ ID NO: 13 and a light chain variable region as shown in SEQ ID NO: 15 , or selected from comprising a heavy chain variable region as shown in SEQ ID NO: 14 and a light chain variable region as shown in SEQ ID NO: 16, or selected from a combination of the above.
  • the anti-PD-L1 antibody is selected from the heavy chain amino acid sequence shown in SEQ ID NO: 17 and the light chain amino acid sequence shown in SEQ ID NO: 18, or selected from the amino acid sequence shown in SEQ ID NO: 19 A heavy chain amino acid sequence and a light chain amino acid sequence as shown in SEQ ID NO:20, or selected from a heavy chain amino acid sequence as shown in SEQ ID NO:21 and a light chain amino acid sequence as shown in SEQ ID NO:18, or A combination of any of the above options.
  • the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4; A heavy chain CDR2 region with at least 80% homology to the amino acid sequence shown in :2 or SEQ ID NO: 5; at least 80% homology to the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6
  • the heavy chain CDR3 region; the light chain CDR1 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 10; the same as shown in SEQ ID NO: 8 or SEQ ID NO: 11 A light chain CDR2 region with at least 80% homology to the amino acid sequence; a light chain CDR3 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO:9 or SEQ ID NO:12.
  • the pharmaceutical composition of anti-PD-L1 antibody contains 600-2400 mg of anti-PD-L1 antibody.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains an anti-PD-L1 antibody selected from 600mg, 900mg, 1200mg, 1500mg, 1800mg, 2100mg, 2400mg, or the range formed by any of the above values.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains 600-2100 mg, or 900 mg-1500 mg of the anti-PD-L1 antibody; wherein the pharmaceutical composition of the anti-PD-L1 antibody can be multi-dose or unit dose form exists.
  • the pharmaceutical composition of the anti-PD-L1 antibody contains 300 mg, 600 mg or 1200 mg of the anti-PD-L1 antibody. In some embodiments of the present application, there is provided a pharmaceutical composition formulated as a unit dose of anti-PD-L1 antibody, which contains 300 mg, 600 mg or 1200 mg of anti-PD-L1 antibody.
  • the pharmaceutical composition of the anti-PD-L1 antibody is a solution for injection. In some embodiments, the pharmaceutical composition of the anti-PD-L1 antibody is an aqueous solution for injection. In some embodiments of the present application, the pharmaceutical composition of the anti-PD-L1 antibody comprises one or more of a buffer, an isotonic regulator, a stabilizer and/or a surfactant. In particular, the pharmaceutical composition of the anti-PD-L1 antibody comprises 1-150 mg/mL anti-PD-L1 antibody (such as monoclonal antibody), 3-50 mM buffer, 2-150 mg/mL isotonicity regulator/stabilizer and 0.01-0.8 mg/mL surfactant, and pH 4.5-6.8.
  • the pharmaceutical composition of the anti-PD-L1 antibody is calculated by w/v, and the concentration of the anti-PD-L1 monoclonal antibody is 5-150 mg/mL; in some embodiments, the concentration is 10 -60 mg/mL; in some embodiments the concentration is 10-30 mg/mL.
  • the mass volume concentration of anti-PD-L1 monoclonal antibody is 10mg/mL, 20mg/mL, 30mg/mL, 40mg/mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, 90mg/mL mL, 100 mg/mL, 110 mg/mL, or 120 mg/mL; in some embodiments, the concentration is 10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, or 60 mg/mL; in some In embodiments, the concentration is 10 mg/mL, 20 mg/mL or 30 mg/mL.
  • the mass volume concentration of the anti-PD-L1 monoclonal antibody is 10 mg/mL. In other embodiments, the mass volume concentration of the anti-PD-L1 monoclonal antibody is 30 mg/mL. In other embodiments, the mass volume concentration of the anti-PD-L1 monoclonal antibody is 60 mg/mL.
  • the buffer is a histidine salt buffer.
  • the concentration of the histidine salt buffer is 5-30mM, in some embodiments, the concentration is 10-25mM; in some embodiments, the concentration is 10-20mM; in some embodiments, the The concentration is 10-15mM.
  • the concentration of the histidine salt buffer is 5mM, 10mM, 15mM, 20mM, 25mM or 30mM.
  • the concentration of the histidine salt buffer is 10 mM.
  • the concentration of the histidine salt buffer is 15 mM.
  • the concentration of the histidine salt buffer is 20 mM.
  • the histidine salt buffer contains histidine and hydrochloric acid.
  • the isotonic regulator/stabilizer is 20-150 mg/mL sucrose in w/v calculation; in some embodiments, the isotonic regulator/stabilizer is 40 mg/mL -100 mg/mL sucrose; in some embodiments, the isotonicity adjuster/stabilizer is 60-80 mg/mL sucrose. In some embodiments, the concentration of sucrose is 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL or 100 mg/mL. In some embodiments, the concentration of sucrose is 60 mg/mL. In some embodiments, the concentration of sucrose is 70 mg/mL. In some embodiments, the concentration of sucrose is 80 mg/mL. In some embodiments, the concentration of sucrose is 90 mg/mL.
  • the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188; in some embodiments, the surfactant is selected from polysorbate 80 or Polysorbate 20; in some embodiments, the surfactant is selected from polysorbate 80.
  • the concentration of the surfactant is 0.05-0.6 mg/mL calculated by w/v; in some embodiments, the concentration is 0.1-0.4 mg/mL; in some embodiments, the Said concentration is 0.2 ⁇ 0.3mg/mL.
  • the surfactant is 0.01-0.8 mg/mL polysorbate 80 or polysorbate 20 calculated by w/v.
  • the surfactant is polysorbate 80 at 0.05-0.6 mg/mL; in some embodiments, the surfactant is polysorbate 80 at 0.1-0.4 mg/mL; in some In embodiments, the surfactant is 0.2-0.3 mg/mL polysorbate 80; in some embodiments, the surfactant is 0.2 mg/mL polysorbate 80.
  • the content of polysorbate 80 in the pharmaceutical composition is 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL or 0.6 mg/mL; In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL or 0.5 mg/mL; in some embodiments, polysorbate 80 in the pharmaceutical composition The content of polysorbate 80 is 0.2 mg/mL, 0.3 mg/mL or 0.4 mg/mL; in some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.2 mg/mL.
  • the content of polysorbate 80 in the pharmaceutical composition is 0.1 mg/mL. In other embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.2 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.3 mg/mL. In other embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.4 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is 0.5 mg/mL.
  • the pH value of the aqueous solution of the pharmaceutical composition is selected from 4.0 to 6.8; in some embodiments, the pH value is 4.5 to 6.5; in some embodiments, the pH value is 5.5 to 6.0; in some embodiments, the pH is 5.5. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 4.5, 4.8, 5.0, 5.2, 5.4, 5.5, 5.6, 5.8, or 6.0, and in some embodiments, the pH is 5.0, 5.2, 5.4, 5.5 or 5.6; in some embodiments, the pH is 5.5. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.0. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.2.
  • the pH of the aqueous pharmaceutical composition is 5.4. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.5. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.6. In some embodiments, the pH of the aqueous pharmaceutical composition is 5.8. In some embodiments, the pH of the aqueous pharmaceutical composition is 6.0.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 20 mg/mL, (b) sucrose with a mass volume concentration of 70 mg/mL, (c) Polysorbate 80 with a mass volume concentration of 0.1 mg/mL, (d) histidine with a molar concentration of 20 mM, and (e) an appropriate amount of hydrochloric acid to adjust the pH of the composition to 5.0.
  • the pharmaceutical composition comprises: (a) anti-PD-L1 monoclonal antibody with a mass volume concentration of 20 mg/mL, (b) sucrose with a mass volume concentration of 70 mg/mL, (c) Polysorbate 80 with a mass volume concentration of 0.1 mg/mL, (d) histidine with a molar concentration of 20 mM, and (e) an appropriate amount of hydrochloric acid to adjust the pH of the composition to 5.0.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 10 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH value of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 50 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.3 mg/ml, (d) histidine with a molar concentration of 10 mM, (e) an appropriate amount of hydrochloric acid, and adjust the pH of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 100 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.5 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH value of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 30 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH value of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 60 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 10 mM, (e) optional hydrochloric acid in an appropriate amount, and adjust the pH value of the composition to 5.5.
  • the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of 10 mg/mL, (b) sucrose with a mass volume concentration of 70 mg/mL, (c ) polysorbate 80 with a mass volume concentration of 0.4 mg/mL, (d) histidine with a molar concentration of 20 mM, (e) an appropriate amount of acetic acid, and adjust the pH of the composition to 6.5.
  • the pharmaceutical composition comprises: (a) anti-PD-L1 monoclonal antibody with a mass volume concentration of 10 mg/mL, (b) sucrose with a mass volume concentration of 80 mg/mL, ( c) polysorbate 80 with a mass volume concentration of 0.2 mg/mL, (d) histidine with a molar concentration of 20 mM, and (e) an appropriate amount of hydrochloric acid to adjust the pH of the composition to 5.5.
  • the pharmaceutical composition is a water-soluble injection; in some embodiments, the water-soluble injection includes but is not limited to non-lyophilized water-soluble preparations or lyophilized powder reconstituted water-soluble formulations.
  • the pharmaceutical composition is a lyophilized formulation.
  • the lyophilized preparation refers to a preparation in which an aqueous solution undergoes a freeze-drying process, in which the substance is first frozen, then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent reaches a value that no longer supports biological activity or chemical reaction.
  • the lyophilized formulations of the present application can also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the gastric cancer includes but not limited to adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, low adhesion carcinoma or undifferentiated carcinoma.
  • the gastric cancer includes but not limited to tubular adenocarcinoma, parietal cell adenocarcinoma, mixed adenocarcinoma, papillary adenocarcinoma, mucoepidermoid carcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, Low adhesion carcinoma, hepatoid adenocarcinoma, Paneth cell carcinoma.
  • the gastric cancer is non-HER2-positive gastric cancer.
  • the non-HER2-positive gastric cancer includes HER2-negative or undetermined HER2 status gastric cancer.
  • the gastric cancer is advanced gastric cancer. In some embodiments of the present application, the gastric cancer is refractory gastric cancer.
  • the gastric cancer is recurrent and/or metastatic gastric cancer.
  • the gastric cancer is recurrent and/or metastatic advanced gastric cancer.
  • the gastric cancer is unresectable locally advanced or metastatic gastric cancer.
  • the patient with gastric cancer has not received drug treatment before, or has previously received drug treatment but the treatment failed or could not be tolerated.
  • the drug therapy includes chemotherapy, targeted drug therapy and immunotherapy.
  • the drugs used in chemotherapy include but are not limited to one of taxanes, vinblastines, platinums, fluorouracils, camptothecins, anthracyclines, and podophyllin or more.
  • the taxanes include but are not limited to one or more of paclitaxel, paclitaxel liposomes, albumin-bound paclitaxel and docetaxel (docetaxel);
  • the vinblastines include but Not limited to one or more selected from vinblastine, vincristine, vindesine, vinorelbine, vinflunine, norvinblastine;
  • the platinums include but are not limited to those selected from rice One or more of platinum, cisplatin, carboplatin, bicycloplatin, nedaplatin, oxaliplatin, lobaplatin, triplatin tetranitrate, phenanthrene, picoplatin, and satraplatin;
  • the fluorouracil Classes include but are not limited to those
  • the targeted drugs include but are not limited to EGFR antagonists, VEGF inhibitors, HER2 inhibitors, PARP inhibitors, PI3K/Akt/mTOR pathway inhibitors, epigenetic modification inhibitors, One or more of HDAC inhibitors or FGFR inhibitors.
  • the EGFR antagonists include but are not limited to trastuzumab (trastuzumab), cetuximab (cetuximab), icotinib (icotinib), gefitinib (gefitinib) ), Erlotinib (erlotinib), lapatinib (lapatinib) in one or more.
  • the HER2 inhibitors include but are not limited to Trastuzumab (Trastuzumab), Inetetamab (Inetetamab), Pertuzumab (Pertuzumab), T-DM1, Enhertu , pyrotinib, neratinib, tucatinib, Phesgo, margotuximab (Margenza).
  • the VEGF inhibitors include but are not limited to bevacizumab, ranibizumab, axitinib, motesanib , aflibercept, cediranib, nintedanib, sorafenib, apatinib, or sunitinib.
  • the PARP inhibitor includes, but is not limited to, one or more of olaparib, niraparib, or rucaparib.
  • the PI3K/Akt/mTOR pathway inhibitors include but are not limited to NVP-BKM120, XL147, perifosine, rapamycin, temsirolimus ( One or more of temsirolimus, everolimus, sirolimus, or ridaforolimus.
  • the epigenetic modification inhibitors include but are not limited to azacitidine (azacitidine), decitabine (decitabine), zebularine, camrabine (fazarabine), romididine One or more of romidepsin, vorinostat, belinostat, or chidamide.
  • the HDAC inhibitors include but are not limited to trichostatin A (trichostatin A), suberoylanilide hydroxamic acid (suberoylanilidehydroxamic acid), or sodium butyrate (sodiumbutyrate, NaB) one or more of.
  • the FGFR inhibitor includes but is not limited to dovitinib, or NVP-BGJ398.
  • the immunotherapy drugs include but are not limited to one of PD-1/PD-L1 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors or Various.
  • the PD-1/PD-L1 inhibitors include but are not limited to atezolizumab, nivolumab, or pembrolizumab ), durvalumab, avelumab, and cemiplimab.
  • the CTLA-4 inhibitor includes, but is not limited to, one or more of Ipilimumab, Tremelimumab, AGEN1884, and KN046.
  • the LAG-3 inhibitor includes, but is not limited to, one or more of relatlimab, fianlimab, IMP321, BMS-986016, and GSK 2831781.
  • the TIM-3 inhibitor includes, but is not limited to, one or more of MBG453, TSR-022, BMS-986258, RO7121661, and LY3321367.
  • the esophagogastric junction cancer includes adenocarcinoma of esophagogastric junction (AEG).
  • AEG adenocarcinoma of esophagogastric junction
  • the EGJ cancer comprises non-HER2-positive EGJ cancer.
  • the EGJ cancer is non-HER2 positive EGJ adenocarcinoma.
  • the non-HER2 positive includes HER2 negative or HER2 status cannot be determined.
  • the esophagogastric junction cancer is advanced esophagogastric junction cancer. In some embodiments of the present application, the esophagogastric junction cancer is refractory esophagogastric junction cancer. In some embodiments of the present application, the esophagogastric junction cancer is refractory esophagogastric junction adenocarcinoma.
  • the esophagogastric junction cancer is recurrent and/or metastatic esophagogastric junction cancer. In some embodiments of the present application, the esophagogastric junction cancer is recurrent and/or metastatic esophagogastric junction adenocarcinoma.
  • the esophagogastric junction cancer is recurrent and/or metastatic advanced esophagogastric junction cancer. In some embodiments of the present application, the esophagogastric junction cancer is recurrent and/or metastatic advanced esophagogastric junction adenocarcinoma.
  • the esophagogastric junction cancer is unresectable locally advanced or metastatic esophagogastric junction adenocarcinoma.
  • the patient with esophagogastric junction cancer has not received drug treatment before, or has previously received drug treatment but failed or cannot tolerate the treatment.
  • the drug therapy includes chemotherapy, targeted drug therapy and immunotherapy.
  • the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be simultaneously, successively or sequentially medication.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the third therapeutic agent are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or sequentially .
  • each of the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, oxaliplatin, and capecitabine is in the form of a pharmaceutical composition, which can be simultaneously, sequentially or sequentially.
  • the anti-PD-L1 antibody and anlotinib are each administered at intervals. In some embodiments, the antibody and anlotinib are administered in the same or different dosage regimens, respectively. In some embodiments, the antibody and anlotinib are administered in different dosage regimens. In some embodiments of the present application, the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the third therapeutic agent are each administered at intervals and in different dosage regimens. medication.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, oxaliplatin, and capecitabine are each administered at intervals, respectively in different doses.
  • the dosing regimen is administered.
  • the anti-PD-L1 antibody in the use or treatment method, can be used every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) administered once. In a specific embodiment, the anti-PD-L1 antibody is administered every 3 weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time.
  • the anlotinib or a pharmaceutically acceptable salt thereof can be administered in a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for 2 consecutive weeks, followed by a 1-week off schedule.
  • the oxaliplatin can be administered every 2 weeks (q2w), every 3 weeks (q3w). In a specific embodiment, oxaliplatin is administered every 3 weeks. In some embodiments, the oxaliplatin is administered at a dose of 85-130 mg/m 2 each time.
  • the capecitabine can be administered twice a day (one time in the morning and one time in the evening), with a single dose of 1000-1250 mg/m 2 , continuously administered for 2 weeks, with a 1-week rest period.
  • the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof have the same or different treatment cycles, respectively.
  • the anti-PD-L1 antibody and anlotinib have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks or every 4 weeks is a treatment cycle.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the third therapeutic agent have the same or different treatment cycles, respectively.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, oxaliplatin, and capecitabine have the same or different treatment cycles, respectively.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, oxaliplatin and capecitabine have the same treatment cycle, such as every 1 week, every 2 weeks , Every 3 weeks or every 4 weeks is a treatment cycle.
  • the use or treatment method includes, administering an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, and a third therapeutic agent for initial treatment; then, any Optionally administer anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof for maintenance treatment.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the third therapeutic agent have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle. In some embodiments, 3 weeks (21 days) is one treatment cycle.
  • the initial treatment includes 0 to 10 treatment cycles, preferably 1 to 10 treatment cycles, more preferably 1 to 6 treatment cycles, most preferably 6 treatment cycles. In some embodiments, the initial treatment includes 0 to 10 continuous treatment cycles from the first administration, preferably 1 to 10 continuous treatment cycles, further preferably 1 to 6 continuous treatment cycles, most preferably continuous 6 treatment cycles.
  • 3 weeks is a treatment cycle
  • the PD-L1 antibody is administered on the first day of each cycle, and on the first day of each cycle.
  • Anlotinib or a pharmaceutically acceptable salt thereof was given once a day for 14 days.
  • 21 days is a treatment cycle
  • PD-L1 antibody and oxaliplatin are administered on the first day of each cycle, and on the first day of each cycle.
  • - Administer anlotinib or its pharmaceutically acceptable salt once a day for 14 days, and capecitabine twice a day on days 1-14 of each cycle.
  • the use or treatment method includes, every 3 weeks (21 days) as a treatment cycle, administering anti-PD-L1 antibody and oxaliplatin on the first day of each cycle, Anlotinib or its pharmaceutically acceptable salt and capecitabine are given for initial treatment on the 1st to 14th days of each cycle; then, optionally, every 3 weeks is a treatment cycle, and in each cycle Anti-PD-L1 antibody was administered on the first day and anlotinib or its pharmaceutically acceptable salt was administered on the first to 14th day of each cycle for maintenance treatment.
  • the initial treatment includes 0 to 10 treatment cycles, preferably 1 to 10 treatment cycles, more preferably 1 to 6 treatment cycles, most preferably 6 treatment cycles.
  • the initial treatment includes 0 to 10 continuous treatment cycles from the first administration, preferably 1 to 10 continuous treatment cycles, further preferably 1 to 6 continuous treatment cycles, most preferably continuous 6 treatment cycles.
  • the use or method of treatment includes at least 1 to 10 treatment cycles of initial treatment (anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, oxaliplatin and capecitabine), preferably 1 to 6 initial treatment cycles.
  • initial treatment anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, oxaliplatin and capecitabine
  • maintenance treatment anti-PD-L1 antibody and anlotinib or its pharmaceutically acceptable salt
  • the anti-PD-L1 antibody may comprise a /kg, 0.1 to 10mg/kg, 1 to 15mg/kg, 1 to 20mg/kg, 1 to 3mg/kg, 3 to 10mg/kg, 3 to 15mg/kg, 3 to 20mg/kg, 3 to 30mg/kg , 10 to 20 mg/kg, or 15 to 20 mg/kg to the subject; or 60 mg to 2400 mg, 90 mg to 1800 mg, 120 mg to 1500 mg, 300 mg to 900 mg, 600 mg to 900 mg, 300 mg to 1200 mg, 600 mg to 1200 mg, or a dose of 900 mg to 1200 mg is administered to the subject.
  • 21 days is a treatment cycle, 1200 mg of PD-L1 antibody is administered on the first day of each cycle, and 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • 21 days is a treatment cycle, and 1200 mg of PD-L1 antibody is given on the first day of each cycle and oxaliplatin is given at a dose of 130 mg/m 2 .
  • capecitabine can be administered at a single dose of 1000 mg/m 2 .
  • every 3 weeks (21 days) is a treatment cycle, and 1200 mg of PD-L1 antibody is administered on the first day of each cycle and oxaliplatin is administered at a dose of 130 mg/m 2 .
  • 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or its pharmaceutically acceptable salt was administered once a day and twice a day on the 1st to 14th day of each cycle (morning and evening each 1 times), capecitabine can be administered at a single dose of 1000 mg /m2 for initial treatment; then, optionally, every 3 weeks as a treatment cycle, 1200 mg anti-PD therapy is administered on the first day of each cycle -L1 antibody and 6mg, 8mg, 10mg and/or 12mg of anlotinib or its pharmaceutically acceptable salt once a day on the 1st to 14th day of each cycle for maintenance treatment until the patient cannot tolerate or disease progress.
  • the initial treatment includes 0 to 10 treatment cycles, preferably 1 to 10 treatment cycles, more preferably 1 to 6 treatment cycles, most preferably 6 treatment cycles. In some embodiments, the initial treatment includes 0 to 10 continuous treatment cycles from the first administration, preferably 1 to 10 continuous treatment cycles, further preferably 1 to 6 continuous treatment cycles, most preferably continuous 6 treatment cycles.
  • the components in the pharmaceutical combination of the present application can be administered independently, or some or all of them can be administered in suitable various ways, including but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous route) ).
  • the components of the pharmaceutical combination of the present application can be administered independently or part or all of them together orally or by injection, such as intravenous injection or intraperitoneal injection.
  • the components in the pharmaceutical combination of the present application can be each independently, or some or all of them are suitable dosage forms together, including but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric capsules, etc.) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral administration
  • suitable dosage forms together including but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric capsules, etc.) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral administration
  • suitable dosage forms together including but not limited to, tablets
  • the components in the pharmaceutical combination of the present application may each independently, or part or all of them jointly contain pharmaceutically acceptable carriers and/or excipients.
  • the drug combination of the present application can safely and effectively treat gastric cancer and/or esophagogastric junction cancer.
  • the drug combination of the present application can safely and effectively treat non-HER2 positive gastric cancer and/or esophagogastric junction cancer. In some embodiments, the drug combination of the present application can safely and effectively treat non-HER2 positive gastric cancer and/or esophagogastric junction adenocarcinoma.
  • the DCR (disease control rate) of the drug combination of the present application reaches or exceeds 60%; reaches or exceeds 70%; reaches or exceeds 80%; reaches or exceeds More than 90%; reach or exceed 95%; even reach 100%.
  • a patient with gastric cancer and/or EGJ cancer especially a patient with non-HER2-positive gastric cancer and/or EGJ cancer, more especially a patient with non-HER2-positive gastric cancer and/or EGJ adenocarcinoma
  • the DCR reaches or exceeds 60%; reaches or exceeds 70%; reaches or exceeds 80%; reaches or exceeds 90%; reaches or exceeds 95%.
  • the DCR reaches or exceeds 60%; reaches or exceeds 70%; reaches or exceeds 80%; reaches or exceeds 90%; reaches or exceeds 95%; even reaches 100%.
  • the ORR (objective response rate) of the drug combination of the present application reaches or exceeds 40%; reaches or exceeds 55%; reaches or exceeds 65%; reaches or exceeds More than 75%; 80% or more; 85% or more; 90% or more.
  • a patient with gastric cancer and/or EGJ cancer especially a patient with non-HER2-positive gastric cancer and/or EGJ cancer, more especially a patient with non-HER2-positive gastric cancer and/or EGJ adenocarcinoma
  • the ORR reaches or exceeds 40%; reaches or exceeds 55%; reaches or exceeds 65%; reaches or exceeds 75%; reaches or exceeds 80%.
  • the ORR reaches or exceeds 40%; reaches or exceeds 55%; reaches or exceeds 65%; reaches or exceeds 75%; reaches or exceeds 80%; reaches or exceeds 85% ;Meet or exceed 90%.
  • the drug combination of the present application can significantly prolong PFS (progression-free survival) and OS (overall survival) in patients with gastric cancer and/or esophagogastric junction cancer.
  • the PFS is greater than 6 months; 7 months or greater; 8 months or greater; 9 months or greater; 10 months or greater; 11 months or greater; or more than 12 months.
  • the drug combination of the present application has a synergistic effect and better safety in the treatment of gastric cancer and/or esophagogastric junction cancer.
  • ORR is calculated according to the ratio of the number of objective response cases (PR+CR) assessed by IRC to the total number of cases and the 95% CI.
  • the amount of anlotinib or a pharmaceutically acceptable salt thereof refers to the amount of the active ingredient anlotinib free base.
  • dose refers to the dose administered to a patient regardless of the patient's weight or body surface area (BSA), e.g., a 60 kg human and a 100 kg human will receive the same dose of antibody (e.g., 240 mg anti-PD-1 antibody ).
  • BSA body surface area
  • mg/ m2 refers to the dose of the drug used per square meter of body surface area of the subject.
  • the term "pharmaceutical combination” refers to two or more active ingredients administered simultaneously or sequentially (administered in the form of the respective active ingredients themselves, or in the form of their respective pharmaceutically acceptable salts or esters, etc. administration in the form of derivatives, prodrugs or compositions).
  • the active substances may be administered to the subject simultaneously, each as a single formulation, or sequentially, each as a single formulation, in any order.
  • antibody refers to a binding protein having at least one antigen binding domain.
  • Antibodies and fragments thereof of the present application may be whole antibodies or any fragments thereof. Accordingly, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), Fd fragments, and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof described herein can be of the IgG1, IgG2, IgG3 or IgG4 isotype.
  • the term "isotype" refers to the antibody class encoded by the heavy chain constant region genes.
  • the anti-PD-L1 antibodies and fragments thereof described herein are of the IgG1 or IgG4 isotype.
  • the PD-L1 antibodies and fragments thereof of the present application may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans.
  • PD-L1 antibodies and fragments thereof can be chimeric antibodies, humanized antibodies or fully human antibodies.
  • the anti-PD-L1 antibody is an antibody produced by a hybridoma cell line derived from mice.
  • the anti-PD-L1 antibody is a murine antibody.
  • the anti-PD-L1 antibody is a chimeric antibody.
  • the chimeric antibody is a mouse-human chimeric antibody.
  • the antibody is a humanized antibody.
  • the antibody is derived from a murine antibody and is humanized.
  • a “humanized antibody” is an antibody that contains complementarity determining regions (CDRs) derived from a non-human antibody; and framework and constant regions derived from a human antibody.
  • CDRs complementarity determining regions
  • an anti-PD-L1 antibody described herein can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions.
  • a humanized antibody described herein binds to the same epitope on PD-L1 as the murine antibody from which the CDRs of said antibody are derived.
  • the anti-PD-L1 antibody is a humanized antibody.
  • framework sequences suitable for use in the present application include those framework sequences that are structurally similar to the framework sequences provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or revert mutations to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to mutations exemplified herein, including back mutations to germline sequences.
  • one or more amino acids in the human framework regions of the VH and/or VL of a humanized antibody described herein are backmutated to the corresponding amino acid in the parental murine antibody.
  • the VH and VL of humanized 5G11 and humanized 13C5 several positions of the framework amino acids of the above template human antibody were backmutated to the corresponding amino acid sequences in the mouse 5G11 and 13C5 antibodies.
  • amino acids at positions 53 and/or 60 and/or 67 of the light chain variable region are backmutated to the corresponding amino acids found at said positions in the mouse 5G11 or 13C5 light chain variable region. amino acid.
  • amino acids at positions 24 and/or 28 and/or 30 and/or 49 and/or 73 and/or 83 and/or 94 of the heavy chain variable region are backmutated to mouse 5G11 or the corresponding amino acid found at said position in the 13C5 heavy chain variable region.
  • the humanized 5G11 antibody comprises a light chain variable region in which the amino acid at position 60 is mutated from Ser(S) to Asp(D), and the amino acid at position 67 is mutated from Ser(S) is Tyr (Y); and the heavy chain variable region, wherein the amino acid at position 24 is mutated from Phe (F) to Val (V), and the amino acid at position 49 is mutated from Ala (A) to Gly (G), The amino acid at position 73 was mutated from Thr(T) to Asn(N), and the amino acid at position 83 was mutated from Thr(T) to Asn(N).
  • the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr (Y) to Lys (K); and a heavy chain variable region in which the amino acid at position 28 is the amino acid is mutated from Thr (T) to Ile (I), the amino acid at position 30 is mutated from Ser (S) to Arg (R), the amino acid at position 49 is mutated from Ser (S) to Ala (A), and The amino acid at position 94 was mutated from Tyr (Y) to Asp (D). Additional or alternative backmutations can be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibodies.
  • the present application also includes humanized antibodies that bind PD-L1 and that comprise framework modifications corresponding to the exemplary modifications described herein with respect to any suitable framework sequence, as well as otherwise modifying the antibodies Additional framework decorations for properties.
  • antibodies described herein also include hybridomas 13C5, 5G11, and any hybridoma that produces an antibody disclosed herein.
  • the application also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein.
  • the present application also includes expression vectors comprising the isolated polynucleotides, and host cells comprising the expression vectors.
  • Isolated antibody means an antibody that is substantially free of other antibodies that have a different antigen specificity (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind other than PD-1). Antibodies to antigens). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity with other antigens, such as PD-1 molecules from different species. Furthermore, an isolated antibody can be substantially free of other cellular material and/or chemicals.
  • mAb refers to an antibody molecule of single molecular composition (i.e., an antibody molecule whose basic sequence is substantially identical and which exhibits a single binding specificity and affinity for a particular epitope ) non-naturally occurring preparations.
  • a mAb is an example of an isolated antibody.
  • mAbs can be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.
  • the antibodies and antigen-binding fragments thereof described herein are specific for PD-L1. In one embodiment, the antibody or/and fragment thereof is specific for PD-L1. In one embodiment, the antibodies and fragments described herein bind human or primate PD-L1, but do not bind PD-L1 from any other mammal. In another embodiment, the antibody or/and fragment thereof does not bind mouse PD-L1.
  • the terms "human PD-L1", “hPD-L1” and “huPD-L1” etc. are used interchangeably herein and refer to human PD-L1 and variants or isoforms of human PD-L1. "Specific" means that antibodies and fragments thereof bind PD-L1 with greater affinity than any other target.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.
  • the term "effective amount” means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the The amount of a compound of the present application required for the onset of one or more symptoms of a particular disease, condition or disorder as described.
  • the amount of an active substance e.g., an antibody or compound of the present application
  • a “therapeutically effective amount” may vary depending on factors such as the individual's disease state, age, sex, and weight, and the effect of the therapeutic agent or combination of therapeutic agents on the individual. Ability to answer required. Effective amounts can also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.
  • administration or “administration” are used interchangeably to refer to the physical introduction into a subject of a composition comprising a therapeutic agent using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration of immune checkpoint inhibitors include parenteral routes of administration (including but not limited to intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other gastrointestinal external route of administration), such as by injection or infusion.
  • parenteral administration or “parenteral administration” are used herein interchangeably and generally refer to modes of administration other than enteral and topical administration by injection, and include But not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular , subarachnoid, intraspinal, epidural, and intrasternal injections and infusions, and in vivo electroporation.
  • the immune checkpoint inhibitor e.g., anti-PD-1 antibody or anti-PD-L1 antibody
  • the immune checkpoint inhibitor is administered non-parenterally; in certain embodiments, orally; other non-gastric Parenteral routes include topical, epidermal or mucosal administration, eg, intranasal, intravaginal, intrarectal, sublingual or topical administration. Administration can also be performed, eg, once, multiple times, and/or over one or more extended periods of time.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response or other problems or complications.
  • pharmaceutically acceptable salt includes salts of free bases and acids or salts of acids and free bases, including, for example, hydrochlorides, hydrobromides, nitrates, sulfates, phosphates, formates, Acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate, or p-toluenesulfonate;
  • the pharmaceutically acceptable salt is hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate , methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.
  • the molar ratio of the acid to the free base is 1:0.2 to 1:5; in some embodiments, the molar ratio is 1:0.5 , 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • the term “subject” or “patient” is used interchangeably herein.
  • the term “subject” or “patient” is a mammal.
  • the subject or patient is a mouse.
  • the subject or patient is a human.
  • unit dose refers to the smallest packaging unit containing a certain amount of medicine.
  • a box of medicine has seven capsules, and each capsule is a unit dose; or each bottle of injection is a unit dose.
  • multiple dose consists of a number of unit doses.
  • pharmaceutical composition refers to a mixture of one or more active ingredients of the present application or its pharmaceutical combination and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound of the present application, or a pharmaceutical combination thereof, to a subject.
  • fluorouracil antineoplastic drug refers to a drug containing a fluorinated derivative of uracil with antitumor activity, or a drug that can be converted into 5-fluorouracil in vivo, and the fluorouracil antineoplastic drug includes but is not limited to selected One or more of capecitabine, 5-fluorouracil, bisfururacil, doxifluridine, trifluridine, tegafur, carmofur, S-1, and ufuridine.
  • platinum-based antineoplastic drug refers to a drug containing a platinum complex with anti-tumor activity. , oxaliplatin, lobaplatin (Lobaplatin), triplatin tetranitrate, phenanthroplatin, picoplatin, and satraplatin.
  • paclitaxel antineoplastic drug refers to a drug containing paclitaxel and its derivatives with antitumor activity. One or more of docetaxel.
  • gastroesophageal junction cancer may also be referred to as gastroesophageal junction cancer.
  • AEG adenocarcinoma of esophagogastric junction
  • adenocarcinoma of the gastroesophageal junction may also be referred to as adenocarcinoma of the gastroesophageal junction.
  • initial treatment refers to giving the patient anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, and a third therapeutic agent in repeated cycles.
  • initial treatment refers to administering anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, capecitabine and oxaliplatin to the patient in repeated cycles.
  • maintenance therapy refers to administering anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof to the patient in repeated cycles.
  • the "repeat cycle” refers to 0, 1 or more consecutive treatment cycles.
  • the anti-PD-L1 antibody in the example was prepared according to the method described in WO2016022630, and after affinity chromatography, the eluate containing the antibody was obtained according to a conventional antibody purification method.
  • Example 1 Phase II clinical trial of gastric cancer and/or esophagogastric junction cancer
  • Subjects with gastric cancer and/or esophagogastric junction cancer who meet the inclusion criteria will first receive 6 cycles of initial treatment (four cycles of anti-PD-L1 antibody, anlotinib hydrochloride, oxaliplatin and capecitabine). drug combination regimen), and then receive maintenance therapy (anti-PD-L1 antibody and anlotinib hydrochloride double-drug combination regimen) until disease progression, unacceptable toxicity, withdrawal of informed consent, loss of follow-up or death, or other The investigator judges that the treatment should be stopped, whichever occurs first.
  • RECIST version 1.1 there is at least one measurable lesion or evaluable lesion; the measurable lesion should not have received local treatment such as radiotherapy (the lesion located in the area of previous radiotherapy, if it is confirmed to have progressed, and meets the criteria of RECIST1.1 , can also be used as the target lesion);
  • local treatment such as radiotherapy (the lesion located in the area of previous radiotherapy, if it is confirmed to have progressed, and meets the criteria of RECIST1.1 , can also be used as the target lesion);
  • ECOG PS score 0-1 points; the expected survival time is more than 3 months.
  • Anti-PD-L1 antibody injection hu5G11-hIgG1 1200mg anti-PD-L1 antibody injection diluted to 100mL with normal saline, and the infusion time is about 40 minutes (flush the tube with normal saline before and after infusion).
  • the anti-PD-L1 antibody injection is administered on the first day, and administered once every 21 days, that is, 21 days is a treatment cycle (d1/q3w).
  • Anlotinib hydrochloride capsules (the active ingredient is anlotinib dihydrochloride): once a day (orally taken on an empty stomach before breakfast), 1 capsule (10mg) each time. Continuous oral administration for 2 weeks and rest for 1 week, that is, 21 days is a treatment cycle, and the drug is administered on the 1st to 14th day of each cycle. In the absence of special circumstances, it is recommended to take it at a fixed time every day (ie, Anlotinib Hydrochloride Capsules: 10mg/qd, d1-14/q3w).
  • Oxaliplatin 130mg/m 2 per dose, intravenous drip, administered on the first day, once every 21 days, that is, 21 days is a treatment cycle (d1/q3w).
  • Capecitabine 1000mg/m 2 per dose, twice a day (orally, once in the morning and once in the evening), orally for 2 consecutive weeks and then rest for 1 week, that is, 21 days is a treatment cycle, and in the 1st to 14th days of each cycle Daily administration (d1-14/q3w).
  • RECIST 1.1 and iRECIST standards were used to evaluate the drug efficacy. The evaluation was based on RECIST 1.1 standard, and the curative effect was confirmed by iRECIST standard. That is, subjects who are judged as progressive disease (PD) according to the RECIST 1.1 standard will be further confirmed according to the iRECIST standard, so as to decide whether to take further medication for observation.
  • PD progressive disease
  • the treatment regimen in the trial has shown surprising efficacy in the treatment of gastric cancer and/or esophagogastric junction adenocarcinoma with a safety profile and manageable adverse events.
  • the test shows that the four-drug combination regimen of anti-PD-L1 antibody, anlotinib hydrochloride, oxaliplatin and capecitabine and the double-drug combination regimen of anti-PD-L1 antibody and anlotinib hydrochloride can be safe and effective.
  • Subjects have clinical benefits in the treatment of gastric cancer and/or esophagogastric junction adenocarcinoma, and the four-drug combination regimen can be used as the first-line treatment for gastric cancer and/or esophagogastric junction adenocarcinoma.

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Abstract

一种用于治疗胃癌和/或食管胃结合部癌的联用药物，其包括抗PD-L1抗体和安罗替尼或其药学上可接受的盐，所述药物组合进一步包括至少一种第三治疗剂。另外，还提供了含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合或药物组合物在制备用于治疗胃癌和/或食管胃结合部癌的药物中的用途。

Description

用于治疗胃癌和/或食管胃结合部癌的联用药物 技术领域
本申请属于生物医药领域，具体涉及用于治疗胃癌和/或食管胃结合部癌的联用药物。
背景技术
胃癌(Gastric carcinoma)是起源于胃黏膜上皮的恶性肿瘤，是最常见的消化道恶性肿瘤，也是全世界癌症死亡的主要原因之一。预估有超过一半的胃癌病例和死亡发生在我国，2015年，我国胃癌新增病例约67.9万例，死亡49.8万人，是仅次于肺癌的第二大癌症。
目前，在胃癌的治疗手段中，外科手术占有主导地位，也是当前能够达到治愈目的的重要治疗方法。然而，由于我国胃癌的早期诊断率较低，导致手术后的5年生存率仅为20％～30％，故大多数胃癌患者仅通过手术难以达到治愈目的，还需要接受化疗、放疗等综合治疗。另外，局部晚期的胃癌患者经过术前化疗后有可能为手术切除创造条件；术后具有复发、转移的高危风险的患者需要接受术后辅助化疗。因此，化疗在胃癌的综合治疗中仍然占有重要地位，目前，晚期胃癌一线治疗以氟尿嘧啶类抗肿瘤药物(5-FU、卡培他滨、替吉奥)为基础，联合铂类(奥沙利铂、顺铂)和/或紫杉醇类抗肿瘤药物组成二药或三药化疗方案为主，但中位总生存时间(median overall survival，mOS)不超过1年。同时多数胃癌患者会因病情恶化而无法耐受后续治疗，一线治疗是胃癌患者取得疗效的最佳机会，因此需要积极探索研究新的治疗药物或治疗方法。
此外，食管胃结合部(esophagogastric junction，EGJ)是指食管和胃之间的一条虚拟解剖交界线，特指的一个区域，可通过以下方式进行定位：消化道钡餐检查中为食管下段最狭窄的区域；内镜下为食管下段的纵向栅栏状血管或胃近端纵行皱襞的上缘线；病理学上为鳞状上皮与柱状上皮的交界区；大体标本上为食管与胃管腔直径变化的区域。近年来食管胃结合部癌(esophagogastric junction cancer)的发病率出现增高趋势，尤其是食管胃结合部腺癌(adenocarcinoma of esophagogastric junction，AEG)。中国的一项长期随访研究数据显示，AEG患者5年生存率约为30％，10年生存率只有13.3％。因此，积极探索研究食管胃结合部癌新的治疗药物或治疗方法具有重要意义。
发明内容
一方面，本申请提供一种用于治疗胃癌和/或食管胃结合部癌的药物组合，其包括：抗PD-L1抗体，和安罗替尼或其药学上可接受的盐。在一些实施方案中，所述药物组合进一步包括至少一种第三治疗剂，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种。在一些实施方案中，所述氟尿嘧啶类抗肿瘤药物包括但不限于选自卡培他滨、5-氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、三氟尿苷、替加氟、卡莫氟、替吉奥、优福定中的一种或多种；所述铂类抗肿瘤药物包括但不限于选自米铂、顺铂、卡铂、双环铂、奈达铂、奥沙利铂、洛铂(Lobaplatin)、四硝酸三铂、菲铂、吡铂、沙铂中的一种或多种；所述紫杉醇类抗肿瘤药物包括但不限于选自紫杉醇、紫杉醇脂质体、白蛋白结合型紫杉醇、多西他赛中的一种或多种。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或奥沙利铂。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或奥沙利铂。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或顺铂。在一些实施方案中，所述第三治疗剂包括5-氟尿嘧啶和/或奥沙利铂。在一些实施方案中，所述抗PD-L1抗体为抗PD-L1人源化单克隆抗体。在一些实施方案中，所述第三治疗剂包括：选自卡培他滨、5-氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、三氟尿苷、替加氟、卡莫氟、替吉奥和优福定中的一种或多种；以及选自顺铂、卡铂、奈达铂和奥沙利铂中的至少一种。在一些实施方案中，所述第三治疗剂包括：卡培他滨，以及选自顺铂、卡铂、奈达铂和奥沙利铂中的至少一种。
在一些实施方案中，本申请提供一种用于治疗非HER2阳性的胃癌和/或食管胃结合部癌的药物组合，其包括：抗PD-L1抗体，和安罗替尼或其药学上可接受的盐。在一些实施方案中，所述药物组合进一步包括至少一种上述第三治疗剂。
在一些实施方案中，所述的药物组合还进一步包括药学上可接受的载体。
又一方面，本申请还提供一种用于治疗胃癌和/或食管胃结合部癌的药物组合，其包括在初始治疗期间向有需要的患者给予的第一药物组合，以及任选地，在维持治疗期间向有需要的患者给予的第二药物组合，所述第一药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐、和至少一种第三治疗剂，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种；所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或奥沙利铂。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或奥沙利铂。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或顺铂。在一些实施方案中，所述第三治疗剂包括5-氟尿嘧啶和/或奥沙利铂。在一些实施方案中，所述初始治疗包括0到10个治疗周期，优选1到10个治疗周期，进一步优选1到6个治疗周期，最优选6个治疗周期。在一些实施方案中，所述初始治疗包括从首次给药起的连续的0到10个治疗周期，优选连续的1到10个治疗周期，进一步优选连续的1到6个治疗周期，最优选连续的6个治疗周期。本文中，所述维持治疗为在初始治疗之后的进行的治疗。
在一些实施方案中，本申请提供一种用于治疗非HER2阳性的胃癌和/或食管胃结合部癌的药物组合，其包括在初始治疗期间向有需要的患者给予的第一药物组合，以及任选地，在维持治疗期间向有需要的患者给予的第二药物组合，所述第一药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐、和至少一种第三治疗剂，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种；所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。在一些实施方案中，所述初始治疗包括0到10个治疗周期，优选1到10个治疗周期，进一步优选1到6个治疗周期，最优选6个治疗周期。在一些实施方案中，所述初始治疗包括从首次给药起的连续的0到10个治疗周期，优选连续的1到10个治疗周期，进一步优选连续的1到6个治疗周期，最优选连续的6个治疗周期。
在一些实施方案中，所述的药物组合还进一步包括药学上可接受的载体。
另一方面，本申请提供了含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗胃癌和/或食管胃结合部癌的药物中的用途。在一些实施方案中，本申请提供了含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗非HER2阳性的胃癌和/或食管胃结合部癌的药物中的用途。在一些实施方案中，所述药物组合进一步包括至少一种第三治疗剂，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物、紫杉醇类抗肿瘤药物中的一种或多种。
再一方面，本申请提供了含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合用于治疗胃癌和/或食管胃结合部癌的用途。在一些实施方案中，本申请提供了含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合用于治疗非HER2阳性的胃癌和/或食管胃结合部癌的用途。在一些实施方案中，所述药物组合进一步包括至少一种第三治疗剂，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物、紫杉醇类抗肿瘤药物中的一种或多种。
再一方面，本申请还提供了一种胃癌和/或食管胃结合部癌的治疗方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。在一些实施方案中，所述治疗方法进一步包括向有需要的患者给予治疗有效量的至少一种第三治疗剂。在一些实施方案中，所述治疗方法包括，给予抗PD-L1抗体、和安罗替尼或其药学上可接受的盐、和第三治疗剂进行初始治疗；然后，任选地给予抗PD-L1抗体和安罗替尼或其药学上可接受的盐进行维持治疗。在一些实施方案中，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或奥沙利铂。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或奥沙利铂。
在一些实施方案中，申请还提供了一种非HER2阳性胃癌和/或食管胃结合部癌的治疗方法，其包括向有需要的患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。在一些实施方案中，所述治疗方法进一步包括向有需要的患者给予治疗有效量的至少一种第三治疗剂。在一些实施方案中，所述治疗方法包括，给予抗PD-L1抗体、和安罗替尼或其药学上可接受的盐、和第三治疗剂进行初始治疗；然 后，任选地给予抗PD-L1抗体和安罗替尼或其药学上可接受的盐进行维持治疗。
在一些实施方案中，抗PD-L1抗体和安罗替尼或其药学上可接受的盐可同时、先后或者依次序给药。在一些实施方案中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐和第三治疗剂可同时、先后或者依次序给药。在一些实施方案中，本申请还提供了一种胃癌和/或食管胃结合部癌的治疗方法，其包括向有需要的患者给予治疗有效量的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合。在一些实施方案中，申请还提供了一种非HER2阳性胃癌和/或食管胃结合部癌的治疗方法，其包括向有需要的患者给予治疗有效量的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合。在一些实施方案中，所述药物组合进一步包括至少一种第三治疗剂。在一些实施方案中，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种。
再一方面，本申请提供了用于治疗胃癌和/或食管胃结合部癌的试剂盒，或提供了用于治疗非HER2阳性的胃癌和/或食管胃结合部癌的试剂盒，其包括：抗PD-L1抗体；和安罗替尼或其药学上可接受的盐。在一些实施方案中，抗PD-L1抗体包含在第一隔室中，以及安罗替尼或其药学上可接受的盐包含在第二隔室中，可同时、先后或者依次序给予有需要的患者。在一些实施方案中，该试剂盒进一步包含抗PD-L1抗体和安罗替尼或其药学上可接受的盐联合使用的说明。在一些实施方案中，所述试剂盒包括：抗PD-L1抗体的药物组合物；和安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请提供了用于治疗胃癌和/或食管胃结合部癌的试剂盒，或提供了用于治疗非HER2阳性的胃癌和/或食管胃结合部癌的试剂盒，其包括：抗PD-L1抗体；和安罗替尼或其药学上可接受的盐；和至少一种第三治疗剂。在一些实施方案中，抗PD-L1抗体包含在第一隔室中，安罗替尼或其药学上可接受的盐包含在第二隔室中，第三治疗剂包含在其他隔室中，可选地根据第三治疗剂的种类可视情况增加试剂盒中隔室的数量，抗PD-L1抗体、安罗替尼或其药学上可接受的盐；和至少一种第三治疗剂可同时、先后或者依次序给予有需要的患者。在一些实施方案中，该试剂盒进一步包含抗PD-L1抗体、安罗替尼或其药学上可接受的盐和第三治疗剂联合使用的说明。在一些实施方案中，所述试剂盒包括：抗PD-L1抗体的药物组合物；和安罗替尼或其药学上可接受的盐的药物组合物；和第三治疗剂的药物组合物。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：抗PD-L1抗体的药物组合物，和安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述药物组合进一步包括至少一种第三治疗剂的药物组合物。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或奥沙利铂。在一具体实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：抗PD-L1抗体的药物组合物，和安罗替尼或其药学上可接受的盐的药物组合物，和卡培他滨的药物组合物，和奥沙利铂的药物组合物。
在一些实施方案中，所述的药物组合物进一步含有药学上可接受的载体。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：600～2400mg的抗PD-L1抗体的药物组合物。在一些实施方案中，所述抗PD-L1抗体的药物组合物为单位剂量或者多剂量。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：6mg～12mg安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述安罗替尼或其药学上可接受的盐的药物组合物以单位剂量为6mg、8mg、10mg和/或12mg的形式给药。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：600～2400mg的抗PD-L1抗体的药物组合物和单位剂量为6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物，其中抗PD-L1抗体的药物组合物为单位剂量或者多剂量。在一些实施方案中，所述药物组合包括：600～2400mg的抗PD-L1抗体以多剂量形式提供的药物组合物和单位剂量为6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述药物组合为适用于在单个治疗周期(例如21天的一个治疗周期)内施用的制剂，包括：含600～2400mg的抗PD-L1抗体的药物组合物和含84～168mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，所述适用于在单个治疗周期(例如21天的一个治疗周期)内施用的制剂进一步包括：含65～780mg奥沙利铂的药物组合物，和/或含14000～168000mg卡培他滨的药物组合物。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合，其包括：重量比为(0.35～29):1、(3.5～29):1、(3.5～14.5):1、或(7～14.5):1的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。其中，抗PD-L1抗体和安罗替尼或其药学上可接受的盐可分开地包装或者包装在一起。其中，安罗替尼可以多个等份(例如2等份、7等份、14等份、28等份或更多等份)进行包装；抗PD-L1抗体能够以单等份或多个等份(例如2等份、4等份或更多等份)进行包装。在一些实施方式中，所述药物组合进一步包含奥沙利铂和/或卡培他滨，其中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐、奥沙利铂和卡培他滨的重量比为(600～2400):(84～168):(65～780):(14000～168000)。其中，奥沙利铂和卡培他滨可以单等份或多个等份(例如2等份、4等份或更多等份)进行包装。
在一些实施方案中，对于本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合，其中所述抗PD-L1抗体和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后或依次给药。
给予抗PD-L1抗体的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。例如，给予抗PD-L1抗体的日剂量可为600～2400mg。在一些实施方案中，给予抗PD-L1抗体的日剂量可为600、800、1000、1200、1400、1600、1800、2000、2200或2400mg。在一些实施方案中，抗PD-L1抗体以胃肠外给药的方式给药。在一些实施方案中，抗PD-L1抗体以静脉内给药的方式给药。在一些实施方案中，抗PD-L1抗体的药物组合物的浓度为10～60mg/mL。在一些实施方案中，抗PD-L1抗体的药物组合物的浓度为10、20、30、40、50或者60mg/mL。
抗PD-L1抗体的给药方案可根据药物的活性、毒性以及患者的耐受性等来综合确定。在一些实施方案中，抗PD-L1抗体每1周、每2周、每3周、或者每4周为一个治疗周期。在一些实施方案中，抗PD-L1抗体每周、每2周、每3周、或者每4周施用一次。在一些实施方案中，每个治疗周期抗PD-L1抗体的剂量为600～2400mg。在一些具体实施方案中，每个治疗周期抗PD-L1抗体的剂量为1200mg。在一些实施方案中，所述抗PD-L1抗体每3周给药一次，每次以600～2400mg的剂量施用。在一些实施方案中，所述安罗替尼或其药学上可接受的盐以6mg、8mg、10mg或者12mg的日剂量，连续用药2周，停1周的给药方案给药。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括抗PD-L1抗体的药物组合物和安罗替尼或其药学上可接受的盐的药物组合物，其中抗PD-L1抗体的药物组合物被制备为适合第一次给药时向患者给予600～2400mg的抗PD-L1抗体的单位剂量或多剂量，所述安罗替尼或其药学上可接受的盐的药物组合物被制备为适合连续14天、每天向患者给予6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的单位剂量。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：抗PD-L1抗体浓度为10～60mg/mL的药物组合物，和单位剂量为6mg、8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：抗PD-L1抗体浓度为30mg/mL的药物组合物，和单位剂量为8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：抗PD-L1抗体浓度为10mg/mL的药物组合物，和单位剂量为8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合包括：1200mg的抗PD-L1抗体以多剂量形式提供的药物组合物，和单位剂量为8mg、10mg和/或12mg安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，本申请所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合进一步包括至少一种第三治疗剂，其中所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐和第三治疗剂各自呈药物组合物的形式，可同时、先后或依次给药。在一些实施方案中，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种。在一些实施方案中，所述第三治疗剂包 括卡培他滨和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或奥沙利铂。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或奥沙利铂。在一些实施方案中，所述的含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合进一步包括卡培他滨的药物组合物和奥沙利铂的药物组合物。在一些实施方案中，所述奥沙利铂每3周给药一次，以静脉滴注的方式施用。在一些实施方案中，所述卡培他滨口服给药，并以连续用药2周，停1周的给药方案给药。在一些实施方案中，所述奥沙利铂每3周给药一次，每次以130mg/m 2的剂量，以静脉滴注的方式施用。在一些实施方案中，所述卡培他滨以1000mg/m 2的单次剂量，口服给药，每日给药两次，并以连续用药2周，停1周的给药方案给药。
在一些实施方案中，所述的试剂盒为适用于在单个治疗周期(例如21天的一个治疗周期)内施用的试剂盒，包括含600～2400mg的抗PD-L1抗体的药物组合物和含84～168mg安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述的试剂盒进一步包括卡培他滨的药物组合物和奥沙利铂的药物组合物。
在一些实施方案中，提供了一种治疗胃癌和/或食管胃结合部癌的方法，其包括：向有需要的患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。在一些实施方案中，抗PD-L1抗体和安罗替尼或其药学上可接受的盐同时、先后、依次给药。在一些实施方案中，抗PD-L1抗体每1周、每2周、每3周、或者每4周给药一次。在一些实施方案中，抗PD-L1抗体每次以600～2400mg的剂量给药。在一些实施方案中，抗PD-L1抗体的单次给药剂量为600、800、1000、1200、1400、1600、1800、2000、2200或2400mg。在一些实施方案中，安罗替尼或其药学上可接受的盐以6mg～12mg的日剂量给药。在一些实施方案中，安罗替尼或其药学上可接受的盐以8mg～12mg的日剂量给药。在一些实施方案中，安罗替尼或其药学上可接受的盐以6mg、8mg、10mg或者12mg的日剂量给药。在一些实施方案中，安罗替尼或其药学上可接受的盐以每日一次6mg、8mg、10mg或者12mg的剂量给药。在一些实施方案中，安罗替尼或其药学上可接受的盐以连续用药2周，停1周的给药方案给药。在一些实施方案中，每3周为一个治疗周期。在一些实施方案中，21天为一个治疗周期，在每个治疗周期的第一天向患者给予抗PD-L1抗体。在一些实施方案中，每3周为一个治疗周期，抗PD-L1抗体在每个周期的第一天给药，安罗替尼或其药学上可接受的盐在每个周期的第1～14天给药。在一些实施方案中，抗PD-L1抗体以胃肠外给药的方式给药。在一些实施方案中，抗PD-L1抗体的药物组合物的浓度为10～60mg/mL。在一些实施方案中，抗PD-L1抗体的药物组合物的浓度为10、20、30、40、50或者60mg/mL。在一些实施方案中，安罗替尼或其药学上可接受的盐口服给药。
在一些实施方案中，所述治疗胃癌和/或食管胃结合部癌的方法进一步包括向有需要的患者给予治疗有效量的至少一种第三治疗剂。在一些实施方案中，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或奥沙利铂。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或奥沙利铂。在一些实施方案中，所述方法包括每次以130mg/m 2的剂量给予所述奥沙利铂；且每次以1000mg/m 2的剂量给予所述卡培他滨。在一些实施方案中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐、奥沙利铂和卡培他滨同时、先后、依次给药。在一些实施方案中，抗PD-L1抗体、安罗替尼、奥沙利铂和卡培他滨具有相同的治疗周期，例如每1周、每2周、每3周或者每4周为一个治疗周期。在一些实施方案中，每3周为一个治疗周期，抗PD-L1抗体和奥沙利铂在每个周期的第一天给药，安罗替尼或其药学上可接受的盐和卡培他滨在每个周期的第1～14天给药。在一些实施方案中，所述方法包括，给予抗PD-L1抗体、和安罗替尼或其药学上可接受的盐、和第三治疗剂进行初始治疗；然后，任选地给予抗PD-L1抗体和安罗替尼或其药学上可接受的盐进行维持治疗。在一些实施方案中，所述方法包括，每3周为一个治疗周期，在每个周期的第一天给予抗PD-L1抗体和奥沙利铂，在每个周期的第1～14天给予安罗替尼或其药学上可接受的盐和卡培他滨进行初始治疗；然后，任选地，每3周为一个治疗周期，在每个周期的第一天给予抗PD-L1抗体和在每个周期的第1～14天给予安罗替尼或其药学上可接受的盐进行维持治疗。在一些实施方案中，所述初始治疗包括0到10个治疗周期，优选1到10个治疗周期，进一步优选1到6个治疗周期，最优选6个治疗周期。在一些实施方案中，所述初始治疗包括从首次给药起的连续的0到10个治疗周期，优选连续的1到10个治疗周期，进一步优选连续的1到6 个治疗周期，最优选连续的6个治疗周期。
再一方面，本申请提供了一种治疗胃癌和/或食管胃结合部癌的方法，其包括：(1)获得或者已经获得患者的生物样本；(2)对生物样本进行检测或者已经对生物样本进行了检测；(3)确定样本是否为HER2/neu阴性(或HER2/neu状态无法明确)，如果检测结果为HER2/neu阴性(或HER2/neu状态无法明确)时，则向患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐；优选地，在一些实施方案中，进一步向患者给予治疗有效量的第三治疗剂；或者(3’)确定样本是否为HER2/neu阴性(或HER2/neu状态无法明确)，如果检测结果为HER2/neu阴性(或HER2/neu状态无法明确)时，则向患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐和第三治疗剂进行初始治疗；然后，任选地给予抗PD-L1抗体和安罗替尼或其药学上可接受的盐进行维持治疗，直到患者无法耐受或疾病进展。在一些实施方案中，所述初始治疗包括0到10个治疗周期，优选1到10个治疗周期，进一步优选1到6个治疗周期，最优选6个治疗周期。在一些实施方案中，所述初始治疗包括从首次给药起的连续的0到10个治疗周期，优选连续的1到10个治疗周期，进一步优选连续的1到6个治疗周期，最优选连续的6个治疗周期。在一些实施方案中，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物和/或铂类抗肿瘤药物和/或紫杉醇类抗肿瘤药物中的一种或多种。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或铂类抗肿瘤药物。在一些实施方案中，所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或奥沙利铂。在一些实施方案中，所述第三治疗剂包括卡培他滨和/或奥沙利铂。
安罗替尼或其药学上可接受的盐
安罗替尼的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
Figure PCTCN2022107363-appb-000001
所述药学上可接受的盐包括但不限于安罗替尼与选自以下的酸所形成的盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸。在一些实施方案中，所述药学上可接受的盐为盐酸盐和马来酸盐；在一些实施方案中，所述药学上可接受的盐为二盐酸盐。
本申请中涉及的安罗替尼或其药学上可接受的盐的剂量，除非另有说明，均基于安罗替尼游离碱的分子量。
安罗替尼或其药学上可接受的盐可通过多种途径给药，该途径包括经胃肠道给药以及肠胃外给药途径，包括但不限于口服、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。给予安罗替尼或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。例如，给予安罗替尼或其药学上可接受的盐的日剂量可为2毫克至20毫克，在一些实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量可为2、3、4、5、6、7、8、9、10、11、12、13、14、15和16毫克。安罗替尼或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，安罗替尼或其药学上可接受的盐以口服固体制剂每天给药一次。
安罗替尼或其药学上可接受的盐的给药方案可根据药物的活性、毒性以及患者的耐受性等来综合确 定。优选地，以间隔给药的方式给予安罗替尼或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予安罗替尼或其药学上可接受的盐。例如给药期和停药期的以天数计的比值为2:(0.5～5)、2:(0.5～3)、2:(0.5～2)、或者2:(0.5～1)。在一些实施方案中，连续给药2周停药2周。在一些实施方案中，连续给药2周停药1周。在一些实施方案中，连续给药5天停药2天。例如安罗替尼或其药学上可接受的盐可以每日一次6mg、8mg、10mg或者12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
安罗替尼或其药学上可接受的盐的药物组合物
在本申请的一些实施方案中，所述安罗替尼或其药学上可接受的盐的药物组合物的单位剂量包括6mg、8mg、10mg、或12mg的安罗替尼。
在本申请的一些实施方案中，按照给药2周停1周的治疗周期，每个周期给予所述安罗替尼或其药学上可接受的盐的药物组合物的总剂量包括84～168mg。在部分方案中，所述安罗替尼或其药学上可接受的盐的药物组合物的总剂量包括选自84mg、112mg、140mg、168mg或上述任意值形成的范围。在部分方案中，所述安罗替尼或其药学上可接受的盐的药物组合物的总剂量包括112mg～168mg。
在一些实施方案中，所述药物组合物包括但不限于适合口服、肠道外、局部给药的制剂。在一些实施方案中，所述药物组合物为适合口服的制剂。在一些实施方案中，所述药物组合物为适合口服的固体制剂。在一些实施方案中，所述药物组合物包括但不限于片剂、胶囊。
奥沙利铂
奥沙利铂的化学名为(1R-反式)-(1,2-环己烷二胺-N,N’)[草酸(2-)-O,O’]合铂，其具有如下的结构式：
Figure PCTCN2022107363-appb-000002
奥沙利铂可通过多种途径给药，包括经胃肠道给药以及肠胃外给药途径，包括但不限于口服、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过注射给药。
本申请中奥沙利铂的单次给药剂量可为65～130mg/m 2；在一些实施方案中，单次给药剂量可为85～130mg/m 2。在一些实施方案中，奥沙利铂以注射剂每2周给药一次。在一些实施方案中，奥沙利铂以注射剂每3周给药一次，例如奥沙利铂在每个周期的第一天以130mg/m 2的剂量注射给药。其中，根据本领域技术人员的常识，可以理解的是，mg/m 2是指受试者每平方米体表面积所用的药物的剂量。
奥沙利铂的药物组合物
在本申请一些实施方案中，所述奥沙利铂的药物组合物包括但不限于适合静脉内、口服、肠道外、局部给药的制剂；在一些实施方案中，所述药物组合物为适合注射的制剂；在一些实施方案中，所述药物组合物包括但不限于冻干粉注射剂。
卡培他滨
卡培他滨的化学名为[1-(5-脱氧-β-D-呋喃核糖基)-5-氟-2-氧代-1,2-二氢嘧啶-4-基]氨基甲酸戊酯，其具有如下的结构式：
Figure PCTCN2022107363-appb-000003
卡培他滨可通过多种途径给药，该途径包括经胃肠道给药以及肠胃外给药途径，包括但不限于口服、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。
本申请中卡培他滨的单次给药剂量可为1000～1250mg/m 2；在一些实施方案中，单次给药剂量可为1000mg/m 2。在一些实施方案中，卡培他滨以1000mg/m 2的单剂量，每日给药两次，以连续用药2周，停1周的给药方案给药。其中，根据本领域技术人员的常识可以理解的是，mg/m 2是指受试者每平方米体表面积所用的药物的剂量。
卡培他滨的药物组合物
在本申请一些实施方案中，所述卡培他滨的药物组合物包括但不限于适合静脉内、口服、肠道外、局部给药的制剂；在一些实施方案中，所述药物组合物为适合口服的制剂；在一些实施方案中，所述药物组合物包括但不限于片剂。
抗PD-L1抗体
在本申请的一些实施方案中，所述抗PD-L1抗体为WO2016022630或CN107001463A中的抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链CDR3区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：选自SEQ ID NO:1或SEQ ID NO:4的重链CDR1区；选自SEQ ID NO:2或SEQ ID NO:5的重链CDR2区；选自SEQ ID NO:3或SEQ ID NO:6的重链CDR3区；选自SEQ ID NO:7或SEQ ID NO:10的轻链CDR1区；选自SEQ ID NO:8或SEQ ID NO:11的轻链CDR2区；选自SEQ ID NO:9或SEQ ID NO:12的轻链CDR3区。
在本申请的一些实施方案中，本文所述的分离的抗PD-L1抗体包含：具有以SEQ ID NO:1示出的氨基酸序列的重链CDR1区，具有以SEQ ID NO:2示出的氨基酸序列的重链CDR2区，具有以SEQ ID NO:3示出的氨基酸序列的重链CDR3区；以及具有以SEQ ID NO:7示出的氨基酸序列的轻链CDR1区，具有以SEQ ID NO:8示出的氨基酸序列的轻链CDR2区，具有以SEQ ID NO:9示出的氨基酸序列的轻链CDR3区。
本文所述的各CDR区及其上述的各种变体能够特异性地识别并结合PD-L1，从而有效地阻断PD-L1和PD-1之间的信号传导。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:13或SEQ ID NO:14所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的重链可变区；与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80％(例如81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％)同源性的轻链可变区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:13所示的重链可变区；如SEQ ID NO:15所示的轻链可变区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:14所示的重链可变区；如SEQ ID NO:16所示的轻链可变区。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:17所示的重链氨基酸序列；如SEQ ID NO:18所示的轻链氨基酸序列。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:19所示的重链氨基酸序列；如SEQ ID NO:20所示的轻链氨基酸序列。
在本申请的一些实施方案中，所述抗PD-L1抗体包含如下氨基酸序列：如SEQ ID NO:21所示的重链氨基酸序列；如SEQ ID NO:18所示的轻链氨基酸序列。
在一个具体实施方案中，本申请提供的抗PD-L1人源化单抗包含选自SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO:17、SEQ ID NO:18、SEQ ID NO:19、SEQ ID NO:20、SEQ ID NO:21中的一个或多个的保守置换变体。包含所述保守置换变体的抗PD-L1人源化单抗保留了特异性地识别并结合PD-L1的能力。
在本申请的一些实施方案中，所述抗PD-L1抗体可为IgG1或IgG4抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体为IgG1抗体。在部分实施方案中，所述抗PD-L1抗体为糖基化的IgG1抗体。
在本申请的一些实施方案中，所述抗PD-L1抗体包含选自13C5或5G11抗体的重链互补决定区(CDR)，和选自13C5或5G11抗体的轻链互补决定区。在一个实施方案中，本申请所述的抗PD-L1抗体，其包含选自ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变重链，和选自ch5G11-hIgG1、ch5G11-hIgG4、ch13C5-hIgG1、ch13C5-hIgG4嵌合抗体的可变轻链。在一个实施方案中，本申请所述的抗PD-L1抗体，其包含选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变重链，和选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变轻链。可以参考专利文献WO2016022630或CN107001463A的记载：13C5、ch13C5-hIgG1、ch13C5-hIgG4、hu13C5-hIgG1或hu13C5-hIgG4的HCDR1序列为SYGMS(SEQ ID NO:4)，HCDR2序列为SISSGGSTYYPDSVKG(SEQ ID NO:5)，HCDR3序列为GYDSGFAY(SEQ ID NO:6)，LCDR1序列为ASQSVSTSSSSFMH(SEQ ID NO:10)，LCDR2序列为YASNLES(SEQ ID NO:11)，LCDR3序列为QHSWEIPYT(SEQ ID NO:12)；5G11、ch5G11-hIgG1、ch5G11-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4的HCDR1序列为TYGVH(SEQ ID NO:1)，HCDR2序列为VIWRGVTTDYNAAFMS(SEQ ID NO:2)，HCDR3序列为LGFYAMDY(SEQ ID NO:3)，LCDR1序列为KASQSVSNDVA(SEQ ID NO:7)，LCDR2序列为YAANRYT(SEQ ID NO:8)，LCDR3序列为QQDYTSPYT(SEQ ID NO:9)。
在本申请的一些实施方案中，所述药物组合中的抗PD-L1抗体可以选自一种或多种。如本申请所用，术语“多种”可以是多于一种，例如，两种、三种、四种、五种或更多种。例如，在本申请的一些实施方案中，所述抗PD-L1抗体选自包含如SEQ ID NO:13所示的重链可变区和如SEQ ID NO:15所示的轻链可变区，或选自包含如SEQ ID NO:14所示的重链可变区和如SEQ ID NO:16所示的轻链可变区，或选自上述的组合。又例如，所述抗PD-L1抗体选自如SEQ ID NO:17所示的重链氨基酸序列和如SEQ ID NO:18所示的轻链氨基酸序列，或选自如SEQ ID NO:19所示的重链氨基酸序列和如SEQ ID NO:20所示的轻链氨基酸序列，或选自如SEQ ID NO:21所示的重链氨基酸序列和如SEQ ID NO:18所示的轻链氨基酸序列，或选自上述任选多种的组合。
在一些实施方案中，抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
抗PD-L1抗体的药物组合物
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物含有600～2400mg的抗PD-L1抗体。在部分方案中，所述抗PD-L1抗体的药物组合物含有选自600mg、900mg、1200mg、1500mg、1800mg、2100mg、2400mg、或上述任意值形成的范围的抗PD-L1抗体。在部分方案中，所述抗PD-L1抗体的药物组合物含有600～2100mg、或900mg～1500mg的抗PD-L1抗体；其中所述抗PD-L1抗体的药物组合物可以多剂量或者单位剂量形式存在。
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物中含300mg、600mg或者1200mg的抗PD-L1抗体。在本申请的一些实施方案中，提供了一种配制成单位剂量的抗PD-L1抗体的药物组合物，其含有300mg、600mg或1200mg的抗PD-L1抗体。
在一些实施方案中，所述抗PD-L1抗体的药物组合物为注射用溶液剂。在一些实施方案中，所述抗PD-L1抗体的药物组合物为注射用水溶液。在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物包含缓冲液、等渗调节剂、稳定剂和/或表面活性剂中的一种或多种。特别地，所述抗PD-L1抗体的药物组合物包含1～150mg/mL抗PD-L1抗体(例如单抗)、3～50mM缓冲液、2～150mg/mL等渗调节剂/稳定剂和0.01～0.8mg/mL表面活性剂，且pH为4.5～6.8。
在本申请的一些实施方案中，所述抗PD-L1抗体的药物组合物以w/v计算，抗PD-L1单抗浓度为5～150mg/mL；在一些实施方案中所述浓度为10～60mg/mL；在一些实施方案中所述浓度为10～30mg/mL。在一些具体方案中，抗PD-L1单抗质量体积浓度为10mg/mL、20mg/mL、30mg/mL、40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL、100mg/mL、110mg/mL或120mg/mL；在一些实施方案中，所述浓度为10mg/mL、20mg/mL、30mg/mL、40mg/mL、50mg/mL或60mg/mL；在一些实施方案中，所述浓度为10mg/mL、20mg/mL或30mg/mL。在一些实施方案中，抗PD-L1单抗质量体积浓度为10mg/mL。在另一些实施方案中，抗PD-L1单抗质量体积浓度为30mg/mL。在另一些实施方案中，抗PD-L1单抗质量体积浓度为60mg/mL。
在本申请的一些实施方案中，所述缓冲液为组氨酸盐缓冲液。所述组氨酸盐缓冲液浓度为5～30mM，在一些实施方案中，所述浓度为10～25mM；在一些实施方案中，所述浓度为10～20mM；在一些实施方案中，所述浓度为10～15mM。在一些具体方案中，所述组氨酸盐缓冲液浓度为5mM、10mM、15mM、20mM、25mM或30mM。在一些实施方案中，所述组氨酸盐缓冲液浓度为10mM。在另一些实施方案中，所述组氨酸盐缓冲液浓度为15mM。在另一些实施方案中，所述组氨酸盐缓冲液浓度为20mM。其中，所述组氨酸盐缓冲液包含组氨酸和盐酸。
在本申请的一些实施方案中，以w/v计算，所述等渗调节剂/稳定剂为20～150mg/mL的蔗糖；在一些实施方案中，所述等渗调节剂/稳定剂为40～100mg/mL的蔗糖；在一些实施方案中，所述等渗调节剂/稳定剂为60～80mg/mL的蔗糖。在一些具体方案中，所述蔗糖的浓度为40mg/mL、50mg/mL、60mg/mL、70mg/mL、80mg/mL、90mg/mL或100mg/mL。在一些具体实施方案中，所述蔗糖的浓度为60mg/mL。在一些具体实施方案中，所述蔗糖的浓度为70mg/mL。在一些具体实施方案中，所述蔗糖的浓度为80mg/mL。在一些具体实施方案中，所述蔗糖的浓度为90mg/mL。
在本申请的一些实施方案中，所述表面活性剂选自聚山梨酯80、聚山梨酯20、泊洛沙姆188；在一些实施方案中，所述表面活性剂选自聚山梨酯80或聚山梨酯20；在一些实施方案中，所述表面活性剂选自聚山梨酯80。在一些方案中，以w/v计算，所述表面活性剂的浓度为0.05～0.6mg/mL；在一些实施方案中，所述浓度为0.1～0.4mg/mL；在一些实施方案中，所述浓度为0.2～0.3mg/mL。
在本申请的一些实施方案中，以w/v计算，所述表面活性剂为0.01～0.8mg/mL的聚山梨酯80或聚山梨酯20。在一些具体方案中，所述表面活性剂为0.05～0.6mg/mL的聚山梨酯80；在一些实施方案中，所述表面活性剂为0.1～0.4mg/mL的聚山梨酯80；在一些实施方案中，所述表面活性剂为0.2～0.3mg/mL的聚山梨酯80；在一些实施方案中，所述表面活性剂为0.2mg/mL的聚山梨酯80。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.1mg/mL、0.2mg/mL、0.3mg/mL、0.4mg/mL、0.5mg/mL或0.6mg/mL；在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL、0.3mg/mL、0.4mg/mL或0.5mg/mL；在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL、0.3mg/mL或0.4mg/mL；在一些 实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.1mg/mL。在另一些实施方案中，所述药物组合物中聚山梨酯80含量为0.2mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.3mg/mL。在另一些实施方案中，所述药物组合物中聚山梨酯80含量为0.4mg/mL。在一些实施方案中，所述药物组合物中聚山梨酯80含量为0.5mg/mL。
在本申请的一些实施方案中，所述药物组合物的水溶液pH值选自4.0～6.8；在一些实施方案中，所述pH值为4.5～6.5；在一些实施方案中，所述pH值为5.5～6.0；在一些实施方案中，所述pH值为5.5。在一些实施方案中，药物组合物水溶液的pH值为4.5、4.8、5.0、5.2、5.4、5.5、5.6、5.8或6.0，在一些实施方案中，所述pH值为5.0、5.2、5.4、5.5或5.6；在一些实施方案中，所述pH值为5.5。在一些实施方案中，药物组合物水溶液的pH值为5.0。在一些实施方案中，药物组合物水溶液的pH值为5.2。在一些实施方案中，药物组合物水溶液的pH值为5.4。在一些实施方案中，药物组合物水溶液的pH值为5.5。在一些实施方案中，药物组合物水溶液的pH值为5.6。在一些实施方案中，药物组合物水溶液的pH值为5.8。在一些实施方案中，药物组合物水溶液的pH值为6.0。
在本申请的一些具体实施方案中，所述药物组合物包含：(a)质量体积浓度为20mg/mL的抗PD-L1抗体，(b)质量体积浓度为70mg/mL的蔗糖，(c)质量体积浓度为0.1mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.0。本申请的一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为20mg/mL的抗PD-L1单抗，(b)质量体积浓度为70mg/mL的蔗糖，(c)质量体积浓度为0.1mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.0。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为10mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为50mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.3mg/ml的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为100mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.5mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为30mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为60mg/mL的抗PD-L1抗体，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为10mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为10mg/mL的抗PD-L1抗体，(b)质量体积浓度为70mg/mL的蔗糖，(c)质量体积浓度为0.4mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选醋酸适量，调节组合物的pH值为6.5。
在本申请的另一个具体实施方案中，所述药物组合物包含：(a)质量体积浓度为10mg/mL的抗PD-L1单抗，(b)质量体积浓度为80mg/mL的蔗糖，(c)质量体积浓度为0.2mg/mL的聚山梨酯80，(d)摩尔浓度为20mM的组氨酸，(e)任选盐酸适量，调节组合物的pH值为5.5。
在本申请的另一个具体实施方案中，药物组合物为水溶性注射液；在一些实施方案中，所述水溶性注射液包括但不限于未经冻干的水溶性制剂或冻干粉重构的水溶性制剂。在另一些方案中，药物组合物为冻干制剂。所述冻干制剂是指水溶液经历冻干过程制备的制剂，在该过程中物质首先被冷冻，然后先通过升华降低溶剂数量(初级干燥过程)，然后通过脱附作用降低溶剂数量(二级干燥过程)，直到溶剂数量为不再支持生物学活性或化学反应的值。本申请的冻干制剂还可以通过本领域已知的其它方法干燥，如喷雾干 燥和鼓泡干燥(bubble drying)。
胃癌
本申请中，所述的胃癌包括但不限于腺癌、腺鳞癌、鳞状细胞癌、低黏附性癌或未分化癌。
在本申请的一些实施方案中，所述的胃癌包括但不限于管状腺癌、壁细胞腺癌、混合型腺癌、乳头状腺癌、黏液表皮样癌、黏液腺癌、印戒细胞癌、低黏附性癌、肝样腺癌、潘氏细胞癌。
在本申请的一些实施方案中，所述的胃癌为非HER2阳性的胃癌。在一些实施方案中，所述非HER2阳性的胃癌包括HER2阴性或HER2状态无法确定的胃癌。
在本申请的一些实施方案中，所述的胃癌为晚期胃癌。在本申请的一些实施方案中，所述的胃癌为难治性胃癌。
在本申请的一些实施方案中，所述的胃癌为复发性和/或转移性的胃癌。
在本申请的一些实施方案中，所述的胃癌为复发性和/或转移性的晚期胃癌。
在本申请的一些实施方案中，所述的胃癌为不可切除的局部晚期或转移性胃癌。
在本申请的一些实施方案中，所述的胃癌的患者在先未接受过药物治疗，或者在先接受过药物治疗但治疗失败或不能耐受。
在本申请的一些实施方案中，所述药物治疗包括化疗、靶向药物治疗和免疫治疗。
在本申请的一些实施方案中，所述化疗所用药物包括但不限于紫杉烷类、长春碱类、铂类、氟尿嘧啶类、喜树碱类、蒽环类化合物、鬼臼类中的一种或多种。其中所述紫杉烷类包括但不限于为紫杉醇、紫杉醇脂质体、白蛋白结合的紫杉醇以及多烯紫杉醇(多西他赛)中的一种或多种；所述的长春碱类包括但不限于选自长春碱、长春新碱、长春地辛、长春瑞滨、长春富宁(vinflunine)、去甲长春花碱中的一种或多种；所述铂类包括但不限于选自米铂、顺铂、卡铂、双环铂、奈达铂、奥沙利铂、洛铂(Lobaplatin)、四硝酸三铂、菲铂、吡铂、沙铂中的一种或多种；所述氟尿嘧啶类包括但不限于选自阿糖胞苷、阿扎胞苷、安西他滨、卡培他滨、吉西他滨、5-氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、三氟尿苷、替加氟、卡莫氟、替吉奥、优福定中的一种或多种；所述喜树碱类包括但不限于为喜树碱、羟基喜树碱、伊立替康、拓扑替康中的一种或多种；所述蒽环类包括但不限于为表柔比星(表阿霉素)、阿霉素、柔红霉素、吡柔比星、氨柔比星、伊达柔比星、米托蒽醌、阿柔比星、戊柔比星、佐柔比星、匹杉琼、吡喃阿霉素、脂质体阿霉素中的一种或多种；所述鬼臼类包括但不限于为依托泊苷(足叶乙苷)、替尼铂苷、表鬼臼毒吡喃葡萄糖甙中的一种或多种。
在本申请的一些实施方案中，所述靶向药物包括但不限于EGFR拮抗剂、VEGF抑制剂、HER2抑制剂、PARP抑制剂、PI3K/Akt/mTOR通路抑制剂、表观遗传修饰抑制剂、HDAC抑制剂、或FGFR抑制剂中的一种或多种。
在本申请的一些实施方案中，所述EGFR拮抗剂包括但不限于曲妥珠单抗(trastuzumab)、西妥昔单抗(cetuximab)、埃克替尼(icotinib)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、拉帕替尼(lapatinib)中的一种或多种。在本申请的一些实施方案中，所述HER2抑制剂包括但不限于曲妥珠单抗(Trastuzumab)、伊尼妥单抗(Inetetamab)、帕妥珠单抗(Pertuzumab)、T-DM1、Enhertu、吡咯替尼(pyrotinib)、奈拉替尼(neratinib)、妥卡替尼(Tucatinib)、Phesgo、玛格妥昔单抗(Margenza)。在本申请的一些实施方案中，所述VEGF抑制剂包括但不限于贝伐珠单抗(bevacizumab)、雷珠单抗(ranibizumab)、阿昔替尼(axitinib)、莫替沙尼(motesanib)、阿柏西普(aflibercept)、西地尼布(cediranib)、尼达尼布(nintedanib)、索拉非尼(sorafenib)、阿帕替尼(apatinib)或舒尼替尼(sunitinib)。在本申请的一些实施方案中，所述PARP抑制剂包括但不限于奥拉帕利(olaparib)、尼拉帕利(niraparib)、或芦卡帕利(rucaparib)中的一种或多种。在本申请的一些实施方案中，所述PI3K/Akt/mTOR通路抑制剂包括但不限于NVP-BKM120、XL147、哌立福新(perifosine)、雷帕霉素(rapamycin)、坦罗莫司(temsirolimus)、依维莫司(everolimus)、西罗莫司(sirolimus)、或地磷莫司(ridaforolimus)中的一种或多种。在本申请的一些实施方案中，所述表观遗传修饰抑制剂包括但不限于阿扎胞苷(azacitidine)、地西他滨(decitabine)、zebularine、法扎拉滨(fazarabine)、罗米地新(romidepsin)、伏林司他(vorinostat)、贝林司他(belinostat)、或西达本胺(chidamide)中的一 种或多种。在本申请的一些实施方案中，所述HDAC抑制剂包括但不限于曲古菌素A(trichostatin A)、辛二酰苯胺异羟肟酸(suberoylanilidehydroxamic acid)、或丁酸钠(sodiumbutyrate，NaB)中的一种或多种。在本申请的一些实施方案中，所述FGFR抑制剂包括但不限于度维替尼(dovitinib)、或NVP-BGJ398。
在本申请的一些实施方案中，所述免疫治疗药物包括但不限于PD-1/PD-L1抑制剂、CTLA-4抑制剂、LAG-3抑制剂、TIM-3抑制剂中的一种或多种。在本申请的一些实施方案中，所述PD-1/PD-L1抑制剂包括但不限于阿特珠单抗(atezolizumab)、纳武利尤单抗(nivolumab)、或帕博利珠单抗(pembrolizumab)、德瓦鲁单抗(durvalumab)、阿维鲁单抗(avelumab)、西米普利单抗(cemiplimab)中的一种或多种。在本申请的一些实施方案中，所述CTLA-4抑制剂包括但不限于伊匹单抗(Ipilimumab)、替西木单抗(Tremelimumab)、AGEN1884、KN046中的一种或多种。在本申请的一些实施方案中，所述LAG-3抑制剂包括但不限于relatlimab、fianlimab、IMP321、BMS-986016、GSK 2831781中的一种或多种。在本申请的一些实施方案中，所述TIM-3抑制剂包括但不限于MBG453、TSR-022、BMS-986258、RO7121661、LY3321367中的一种或多种。
食管胃结合部癌
在本申请的一些实施方案中，所述的食管胃结合部癌包括食管胃结合部腺癌(adenocarcinoma of esophagogastric junction，AEG)。
在本申请的一些实施方案中，所述的食管胃结合部癌包括非HER2阳性的食管胃结合部癌。在一些实施方案中，所述的食管胃结合部癌为非HER2阳性的食管胃结合部腺癌。在一些实施方案中，所述非HER2阳性包括HER2阴性或HER2状态无法确定。
在本申请的一些实施方案中，所述的食管胃结合部癌为晚期食管胃结合部癌。在本申请的一些实施方案中，所述的食管胃结合部癌为难治性食管胃结合部癌。在本申请的一些实施方案中，所述的食管胃结合部癌为难治性食管胃结合部腺癌。
在本申请的一些实施方案中，所述的食管胃结合部癌为复发性和/或转移性的食管胃结合部癌。在本申请的一些实施方案中，所述的食管胃结合部癌为复发性和/或转移性的食管胃结合部腺癌。
在本申请的一些实施方案中，所述的食管胃结合部癌为复发性和/或转移性的晚期食管胃结合部癌。在本申请的一些实施方案中，所述的食管胃结合部癌为复发性和/或转移性的晚期食管胃结合部腺癌。
在本申请的一些实施方案中，所述的食管胃结合部癌为不可切除的局部晚期或转移性食管胃结合部腺癌。
在本申请的一些实施方案中，所述的食管胃结合部癌的患者在先未接受过药物治疗，或者在先接受过药物治疗但治疗失败或不能耐受。
在本申请的一些实施方案中，所述药物治疗包括化疗、靶向药物治疗和免疫治疗。
药物组合的给药方案
在本申请的一些实施方案中，上述用途或者治疗方法中，所述抗PD-L1抗体和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后或依次给药。在本申请的一些实施方案中，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐、第三治疗剂各自呈药物组合物的形式，可同时、先后或依次给药。在本申请的一些实施方案中，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐、奥沙利铂和卡培他滨各自呈药物组合物的形式，可同时、先后或依次给药。
在本申请的一些实施方案中，上述用途或者治疗方法中，所述抗PD-L1抗体和安罗替尼各自以间隔给药的方式给药。在一些实施方案中，所述抗体和安罗替尼分别以相同或者不同的给药方案进行给药。在一些实施方案中，所述抗体和安罗替尼分别以不同的给药方案进行给药。在本申请的一些实施方案中，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐和第三治疗剂各自以间隔给药的方式，分别以不同的给药方案进行给药。在本申请的一些实施方案中，所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐、奥沙利铂和卡培他滨各自以间隔给药的方式，分别以不同的给药方案进行给药。
在本申请的一些实施方案中，所述用途或治疗方法中，所述抗PD-L1抗体可以每1周(q1w)、每2周(q2w)、每3周(q3w)、或者每4周(q4w)施用一次。在一个具体的实施方案中，每3周给予抗PD-L1 抗体一次。在一些实施方案中，所述抗PD-L1抗体每次以600～2400mg的剂量施用。
所述安罗替尼或其药学上可接受的盐可以每日一次6mg、8mg、10mg或者12mg的剂量，连续用药2周，停1周的给药方案给药。
所述奥沙利铂可以每2周(q2w)、每3周(q3w)施用一次。在一个具体的实施方案中，每3周给予奥沙利铂一次。在一些实施方案中，所述奥沙利铂每次以85～130mg/m 2的剂量施用。
所述卡培他滨可以每天两次(早晚各1次)，1000～1250mg/m 2的单次剂量，连续用药2周，停1周的给药方案给药。
在一些实施方案中，抗PD-L1抗体和安罗替尼或其药学上可接受的盐分别具有相同或者不同的治疗周期。在一些具体的实施方案中，抗PD-L1抗体和安罗替尼具有相同的治疗周期，例如每1周、每2周、每3周或者每4周为一个治疗周期。在一些实施方案中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐和第三治疗剂分别具有相同或者不同的治疗周期。在一些实施方案中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐、奥沙利铂和卡培他滨分别具有相同或者不同的治疗周期。在一些具体的实施方案中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐、奥沙利铂和卡培他滨具有相同的治疗周期，例如每1周、每2周、每3周或者每4周为一个治疗周期。
在本申请的一些实施方案中，所述用途或者治疗方法包括，给予抗PD-L1抗体，和安罗替尼或其药学上可接受的盐，和第三治疗剂进行初始治疗；然后，任选地给予抗PD-L1抗体和安罗替尼或其药学上可接受的盐进行维持治疗。在一些实施方案中，抗PD-L1抗体、安罗替尼或其药学上可接受的盐和第三治疗剂分别具有相同的治疗周期，例如每1周、每2周、每3周或者每4周为一个治疗周期。在一些实施方案中，3周(21天)为一个治疗周期。在一些实施方案中，所述初始治疗包括0到10个治疗周期，优选1到10个治疗周期，进一步优选1到6个治疗周期，最优选6个治疗周期。在一些实施方案中，所述初始治疗包括从首次给药起的连续的0到10个治疗周期，优选连续的1到10个治疗周期，进一步优选连续的1到6个治疗周期，最优选连续的6个治疗周期。
在本申请的一些实施方案中，所述用途或者治疗方法中，3周(21天)为一个治疗周期，在每个周期的第一天给予PD-L1抗体，在每个周期的第1-14天每天一次给予安罗替尼或其药学上可接受的盐。在本申请的一些实施方案中，所述用途或者治疗方法中，21天为一个治疗周期，在每个周期的第一天给予PD-L1抗体和奥沙利铂，在每个周期的第1-14天每天一次给予安罗替尼或其药学上可接受的盐，在每个周期的第1-14天每天两次给予卡培他滨。
在本申请的一些实施方案中，所述用途或者治疗方法包括，每3周(21天)为一个治疗周期，在每个周期的第一天给予抗PD-L1抗体和奥沙利铂，在每个周期的第1～14天给予安罗替尼或其药学上可接受的盐和卡培他滨进行初始治疗；然后，任选地，每3周为一个治疗周期，在每个周期的第一天给予抗PD-L1抗体和在每个周期的第1～14天给予安罗替尼或其药学上可接受的盐进行维持治疗。在一些实施方案中，所述初始治疗包括0到10个治疗周期，优选1到10个治疗周期，进一步优选1到6个治疗周期，最优选6个治疗周期。在一些实施方案中，所述初始治疗包括从首次给药起的连续的0到10个治疗周期，优选连续的1到10个治疗周期，进一步优选连续的1到6个治疗周期，最优选连续的6个治疗周期。
在本申请的一些实施方案中，所述用途或者治疗方法包括至少1到10个治疗周期的初始治疗(抗PD-L1抗体、安罗替尼或其药学上可接受的盐、奥沙利铂和卡培他滨)，优选1到6个治疗周期的初始治疗。在完成初始治疗后，进行维持治疗(抗PD-L1抗体和安罗替尼或其药学上可接受的盐)，直到患者无法耐受或疾病进展。
在本申请的一些实施方案中，所述用途或者治疗方法中，其中所述抗PD-L1抗体可以包括选自0.01至40mg/kg、0.1至30mg/kg、0.1至20mg/kg、0.1至15mg/kg、0.1至10mg/kg、1至15mg/kg、1至20mg/kg、1至3mg/kg、3至10mg/kg、3至15mg/kg、3至20mg/kg、3至30mg/kg、10至20mg/kg、或15至20mg/kg的剂量给予受试者；或者以60mg至2400mg、90mg至1800mg、120mg至1500mg、300mg至900mg、600mg至900mg、300mg至1200mg、600mg至1200mg、或900mg至1200mg的剂量施用于受试者。
在所述用途或者治疗方法的一些实施方案中，21天为一个治疗周期，在每个周期的第一天给予1200mg的PD-L1抗体，在每个周期的第1～14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。在所述用途或者治疗方法的一些实施方案中，21天为一个治疗周期，在每个周期的第一天给予1200mg的PD-L1抗体和以130mg/m 2的剂量给予奥沙利铂，在每个周期的第1～14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐，在每个周期的第1～14天每天两次(早晚各1次)，可以以1000mg/m 2的单次给药剂量给予卡培他滨。
在一些实施方案中，每3周(21天)为一个治疗周期，在每个周期的第一天给予1200mg的PD-L1抗体和以130mg/m 2的剂量给予奥沙利铂，在每个周期的第1～14天每天一次给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐和在每个周期的第1～14天每天两次(早晚各1次)，可以以1000mg/m 2的单次给药剂量给予卡培他滨进行初始治疗；然后，任选地，每3周为一个治疗周期，在每个周期的第一天给予1200mg抗PD-L1抗体和在每个周期的第1～14天每天一次给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐进行维持治疗，直到患者无法耐受或疾病进展。在一些实施方案中，所述初始治疗包括0到10个治疗周期，优选1到10个治疗周期，进一步优选1到6个治疗周期，最优选6个治疗周期。在一些实施方案中，所述初始治疗包括从首次给药起的连续的0到10个治疗周期，优选连续的1到10个治疗周期，进一步优选连续的1到6个治疗周期，最优选连续的6个治疗周期。
施用方式
下述内容并非限制本申请药物组合的施用方式。
本申请的药物组合中的组分可以各自独立地、或者其中的部分或全部共同以适合的各种途径施用，包括但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。在一些实施方案中，本申请的药物组合的组分可以各自独立地、或者其中的部分或全部共同口服施用或注射施用，例如静脉注射或腹腔注射。
本申请的药物组合中的组分可以各自独立地、或者其中的部分或全部共同是适合的剂型，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
本申请的药物组合中的组分可以各自独立地、或者其中的部分或全部共同含有药学上可接受的载体和/或赋形剂。
在一些实施方案中，本申请的药物组合可安全、有效地治疗胃癌和/或食管胃结合部癌。
在一些实施方案中，本申请的药物组合可安全、有效地治疗非HER2阳性的胃癌和/或食管胃结合部癌。在一些实施方案中，本申请的药物组合可安全、有效地治疗非HER2阳性的胃癌和/或食管胃结合部腺癌。
在一些实施方案中，本申请的药物组合在胃癌和/或食管胃结合部癌患者中，DCR(疾病控制率)达到或超过60％；达到或超过70％；达到或超过80％；达到或超过90％；达到或超过95％；甚至达到100％。
在一些实施方案中，胃癌和/或食管胃结合部癌患者、尤其是非HER2阳性的胃癌和/或食管胃结合部癌患者、更尤其是非HER2阳性的胃癌和/或食管胃结合部腺癌患者在接受本申请中的药物组合物的初始治疗后，DCR达到或超过60％；达到或超过70％；达到或超过80％；达到或超过90％；达到或超过95％。然后，在接受本申请中的药物组合维持治疗后，DCR达到或超过60％；达到或超过70％；达到或超过80％；达到或超过90％；达到或超过95％；甚至达到100％。
在一些实施方案中，本申请的药物组合在胃癌和/或食管胃结合部癌患者中，ORR(客观缓解率)达到或超过40％；达到或超过55％；达到或超过65％；达到或超过75％；达到或超过80％；达到或超过85％；达到或超过90％。
在一些实施方案中，胃癌和/或食管胃结合部癌患者、尤其是非HER2阳性的胃癌和/或食管胃结合部癌患者、更尤其是非HER2阳性的胃癌和/或食管胃结合部腺癌患者在接受本申请中的药物组合的初始治疗后，ORR达到或超过40％；达到或超过55％；达到或超过65％；达到或超过75％；达到或超过80％。然后，接受本申请中的药物组合的维持治疗后，ORR达到或超过40％；达到或超过55％；达到或超过65％；达到或超过75％；达到或超过80％；达到或超过85％；达到或超过90％。
在一些实施方案中，本申请的药物组合在胃癌和/或食管胃结合部癌患者中，可显著延长患者的PFS(无进展生存期)和OS(总生存期)。在一些实施方案中，所述PFS超过6个月；达到或超过7个月；达到或超过8个月；达到或超过9个月；达到或超过10个月；达到或超过11个月；达到或超过12个月。
在一些实施方案中，本申请的药物组合在治疗胃癌和/或食管胃结合部癌中，具有协同作用，并且具有较佳的安全性。
在一些实施方案中，根据计算IRC评估的客观缓解例数(PR+CR)占总病例数的比率及95％CI，来计算ORR。
定义和说明
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本申请中出现商品名时，意在指代其对应的商品或其活性成分。
本文中，除非另有说明，其中涉及安罗替尼或其药学上可接受的盐的量，均是指其中活性成分安罗替尼游离碱的量。
除非另有说明，术语“剂量”是指不考虑患者的重量或体表面积(BSA)施用给患者的剂量，例如，60kg人和100kg人将接受相同剂量的抗体(例如，240mg抗PD-1抗体)。另外，根据本领域技术人员的常识，可以理解的是，mg/m 2是指受试者每平方米体表面积所用的药物的剂量。
如文本所用，术语“药物组合”是指同时或先后施用的两种或两种以上的活性成分(以各自的活性成分本身的形式施用，或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。所述活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的结合蛋白。本申请的抗体和其片段可以是整个抗体或其任何片段。因此，本申请的抗体和片段包括单克隆抗体或其片段和抗体变体或其片段，以及免疫缀合物。抗体片段的实例包括Fab片段、Fab'片段、F(ab')2片段、Fv片段、分离的CDR区、单链Fv分子(scFv)、Fd片段和本领域已知的其它抗体片段。抗体和其片段还可以包括重组多肽、融合蛋白和双特异性抗体。本文所述的抗PD-L1抗体和其片段可以是IgG1、IgG2、IgG3或IgG4同种型。术语“同种型”是指由重链恒定区基因编码的抗体种类。在一个实施方案中，本文所述的抗PD-L1抗体和其片段是IgG1或IgG4同种型。本申请的PD-L1抗体和其片段可以衍生自任何物种，其包括但不限于小鼠、大鼠、兔、灵长类动物、美洲驼和人。PD-L1抗体和其片段可以是嵌合抗体、人源化抗体或完整的人抗体。在一个实施方案中，抗PD-L1抗体是由源自小鼠的杂交瘤细胞系产生的抗体。因此，在一个实施方案中，抗PD-L1抗体是鼠类抗体。在另一个实施方案中，抗PD-L1抗体是嵌合抗体。在另一个实施方案中，嵌合抗体是小鼠-人嵌合抗体。在另一个实施方案中，抗体是人源化抗体。在另一个实施方案中，抗体衍生自鼠类抗体并且是人源化的。
“人源化抗体”是下述抗体：所述抗体含有衍生自非人抗体的互补决定区(CDR)；和衍生自人抗体的框架区以及恒定区。例如，本文所述的抗PD-L1抗体可以包含衍生自一种或多种鼠类抗体的CDR以及人框架区和恒定区。因此，在一个实施方案中，本文所述的人源化抗体与所述抗体的CDR所衍生自的鼠类抗体结合PD-L1上的相同表位。在一些实施方案中，所述的抗PD-L1抗体为人源化抗体。包含本文提供的重链CDR和轻链CDR的另外的抗PD-L1抗体或其变体可以使用任何人框架序列产生，并且也包括在本申请中。在一个实施方案中，适用于在本申请中使用的框架序列包括在结构上与本文提供的框架序列类似的那些框架序列。可以在框架区中进行另外修饰以改进本文提供的抗体的特性。此类另外的框架修饰可以包括化学修饰；点突变以降低免疫原性或去除T细胞表位；或使突变回复为原始种系序列中的残基。在一些实施方案中，此类修饰包括对应于本文示例的突变的那些修饰，包括对种系序列的回复突变。例如，在一个实施方案中，本文所述的人源化抗体的VH和/或VL的人框架区中的一个或多个氨基酸被回复突变为亲本鼠类抗体中对应的氨基酸。例如，对于人源化5G11和人源化13C5的VH和VL，上述模板人抗体的框架氨基酸的几个位点被回复突变为小鼠5G11和13C5抗体中对应的氨基酸序列。在一个实施方案中，轻链可变区的位置53和/或60和/或67处的氨基酸被回复突变为在小鼠5G11或13C5轻链可变区中的所述位置处发现的对应的氨基酸。在另一个实施方案中，重链可变区的位置24和/或28和/或30和/或49和/ 或73和/或83和/或94处的氨基酸被回复突变为在小鼠5G11或13C5重链可变区中的所述位置处发现的对应的氨基酸。在一个实施方案中，人源化5G11抗体包含轻链可变区，其中在位置60处的氨基酸从Ser(S)突变为Asp(D)，并且在位置67处的氨基酸从Ser(S)突变为Tyr(Y)；以及重链可变区，其中在位置24处的氨基酸从Phe(F)突变为Val(V)，在位置49处的氨基酸从Ala(A)突变为Gly(G)，在位置73处的氨基酸从Thr(T)突变为Asn(N)，并且在位置83处的氨基酸从Thr(T)突变为Asn(N)。在一个实施方案中，人源化13C5抗体包含轻链可变区，其中在位置53处的氨基酸从Tyr(Y)突变为Lys(K)；以及重链可变区，其中在位置28处的氨基酸从Thr(T)突变为Ile(I)，在位置30处的氨基酸从Ser(S)突变为Arg(R)，在位置49处的氨基酸从Ser(S)突变为Ala(A)，并且在位置94处的氨基酸从Tyr(Y)突变为Asp(D)。另外的或另选的回复突变可以在本文提供的人源化抗体的框架区中进行以改进抗体的特性。本申请还包括下述人源化抗体，所述人源化抗体结合PD-L1并且包含对应于本文所述的相对于任何合适的框架序列的示例性修饰的框架修饰，以及以其它方式改进抗体特性的其它框架修饰。
对于本申请所述的结合PD-L1的分离的抗体或其片段，其中所述抗体可以由杂交瘤产生，所述杂交瘤选自由本文称为13C5、5G11的杂交瘤组成的组。因此，本申请所述的抗体还包括杂交瘤13C5、5G11，以及产生本文公开的抗体的任何杂交瘤。本申请还提供了编码本文提供的抗体和其片段的分离的多核苷酸。本申请还包括包含分离的多核苷酸的表达载体，和包含所述表达载体的宿主细胞。
“分离的抗体”表示这样的抗体：其基本上不含有具有不同抗原特异性的其它抗体(例如，分离的特异性地结合PD-1的抗体基本上不含有特异性地结合除PD-1以外的抗原的抗体)。但是，分离的特异性地结合PD-1的抗体可以具有与其它抗原(诸如来自不同物种的PD-1分子)的交叉反应性。此外，分离的抗体可以基本上不含有其它细胞材料和/或化学物质。
术语“单克隆抗体”(“mAb”)表示单一分子组成的抗体分子(即，这样的抗体分子：其基本序列是基本上相同的，并且其表现出对特定表位的单一结合特异性和亲和力)的非天然存在的制备物。mAb是分离的抗体的一个例子。通过本领域技术人员已知的杂交瘤技术、重组技术、转基因技术或其它技术，可以生产mAb。
本文所述的抗体和其抗原结合片段对PD-L1是特异性的。在一个实施方案中，抗体或/和其片段对PD-L1是特异性的。在一个实施方案中，本文所述的抗体和片段结合人或灵长类动物PD-L1，但不结合来自任何其它哺乳动物的PD-L1。在另一个实施方案中，抗体或/和其片段不结合小鼠PD-L1。术语“人PD-L1”、“hPD-L1”和“huPD-L1”等在本文中可互换使用，并且是指人PD-L1和人PD-L1的变体或同种型。“特异性”意指抗体和其片段以比任何其他靶标更大的亲和力结合PD-L1。
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的活性物质(例如本申请的抗体或化合物)的量可根据一些因素而变化，诸如个体的疾病状态、年龄、性别和重量，以及治疗剂或治疗剂组合在个体中引发所需应答的能力。有效量也可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“施用”或“给予”可互换使用，表示使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的组合物。免疫检查点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)的施用途径包括胃肠外施用途径(包括但不限于静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径)，例如通过注射或输注。在一些实施方案中，本文中使用的短语“胃肠外施用”或“胃肠外给药”可互换使用，通常是指通过注射进行的除了肠内和局部施用以外的施用模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、淋巴管内、病灶内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。在某些实施方案中，所述免疫检查点抑制剂(例如，抗PD-1抗体或抗PD-L1抗体)通过非胃肠外途径施用；在某些实施方案中，口服施用；其它非胃肠外途径包括局部、表皮或粘膜施用，例如，鼻内、阴道内、直肠内、舌下或局 部施用。还可以执行施用，例如，一次、多次，和/或在一个或多个延长的时间段中。
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言，它们适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症。
术语“药学上可接受的盐”包括游离碱与酸形成的盐或酸与游离碱形成的盐，例如包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐或对甲基苯磺酸盐；在一些实施方案中，所述药学上可接受的盐为盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐、对甲基苯磺酸盐、钠盐、钾盐、铵盐、氨基酸盐等。本申请中，当形成药学上可接受的盐时，所述酸与游离碱的摩尔量之比为1:0.2～1:5；在一些实施方案中，所述摩尔量之比为1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。
在本文中，术语“受试者”或“患者”可互换使用。在一些实施方案中，术语“受试者”或“患者”是哺乳动物。在部分实施方案中，所述受试者或患者是小鼠。在部分实施方案中，所述受试者或患者是人。
术语“单位剂量”，是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单位剂量；或者每瓶注射液为单位剂量。
术语“多剂量”由多个单位剂量组成。
术语“药物组合物”是指一种或多种本申请的活性成分或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
术语“氟尿嘧啶类抗肿瘤药物”是指含具有抗肿瘤活性的尿嘧啶的氟代衍生物的药物，或可在体内转变为5-氟尿嘧啶的药物，所述氟尿嘧啶类抗肿瘤药物包括但不限于选自卡培他滨、5-氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、三氟尿苷、替加氟、卡莫氟、替吉奥、优福定中的一种或多种。
术语“铂类抗肿瘤药物”是指含具有抗肿瘤活性的铂配合物的药物，所述铂类抗肿瘤药物包括但不限于选自米铂、顺铂、卡铂、双环铂、奈达铂、奥沙利铂、洛铂(Lobaplatin)、四硝酸三铂、菲铂、吡铂、沙铂中的一种或多种。
术语“紫杉醇类抗肿瘤药物”是指含具有抗肿瘤活性的紫杉醇及其衍生物的药物，所述紫杉醇类抗肿瘤药物包括但不限于选自紫杉醇、紫杉醇脂质体、白蛋白结合型紫杉醇、多西他赛中的一种或多种。
术语“食管胃结合部癌”(esophagogastric junction cancer)也可称为胃食管结合部癌。
术语“食管胃结合部腺癌”(adenocarcinoma of esophagogastric junction，AEG)也可称为胃食管结合部腺癌。
术语“初始治疗”是指在重复周期中，给予患者抗PD-L1抗体、和安罗替尼或其药学上可接受的盐、和第三治疗剂。在一些实施方案中，初始治疗是指在重复周期中，给予患者抗PD-L1抗体、安罗替尼或其药学上可接受的盐、卡培他滨和奥沙利铂。
术语“维持治疗”是指在重复周期中，给予患者抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。
所述的“重复周期”是指0个、1个或者多个连续的治疗周期。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
在本文中，除非另有说明，本文所使用的表示成分的量、测量值或反应条件的所有数字应理解为在所有情况下均由术语“约”修饰。当与百分比相连时，术语“约”可以表示例如±0.1％、优选±0.05％、更优选±0.01％。
除非上下文另有明确指示，单数术语涵盖复数的指示对象，反之亦然。类似地，除非上下文另有明确指示，词语“或”意在包括“和”。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的 承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
为清楚起见，进一步用实施例来阐述本申请，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。实施例中抗PD-L1抗体按WO2016022630中所述方法制得，经亲和层析后，按常规的抗体纯化方法得到含有该抗体的洗脱液。
实施例1胃癌和/或食管胃结合部癌的II期临床试验
符合入选标准的胃癌和/或食管胃结合部癌受试者，首先接受6个治疗周期的初始治疗(抗PD-L1抗体、盐酸安罗替尼、奥沙利铂和卡培他滨的四药联合方案)，然后接受维持治疗(抗PD-L1抗体和盐酸安罗替尼的双药联合方案)直至疾病进展、发生不可耐受的毒性、撤销知情同意书、失访或死亡、或其他研究者判断应停止治疗的情况，以先发生者为准。
1.1主要入选标准：
1)经病理学(组织学或细胞学)检查证实是HER2/neu阴性(或者HER2/neu状态无法明确)的不可切除的局部晚期或转移性胃癌或胃食管结合部腺癌(包括印戒细胞癌、粘液腺癌、肝样腺癌)；
2)既往(新)辅助化疗/辅助放疗结束至疾病复发时间>6个月；
3)根据RECIST1.1版，至少有一个可测量病灶或可评估病灶；可测量病灶应未接受过放疗等局部治疗(位于既往放疗区域内的病灶，如果证实发生进展，并符合RECIST1.1标准，也可选做靶病灶)；
4)年龄：18-75周岁；
5)ECOG PS评分：0-1分；预计生存期超过3个月。
1.2试验药
抗PD-L1抗体注射剂hu5G11-hIgG1：1200mg抗PD-L1抗体注射液用生理盐水稀释至100mL，输注时间约40min(输注前后均用生理盐水冲管)。抗PD-L1抗体注射剂在第一天给药，每21天给药一次，即21天为一个治疗周期(d1/q3w)。
盐酸安罗替尼胶囊(活性成分为安罗替尼二盐酸盐)：每日1次(早餐前空腹口服)，每次1粒(10mg)。连续口服2周停1周，即21天为一治疗周期，在每个周期的第1～14天给药。无特殊情况，建议每天固定时间服用，(即，盐酸安罗替尼胶囊：10mg/qd，d1-14/q3w)。
研究者可根据疾病的状况以及安全性等方面，调整盐酸安罗替尼胶囊的剂量，例如：12mg、10mg、8mg。
奥沙利铂：每次剂量130mg/m 2，静脉滴注，在第一天给药，每21天给药一次，即21天为一个治疗周期(d1/q3w)。
卡培他滨：每次剂量1000mg/m 2，每日两次(口服，早晚各一次)，连续口服2周停1周，即21天为一治疗周期，在每个周期的第1～14天给药(d1-14/q3w)。
1.3评价标准
安全性评价标准：采用NCI CTC AE 5.0标准评价药物的不良反应。
有效性评价标准：采用RECIST 1.1、iRECIST标准评价药物疗效。以RECIST 1.1标准评价为主，同时使用iRECIST标准对疗效进行确认。即按RECIST 1.1标准判定为疾病进展(PD)的受试者，按iRECIST标准进一步确认，从而决定是否进一步用药观察。
1.4终点指标
主要终点：客观缓解率(ORR)
次要终点：(1)药物安全性；(2)疾病控制率(DCR)；(3)客观缓解率(ORR)；(4)缓解持续时间(DOR)；(5)无进展生存期(PFS)以及总生存期(OS)。
1.5结果
初步研究显示，接受初始治疗(抗PD-L1抗体、盐酸安罗替尼、奥沙利铂和卡培他滨的四药联合方案)后，受试者的ORR超过40％、甚至达到或超过90％，接受维持治疗(抗PD-L1抗体和盐酸安罗替尼的双药联合方案)后，受试者的ORR获得进一步提高。有数据显示，在10例可进行疗效评估的受试者中，根据最佳疗效统计，其中有4名受试者(4/10)完全缓解，5名受试者(5/10)部分缓解，1名受试者(1/10)疾病稳定，ORR达到了90％，DCR达到了100％。此外其中3名受试者停止治疗，初步的中位PFS已经超过6个月。试验中的治疗方案在治疗胃癌和/或食管胃结合部腺癌方面表现出了令人惊讶的疗效，且具有安全性，不良事件可控。试验表明抗PD-L1抗体、盐酸安罗替尼、奥沙利铂和卡培他滨的四药联合方案和抗PD-L1抗体和盐酸安罗替尼的双药联合方案均可以安全、有效地治疗胃癌和/或食管胃结合部腺癌，受试者有临床获益，并且四药联合方案可以作为胃癌和/或食管胃结合部腺癌的一线治疗方案。
本领域技术人员将认识到，本申请的范围并不限于上文描述的各种具体实施方式和实施例，而是能够在不脱离本申请的精神的情况下，进行各种修改、替换、或重新组合，这都落入了本申请的保护范围内。

Claims (43)

  1. 含抗PD-L1抗体和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗胃癌和/或食管胃结合部癌的药物中的用途。
  2. 根据权利要求1所述的用途，其中所述药物组合进一步包括至少一种第三治疗剂，所述第三治疗剂为选自氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种。
  3. 根据权利要求2所述的用途，其中所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或铂类抗肿瘤药物，优选地包括卡培他滨和/或奥沙利铂。
  4. 根据权利要求1-3任一项所述的用途，其中所述药物组合包括在初始治疗期间向有需要的患者给予的第一药物组合，以及任选地，在维持治疗期间向有需要的患者给予的第二药物组合，所述第一药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐、和至少一种第三治疗剂，所述第二药物组合包括抗PD-L1抗体、和安罗替尼或其药学上可接受的盐。
  5. 根据权利要求4所述的用途，其中，所述初始治疗包括0到10个治疗周期，优选1到10个治疗周期，进一步优选1到6个治疗周期，最优选6个治疗周期。
  6. 根据权利要求1-5任一项所述的用途，其中抗PD-L1抗体被制备成药物组合物，所述药物组合物中抗PD-L1抗体的浓度为10～60mg/mL，或者10、20、30、40、50或者60mg/mL。
  7. 根据权利要求1-6任一项所述的用途，其中所述药物组合为适用于在单个治疗周期(例如21天的一个治疗周期)内施用的制剂，包括：含600-2400mg抗PD-L1抗体的药物组合物和含84-168mg安罗替尼或其药学上可接受的盐的药物组合物。
  8. 根据权利要求7所述的用途，其中所述适用于在单个治疗周期内施用的制剂进一步包括：含65～780mg奥沙利铂的药物组合物，和/或含14000～168000mg卡培他滨的药物组合物。
  9. 根据权利要求1-8任一项所述的用途，其中抗PD-L1抗体或其药物组合物的单次给药剂量为600、800、1000、1200、1400、1600、1800、2000、2200或2400mg，安罗替尼或其药学上可接受的盐的单次给药剂量为6mg-12mg，或者6mg、8mg、10mg或者12mg。
  10. 根据权利要求3-9任一项所述的用途，其中奥沙利铂以130mg/m 2的剂量给药。
  11. 根据权利要求3-10任一项所述的用途，其中卡培他滨以1000mg/m 2的单次剂量、每日两次的方式给药。
  12. 根据权利要求1-11任一项所述的用途，其中抗PD-L1抗体和安罗替尼或其药学上可接受的盐可同时、先后或者依次序给药。
  13. 根据权利要求2-12任一项所述的用途，其中所述抗PD-L1抗体、安罗替尼或其药学上可接受的盐和第三治疗剂可同时、先后或者依次序给药。
  14. 根据权利要求1-13任一项所述的用途，其中每3周为一个治疗周期，抗PD-L1抗体在每个周期的第1天给药，安罗替尼或其药学上可接受的盐在每个周期的第1-14天给药。
  15. 根据权利要求3-14任一项所述的用途，其中每3周为一个治疗周期，奥沙利铂在每个周期的第1天给药，卡培他滨在每个周期的第1-14天给药。
  16. 根据权利要求1-15任一项所述的用途，其中胃癌包括管状腺癌、壁细胞腺癌、混合型腺癌、乳头状腺癌、黏液表皮样癌、黏液腺癌、印戒细胞癌、低黏附性癌、肝样腺癌、潘氏细胞癌。
  17. 根据权利要求1-16任一项所述的用途，其中胃癌和/或食管胃结合部癌为非HER2阳性的胃癌和/或食管胃结合部腺癌；
    或者，胃癌和/或食管胃结合部癌为晚期和/或难治性和/或复发性和/或转移性的胃癌、和/或食管胃结合部腺癌。
  18. 治疗胃癌和/或食管胃结合部癌的方法，包括：向有需要的患者给予治疗有效量的抗PD-L1抗体和安罗替尼或其药学上可接受的盐。
  19. 根据权利要求18所述的方法，其包括进一步向有需要的患者给予治疗有效量的至少一种第三治疗剂， 所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种。
  20. 根据权利要求19所述的方法，其中所述第三治疗剂包括氟尿嘧啶类抗肿瘤药物和/或铂类抗肿瘤药物，优选地包括卡培他滨和/或奥沙利铂。
  21. 根据权利要求19或20所述的方法，其包括给予抗PD-L1抗体、和安罗替尼或其药学上可接受的盐、和第三治疗剂进行初始治疗；然后，任选地给予抗PD-L1抗体和安罗替尼或其药学上可接受的盐进行维持治疗。
  22. 根据权利要求21所述的方法，其中，所述初始治疗包括0到10个治疗周期，优选1到10个治疗周期，进一步优选1到6个治疗周期，最优选6个治疗周期。
  23. 根据权利要求18-22任一项所述的方法，其中抗PD-L1抗体的单次给药剂量为600～2400mg或者600、800、1000、1200、1400、1600、1800、2000、2200或2400mg。
  24. 根据权利要求18-23任一项所述的方法，其中安罗替尼或其药学上可接受的盐的单次给药剂量为6mg-12mg，或者6mg、8mg、10mg或者12mg。
  25. 根据权利要求20-24任一项所述的方法，其中奥沙利铂以130mg/m 2的剂量给药。
  26. 根据权利要求20-25任一项所述的方法，其中卡培他滨以1000mg/m 2的单次剂量、每日两次的方式给药。
  27. 根据权利要求18-26任一项所述的方法，其中抗PD-L1抗体、安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后或依次给药。
  28. 根据权利要求19-27任一项所述的方法，其中抗PD-L1抗体、安罗替尼或其药学上可接受的盐和第三治疗剂各自呈药物组合物的形式，可同时、先后或依次给药。
  29. 根据权利要求18-28任一项所述的方法，其中每周、每2周、每3周、或者每4周为一个治疗周期。
  30. 根据权利要求18-29任一项所述的方法，其中每3周为一个治疗周期，抗PD-L1抗体在每个周期的第1天给药，安罗替尼或其药学上可接受的盐在每个周期的第1-14天给药。
  31. 根据权利要求20-30任一项所述的方法，其中每3周为一个治疗周期，奥沙利铂在每个周期的第1天给药，卡培他滨在每个周期的第1-14天给药。
  32. 根据权利要求18-31任一项所述的方法，其中胃癌和/或食管胃结合部癌为非HER2阳性的胃癌和/或食管胃结合部腺癌。
  33. 根据权利要求18-32任一项所述的方法，其中胃癌和/或食管胃结合部癌为晚期和/或难治性和/或复发性和/或转移性的胃癌、和/或食管胃结合部腺癌。
  34. 治疗胃癌和/或食管胃结合部癌的药物组合，其包括：抗PD-L1抗体，和安罗替尼或其药学上可接受的盐。
  35. 根据权利要求34所述的药物组合，其进一步包括至少一种第三治疗剂，所述第三治疗剂为氟尿嘧啶类抗肿瘤药物、铂类抗肿瘤药物和紫杉醇类抗肿瘤药物中的一种或多种，优选所述第三治疗剂包括卡培他滨和/或奥沙利铂。
  36. 根据权利要求34或35所述的药物组合，其包装于同一试剂盒中，所述试剂盒还包括治疗胃癌和/或食管胃结合部癌的说明。
  37. 根据权利要求34-36任一项所述的药物组合，其包括：含600～2400mg的抗PD-L1抗体以多剂量形式提供的药物组合物和单位剂量为6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐的药物组合物。
  38. 根据权利要求34-37任一项所述的药物组合，其中抗PD-L1抗体的药物组合物为注射用溶液；安罗替尼或其药学上可接受的盐的药物组合物为口服固体制剂。
  39. 根据权利要求1-17任一项所述的用途、或权利要求18-33任一项所述的方法、或权利要求34-38任一项所述的药物组合，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:1或SEQ ID NO:4所 示的氨基酸序列有至少80％同源性的重链CDR1区；与SEQ ID NO:2或SEQ ID NO:5所示的氨基酸序列有至少80％同源性的重链CDR2区；与SEQ ID NO:3或SEQ ID NO:6所示的氨基酸序列有至少80％同源性的重链CDR3区；与SEQ ID NO:7或SEQ ID NO:10所示的氨基酸序列有至少80％同源性的轻链CDR1区；与SEQ ID NO:8或SEQ ID NO:11所示的氨基酸序列有至少80％同源性的轻链CDR2区；与SEQ ID NO:9或SEQ ID NO:12所示的氨基酸序列有至少80％同源性的轻链CDR3区。
  40. 根据权利要求1-17任一项所述的用途、或权利要求18-33任一项所述的方法、或权利要求34-38任一项所述的药物组合，其中，所述抗PD-L1抗体包含如下氨基酸序列：选自SEQ ID NO:1或SEQ ID NO:4的重链CDR1区；选自SEQ ID NO:2或SEQ ID NO:5的重链CDR2区；选自SEQ ID NO:3或SEQ ID NO:6的重链CDR3区；选自SEQ ID NO:7或SEQ ID NO:10的轻链CDR1区；选自SEQ ID NO:8或SEQ ID NO:11的轻链CDR2区；选自SEQ ID NO:9或SEQ ID NO:12的轻链CDR3区。
  41. 根据权利要求1-17任一项所述的用途、或权利要求18-33任一项所述的方法、或权利要求34-38任一项所述的药物组合，其中，所述抗PD-L1抗体包含：具有以SEQ ID NO:1示出的氨基酸序列的重链CDR1区，具有以SEQ ID NO:2示出的氨基酸序列的重链CDR2区，具有以SEQ ID NO:3示出的氨基酸序列的重链CDR3区；以及具有以SEQ ID NO:7示出的氨基酸序列的轻链CDR1区，具有以SEQ ID NO:8示出的氨基酸序列的轻链CDR2区，具有以SEQ ID NO:9示出的氨基酸序列的轻链CDR3区。
  42. 根据权利要求1-17任一项所述的用途、或权利要求18-33任一项所述的方法、或权利要求34-38任一项所述的药物组合，其中，所述抗PD-L1抗体包含如下氨基酸序列：与SEQ ID NO:13或SEQ ID NO:14所示的氨基酸序列有至少80％同源性的重链可变区；与SEQ ID NO:15或SEQ ID NO:16所示的氨基酸序列有至少80％同源性的轻链可变区。
  43. 根据权利要求1-17任一项所述的用途、或权利要求18-33任一项所述的方法、或权利要求34-38任一项所述的药物组合，其中，所述抗PD-L1抗体包含：选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变重链，和选自hu13C5-hIgG1、hu13C5-hIgG4、hu5G11-hIgG1或hu5G11-hIgG4人源化抗体的可变轻链。
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