WO2023030532A1 - Combinaison de médicaments pour le traitement du cancer de l'œsophage - Google Patents

Combinaison de médicaments pour le traitement du cancer de l'œsophage Download PDF

Info

Publication number
WO2023030532A1
WO2023030532A1 PCT/CN2022/117225 CN2022117225W WO2023030532A1 WO 2023030532 A1 WO2023030532 A1 WO 2023030532A1 CN 2022117225 W CN2022117225 W CN 2022117225W WO 2023030532 A1 WO2023030532 A1 WO 2023030532A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
seq
anlotinib
drug
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2022/117225
Other languages
English (en)
Chinese (zh)
Inventor
蒋淼
于鼎
王训强
张喜全
吴凤秀
Original Assignee
正大天晴药业集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202280049989.8A priority Critical patent/CN117642181A/zh
Publication of WO2023030532A1 publication Critical patent/WO2023030532A1/fr

Links

Classifications

    • 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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the application belongs to the field of biomedicine, in particular to a drug combination for treating esophageal cancer.
  • Esophageal cancer is a common malignant tumor in my country. Because of its high incidence, strong aggressiveness and poor prognosis, it poses a serious threat and impact on people's health and life. According to the latest data released by the World Health Organization, there will be 604,000 new cases of esophageal cancer in the world in 2020, ranking 8th in incidence, and 544,000 deaths, ranking 6th. In China, 324,000 new cases of esophageal cancer The morbidity rate ranks 6th, and the death toll is 301,000, ranking 4th, both of which are higher than the world average. In terms of histological types, about 95% of esophageal cancer patients in China are esophageal squamous cell carcinoma (ESCC). Since most ESCC patients have no obvious symptoms in the early stage, nearly half of the patients' tumors have metastasized at the time of diagnosis.
  • ESCC esophageal squamous cell carcinoma
  • surgical treatment is one of the main radical treatments for esophageal cancer, especially for early and middle-stage patients, but the 5-year survival rate of patients after surgery is only 20% to 30%.
  • the treatment of patients with advanced ESCC is still based on standard chemotherapy/radiotherapy, and the application of targeted drugs is still in the exploratory stage.
  • platinum-containing double-drug chemotherapy is the preferred first-line treatment for advanced ESCC, and platinum-containing triple-drug chemotherapy can be used for patients with better physical condition.
  • the curative effect of the current first-line treatment schemes cannot meet the treatment needs, and more new treatment schemes with strong specificity, specific targets, less toxic and side effects, and significant curative effects need to be further developed to achieve the expected therapeutic effect.
  • the present application provides a drug combination for treating esophageal cancer, which includes: anti-PD-L1 antibody and chemotherapy drugs.
  • the chemotherapeutic drugs include but are not limited to platinum-based antineoplastic drugs (including but not limited to oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, miplatin, lobaplatin, picoplatin (picoplatin)), camptothecin antineoplastic drugs (including but not limited to camptothecin, hydroxycamptothecin, aminocamptothecin, irinotecan, topotecan, exinotecan, rubitecan, le Totecan (lurtotecan, gematecan, karenitecin), taxane antineoplastic drugs (including but not limited to paclitaxel, paclitaxel liposome, albumin-bound paclitaxel, and docetaxel), nitrogen mustard anticancer drugs Tumor drugs (including but not limited to cyclophosphamide, ifosfamide, chlorambucil, melphalan, bendamus), platinum-based
  • the chemotherapeutic drug is selected from one or more of platinum anti-tumor drugs and taxane anti-tumor drugs.
  • the platinum-based antineoplastic drugs include but are not limited to one or more of cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, miplatin or lobaplatin .
  • the taxane antitumor drugs include, but are not limited to, one or more of paclitaxel, paclitaxel liposome, nab-paclitaxel, and docetaxel.
  • the chemotherapeutic drug is selected from one or more of platinum-based antineoplastic drugs and paclitaxel. In some embodiments, the chemotherapeutic drug is selected from one or more of cisplatin and taxane antineoplastic drugs. In some embodiments, the chemotherapy drug is selected from one or more of cisplatin, nedaplatin, oxaliplatin, paclitaxel, paclitaxel liposome, nab-paclitaxel and docetaxel. In some embodiments, the chemotherapeutic drug is selected from one or more of cisplatin and paclitaxel. In some embodiments, the chemotherapeutic drugs are cisplatin and paclitaxel.
  • the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • the drug combination includes an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, a platinum-based antineoplastic drug, and a taxane-based antineoplastic drug.
  • the drug combination includes: anti-PD-L1 antibody; anlotinib or a pharmaceutically acceptable salt thereof; at least one selected from cisplatin, nedaplatin, and oxaliplatin; And, at least one selected from paclitaxel, paclitaxel liposome, albumin-bound paclitaxel, and docetaxel.
  • the drug combination includes anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, cisplatin and paclitaxel.
  • the present application provides a drug combination for treating esophageal cancer, which includes a first drug combination, and optionally, a second drug combination.
  • the drug combination comprises a first drug combination administered to a patient in need during a first treatment period, and optionally a second drug combination administered to a patient in need thereof during a second treatment period.
  • the treatment cycle of the first treatment stage is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, further preferably 4 to 6 treatment cycles, most preferably 6 treatment cycles.
  • the first drug combination includes an anti-PD-L1 antibody and a chemotherapy drug. In some embodiments, the first drug combination includes an anti-PD-L1 antibody and a chemotherapy drug, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the second pharmaceutical combination includes an anti-PD-L1 antibody. In some embodiments, the second pharmaceutical combination includes an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.
  • the drug combination comprises a first drug combination administered to a patient in need during a first treatment period, and optionally a second drug combination administered to a patient in need during a second treatment period , the first drug combination includes anti-PD-L1 antibody and chemotherapy drugs, and the second drug combination includes anti-PD-L1 antibody.
  • the treatment cycle of the first treatment stage is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, further preferably 4 to 6 treatment cycles, most preferably 6 treatment cycles.
  • the drug combination comprises a first drug combination administered to a patient in need during a first treatment period, and optionally a second drug combination administered to a patient in need during a second treatment period , the first drug combination includes an anti-PD-L1 antibody and a chemotherapy drug, and anlotinib or a pharmaceutically acceptable salt thereof, and the second drug combination includes an anti-PD-L1 antibody, and anlotinib or its pharmaceutically acceptable salt.
  • the treatment cycle of the first treatment stage is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, further preferably 4 to 6 treatment cycles, most preferably 6 treatment cycles.
  • the pharmaceutical combination further includes a pharmaceutically acceptable carrier.
  • the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody and a pharmaceutical composition comprising a chemotherapy drug.
  • the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody and a pharmaceutical composition comprising a chemotherapy drug.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-PD-L1 antibody, a pharmaceutical composition containing chemotherapy drugs, and a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof.
  • the above-mentioned drug combination of the present application is packaged in the same kit, and the kit also includes instructions for treating esophageal cancer.
  • the kit for treating esophageal cancer includes: anti-PD-L1 antibody and chemotherapy drugs.
  • the anti-PD-L1 antibody is contained in the first compartment, and the chemotherapeutic drug is contained in other compartments.
  • the number of compartments in the kit can be increased according to the type of chemotherapeutic drug, and can be simultaneously , successively or sequentially to patients in need.
  • the kit further comprises instructions for using the anti-PD-L1 antibody in combination with a chemotherapy drug to treat esophageal cancer.
  • the kit comprises: a pharmaceutical composition comprising an anti-PD-L1 antibody; and a pharmaceutical composition comprising a chemotherapy drug.
  • the kit for treating esophageal cancer includes: anti-PD-L1 antibody and chemotherapy drugs, 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
  • the chemotherapy drug is contained in other compartments, optionally According to the type of chemotherapy drugs, the number of compartments in the kit can be increased according to the situation, and can be given to patients in need simultaneously, sequentially or sequentially.
  • the kit further comprises instructions for using anti-PD-L1 antibody, chemotherapy drugs, and anlotinib or a pharmaceutically acceptable salt thereof in combination to treat esophageal cancer.
  • the kit includes: a pharmaceutical composition containing an anti-PD-L1 antibody; and a pharmaceutical composition containing a chemotherapy drug; and a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof .
  • the above-mentioned kit is a kit 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 anti-PD-L1 antibody.
  • 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 treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.
  • 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 can be 600-2400 mg, in some embodiments, the daily dose of anti-PD-L1 antibody can be 600, 800, 1000, 1200, 1400, 1600, 1800, 2000, 2200 or 2400mg.
  • the anti-PD-L1 antibody is administered parenterally.
  • the anti-PD-L1 antibody is administered intravenously.
  • the concentration of the anti-PD-L1 antibody in the pharmaceutical composition containing the anti-PD-L1 antibody is 10-60 mg/mL. In some embodiments, the concentration of the anti-PD-L1 antibody in the pharmaceutical composition containing the 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 daily dose of paclitaxel may be 67.5-810 mg, preferably 135-405 mg. In some embodiments, the daily dose of cisplatin may be 30-450 mg, preferably 60-225 mg.
  • the pharmaceutical combination containing anti-PD-L1 antibody and chemotherapy drug described in this application includes a pharmaceutical composition containing anti-PD-L1 antibody and a pharmaceutical composition containing chemotherapy drug, wherein anti-PD-L1 antibody
  • the pharmaceutical composition of the invention is prepared into a unit dose or multi-dose form suitable for administering 600-2400 mg of the anti-PD-L1 antibody to the patient during the first administration.
  • the pharmaceutical combination comprising an anti-PD-L1 antibody, a chemotherapy drug and anlotinib or a pharmaceutically acceptable salt thereof described herein includes a pharmaceutical composition comprising an anti-PD-L1 antibody, and a pharmaceutical composition comprising A pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing chemotherapy drugs, wherein the pharmaceutical composition containing an anti-PD-L1 antibody is prepared to be administered to a patient for the first time 600 ⁇ 2400 mg of anti-PD-L1 antibody in unit dose or multi-dose form, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared to be suitable for 14 consecutive days, and 6 mg, 8 mg is given to the patient every day , 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof in unit dosage form.
  • the pharmaceutical combination containing anti-PD-L1 antibody and chemotherapy drugs described in this application includes: a pharmaceutical composition containing anti-PD-L1 antibody with an anti-PD-L1 antibody concentration of 10-60 mg/mL.
  • the drug combination comprising anti-PD-L1 antibody, chemotherapy drug and anlotinib or a pharmaceutically acceptable salt thereof described in this application includes: the concentration of anti-PD-L1 antibody is 10-60 mg/mL
  • the pharmaceutical combination containing anti-PD-L1 antibody and chemotherapy drugs described in this application includes: a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses.
  • the drug combination comprising anti-PD-L1 antibody, chemotherapy drug and anlotinib or a pharmaceutically acceptable salt thereof described in this application comprises: containing 1200 mg of anti-PD-L1 antibody in multiple dosage form The provided pharmaceutical composition, and the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof with a unit dose of 8 mg, 10 mg and/or 12 mg.
  • the drug combination containing anti-PD-L1 antibody and chemotherapy drugs described in this application is a preparation suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days), including 600-2400 mg of anti-PD-L1 Pharmaceutical compositions of L1 antibodies.
  • the drug combination comprising an anti-PD-L1 antibody, a chemotherapy drug, and anlotinib or a pharmaceutically acceptable salt thereof described herein is suitable for use in a single treatment cycle (for example, a treatment of 21 days).
  • the preparations administered in cycle) include a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a pharmaceutical composition containing 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the preparation suitable for administration in a single treatment cycle further includes: a pharmaceutical composition containing 90-1350 mg, preferably 180-675 mg, of cisplatin.
  • the preparation suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days) further includes: a pharmaceutical composition containing 67.5-810 mg, preferably 135-405 mg, of paclitaxel.
  • the drug combination containing anti-PD-L1 antibody, chemotherapy drug and anlotinib or a pharmaceutically acceptable salt thereof described in this application includes a weight ratio of (0.35-29):1, preferably (3.5-29 ):1, more preferably (3.5-14.5):1, most preferably (7-14.5):1 anti-PD-L1 antibody and anlotinib.
  • the anti-PD-L1 antibody and anlotinib can be packaged separately or packaged together.
  • anlotinib can be packaged in multiple equal parts (such as 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 a single equal part or Multiple aliquots (eg, 2, 4 or more aliquots) are packaged.
  • the pharmaceutical combination described in this application comprises anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, cisplatin and paclitaxel, wherein, anti-PD-L1 antibody, anlotinib Or the weight ratio of its pharmaceutically acceptable salt, cisplatin and paclitaxel is (600 ⁇ 2400):(84 ⁇ 168):(90 ⁇ 1350):(67.5 ⁇ 810), preferably (600 ⁇ 2400):(84 ⁇ 168):(180 ⁇ 675):(135 ⁇ 405).
  • the cisplatin and paclitaxel can be packaged in single or multiple aliquots (eg 2, 3, 6 or more aliquots).
  • the chemotherapeutic drug is selected from one or more of platinum-based anti-tumor drugs and taxane-based anti-tumor drugs. In some embodiments, the chemotherapeutic drug is selected from one or more of platinum-based antineoplastic drugs and paclitaxel. In some embodiments, the chemotherapeutic drug is selected from one or more of cisplatin and taxane antineoplastic drugs. In some embodiments, the chemotherapeutic drugs are cisplatin and paclitaxel.
  • the present application also provides the use of the pharmaceutical combination of the present application or the kit of the present application in preparing a medicine for treating esophageal cancer in a patient.
  • the present application also provides a method for treating esophageal cancer, comprising administering an effective amount of the drug combination of the present application, or the kit of the present application to a patient in need.
  • the application also provides the use of the drug combination of the application or the kit of the application for treating esophageal cancer in a patient.
  • the present application also provides the drug combination of the present application, or the kit of the present application for treating esophageal cancer in a patient.
  • the method for treating esophageal cancer provided herein includes administering a therapeutically effective amount of anti-PD-L1 antibody and chemotherapy drugs to a patient in need.
  • the method of treatment comprises administering a first drug combination to a patient in need thereof during a first treatment period; and optionally, administering a second drug combination to a patient in need thereof during a second treatment period.
  • the first drug combination includes an anti-PD-L1 antibody, and a chemotherapy drug.
  • the second pharmaceutical combination includes an anti-PD-L1 antibody.
  • the method for treating esophageal cancer includes administering a therapeutically effective amount of anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs to a patient in need.
  • the method of treatment comprises administering a first drug combination to a patient in need thereof during a first treatment period; and optionally, administering a second drug combination to a patient in need thereof during a second treatment period.
  • the first drug combination includes an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapy drug.
  • the second pharmaceutical combination includes an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the treatment cycle of the first treatment stage is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, further preferably 4 to 6 treatment cycles, most preferably 6 treatment cycles.
  • the chemotherapeutic drug is selected from one or more of platinum-based anti-tumor drugs and taxane-based anti-tumor drugs. In some embodiments, the chemotherapeutic drug is selected from one or more of platinum-based antineoplastic drugs and paclitaxel. In some embodiments, the chemotherapeutic drug is selected from one or more of cisplatin and taxane antineoplastic drugs. In some embodiments, the chemotherapy drug is selected from one or more of cisplatin, nedaplatin, oxaliplatin, paclitaxel, paclitaxel liposome, nab-paclitaxel and docetaxel. In some embodiments, the chemotherapeutic drugs are cisplatin and paclitaxel.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
  • the anti-PD-L1 antibody is administered once every week, every 2 weeks, every 3 weeks, or every 4 weeks; further, the anti-PD-L1 antibody is administered once every 3 weeks; preferably, the The anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time; further, the anti-PD-L1 antibody is administered at a dose of 1200 mg each time.
  • the anlotinib is administered in a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for 2 consecutive weeks with a 1-week rest.
  • the paclitaxel is administered once every week, every 2 weeks, every 3 weeks, or every 4 weeks; further, the paclitaxel is administered once every 3 weeks; preferably, the paclitaxel is administered once every 67.5- A dose of 810 mg, preferably 135-405 mg is administered.
  • the cisplatin is administered once a day, with continuous medication for the first 3 days of each treatment cycle and drug withdrawal for the rest of the time; preferably, the cisplatin is dosed at 30-450 mg each time, preferably Doses of 60-225 mg are administered.
  • 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 of Anlotinib 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, caproic 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, cinnamon 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 , trimethylace
  • 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 through a variety of routes, including gastrointestinal and parenteral routes of administration, including but not limited to oral, intraperitoneal, intravenous, Intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal and intrathecal administration. 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 a pharmaceutically acceptable salt thereof can be comprehensively determined according to the activity, toxicity and tolerance of the drug.
  • 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.
  • the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof includes 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is provided in a single dose.
  • the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is an oral solid preparation.
  • every 3 weeks is a treatment cycle, and the anlotinib or a pharmaceutically acceptable salt thereof is administered in each treatment cycle.
  • the total dose is 84-168mg.
  • the total dose 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-mentioned values.
  • the total dose of the anlotinib or a pharmaceutically acceptable salt thereof includes 112 mg to 168 mg.
  • the pharmaceutical composition includes but not limited to formulations suitable for oral, parenteral, and 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 not limited to tablets and capsules.
  • the chemotherapeutic drugs include but not limited to cyclophosphamide, ifosfamide, vincristine, prednisone, prednisolone, anthracycline antineoplastic drugs (including but not limited to multi- Ruubicin, epirubicin, pirarubicin, amrubicin, arubicin, idarubicin, daunorubicin, mitoxantrone), platinum antineoplastic drugs, camptothecins (including but not limited to camptothecin, hydroxycamptothecin, irinotecan, topotecan), taxane antineoplastic drugs, dexamethasone, methotrexate, cytarabine, bendamustine , fludarabine, mitoxantrone, etoposide, procarbazine, gemcitabine, methylprednisolone sodium succinate, mesna, fluorouracil antine
  • the chemotherapeutic drugs include but not limited to one or more of platinum-based anti-tumor drugs and taxane-based anti-tumor drugs.
  • the platinum-based antineoplastic drugs include but are not limited to one or more of cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, miplatin or lobaplatin .
  • the taxane antitumor drugs include, but are not limited to, one or more of paclitaxel, paclitaxel liposome, nab-paclitaxel, and docetaxel.
  • the chemotherapeutic drug is selected from one or more of platinum-based antineoplastic drugs and paclitaxel. In some embodiments, the chemotherapeutic drug is selected from one or more of cisplatin and taxane antineoplastic drugs. In some embodiments, the chemotherapeutic drugs are cisplatin and paclitaxel.
  • paclitaxel is administered at a dose of 135-175 mg/m 2 , preferably at a dose of 135 mg/m 2 .
  • mg/ m2 refers to the dose of the drug used per square meter of body surface area of the subject.
  • cisplatin is administered at a dose of 50-100 mg/m 2 , preferably at a dose of 60-75 mg/m 2 .
  • mg/ m2 refers to the dose of the drug used per square meter of body surface area of the subject.
  • the anti-PD-L1 antibody is one or more of the antibodies disclosed in CN107001463A.
  • the anti-PD-L1 antibody is an isolated anti-PD-L1 antibody. In some embodiments of the present application, the anti-PD-L1 antibody is an anti-PD-L1 humanized monoclonal antibody. In some embodiments of the present application, the anti-PD-L1 antibody is an isolated anti-PD-L1 humanized monoclonal antibody. In some embodiments, the anti-PD-L1 antibody can be an IgG1 or IgG4 antibody. In some embodiments of the present application, 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 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: 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 NO:2 or SEQ ID NO:5; or at least 80% identical to the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6 Homogenous heavy chain CDR3 region; or 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; or with SEQ ID NO:8 or SEQ ID NO A light chain CDR2 region with at least 80% homology to the amino acid sequence shown in: 11; or 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 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 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 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 a variable heavy chain selected from ch5G11-hIgG1, ch5G11-hIgG1, Variable light chains of ch5G11-hlgG4, ch13C5-hlgG1, ch13C5-hlgG4 chimeric antibodies.
  • the anti-PD-L1 antibody described herein 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-hIgG1 , hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody variable light chain.
  • 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 comprising a combination selected from 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 pharmaceutical composition containing anti-PD-L1 antibody contains 600-2400 mg of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains an anti-PD-L1 antibody selected from 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2100 mg, 2400 mg, or the range formed by any of the above values. In some schemes, the pharmaceutical composition contains 600-2100 mg, or 900 mg-1500 mg of anti-PD-L1 antibody; wherein the pharmaceutical composition containing the anti-PD-L1 antibody can exist in multiple doses or unit doses.
  • the pharmaceutical composition contains 300 mg, 600 mg or 1200 mg of anti-PD-L1 antibody. In some embodiments of the present application, there is provided a pharmaceutical composition formulated as a unit dose, which contains 300 mg, 600 mg or 1200 mg of anti-PD-L1 antibody.
  • the pharmaceutical composition containing anti-PD-L1 antibody is a solution for injection. In some embodiments, the pharmaceutical composition containing anti-PD-L1 antibody is an aqueous solution for injection. In some embodiments of the present application, the pharmaceutical composition containing an 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 containing 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 isotonic regulator/stabilizer And 0.01 ⁇ 0.8mg/mL surfactant, and the pH is 4.5 ⁇ 6.8.
  • the pharmaceutical composition containing anti-PD-L1 antibody is calculated by w/v, and the concentration of 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 present application provides a drug combination for treating esophageal cancer, which includes an anti-PD-L1 antibody and chemotherapy drugs.
  • the drug combination comprising anti-PD-L1 antibody and chemotherapy drug is a fixed combination.
  • the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.
  • the drug combination comprising anti-PD-L1 antibody and chemotherapy drug is a non-fixed combination.
  • the anti-PD-L1 antibody and chemotherapeutic agent in the non-fixed combination are each in the form of a pharmaceutical composition.
  • each of the anti-PD-L1 antibody and the chemotherapeutic agent in the non-fixed combination (eg, a treatment cycle of 21 days) is each in the form of a pharmaceutical composition.
  • the drug combination containing anti-PD-L1 antibody and chemotherapy drugs includes:
  • the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a light chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody region; in one embodiment, the anti-PD-L1 antibody comprises a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11 - the variable light chain of a hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody; in one embodiment, the anti-PD-L1 antibody comprises a variable light chain selected from the group consisting of hu13
  • the pharmaceutical combination containing anti-PD-L1 antibody and chemotherapy drugs includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody.
  • the pharmaceutical composition containing the anti-PD-L1 antibody is a single dose or multiple doses.
  • the pharmaceutical combination containing anti-PD-L1 antibody and chemotherapy drugs includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses.
  • the pharmaceutical combination containing anti-PD-L1 antibody and chemotherapy drugs includes a pharmaceutical composition containing anti-PD-L1 antibody with an anti-PD-L1 antibody concentration of 10-60 mg/mL. In some embodiments of the present application, the pharmaceutical combination containing anti-PD-L1 antibody and chemotherapy drug includes a pharmaceutical composition containing anti-PD-L1 antibody with an anti-PD-L1 antibody concentration of 30 mg/mL.
  • the drug combination is packaged in the same kit, and the kit also includes instructions for the combined use of PD-L1 antibody and chemotherapy drugs to treat esophageal cancer.
  • the drug combination includes anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs.
  • the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapy drug is a fixed combination.
  • the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.
  • the drug combination comprising anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs is a non-fixed combination.
  • the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the chemotherapeutic agent in the non-fixed combination are each in the form of a pharmaceutical composition.
  • each active ingredient of the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the chemotherapy drug in the non-fixed combination is in the form of a pharmaceutical composition.
  • a pharmaceutical combination comprising a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, most preferably (7- 14.5): 1 anti-PD-L1 antibody and anlotinib.
  • the anti-PD-L1 antibody and anlotinib can be packaged separately or packaged 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 comprises a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a light chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody region; in one embodiment, the anti-PD-L1 antibody comprises a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11 - the variable light chain of a hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody; in one embodiment, the anti-PD-L1 antibody comprises a variable light chain selected from the group consisting of hu13
  • the drug combination includes anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs; or, it includes the above-mentioned anti-PD-L1 antibody, anlotinib A drug combination of nicillin or a pharmaceutically acceptable salt thereof and a chemotherapeutic drug.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof and chemotherapy drugs includes a pharmaceutical composition containing anti-PD-L1 antibody, anlotinib containing A pharmaceutical composition of rotinib or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing chemotherapy drugs.
  • the drug combination is packaged in the same kit, and the kit also includes the combined use of PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof and chemotherapy drugs to treat esophagus Cancer illustration.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs includes: containing 600-2400 mg of anti-PD-L1 antibody
  • the pharmaceutical composition, the single dose is 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition containing the anti-PD-L1 antibody, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof are single dose or multiple doses.
  • the pharmaceutical combination includes: a pharmaceutical composition containing 1200 mg of an anti-PD-L1 antibody provided in multiple doses, and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or The pharmaceutical composition of its pharmaceutically acceptable salt.
  • the drug combination containing anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and chemotherapy drugs includes: the concentration of anti-PD-L1 antibody is 10-60mg/ mL of the pharmaceutical composition containing the anti-PD-L1 antibody, and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg of the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination includes: a pharmaceutical composition containing an anti-PD-L1 antibody with an anti-PD-L1 antibody concentration of 30 mg/mL, and a single dose of 8 mg, 10 mg and/or 12 mg of an anti-PD-L1 antibody-containing A pharmaceutical composition of nigerin or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination comprises a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, most preferably (7-14.5):1 anti-PD-L1 antibody and anlotinib.
  • the anti-PD-L1 antibody and anlotinib can be packaged separately or packaged 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 present application provides a drug combination for treating esophageal cancer, which includes the first drug combination administered to patients in need during the first treatment phase, and optionally, the drug combination administered to patients in need during the second treatment phase The second drug combination administered.
  • the first drug combination can be selected from one or more of the above drug combinations.
  • the first drug combination includes an anti-PD-L1 antibody and a chemotherapy drug. In some embodiments, the first drug combination includes an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapy drug.
  • the second pharmaceutical combination includes an anti-PD-L1 antibody. In some embodiments, the second pharmaceutical combination includes an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the treatment cycle of the first treatment stage is 1 to 10 treatment cycles, preferably 2 to 8 treatment cycles, further preferably 4 to 6 treatment cycles, most preferably 6 treatment cycles.
  • the pharmaceutical combination further includes a pharmaceutically acceptable carrier.
  • the present application provides a kit for treating esophageal cancer, the kit comprising an anti-PD-L1 antibody and a chemotherapy drug, and optionally anlotinib or a pharmaceutically acceptable salt thereof, As well as instructions for combined use in the treatment of esophageal cancer; in some embodiments, a kit for treating esophageal cancer is provided, the kit comprising a pharmaceutical composition containing an anti-PD-L1 antibody, and/or a paclitaxel drug combination drug and/or cisplatin pharmaceutical composition, and optionally a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof, as well as instructions for combined use in the treatment of esophageal cancer; or, the kit includes this application combination of drugs, and instructions for their combined use in the treatment of esophageal cancer.
  • the present application also provides the use of the pharmaceutical combination of the present application, or the kit of the present application, in preparing a medicine for treating esophageal cancer in a patient.
  • the present application also provides a method for treating esophageal cancer in a patient, which includes administering an effective amount of the drug combination of the present application, or the kit of the present application to the patient in need.
  • the present application also provides the use of the pharmaceutical combination of the present application, or the kit of the present application for treating esophageal cancer in a patient.
  • the pharmaceutical combination or kit is as described above.
  • the application further provides the drug combination of the application, or the kit of the application for treating esophageal cancer in a patient.
  • the anti-PD-L1 antibody and chemotherapy drugs, and optionally anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be Simultaneous, sequential or interval administration.
  • the anti-PD-L1 antibody and chemotherapy drugs, and optionally anlotinib or a pharmaceutically acceptable salt thereof are each administered at intervals medication.
  • the anti-PD-L1 antibody and chemotherapeutic drugs, and optionally anlotinib or a pharmaceutically acceptable salt thereof are administered in the same or different dosage regimens, respectively.
  • the anti-PD-L1 antibody and chemotherapeutic drugs, and optionally anlotinib or a pharmaceutically acceptable salt thereof are administered in different dosage regimens.
  • the anti-PD-L1 antibody in the use or treatment method, can be used every 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 once a day at a dosage of 6 mg, 8 mg, 10 mg or 12 mg, administered continuously for 2 weeks, followed by a regimen of 1 week off. medication. At this time, every 3 weeks is a dosing cycle.
  • the chemotherapeutic drugs can be administered according to known dosing regimens.
  • the anti-PD-L1 antibody and chemotherapy drugs, and optionally anlotinib or a pharmaceutically acceptable salt thereof have the same or different administration periods, respectively.
  • anti-PD-L1 antibody and chemotherapeutic drugs, and optionally anlotinib or a pharmaceutically acceptable salt thereof have the same administration cycle, for example, every 1 week, every 2 weeks, every 3 weeks or every 4 weeks is a dosing cycle.
  • 21 days is a dosing cycle
  • the PD-L1 antibody is administered on the first day of each dosing cycle and chemotherapeutic drugs, wherein the chemotherapeutic drugs can be administered according to a known dosing regimen, and optionally anlotinib or a pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each cycle.
  • the PD-L1 antibody is administered once on the first day of each cycle, and/or paclitaxel is administered on the first day of each cycle, and/or on the first day 1-3 of each cycle Give cisplatin.
  • the PD-L1 antibody is administered once on the first day of each cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14 of each cycle, and /or paclitaxel on day 1 of each cycle, and/or cisplatin on days 1-3 of each cycle.
  • 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; or 60 mg to 2400 mg, 90 mg to about 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 900 mg Doses up to 1200 mg are administered to patients.
  • 21 days is a dosing cycle, and 1200 mg of PD-L1 antibody is administered on the first day of each cycle. In some embodiments, 21 days is a dosing cycle, and 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib is administered daily on days 1-14 of each cycle.
  • the dosing regimen of the drug combination, or the use or treatment method includes, in repeated cycles, administering anti-PD-L1 antibody and chemotherapy drugs for the first treatment stage; then, Optionally, in repeated cycles, the anti-PD-L1 antibody is administered for a second treatment phase of treatment.
  • both the first treatment period and the second treatment period are 21 days as a dosing cycle.
  • the PD-L1 antibody and chemotherapy drugs are administered on the first day of each dosing cycle, wherein the chemotherapy drugs can be administered according to known dosing regimens.
  • the chemotherapeutic drug is selected from one or more of platinum-based anti-tumor drugs and taxane-based anti-tumor drugs. In some embodiments, the chemotherapeutic drug is selected from cisplatin and paclitaxel. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each cycle, and/or paclitaxel is administered on the first day of each cycle, and/or on the first day 1-3 of each cycle Give cisplatin. In some embodiments, the treatment cycle of the first treatment stage is 1 to 10 treatment cycles, more preferably 4 to 6 treatment cycles, most preferably 6 treatment cycles.
  • the PD-L1 antibody is administered on the first day of each dosing cycle.
  • the dosing regimen of the drug combination, or the use or treatment method includes, in repeated cycles, administering anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt, and chemotherapeutic drugs for the first treatment phase; then, optionally, in repeated cycles, anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof is administered for the second treatment phase.
  • both the first treatment period and the second treatment period are 21 days as a dosing cycle.
  • the PD-L1 antibody is administered on the first day of each dosing cycle, and anlotinib or its pharmaceutical form is administered daily on days 1-14 of each cycle.
  • the chemotherapeutic drug is selected from one or more of platinum-based anti-tumor drugs and taxane-based anti-tumor drugs. In some embodiments, the chemotherapeutic drug is selected from cisplatin and paclitaxel.
  • the PD-L1 antibody is administered once on the first day of each cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered once a day on days 1-14 of each cycle, and /or paclitaxel on day 1 of each cycle, and/or cisplatin on days 1-3 of each cycle.
  • the treatment cycle of the first treatment stage is 1 to 10 treatment cycles, more preferably 4 to 6 treatment cycles, most preferably 6 treatment cycles.
  • paclitaxel is administered at a dose of 135-175 mg/m 2 , preferably at a dose of 135 mg/m 2 .
  • cisplatin is administered at a dose of 50-100 mg/m 2 , preferably at a dose of 60-75 mg/m 2 .
  • the PD-L1 antibody in the second treatment phase, is administered on the first day of each dosing cycle, and anlotinib or its pharmaceutical drug is administered daily on days 1-14 of each cycle. acceptable salt.
  • the esophageal cancer is unresectable and/or advanced and/or recurrent and/or metastatic esophageal cancer; in some embodiments, the esophageal cancer is unresectable locally advanced esophageal cancer; in some embodiments, the esophageal cancer is unresectable recurrent esophageal cancer; in some embodiments, the esophageal cancer is unresectable metastatic esophageal cancer; in some embodiments In, the esophageal cancer is refractory esophageal cancer.
  • the esophageal cancer includes but not limited to squamous cell carcinoma of the esophagus, adenocarcinoma of the esophagus, and adenosquamous carcinoma of the esophagus.
  • the esophageal cancer is esophageal squamous cell carcinoma.
  • the esophageal cancer is unresectable locally advanced esophageal squamous cell carcinoma; in some embodiments, the esophageal cancer is unresectable recurrent or metastatic esophageal squamous cell carcinoma.
  • the esophageal cancer comprises unresectable recurrent or metastatic squamous cell carcinoma of the esophagus.
  • the patient with esophageal cancer has not received systemic therapy before.
  • the patient with esophageal cancer has previously received at least one chemotherapy drug treatment; in some embodiments, the patient with esophageal cancer has previously received at least one chemotherapy drug treatment and the treatment failed; In some embodiments, the patient with esophageal cancer has previously received neoadjuvant/radical therapy. In some embodiments, the patient with esophageal cancer has previously received adjuvant/curative therapy. In some embodiments, the patient with esophageal cancer relapsed after receiving neoadjuvant/radical therapy. In some embodiments, the patient with esophageal cancer has relapsed after previous adjuvant/curative therapy. In some embodiments, the (neo)adjuvant/curative therapy includes, but is not limited to, chemotherapy, radiotherapy, surgery.
  • 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) ) application.
  • 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 dosing regimen includes a first treatment phase, optionally a second treatment phase.
  • the dosing regimen described in the present application is also applicable to the use of the medicament for treating esophageal cancer in a patient, the method for treating esophageal cancer in a patient, and the use for treating esophageal cancer in a patient described in this application.
  • the first treatment period includes 1-10 treatment cycles, preferably 2-8 treatment cycles, more preferably 4-6 treatment cycles, most preferably 6 treatment cycles.
  • the second treatment period comprises 2-20 treatment cycles. In some embodiments, the second treatment period continues until the clinical benefit is lost or the toxicity is intolerable or the efficacy evaluation is PD or the investigator considers it inappropriate to continue the drug.
  • the treatment cycle is 14 days to 42 days; in some embodiments, the treatment cycle is 14 days, 21 days, 28 days, 35 days or 42 days; in some embodiments In, the treatment cycle is 21 days.
  • the first treatment period has the same treatment period as the second treatment period.
  • the treatment cycles (eg, a single treatment cycle) of the first treatment period and the second treatment period are both 21 days.
  • the anti-PD-L1 antibody is administered once on the 1st, 2nd, 3rd, 4th, 5th, 6th, or 7th day of each treatment cycle, preferably on the 1st day of each treatment cycle. 1 dose once a day.
  • the anlotinib or a pharmaceutically acceptable salt thereof is administered on day 1-7, day 7-14, day 1-14, or day 7 of each treatment cycle. - Continuous administration for 21 days, preferably on days 1-14 of each treatment cycle.
  • the taxane antitumor drug is administered once on the 1st, 2nd, 3rd, 4th, 5th, 6th, or 7th day of each treatment cycle, preferably once in each treatment cycle Dosing once on the first day of .
  • the platinum-based antineoplastic drug is administered on the 1-3 day, 1-4 day, 1-5 day, 1-6 day, 1-7 day of each treatment cycle day, day 2-4, day 2-5, day 2-6, day 2-7, day 3-5, day 3-6, day 3-7, day 4-6, It is administered continuously on the 4th-7th day, or on the 5th-7th day, preferably on the 1st-3rd day of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) the anti-PD-L1 antibody is administered once a day within days 1-7 of each treatment cycle; and optionally, 2) Taxane antineoplastic drugs are administered once a day within the first 7 days of each treatment cycle; and optionally, 3) platinum antineoplastic drugs are administered continuously on the first 1 to 7 days of each treatment cycle administration; and optionally 4) anlotinib or a pharmaceutically acceptable salt thereof is administered continuously on days 1-28 of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) the anti-PD-L1 antibody is administered once on the first day of each treatment cycle; and optionally, 2) Taxane Alkane antineoplastic drugs are administered once on the first day of each treatment cycle; and optionally, 3) platinum antineoplastic agents are administered continuously on days 1-3 of each treatment cycle; and optionally 4) Anlotinib or a pharmaceutically acceptable salt thereof is administered continuously on the 1st-14th day of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) the anti-PD-L1 antibody is administered once on the first day of each treatment cycle; and optionally, 2) paclitaxel is administered on Dosing once on Day 1 of each treatment cycle; and optionally, 3) cisplatin is administered continuously on Days 1-3 of each treatment cycle; and optionally 4) Anlotinib or its pharmaceutically Acceptable salts are administered continuously on days 1-14 of each treatment cycle.
  • the dosage regimen of the first treatment stage includes: 1) anti-PD-L1 antibody is administered once on the first day of each treatment cycle; and 2) taxane anti-tumor The drug is administered once on the first day of each treatment cycle; and, 3) platinum-based antineoplastic drugs are administered continuously on the first 1-3 days of each treatment cycle; and optionally 4) anlotinib or its The pharmaceutically acceptable salt is administered continuously on the 1st-14th day of each treatment cycle.
  • the dosing regimen of the first treatment phase includes: 1) the anti-PD-L1 antibody is administered once on the first day of each treatment cycle; and 2) paclitaxel is administered once in each treatment cycle and, 3) continuous administration of cisplatin on days 1-3 of each treatment cycle; and optionally 4) anlotinib or a pharmaceutically acceptable salt thereof on each treatment cycle Days 1-14 of the treatment cycle are administered continuously.
  • the dosing regimen of the second treatment stage includes: 1) the anti-PD-L1 antibody is administered once a day within the 1st-7th day of each treatment cycle; optionally, 2 ) Anlotinib or a pharmaceutically acceptable salt thereof is administered continuously on days 1-28 of each treatment cycle.
  • the dosage regimen of the second treatment stage includes: 1) anti-PD-L1 antibody is administered once on the first day of each treatment cycle; and 2) anlotinib or its The pharmaceutically acceptable salt is administered continuously on the 1st-14th day of each treatment cycle.
  • the dosage regimen of the second treatment stage includes: 1) the anti-PD-L1 antibody hu5G11-hIgG1 is administered once on the first day of each treatment cycle; 2) Anlotinib Dihydrochloride was administered continuously on days 1-14 of each treatment cycle.
  • the drug combination of the present application can safely and effectively treat esophageal cancer, especially unresectable and/or advanced and/or recurrent and/or metastatic esophageal cancer. In some embodiments, the drug combination of the present application can safely and effectively treat esophageal squamous cell carcinoma, especially unresectable and/or advanced and/or recurrent and/or metastatic esophageal squamous cell carcinoma. In some embodiments, the drug combination of the present application can provide treatment with higher tolerance in patients, and its anti-tumor effect is better than that of any drug or any two drugs in the combination alone, and/or or fewer adverse reactions and/or complications. In some embodiments, the drug combination of the present application exhibits a more excellent anti-tumor synergistic effect in the treatment of esophageal cancer.
  • the median PFS (progression-free survival) of patients with esophageal cancer can be significantly prolonged after receiving the drug combination therapy of the present application.
  • the patient's median PFS reaches or exceeds 5.5 months; reaches or exceeds 6 months; reaches or exceeds 6.5 months; reaches or exceeds 7 months; reaches or exceeds 8 months; 9 months or more.
  • the ORR (objective response rate) of patients with esophageal cancer is significantly prolonged after receiving the drug combination treatment of the present application.
  • the ORR in the patient is 20% or greater; 30% or greater; 35% or greater; 40% or greater; 50% or greater; 60% or greater; or over 70%; at or over 80%.
  • the patient's ORR reaches or exceeds 70% ; 75% or more; 80% or more; 90% or more.
  • 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).
  • BSA body surface area
  • a 60kg person and a 100kg person will receive the same dose of antibody (eg, 240mg anti-PD-1 antibody).
  • CR complete remission
  • partial response means that the total diameter of the target lesion is reduced by more than 30% compared with the total diameter of the baseline.
  • disease progression refers to the increase of 20% or more in the total diameter of the target lesion compared with the minimum value of the total diameter in the study (including the total diameter at baseline, if it is the minimum value in the study). In addition to a relative increase of more than 20%, the absolute value of the total diameter must also increase by more than 5mm. The appearance of one or more new lesions should also be considered as disease progression.
  • stable disease refers to the shrinkage of the lesion, but not enough for the PR standard; or the enlargement of the lesion, but not enough for the PD standard, and the smallest diameter was used as a reference in the test.
  • best response refers to the best response at all time points from the initial assessment to the last assessment.
  • 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 patient each simultaneously as a single formulation, or each sequentially 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 anti-PD-L1 antibodies and fragments thereof of the present application can be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans.
  • Anti-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 be in 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.
  • the antibody may be produced by a hybridoma selected from the group consisting of hybridomas referred to herein as 13C5, 5G11. Accordingly, antibodies described herein also include hybridomas 13C5, 5G11, and any hybridoma that produces an antibody disclosed herein.
  • the present application also includes 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.
  • the antibody or/and fragment thereof is specific for PD-L1.
  • the antibodies and fragments described herein bind human or primate PD-L1, but do not bind PD-L1 from any other mammal.
  • the antibody or 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.
  • administering means physically introducing a composition comprising a therapeutic agent into a subject 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.
  • a “patient” is a mammal, and in some embodiments, the patient is a human. In some embodiments, the subject is a human.
  • unit dose refers to the smallest packaging unit containing a certain amount of medicine, for example, a box of medicine has seven capsules, each capsule is a unit dose; or each bottle of injection is a unit dose.
  • single dose and “unit dose” have the same meaning and are used interchangeably.
  • 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 the administration of a compound of the present application, or a pharmaceutical combination thereof, to a patient.
  • the term “optional” or “optionally” means that the object or event it modifies exists or does not exist, or occurs or does not occur, for example, "the pharmaceutical combination "Tinib or a pharmaceutically acceptable salt thereof” means that the pharmaceutical combination may or may not contain anlotinib or a pharmaceutically acceptable salt thereof.
  • the anti-PD-L1 antibody in the example can be prepared according to the method described in WO2016022630, and after affinity chromatography, the eluate containing the antibody is obtained according to a conventional antibody purification method.
  • Embodiment 1 clinical trial
  • Subjects who meet the inclusion criteria will be randomly entered into experimental group 1 or experimental group 2, and the treatment is divided into initial treatment phase (ie, the first treatment phase) and maintenance treatment phase (ie, the second treatment phase).
  • initial treatment 4 to 6 cycles, determined by the investigator based on the patient's tolerance
  • patients should receive 6 cycles of initial treatment as much as possible) and then maintain treatment for patients without disease progression (CR ⁇ PR ⁇ SD) until the curative effect
  • the drug was terminated when it was evaluated as disease progression (PD) or when the patient could not tolerate it.
  • Efficacy evaluations were performed every 2 cycles during the initial treatment phase, and efficacy evaluations were performed every 3 cycles during the maintenance treatment phase.
  • At least one measurable lesion should be present; the measurable lesion should not have received local treatment such as radiotherapy (lesions located in the area of previous radiotherapy, if progress is confirmed and meet the RECIST 1.1 standard, can also be used as a target lesion);
  • Age 18-75 years old; ECOG PS score: 0-1 points; expected survival time is more than 3 months.
  • Anti-PD-L1 antibody hu5G11-hIgG1 injection 1200mg anti-PD-L1 antibody injection (specification: 600mg/20ml) is diluted to 250mL with normal saline, and the infusion time is 60 ⁇ 10min (the infusion time starts with the start of anti-PD-L1 infusion Antibody injection is the starting point, the end of the infusion of anti-PD-L1 antibody injection and normal saline (it is recommended to flush the tube with 20mL normal saline) is the end point).
  • the anti-PD-L1 antibody injection is administered on the first day of each cycle, once every 21 days, that is, 21 days is a treatment cycle (d1/q3w). The longest period of use shall not exceed 24 months.
  • 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. Without special circumstances, it is recommended to take it at a fixed time every day. That is, anlotinib hydrochloride capsules: 12mg/qd, d1-14/q3w.
  • Paclitaxel 135mg/m 2 , intravenous infusion, medication on day 1 of each cycle, pretreatment with hormones (dexamethasone, diphenhydramine, cimetidine, etc.) before medication, 3 weeks as a treatment cycle.
  • hormones diexamethasone, diphenhydramine, cimetidine, etc.
  • Cisplatin Administered after paclitaxel, 60-75mg/m 2 , intravenous drip, each cycle is divided into d1-d3 medication, 3 weeks as a treatment cycle.
  • Treatment is divided into an initial treatment phase (ie, the first treatment phase) and a maintenance treatment phase (ie, the second treatment phase).
  • the first stage of treatment (4 to 6 treatment cycles, determined by the investigator based on the patient's tolerance, and patients should receive initial treatment for 6 treatment cycles as much as possible):
  • Test group 1 Every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody injection 1200mg/time, every cycle d1 medication, intravenous infusion;
  • Anlotinib Hydrochloride Capsules 10mg/time, once a day, every cycle d1-d14 medication, continuous medication for 2 weeks, stop for 1 week, orally;
  • Paclitaxel according to the dose of 135mg/ m2 , every cycle d1 medication, hormone pretreatment before medication, intravenous infusion;
  • Cisplatin administered after paclitaxel, at a dose of 60-75mg/m 2 , administered on d1-d3 every cycle, intravenously.
  • Experimental group 2 Every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody injection 1200mg/time, every cycle d1 medication, intravenous infusion;
  • Paclitaxel according to the dose of 135mg/ m2 , every cycle d1 medication, hormone pretreatment before medication, intravenous infusion;
  • Cisplatin administered after paclitaxel, at a dose of 60-75mg/m 2 , administered on d1-d3 every cycle, intravenously.
  • the second stage of treatment (until the curative effect evaluation is disease progression (PD) or the end of the drug when the patient cannot tolerate it):
  • Test group 1 Every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody injection 1200mg/time, every cycle d1 medication, intravenous infusion;
  • Anlotinib Hydrochloride Capsules 10mg/time, once a day, on d1-d14 of each cycle, continuous medication for 2 weeks, pause for 1 week, orally.
  • Experimental group 2 Every 21 days is a treatment cycle.
  • Anti-PD-L1 antibody injection 1200mg/time, administered on day 1 of each cycle, intravenous infusion.
  • Effectiveness evaluation criteria RECIST 1.1 and iRECIST criteria were used to determine the disease status. Based on the RECIST 1.1 evaluation standard, supplemented by the iRECIST standard. That is, patients 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
  • Exploratory indicators biological markers, the relationship between PD-L1 expression and efficacy.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une combinaison de médicaments pour le traitement du cancer de l'œsophage, qui comprend un anticorps anti-PD-L1, un médicament chimiothérapeutique et un un anlotinib facultatif ou un sel pharmaceutiquement acceptable de celui-ci. De plus, l'invention concerne également l'utilisation de la combinaison de médicaments dans la préparation d'un médicament pour le traitement du cancer de l'œsophage.
PCT/CN2022/117225 2021-09-06 2022-09-06 Combinaison de médicaments pour le traitement du cancer de l'œsophage WO2023030532A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280049989.8A CN117642181A (zh) 2021-09-06 2022-09-06 用于治疗食管癌的药物组合

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111040270 2021-09-06
CN202111040270.1 2021-09-06

Publications (1)

Publication Number Publication Date
WO2023030532A1 true WO2023030532A1 (fr) 2023-03-09

Family

ID=85410719

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/117225 WO2023030532A1 (fr) 2021-09-06 2022-09-06 Combinaison de médicaments pour le traitement du cancer de l'œsophage

Country Status (2)

Country Link
CN (1) CN117642181A (fr)
WO (1) WO2023030532A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016022630A1 (fr) * 2014-08-05 2016-02-11 Jiping Zha Anticorps anti-pd-l1
CN111246881A (zh) * 2017-12-14 2020-06-05 江苏恒瑞医药股份有限公司 Pd-1抗体用于治疗肿瘤的用途
WO2020151759A1 (fr) * 2019-01-25 2020-07-30 正大天晴药业集团股份有限公司 Composition pharmaceutique combinée pour le traitement de tumeurs
WO2020187152A1 (fr) * 2019-03-15 2020-09-24 正大天晴药业集团股份有限公司 Composition pharmaceutique combinée pour le traitement du cancer du poumon à petites cellules
CN112121048A (zh) * 2019-06-06 2020-12-25 正大天晴药业集团股份有限公司 用于联合治疗食管癌的喹啉类化合物
CN112168961A (zh) * 2019-07-03 2021-01-05 正大天晴药业集团南京顺欣制药有限公司 治疗结直肠癌的联用药物组合物
CN113018429A (zh) * 2019-12-24 2021-06-25 正大天晴药业集团南京顺欣制药有限公司 治疗卵巢癌的药物组合
CN113117072A (zh) * 2020-01-14 2021-07-16 正大天晴药业集团股份有限公司 喹啉衍生物与pd-1单抗的药物组合

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016022630A1 (fr) * 2014-08-05 2016-02-11 Jiping Zha Anticorps anti-pd-l1
CN107001463A (zh) * 2014-08-05 2017-08-01 中美冠科生物技术（太仓）有限公司 抗pd‑l1抗体
CN111246881A (zh) * 2017-12-14 2020-06-05 江苏恒瑞医药股份有限公司 Pd-1抗体用于治疗肿瘤的用途
WO2020151759A1 (fr) * 2019-01-25 2020-07-30 正大天晴药业集团股份有限公司 Composition pharmaceutique combinée pour le traitement de tumeurs
WO2020187152A1 (fr) * 2019-03-15 2020-09-24 正大天晴药业集团股份有限公司 Composition pharmaceutique combinée pour le traitement du cancer du poumon à petites cellules
CN112121048A (zh) * 2019-06-06 2020-12-25 正大天晴药业集团股份有限公司 用于联合治疗食管癌的喹啉类化合物
CN112168961A (zh) * 2019-07-03 2021-01-05 正大天晴药业集团南京顺欣制药有限公司 治疗结直肠癌的联用药物组合物
CN113018429A (zh) * 2019-12-24 2021-06-25 正大天晴药业集团南京顺欣制药有限公司 治疗卵巢癌的药物组合
CN113117072A (zh) * 2020-01-14 2021-07-16 正大天晴药业集团股份有限公司 喹啉衍生物与pd-1单抗的药物组合

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HUANG JING, XIAO JUXIANG, FANG WENTAO, LU PING, FAN QINGXIA, SHU YONGQIAN, FENG JIFENG, ZHANG SHU, BA YI, ZHAO YANG, LIU YING, BAI: "Anlotinib for previously treated advanced or metastatic esophageal squamous cell carcinoma: A double‐blind randomized phase 2 trial", CANCER MEDICINE, JOHN WILEY & SONS LTD., GB, vol. 10, no. 5, 1 March 2021 (2021-03-01), GB , pages 1681 - 1689, XP093041533, ISSN: 2045-7634, DOI: 10.1002/cam4.3771 *
TANG YONG, OU ZHU’AN, YAO ZHIFANG, QIAO GUIBIN: "A case report of immune checkpoint inhibitor nivolumab combined with anti-angiogenesis agent anlotinib for advanced esophageal squamous cell carcinoma", MEDICINE, WILLIAMS AND WILKINS, BALTIMORE., US, vol. 98, no. 40, 1 January 2019 (2019-01-01), US , pages e17164, XP093041546, ISSN: 0025-7974, DOI: 10.1097/MD.0000000000017164 *
YANG YAN-MING, HONG PAN, XU WEN WEN, HE QING-YU, LI BIN: "Advances in targeted therapy for esophageal cancer", SIGNAL TRANSDUCTION AND TARGETED THERAPY 05 05 2020, vol. 5, no. 1, 7 October 2020 (2020-10-07), pages 229 - 11, XP093041550, ISSN: 2059-3635, DOI: 10.1038/s41392-020-00323-3 *

Also Published As

Publication number Publication date
CN117642181A (zh) 2024-03-01

Similar Documents

Publication Publication Date Title
CN113347996B (zh) 治疗肿瘤的联用药物组合物
WO2020187152A1 (fr) Composition pharmaceutique combinée pour le traitement du cancer du poumon à petites cellules
WO2020249018A1 (fr) Composition pharmaceutique combinée pour le traitement du cancer du poumon positif aux gènes "conducteurs"
WO2020239085A1 (fr) Composition pharmaceutique combinée pour le traitement du mélanome
WO2021219138A1 (fr) Médicament combiné pour le traitement du cancer du rein
WO2022002153A1 (fr) Médicament pour le traitement de tumeur
WO2023030532A1 (fr) Combinaison de médicaments pour le traitement du cancer de l'œsophage
WO2023098798A1 (fr) Association de médicaments pour le traitement du cancer du poumon non à petites cellules
WO2023001283A1 (fr) Association médicamenteuse pour le traitement du cancer gastrique et/ou du cancer de la jonction œsogastrique
WO2022033585A1 (fr) Médicament combiné pour le traitement d'un sarcome des tissus mous
WO2023011631A1 (fr) Composition pharmaceutique pour le traitement du cancer du poumon à petites cellules
US20240316031A1 (en) Combination drug for treatment of gastric carcinoma and/or esophagogastric junction cancer
CN116036265A (zh) 用于癌症的联用药物
CN116370641A (zh) 用于治疗消化系统恶性肿瘤的联用药物
CN116173198A (zh) 用于肝癌术后辅助治疗的联用药物
WO2023232100A1 (fr) Combinaison pharmaceutique pour le traitement d'une tumeur utérine maligne
CN116510005A (zh) 治疗肿瘤的联用药物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22863666

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280049989.8

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22863666

Country of ref document: EP

Kind code of ref document: A1