WO2023040804A1 - 抗pd-1抗体和化疗药的药物组合及其使用方法 - Google Patents

抗pd-1抗体和化疗药的药物组合及其使用方法 Download PDF

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WO2023040804A1
WO2023040804A1 PCT/CN2022/118336 CN2022118336W WO2023040804A1 WO 2023040804 A1 WO2023040804 A1 WO 2023040804A1 CN 2022118336 W CN2022118336 W CN 2022118336W WO 2023040804 A1 WO2023040804 A1 WO 2023040804A1
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cisplatin
cycle
antibody
fluorouracil
paclitaxel
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PCT/CN2022/118336
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English (en)
French (fr)
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王岩
马卓
陈玉玲
李昊宇
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信达生物制药(苏州)有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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

  • This application belongs to the field of anti-tumor drugs, in particular, it relates to a drug combination comprising an anti-PD-1 antibody and a chemotherapeutic drug and its use and method for preventing or treating tumors, especially esophageal cancer.
  • Esophageal cancer refers to malignant tumors derived from the esophageal epithelium from the hypopharynx to the esophagogastric junction.
  • esophageal cancer There are two main histological types of esophageal cancer, adenocarcinoma and squamous cell carcinoma.
  • squamous cell carcinoma accounts for about 90% of the total number of esophageal cancers, while it is less than 30% in the United States, Europe, Australia and other countries.
  • the treatment paradigm for esophageal squamous cell carcinoma is similar in Asian and Western countries.
  • the main treatment for early and mid-stage esophageal cancer is surgery, and more advanced esophageal cancer (with lymph node metastasis or T3-4 stage) will receive surgery after neoadjuvant chemoradiotherapy or radical chemoradiotherapy accordingly.
  • the cumulative survival rates at 1, 5, and 10 years after surgery were 78%, 38%, and 30%, and the median survival time was 2.68 years. [Li Guodong.
  • First-line chemotherapy regimens include cisplatin combined with paclitaxel or 5-fluorouracil, both of which have shown similar efficacy in a retrospective analysis related to the treatment of esophageal squamous cell carcinoma, with a median survival time of about 1 year [Liu Y, Ren Z, Yuan L ,Xu S,Yao Z,Qiao L,Li K.Paclitaxel plus cisplatin vs.5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer.Am J Cancer Res.2016;6:2345-2350] .
  • the median survival times of ECF, ECX, EOF, and EOX treatment groups were 9.9, 9.9, 9.3, and 11.2 months, and the 1-year survival rates were 37.7%, 40.8%, 40.4%, and 46.8%, respectively [Liu Y, Ren Z, Yuan L, Xu S, Yao Z, Qiao L, Li K. Paclitaxel plus cisplatin vs. 5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer. Am J Cancer Res. 2016; 6:2345- 2350].
  • panitumumab failed to prolong survival.
  • a randomized controlled phase 3 study (REAL-3) comparing the EOX regimen with EOX plus panitumumab, panitumumab failed to prolong survival.
  • EOX treatment group 40% had esophageal cancer and 99% had adenocarcinoma.
  • the overall survival time in the EOX treatment group was 11.3 months.
  • phase II clinical study on the efficacy of docetaxel combined with cisplatin in first-line esophageal squamous cell carcinoma 39 subjects were enrolled, the objective response rate was 33.33%, and the disease progression-free period was 5 months.
  • Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus a randomized phase II study of the Hätician Intern Vietnamese Onkologie.Ann 93,7-20]1.6
  • 39 subjects were enrolled, the objective response rate was 48.6%, and the OS was 13 months [Zhang X, Shen L, Li J, Li Y, Li J, Jin M.A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol 2008,31:29-33.].
  • the present application provides a drug combination comprising an anti-PD-1 antibody (such as an anti-PD-1 monoclonal antibody or an antigen-binding fragment thereof) combined with chemotherapy drugs and its use for the prevention or treatment of unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma Uses and methods for cancer, the method may have a better therapeutic effect.
  • the drug combination of the present application comprises: (i) anti-PD-1 antibody; (ii) platinum-based drugs; and (iii) selected from taxane anti-tumor drugs and fluoropyrimidine anti-tumor drugs at least one of .
  • this application also provides two combined treatment options of anti-PD-1 antibody combined with cisplatin + paclitaxel or cisplatin + 5-fluorouracil to adapt to clinical treatment options in different regions and populations. Both combination treatments have Better therapeutic effect.
  • the application provides the following implementations:
  • the present application provides a drug combination, including anti-PD-1 antibody and chemotherapeutic drugs,
  • Anti-PD-1 antibody comprises heavy chain and light chain, and wherein said heavy chain comprises HCDR1, HCDR2, HCDR3, and described HCDR1 comprises the amino acid shown in SEQ ID NO:1 or is made up of shown amino acid sequence;
  • HCDR2 comprises SEQ ID NO The amino acid shown in: 2 or be made up of shown amino acid sequence;
  • HCDR3 comprises the amino acid shown in SEQ ID NO:3 or is made up of shown amino acid sequence;
  • Described light chain comprises LCDR1, LCDR2, LCDR3, and described LCDR1 comprises SEQ ID The amino acid shown in NO:4 or consists of the amino acid sequence shown;
  • LCDR2 contains the amino acid shown in SEQ ID NO:5 or consists of the amino acid sequence shown;
  • LCDR3 contains the amino acid shown in SEQ ID NO:6 or consists of the amino acid shown sequence composition;
  • a drug combination includes an anti-PD-1 antibody and a chemotherapeutic drug
  • the anti-PD-1 antibody comprises VH, VL, wherein the VH comprises SEQ ID NO:7
  • the amino acid sequence of the VL comprises the amino acid sequence shown in SEQ ID NO: 8
  • the anti-PD-1 antibody comprises at least 80% of the amino acid sequence shown in SEQ ID NO: 7 (e.g.
  • a drug combination includes an anti-PD-1 antibody and a chemotherapeutic agent
  • the anti-PD-1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:
  • the amino acid sequence shown in 9, the light chain includes the amino acid sequence shown in SEQ ID NO: 10; in some preferred embodiments, the anti-PD-1 antibody includes the amino acid sequence shown in SEQ ID NO: 9 having at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) A heavy chain of homology, and at least 80% (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) homology to the light chain.
  • various variants of the aforementioned anti-PD-1 antibodies retain the ability to specifically bind to the antigen PD-1.
  • the anti-PD-1 antibody is sintilimab.
  • a drug combination includes an anti-PD-1 antibody and a chemotherapeutic drug
  • the chemotherapeutic drug includes a variety of chemotherapy regimens, for example, the chemotherapeutic drug can be: a platinum drug (such as a cis platinum, carboplatin, nedaplatin, lobaplatin, oxaliplatin, epithioplatin); At least one of the fluoropyrimidine antineoplastic drugs (such as 5-fluorouracil, capecitabine, S-1, tegafur, carmofur, gemcitabine, deoxyfluridine, bisfururacil) A sort of.
  • a platinum drug such as a cis platinum, carboplatin, nedaplatin, lobaplatin, oxaliplatin, epithioplatin
  • At least one of the fluoropyrimidine antineoplastic drugs such as 5-fluorouracil, capecitabine, S-1, tegafur, carmofur, gemcita
  • the platinum drug is cisplatin, nedaplatin, oxaliplatin, or epithioplatinum.
  • the taxane antineoplastic drug is paclitaxel or docetaxel.
  • the fluoropyrimidine antineoplastic drug is 5-fluorouracil, capecitabine, S-1, deoxyfluridine, tegafur, or carmofur.
  • the chemotherapeutic agent comprises cisplatin and at least one selected from paclitaxel and 5-fluorouracil.
  • the chemotherapy drug is a combined chemotherapy regimen of paclitaxel and cisplatin or a combined chemotherapy regimen of 5-fluorouracil and cisplatin.
  • the drug combination includes: anti-PD-1 antibody; platinum drugs; and at least one selected from taxane anti-tumor drugs and fluoropyrimidine anti-tumor drugs.
  • the drug combination includes: sintilimab or its antigen-binding fragment; platinum drugs; and at least one selected from taxane anti-tumor drugs and fluoropyrimidine anti-tumor drugs.
  • the drug combination includes: anti-PD-1 antibody; cisplatin, nedaplatin, oxaliplatin, or thioplatinum; and paclitaxel or docetaxel, 5-fluorouracil, capecita At least one of Bingham, S-1, Deoxyfluridine, Tegafur, or Carmofur. More preferably, the drug combination includes: sintilimab or its antigen-binding fragment; cisplatin, nedaplatin, oxaliplatin, or thioplatin; and paclitaxel or docetaxel, 5- At least one of fluorouracil, capecitabine, S-1, deoxyfluridine, tegafur, or carmofur.
  • the drug combination includes an anti-PD-1 antibody and a chemotherapeutic drug
  • the anti-PD-1 antibody comprises a heavy chain and a light chain
  • the heavy chain comprises the amino acid sequence shown in SEQ ID NO:9
  • the light chain comprises the amino acid sequence shown in SEQ ID NO: 10
  • the chemotherapy drug comprises cisplatin and at least one selected from paclitaxel and 5-fluorouracil.
  • the pharmaceutical combination comprises sintilimab or an antigen-binding fragment thereof, cisplatin, and at least one selected from paclitaxel and 5-fluorouracil.
  • the pharmaceutical combination comprises sintilimab or an antigen-binding fragment thereof, cisplatin, and paclitaxel.
  • the pharmaceutical composition comprises sintilimab or an antigen-binding fragment thereof, cisplatin, and 5-fluorouracil.
  • a drug combination in one embodiment, includes an anti-PD-1 antibody and a chemotherapeutic drug, and the anti-PD-1 antibody and the chemotherapeutic drug are used separately, simultaneously or sequentially.
  • the anti-PD-1 antibody and the chemotherapeutic drug can be packaged separately, and can have conventional dosage forms in the art, such as injections, oral dosage forms (such as tablets, capsules, lozenges, powders, suspensions) wait.
  • a drug combination is provided, the drug combination is used for preventing or treating individual tumor diseases, the tumor is esophageal cancer, preferably, the esophageal cancer is esophageal squamous cell carcinoma, more preferably, all The above esophageal squamous cell carcinoma is unresectable, locally advanced recurrent or metastatic esophageal squamous cell carcinoma.
  • the composition of the drug combination for preventing or treating tumors is as defined above.
  • the individual is a mammal. In preferred embodiments, the individual is a human.
  • kits comprising an effective amount of an anti-PD-1 antibody, and an effective amount of a chemotherapeutic agent; preferably, a package insert is provided with information on the use of an anti-PD-1 antibody in an individual.
  • a kit insert is provided with information on the use of an anti-PD-1 antibody in an individual.
  • the chemotherapeutic drugs can be: platinum drugs (such as cisplatin, carboplatin, nedaplatin, lobaplatin, oxaliplatin, epithioplatin); and antitumor agents selected from taxanes Drugs (such as paclitaxel (including nab-paclitaxel, liposomal paclitaxel), docetaxel, cabazitaxel) and fluoropyrimidine antineoplastic drugs (such as 5-fluorouracil, capecitabine, S-1, tegafur , carmofur, gemcitabine, deoxyfluridine, bisfururacil) at least one.
  • platinum drugs such as cisplatin, carboplatin, nedaplatin, lobaplatin, oxaliplatin, epithioplatin
  • antitumor agents selected from taxanes Drugs (such as paclitaxel (including nab-paclitaxel, liposomal paclit
  • the chemotherapeutic drug can be cisplatin and at least one combination chemotherapy combination selected from paclitaxel and 5-fluorouracil, preferably paclitaxel and cisplatin combination chemotherapy or 5-fluorouracil and cisplatin combination Chemotherapy combination.
  • the kit includes the aforementioned anti-PD-1 antibody and chemotherapeutics packaged separately.
  • the anti-PD-1 antibody and chemotherapeutic agent are each in the form of a drug.
  • the above-mentioned anti-PD-1 antibody and chemotherapeutic agent may be in the form of injection or lyophilized powder for preparing injection respectively.
  • a drug combination comprising an anti-PD-1 antibody and a chemotherapeutic drug or the use of a kit thereof in the preparation of a drug for preventing or treating tumor diseases; preferably, the tumor is esophageal cancer, more preferably Preferably, the esophageal cancer is esophageal squamous cell carcinoma, more preferably, the esophageal squamous cell carcinoma is unresectable, locally advanced recurrent or metastatic esophageal squamous cell carcinoma.
  • a drug combination or kit for preventing or treating tumors is provided, the drug combination or kit includes an anti-PD-1 antibody and a chemotherapeutic drug.
  • the PD-1 antibody and chemotherapeutics are as defined above.
  • a method of treatment comprising: administering to an individual in need thereof a therapeutically effective amount of a drug combination comprising an anti-PD-1 antibody and a chemotherapeutic agent.
  • a method of treatment comprising: administering to an individual in need an effective therapeutic amount of an anti-PD-1 antibody, a platinum-based drug, and an anti-tumor drug selected from taxanes and fluoropyrimidines.
  • a drug combination of at least one of the tumor drugs comprising: administering to an individual in need thereof a therapeutically effective amount of a drug combination comprising an anti-PD-1 antibody and a chemotherapeutic agent.
  • a method of treatment comprising: administering to an individual in need thereof an effective therapeutic amount of a drug combination comprising an anti-PD-1 antibody and a chemotherapeutic drug, the chemotherapeutic drug being cisplatin, and a drug selected from At least one of paclitaxel and 5-fluorouracil; preferably, the chemotherapy drug is a combination of paclitaxel and cisplatin, or a combination of 5-fluorouracil and cisplatin.
  • the single daily dosage of the anti-PD-1 antibody is 10mg-300mg (such as 20mg-250mg, 30mg-200mg), or 1-5mg/kg (such as 2-4mg/kg, 3mg/kg). kg) or 200 mg; or, in some embodiments, in a single treatment cycle (eg, 21 days), the anti-PD-1 antibody is administered at a dose of 10 mg-300 mg (eg, 20 mg-250 mg, 30 mg-200 mg), Or 1-5 mg/kg (eg 2-4 mg/kg, 3 mg/kg) or 200 mg. In some embodiments, in a single treatment cycle, the anti-PD-1 antibody is administered 1-2 times, preferably 1 time.
  • the single daily dosage of paclitaxel is 25mg-700mg (for example, 42.5mg-615mg), or 50-200mg/m 2 (for example, 85-175mg/m 2 ); or, in some embodiments In a single treatment cycle (eg, 21 days), the dosage of paclitaxel is 50mg-700mg (eg, 85mg-615mg), or 100-200mg/m 2 (eg, 175mg/m 2 ).
  • the paclitaxel in the first treatment cycle (for example, 21 days), is administered 1-4 times, preferably 1-2 times, and in a single treatment cycle (for example, 21 days) after the first treatment cycle ), the paclitaxel is given 1-2 times, preferably 1 time.
  • the single daily dosage of 5-fluorouracil is 250mg-4200mg, preferably 300mg-3500mg (such as 350mg-3150mg, 400mg-2800mg), or 500-1200mg/m 2 , preferably 600-1000mg /m 2 (eg, 640-1000 mg/m 2 , 700-900 mg/m 2 , 800 mg/m 2 ); or, in some embodiments, in a single treatment cycle (eg, 21 days), the 5-fluorouracil The dosage is 2500-6000mg/m 2 , preferably 3000-5000mg/m 2 (eg 3200-4000mg/m 2 , 3500-4500mg/m 2 , 4000mg/m 2 ). In some embodiments, the 5-fluorouracil is administered 1-10 times, preferably 4-6 times (eg, 5 times) in a single treatment cycle.
  • the single daily dose of cisplatin is 25mg-350mg (such as 30mg-315mg, 37.5mg-262.5mg), or 50-100mg/m 2 (such as 60-90mg/m 2 , preferably 75mg/m 2 ); or, in some embodiments, in a single treatment cycle (such as 21 days), the dose of cisplatin is 25mg-350mg (such as 30mg-315mg, 37.5mg-262.5mg) , or 50-100 mg/m 2 (eg 60-90 mg/m 2 , preferably 75 mg/m 2 ). In some embodiments, the cisplatin is administered 1-2 times, preferably 1 time, in a single treatment cycle.
  • the anti-PD-1 antibody is administered once on the first day of each treatment cycle (for example, 21 days); the paclitaxel is administered once on the first day of the first treatment cycle (for example, 21 days) and The eighth day is administered once respectively, and is administered once on the first day of each treatment cycle (for example, 21 days) in the second treatment cycle and each treatment cycle thereafter; the 5-fluorouracil is administered once in each treatment cycle ( The cisplatin is administered once a day for 24 hours from the first day to the fifth day of each treatment cycle (for example, 21 days); the cisplatin is administered once on the first day of each treatment cycle (for example, 21 days).
  • the anti-PD-1 antibody is administered once on the first day of each treatment cycle (such as 21 days), and the dosage is 20mg-250mg (such as 30mg-200mg) or 3mg/kg (preferably Specifically, for individuals with a body weight ⁇ 60 kg, the dose is 3 mg/kg; and for individuals with a body weight ⁇ 60 kg, the dose is 200 mg);
  • the paclitaxel is administered once on the first day and the eighth day of the first treatment cycle (for example, 21 days), each administration dose is 43.5mg-306.5mg or 87.5mg/m 2 , and on the second day Administration once on the first day of each treatment cycle (for example, 21 days) in the treatment cycle and subsequent treatment cycles, the dosage is 87.5mg-615mg or 175mg/m 2 ;
  • the 5-fluorouracil is continuously administered once a day for 24 hours from the first day to the fifth day of each treatment cycle (for example, 21 days), and the dosage of each administration is 400mg-2800mg or 800mg/(m 2 ⁇ d) ;
  • the cisplatin is administered once on the first day of each treatment cycle (for example, 21 days), and the dosage is 37.5mg-262.5mg or 75mg/m 2 .
  • a method of treatment wherein a therapeutically effective amount of an anti-PD-1 antibody and a chemotherapeutic drug is a combination of paclitaxel and cisplatin or a combination of 5-fluorouracil and cisplatin ;
  • the single administration of the anti-PD-1 antibody is 100-300 mg or 1-5 mg/kg, preferably 200 mg or 3 mg/kg, and the single administration of paclitaxel is 120-200 mg/m 2 , preferably 175 mg/m 2 , the single administration of 5-fluorouracil is 3000-5000 mg/m 2 , preferably 4000 mg/m 2 , and the single administration of cisplatin is 60-90 mg/m 2 , preferably 75 mg/m 2 .
  • the amount of "single administration” refers to the cumulative amount administered in a single treatment cycle.
  • the PD-1 antibody is as defined above, and the platinum-based drugs, taxane-based anti-tumor drugs and fluoropyrimidine-based anti-tumor drugs are also as defined above.
  • a method of treatment wherein the anti-PD-1 antibody is administered in a single dose of 200 mg or 3 mg/kg, the paclitaxel is administered in a single dose of 175 mg/m 2 , and the 5-fluorouracil is administered in a single dose.
  • a treatment method wherein, the anti-PD-1 antibody is administered once every three weeks as a cycle, and is administered on the first day of each cycle; the paclitaxel is administered every three weeks.
  • Week is a cycle, the first cycle is administered twice, the first day and the eighth day of each cycle are administered, the second cycle and subsequent cycles are administered once per cycle, and the first day of each cycle is administered;
  • the 5- Fluorouracil is a cycle every three weeks, and the first to fifth days of each cycle are continuously administered 24 hours a day;
  • the cisplatin every three weeks is a cycle, administered once in each cycle, and administered on the first day of each cycle.
  • a treatment method wherein, the anti-PD-1 antibody is administered at 200 mg or 3 mg/kg per cycle; the paclitaxel is administered twice in the first cycle, and each administration is 87.5 mg/kg.
  • a method of treatment wherein the tumor is esophageal cancer, preferably esophageal squamous cell carcinoma, more preferably, the esophageal squamous cell carcinoma is unresectable, locally advanced recurrent or metastatic esophageal cancer squamous cell carcinoma.
  • the anti-PD-1 antibody and chemotherapeutic drugs can be administered through conventional administration routes, for example, they can be administered orally, parenterally, etc.
  • the term "and/or" refers to any one of the alternatives or two or more of the alternatives, ie, it means at least one of the alternatives.
  • the terms “comprising” or “comprising” or their equivalents mean the inclusion of stated elements, integers or steps, but not the exclusion of any other elements, integers or steps.
  • the term “comprising” or “comprises” is used, unless otherwise specified, it also covers the situation consisting of the mentioned elements, integers or steps.
  • an antibody variable region comprising of that particular sequence.
  • “Individual” includes mammals. Mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats).
  • the individual is a human, including a child, adolescent, or adult.
  • the term “individual” may also be referred to as "subject", "patient”.
  • treating means slowing, interrupting, arresting, alleviating, stopping, reducing, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.
  • prevention includes the inhibition of the occurrence or development of a disease or disorder or a symptom of a particular disease or disorder.
  • individuals with a family history of the disease are candidates for prophylactic regimens.
  • prophylactic regimens refers to the administration of a drug prior to the onset of signs or symptoms, especially in at-risk individuals.
  • an effective amount refers to the amount or dose of the formulation or composition of the present application, which, after single or multiple doses administered to the patient, produces the desired effect in the treated patient.
  • An effective amount can be readily determined by the attending physician, who is skilled in the art, by considering various factors such as the species of the mammal; its size, age and general health; the particular disease involved; the extent or severity of the disease; the individual patient's response; the particular antibody administered; the mode of administration; the bioavailability characteristics of the formulation administered; the chosen dosing regimen; and the use of any concomitant therapy.
  • a “therapeutically effective amount” refers to an amount effective, at dosages required, and for periods of time required, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the formulations, antibodies or antibody fragments or conjugates or compositions thereof of the present application can elicit a desired response in an individual depending on a variety of factors such as the disease state, age, sex and weight of the individual, and the antibody or antibody portion. ability to change.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the formulation, antibody or antibody fragment or conjugate or composition thereof are outweighed by the therapeutically beneficial effects.
  • anti-PD-1 antibody encompasses monoclonal antibodies, polyclonal antibodies, or antigen-binding fragments thereof that retain the ability of the corresponding intact antibody to specifically bind to an antigen ), preferably an anti-PD-1 monoclonal antibody or an antigen-binding fragment thereof.
  • Anti-PD-1 antibody sintilimab injection, Innovent Biopharmaceutical (Suzhou) Co., Ltd., 10mL: 100mg.
  • Placebo mannitol, histidine, sodium citrate (dihydrate), sodium chloride, disodium edetate, polysorbate 80, citric acid (monohydrate), water for injection.
  • Cisplatin 10mg or 20mg multi-dose bottle, manufacturer: Qilu Pharmaceutical Co., Ltd./Intas Pharmaceuticals India Limited/Intas Pharma India BG is not limited.
  • Paclitaxel 5mL: 30mg, 25mL: 150mg, manufacturer: Haikou Pharmaceutical Factory Co., Ltd./Jiangsu Aosaikang Pharmaceutical Co., Ltd./EBEWE Pharma is not limited.
  • 5-Fluorouracil Injection: 125mg (5mL), 250mg (10mL) each, manufacturer: Tianjin Jinyao Pharmaceutical Co., Ltd./Accord Healthcare, Inc./Intas Pharma India BG is not limited.
  • Subjects must not be suitable for radical treatment, such as radical chemoradiotherapy and/or surgery; Time to recurrence > 6 months.
  • the study drugs in this study were defined as sintilimab, placebo, paclitaxel, 5-fluorouracil and cisplatin.
  • the first administration of the study drug should start on the day of randomization (cycle 1, day 1), but not later than 48 hours after the date of randomization. Discussion with the sponsor is required if no medication is taken beyond 48 hours. Every effort should be made to start the trial treatment on the day of randomization. For all other study treatment cycles, if the subject is unable to go to the center due to holidays or other reasons that are not safe, the administration can be postponed for no more than one week.
  • the specific dosage and treatment plan are shown in Table 1.
  • Sintilimab/placebo should be infused before the administration of chemotherapy drugs, and the dosage of sintilimab/placebo should be calculated according to the actual body weight each time when the body weight is less than 60 kg. There should be at least 1 hour between the end of the sintilimab/placebo infusion and the start of the chemotherapy drug infusion.
  • the administration method of paclitaxel in the first cycle is: 87.5mg/m 2 IV D1, 8 Q3W, and the first day of each cycle starting from the second cycle: 175mg/m 2 IV D1 Q3W.
  • the baseline body weight is used to calculate the body surface area, and the dose of chemotherapy drugs is calculated accordingly.
  • the dose of chemotherapeutic drugs was calculated according to the actual body weight on the day of planned administration. To facilitate dosing, the protocol allows for a deviation of ⁇ 5% in the calculated total dose per infusion.
  • the cumulative dose of 5-fluorouracil in a single cycle is 4000mg/m 2 , and other clinically acceptable administration methods can also be used, such as 1000mg/(m 2 ⁇ d) on days 1-4.
  • a 20% adjustment range can be allowed for the cumulative administration time of a single cycle (ie continuous administration for 4-6 days). If necessary, researchers are allowed to adjust the cumulative dose of a single cycle between 3200-4000mg/m 2 according to the tolerance of the subjects.
  • Sin refers to sintilimab
  • Chemo refers to chemotherapeutic drugs, specifically paclitaxel + cisplatin or cisplatin + 5-fluorouracil, one of which is selected for clinical administration.

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Abstract

包含抗PD-1抗体和化疗药的药物组合及其用于预防或治疗肿瘤、尤其是食管癌的用途和方法。

Description

抗PD-1抗体和化疗药的药物组合及其使用方法 技术领域
本申请属于抗肿瘤药物领域，具体而言，涉及包含抗PD-1抗体和化疗药的药物组合及其用于预防或治疗肿瘤、尤其是食管癌的用途和方法。
背景技术
随着人类平均寿命的延长和生活行为方式的改变，恶性肿瘤已成为严重威胁人类健康的重要疾病，也是对生命威胁最大的疾病。全世界范围内，食管癌的发病率占恶性肿瘤的第8位，死亡率占第6位，主要发生在发展中国家。食管癌的发病率和组织学类型因地理区域而有较大的差别。2017年在美国新发食管癌例数估计将达16,940人，死亡例数大约为15,690人。在美国，食管癌的主要组织学类型为腺癌。食管癌的5年生存率在美国为18.4％，在欧洲为12％。而中国作为全世界食管癌最多的国家，食管癌的发病率和死亡率均高于世界平均水平。据估计，2015年中国新发癌症例数达429万，新发癌症死亡病例281万[Chen W,Zheng R,Baade PD,Zhang S,Zeng H,Bray F,et al.Cancer statistics in China,2015.CA Cancer J Clin 2016,66:115-132]。在所有癌症死因中，食管癌发病率和死亡率分别占第4位和第4位，发病例数和死亡例数分别为47.8万和37.5万。尽管食管癌治疗领域几年来有一定进展，但仍存在巨大的未满足的医学需求。
食管癌是指从下咽部至食管胃结合部之间食管上皮来源的恶性肿瘤。食管癌有两种主要的病理类型，分别为腺癌和鳞状细胞癌。在我国，鳞状细胞癌占食管癌总数的90％左右，而在美国、欧洲、澳大利亚和其它国家则低于30％。
食管鳞癌的治疗模式在亚洲和西方国家是类似的。早中期食管癌的主要治疗手段为手术，更晚期的食管癌(伴淋巴结转移或T3-4分期)会相应地接受新辅助放化疗后的手术或根治性放化疗。一项统计山西省肿瘤医院手术治疗的1510例食管癌患者临床资料的报告中，术后1、5、10年的累计生存率为78％、38％和30％，中位生存时间为2.68年[李国栋.1510例食管癌患者术后生存率及预后影响因素分析.硕士学位论文，2016]。接受过新辅助治疗后的手术和放化疗治疗后的患者，以及出现远处转移的患者通常接受姑息性的化疗。一线化疗方案包括顺铂联合紫杉醇或5-氟尿嘧啶，两者在食管鳞癌治疗有关的回顾性分析中都显示出类似的疗效，中位生存时间约为1年[Liu Y,Ren Z,Yuan L,Xu S,Yao Z,Qiao L,Li K.Paclitaxel plus cisplatin vs.5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer.Am J Cancer Res.2016；6:2345-2350]。
晚期食管癌的随机对照研究较少，通常与胃癌一起研究，一线治疗以含铂双药或三药化疗为主。一项在晚期一线胃癌和食管癌患者中比较卡培他滨和5-氟尿嘧啶以及奥沙利铂和顺铂疗效的随机对照3期临床研究(REAL-2)中，1002名患者以1:1:1:1的比例被随机分配到ECF(表柔比星+顺铂+氟尿嘧啶)、ECX(表柔比星+顺铂+卡培他滨)、EOF(表柔比星+奥沙利铂+氟尿嘧啶)或EOX(表柔比星+奥沙利铂+卡培他滨)4个治疗组中，每个治疗组中食管癌的比例为30％-40％，鳞癌的比例约为10％。ECF、ECX、EOF、EOX治疗组的中位生存时间分别为9.9、9.9、9.3和11.2个月，1年生存率分别为37.7％、40.8％、40.4％和46.8％[Liu Y,Ren Z,Yuan L,Xu S,Yao Z,Qiao L,Li K.Paclitaxel plus cisplatin vs.5-fluorouracil plus cisplatin as first-line treatment for patients with advanced squamous cell esophageal cancer.Am J Cancer Res.2016；6:2345-2350]。在一项比较EOX方案和EOX+帕尼单抗的随机对照3期研究(REAL-3)中，帕尼单抗未能延长生存。275名受试者分配进入EOX治疗组，其中食管癌的比例为40％，腺癌的比例为99％。EOX治疗组的总生存时间为11.3个月。一项在一线食管鳞癌中研究多西他赛联合顺铂疗效的II期临床研究中，入组了39名受试者，客观缓解率为33.33％，无疾病进展期为5个月，总生存为8.5个月[Waddell T,Chau I,Cunningham D,Gonzalez D,Okines AFC,Wotherspoon A,et al.Epirubicin,oxaliplatin,and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer(REAL3):a randomised,open-label phase 3trial.The Lancet Oncology 2013,14:481-489.]。一项在晚期食管癌评估紫杉醇联合顺铂、5-氟尿嘧啶疗效的单臂II期临床研究中，入组61名受试者，其中鳞癌为30名，ORR为48％(腺癌48％，鳞癌50％)，OS为10.8个月[Ilson DH,Ajani J,Bhalla K,Forastiere A,Huang Y,Patel P,et al.Phase II trial of paclitaxel,fluorouracil,and cisplatin in patients with advanced carcinoma of the esophagus.J Clin Oncol 1998,16:1826-1834]。一项在一线食管鳞癌中比较顺铂联合5-氟尿嘧啶对比顺铂联合5-氟尿嘧啶、西妥昔单抗的随机对照研究中，30名受试者接受顺铂联合5-氟尿嘧啶治疗，客观缓解率为13％，疾病控制率为57％，PFS为3.6个月，OS为5.5个月[Lorenzen S,Schuster T,Porschen R,Al-Batran SE,Hofheinz R,Thuss-Patience P,et al.Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus:a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie.Ann Oncol 2009,20:1667-1673.]。一项在中国一线食管鳞癌中评估紫杉醇联合顺铂的单臂研究中，入组39名受试者，客观缓解率为48.6％，OS为13个月[Zhang X,Shen L,Li J,Li Y,Li J,Jin M.A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol 2008,31:29-33.]。
尽管分子靶向药物显著改善了多种类型实体瘤的预后，但迄今为止没有药物在食管鳞癌中显示出明确的功效。近十年癌症免疫疗法的发展迅速，多项临床研究表明免疫检查点抑制剂和过继免疫治疗在实体瘤及血液肿瘤中的功效，在食管鳞癌中也有初步的疗效数据。
一项Pembrolizumab在至少一线系统治疗失败或不能耐受的晚期食管癌(PD-L1表达大于1％)中的Ib期临床研究中(KEYNOTE-028)，ORR为30％(95％CI，13-53)[Toshihiko Doi SAP-P,Shadia Ibrahim Jalal,Hieu Mai-Dang,Sanatan Saraf,Minori Koshiji,Ildiko Csiki,Jaafar Bennouna.Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab(MK-3475).J Clin Oncol 34,2016(suppl 4S；abstr 7)]。一项Nivolumab在至少一线系统治疗失败或不能耐受的晚期食管癌中的II期临床研究中，ORR为17.2％，mOS为12.1个月[Takashi Kojima HH,Kensei Yamaguchi,Shuichi Hironaka,Satoru Iwasa,Ken Kato,Takahiro Tsushima,Hirofumi Yasui,Takashi Ura,Kei Muro,Taroh Satoh,Yuichiro Doki,Atsushi Ohtsu,Yasuo Hamamoto,Yuko Kitagawa.Phase II study of nivolumab(ONO-4538/BMS-936558)in patients with esophageal cancer:Preliminary report of overall survival.J Clin Oncol 34,2016(suppl 4S；abstr TPS175)]。
发明内容
本申请提供包含抗PD-1抗体(例如抗PD-1单克隆抗体或其抗原结合片段)联合化疗药的药物组合及其用于预防或治疗不可切除的局部晚期、复发性或转移性食管鳞癌的用途和方法，该方法可具有较好的治疗效果。在一些实施方式中，本申请的药物组合包含：(i)抗PD-1抗体；(ii)铂类药物；以及(iii)选自紫杉烷类抗肿瘤药物和氟嘧啶类抗肿瘤药物中的至少一种。
作为优选的方案，本申请同时提供抗PD-1抗体联合顺铂+紫杉醇或顺铂+5-氟尿嘧啶两种联合治疗方案，以适应不同地区及人群的临床治疗选择，两种联合治疗方案均具有较好的治疗效果。
具体而言，本申请提供了以下实施方案：
(1)药物组合
一方面，本申请提供一种药物组合，包括抗PD-1抗体和化疗药，
抗PD-1抗体包含重链和轻链，其中所述重链包含HCDR1、HCDR2、HCDR3，所述HCDR1包含SEQ ID NO:1所示的氨基酸或由所示氨基酸序列组成；HCDR2包含SEQ ID NO:2所示的氨基酸或由所示氨基酸序列组成；HCDR3包含SEQ ID NO:3所示的氨基酸或由所示氨基酸序列组成；所述轻链包含LCDR1、LCDR2、LCDR3，所述LCDR1包含SEQ ID NO:4所示的氨基酸或由所示氨基酸序列组成；LCDR2包含SEQ ID NO:5所示的氨基酸或由所示氨基酸序列组成；LCDR3包含SEQ ID NO:6所示的氨基酸或由所示氨基酸序列组成；
-KASGGTFSSYAIS(SEQ ID NO:1)；
-LIIPMFDTAGYAQKFQG(SEQ ID NO:2)；
-ARAEHSSTGTFDY(SEQ ID NO:3)；
-RASQGISSWLA(SEQ ID NO:4)；
-SAASSLQS(SEQ ID NO:5)；
-QQANHLPFT(SEQ ID NO:6)。
在一个实施方式中，提供一种药物组合，所述药物组合包括抗PD-1抗体和化疗药，所述抗PD-1抗体包含VH、VL，其中所述VH包含SEQ ID NO:7所示的氨基酸序列，所述VL包含SEQ ID NO:8所示的氨基酸序列；在一些优选的实施方式中，所述抗PD-1抗体包含与SEQ ID NO:7所示的氨基酸序列具有至少80％(例如至少85％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％)同源性的VH；以及与SEQ ID NO:8所示的氨基酸序列具有至少80％(例如至少85％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％)同源性的VL。
Figure PCTCN2022118336-appb-000001
在一个实施方式中，提供一种药物组合，所述药物组合包括抗PD-1抗体和化疗药，所述抗PD-1抗体包含重链和轻链，其中所述重链包含SEQ ID NO:9所示的氨基酸序列，所述轻链包含SEQ ID NO:10所示 的氨基酸序列；在一些优选的实施方式中，所述抗PD-1抗体包含与SEQ ID NO:9所示的氨基酸序列具有至少80％(例如至少85％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％)同源性的重链，以及与SEQ ID NO:10所示的氨基酸序列具有至少80％(例如至少85％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％)同源性的轻链。
Figure PCTCN2022118336-appb-000002
在本文中，上述抗PD-1抗体的各种变体保留了与抗原PD-1特异性结合的能力。
在一个实施方式中，所述抗PD-1抗体为信迪利单抗。
在一个实施方式中，提供一种药物组合，所述药物组合包括抗PD-1抗体和化疗药，所述化疗药包含多种化疗方案，例如所述化疗药可为：铂类药物(例如顺铂、卡铂、奈达铂、洛铂、奥沙利铂、环硫铂)；以及选自紫杉烷类抗肿瘤药物(例如紫杉醇(包括白蛋白紫杉醇、紫杉醇脂质体)、多西他赛、卡巴它赛)和氟嘧啶类抗肿瘤药物(例如5-氟尿嘧啶、卡培他滨、替吉奥、替加氟、卡莫氟、吉西他滨、脱氧氟尿苷、双呋氟尿嘧啶)中的至少一种。在一些实施方式中，所述铂类药物为顺铂、奈达铂、奥沙利铂、或环硫铂。在一些实施方式中，所述紫杉烷类抗肿瘤药物为紫杉醇或多西他赛。在一些实施方式中，所述氟嘧啶类抗肿瘤药物为5-氟尿嘧啶、卡培他滨、替吉奥、脱氧氟尿苷、替加氟、或卡莫氟。在一些实施方式中，所述化疗药包含顺铂、以及选自紫杉醇和5-氟尿嘧啶中的至少一种。优选地，所述化疗药为紫杉醇及顺铂的联合化疗方案或5-氟尿嘧啶及顺铂的联合化疗方案。
在一些实施方式中，所述药物组合包括：抗PD-1抗体；铂类药物；以及选自紫杉烷类抗肿瘤药物和氟嘧啶类抗肿瘤药物中的至少一种。优选地，所述药物组合包括：信迪利单抗或其抗原结合片段；铂类药物；以及选自紫杉烷类抗肿瘤药物和氟嘧啶类抗肿瘤药物中的至少一种。或者优选地，所述药物组合包括：抗PD-1抗体；顺铂、奈达铂、奥沙利铂、或环硫铂；以及选自紫杉醇或多西他赛、5-氟尿嘧啶、卡培他滨、替吉奥、脱氧氟尿苷、替加氟、或卡莫氟中的至少一种。更优选地，所述药物组合包括：信迪利单抗或其抗原结合片段；顺铂、奈达铂、奥沙利铂、或环硫铂；以及选自紫杉醇或多西他赛、5-氟尿嘧啶、卡培他滨、替吉奥、脱氧氟尿苷、替加氟、或卡莫氟中的至少一种。
在一些实施方式中，所述药物组合包括抗PD-1抗体和化疗药，所述抗PD-1抗体包含重链和轻链，所述重链包含SEQ ID NO:9所示的氨基酸序列，所述轻链包含SEQ ID NO:10所示的氨基酸序列，所述化疗药包含顺铂、以及选自紫杉醇和5-氟尿嘧啶中的至少一种。在一些实施方式中，所述药物组合包含信迪利单抗或其抗原结合片段、顺铂、以及选自紫杉醇和5-氟尿嘧啶中的至少一种。在一个实施方式中，所述药物组合包含信迪利单抗或其抗原结合片段、顺铂以及紫杉醇。在另一个实施方式中，所述药物组合物包含信迪利单抗或其抗原结合片段、顺铂以及5-氟尿嘧啶。
在一个实施方案中，提供一种药物组合，所述药物组合包括抗PD-1抗体和化疗药，所述抗PD-1抗体和化疗药分开、同时或依次使用。在本文中，所述抗PD-1抗体和化疗药可各自分开包装，并且可具有本领域的常规剂型，例如注射剂、口服剂型(例如片剂、胶囊剂、锭剂、散剂、混悬剂)等。
在另一个实施方式中，提供一种药物组合，所述药物组合用于预防或治疗个体肿瘤疾病，所述肿瘤是食管癌，优选地，所述食管癌是食管鳞癌，更优选地，所述食管鳞癌是不可切除的、局部晚期复发性或转移性食管鳞癌。在一些实施方式中，用于预防或治疗肿瘤的药物组合的组成如上文所定义。
在一些实施方式中，所述个体是哺乳动物。在优选的实施方案中，所述个体为人。
在本文中，上述各实施方式中的特征之间可以任意组合，由此得到的各种技术方案也均落在本申请的保护范围内。
(2)成套药盒
在一个实施方式中，提供一种成套药盒，其中包含有效量的抗PD-1抗体，和有效量的化疗药；优选地，还包含包装插页，其印有关于在个体中使用抗PD-1抗体和化疗药的组合预防或治疗癌症的说明书。在此处，所述PD-1抗体如上文定义。在一些实施方式中，所述化疗药可为：铂类药物(例如顺铂、卡铂、奈达铂、洛铂、奥沙利铂、环硫铂)；以及选自紫杉烷类抗肿瘤药物(例如紫杉醇(包括白蛋白紫杉醇、紫杉醇脂质体)、多西他赛、卡巴它赛)和氟嘧啶类抗肿瘤药物(例如5-氟尿嘧啶、卡培他滨、替吉奥、替加氟、卡莫氟、吉西他滨、脱氧氟尿苷、双呋氟尿嘧啶)中的至少一种。在一些实施方式中，所述化疗药可为顺铂、以及选自紫杉醇和5-氟尿嘧啶中的至少一种的联合化疗组合，优选为紫杉醇和顺铂联合化疗组合或5-氟尿嘧啶和顺铂联合化疗组合。
在一些实施方式中，所述成套药盒包含分别单独包装的上述抗PD-1抗体和化疗药。在一些实施方式中，所述抗PD-1抗体和化疗药各自呈药物的形式。例如，上述抗PD-1抗体和化疗药可各自处于注射液或用于配制注射液的冻干粉的形式。
(3)应用
在一个实施方式中，提供一种包含抗PD-1抗体和化疗药的药物组合或其成套药盒在制备预防或治疗肿瘤疾病的药物中的用途；优选地，所述肿瘤是食管癌，更优选地，所述食管癌是食管鳞癌，更优选地，所述食管鳞癌为不可切除的、局部晚期复发性或转移性食管鳞癌。或者，在一个实施方式中，提供一种用于预防或治疗肿瘤的药物组合或成套药盒，所述药物组合或成套药盒包含抗PD-1抗体和化疗药。在此处，所述PD-1抗体和化疗药如上文定义。
(4)治疗方法
在一些实施方案中，提供一种治疗方法，包括：向有需要的个体给予有效治疗量的包含抗PD-1抗体和化疗药的药物组合。在一些实施方案中，提供一种治疗方法，包括：向有需要的个体给予有效治疗量的包含抗PD-1抗体、铂类药物、以及选自紫杉烷类抗肿瘤药物和氟嘧啶类抗肿瘤药物中的至少一种的药物组合。在一些优选的实施方案中，提供一种治疗方法，包括：向有需要的个体给予有效治疗量的包含抗PD-1抗体和化疗药的药物组合，所述化疗药为顺铂、以及选自紫杉醇和5-氟尿嘧啶中的至少一种；优选地，所述化疗药为紫杉醇和顺铂的组合、或者5-氟尿嘧啶和顺铂的组合。
在一些实施方式中，所述抗PD-1抗体的单日给药剂量为10mg-300mg(例如20mg-250mg、30mg-200mg)，或者1-5mg/kg(例如2-4mg/kg、3mg/kg)或200mg；或者，在一些实施方式中，在单个治疗周期(例如21天)中，所述抗PD-1抗体的给药剂量为10mg-300mg(例如20mg-250mg、30mg-200mg)，或者1-5mg/kg(例如2-4mg/kg、3mg/kg)或200mg。在一些实施方式中，在单个治疗周期中，给予1-2次、优选1次所述抗PD-1抗体。
在一些实施方式中，所述紫杉醇的单日给药剂量为25mg-700mg(例如42.5mg-615mg)，或者50-200mg/m 2(例如85-175mg/m 2)；或者，在一些实施方式中，在单个治疗周期(例如21天)中，所述紫杉醇的给药剂量为50mg-700mg(例如85mg-615mg)，或者100-200mg/m 2(例如175mg/m 2)。在一些实施方式中，在第1个治疗周期(例如21天)中，给予1-4次、优选1-2次所述紫杉醇，并且在第1个治疗周期之后的单个治疗周期(例如21天)中，给予1-2次、优选1次所述紫杉醇。
在一些实施方式中，所述5-氟尿嘧啶的单日给药剂量为250mg-4200mg，优选300mg-3500mg(例如350mg-3150mg、400mg-2800mg)，或者500-1200mg/m 2，优选为600-1000mg/m 2(例如，640-1000mg/m 2、700-900mg/m 2、800mg/m 2)；或者，在一些实施方式中，在单个治疗周期(例如21天)中，所述5-氟尿嘧啶的给药剂量为2500-6000mg/m 2，优选为3000-5000mg/m 2(例如3200-4000mg/m 2、3500-4500mg/m 2、4000mg/m 2)。在一些实施方式中，在单个治疗周期中，给予1-10次、优选4-6次(例如5次)所述5-氟尿嘧啶。
在一些实施方式中，所述顺铂的单日给药剂量为25mg-350mg(例如30mg-315mg、37.5mg-262.5mg)，或者50-100mg/m 2(例如60-90mg/m 2，优选为75mg/m 2)；或者，在一些实施方式中，在单个治疗周期(例如21天)中，所述顺铂的给药剂量为25mg-350mg(例如30mg-315mg、37.5mg-262.5mg)，或者50-100mg/m 2(例如60-90mg/m 2，优选为75mg/m 2)。在一些实施方式中，在单个治疗周期中，给予1-2次、优选1次所述顺铂。
在一些实施方式中，所述抗PD-1抗体在每个治疗周期(例如21天)的第一天给药一次；所述紫杉醇在第一个治疗周期(例如21天)的第一天和第八天分别给药一次，并在第二治疗周期及之后的各治疗周期中的每个治疗周期(例如21天)的第一天给药一次；所述5-氟尿嘧啶在每个治疗周期(例如21天)的第一天到第五天每天一次持续给药24小时；所述顺铂在每个治疗周期(例如21天)的第一天给药一次。
在一些实施方式中，所述抗PD-1抗体在每个治疗周期(例如21天)的第一天给药一次，给药剂量为20mg-250mg(例如30mg-200mg)或者3mg/kg(优选地，对体重<60kg的个体而言，给药剂量为3mg/kg； 且对体重≥60kg的个体而言，给药剂量为200mg)；
所述紫杉醇在第一个治疗周期(例如21天)的第一天和第八天分别给药一次，每次的给药剂量为43.5mg-306.5mg或者87.5mg/m 2，并在第二治疗周期及之后的各治疗周期中的每个治疗周期(例如21天)的第一天给药一次，给药剂量为87.5mg-615mg或者175mg/m 2；
所述5-氟尿嘧啶在每个治疗周期(例如21天)的第一天到第五天每天一次持续给药24小时，每次的给药剂量为400mg-2800mg或者800mg/(m 2·d)；
所述顺铂在每个治疗周期(例如21天)的第一天给药一次，给药剂量为37.5mg-262.5mg或者75mg/m 2。
在一个实施方案中，提供一种治疗方法，其中，使用有效治疗量的抗PD-1抗体和化疗药，所述化疗药为紫杉醇和顺铂联合化疗组合或5-氟尿嘧啶和顺铂联合化疗组合；所述抗PD-1抗体单次给药100-300mg或1-5mg/kg，优选为200mg或3mg/kg，所述紫杉醇单次给药120-200mg/m 2，优选为175mg/m 2，所述5-氟尿嘧啶单次给药3000-5000mg/m 2，优选为4000mg/m 2，所述顺铂单次给药60-90mg/m 2，优选为75mg/m 2。在此处，“单次给药”的量是指单个治疗周期内的给药累积量。
在此处，所述PD-1抗体如上文定义，并且所述铂类药物、紫杉烷类抗肿瘤药物和氟嘧啶类抗肿瘤药物同样如上文定义。
在另一个实施方案中，提供一种治疗方法，其中，所述抗PD-1抗体单次给药200mg或3mg/kg，所述紫杉醇单次给药175mg/m 2，所述5-氟尿嘧啶单次给药4000mg/m 2，所述顺铂单次给药75mg/m 2。
在另一个实施方案中，提供一种治疗方法，其中，所述抗PD-1抗体，每三周为一个周期，每周期给药一次，每周期第一天给药；所述紫杉醇，每三周为一个周期，第一周期给药两次，每周期第一天、第八天给药，第二周期及之后周期，每周期给药一次，每周期第一天给药；所述5-氟尿嘧啶每三周为一个周期，每周期第一到五天每天24小时持续给药；所述顺铂，每三周为一个周期，每周期给药一次，每周期第一天给药。
在另一个实施方案中，提供一种治疗方法，其中，所述抗PD-1抗体每周期给药200mg或3mg/kg；所述紫杉醇第一周期给药两次，每次给药87.5mg/m 2，第二周期及之后周期，每周期给药一次，每周期给药175mg/m 2；所述5-氟尿嘧啶每周期给药4000mg/m 2，所述顺铂每周期给药75mg/m 2。
在另一个实施方式中，提供一种治疗方法，其中，所述肿瘤为食管癌，优选为食管鳞癌，更优选地，所述食管鳞癌为不可切除的、局部晚期复发性或转移性食管鳞癌。
在本文中，可通过常规给药途径给予所述抗PD-1抗体和化疗药，例如，可通过口服、胃肠外给予等方式给予。
在本文中，上述各个方面中的实施方式之间或实施方式中的特征之间可以任意组合，并且由此得到的技术方案也落在本申请的保护范围内。
定义
如本文所用，术语“和/或”是指可选项中的任一项或可选项的两项或更多项，即，其表示可选项中的至少一项。
如本文所用，术语“包含”或“包括”或者其等同物是指包括所述的要素、整数或步骤，但是不排除任意其它要素、整数或步骤。在本文中，当使用术语“包含”或“包括”时，除非另有指明，否则也涵盖由所述及的要素、整数或步骤组成的情形。例如，当提及“包含”某个具体序列的抗体可变区时，也旨在涵盖由该具体序列组成的抗体可变区的情形。
“个体”包括哺乳动物。哺乳动物包括但不限于家养动物(例如，牛、羊、猫、狗和马)、灵长类动物(例如，人和非人灵长类动物如猴)、兔、以及啮齿类动物(例如，小鼠和大鼠)。在一些实施方案中，个体是人，包括儿童、青少年或成人。在本文中，术语“个体”还可被称为“受试者”、“患者”。
用于本文时，“治疗”指减缓、中断、阻滞、缓解、停止、降低、或逆转已存在的症状、病症、病况或疾病的进展或严重性。
用于本文时，“预防”包括对疾病或病症或特定疾病或病症的症状的发生或发展的抑制。在一些实施方式中，具有家族病史的个体是预防性方案的候选。通常，术语“预防”是指在病征或症状发生前，特别是在具有风险的个体中发生前的药物施用。
术语“有效量”指本申请的制剂或组合物的量或剂量，其以单一或多次剂量施用患者后，在治疗的患者中产生预期效果。有效量可以由作为本领域技术人员的主治医师通过考虑以下多种因素来容易地确定：诸如哺乳动物的物种；它的大小、年龄和一般健康；涉及的具体疾病；疾病的程度或严重性；个体患者的应答；施用的具体抗体；施用模式；施用制剂的生物利用率特征；选择的给药方案；和任何伴随疗法的使用。
“治疗有效量”指以需要的剂量并持续需要的时间段，有效实现所需治疗结果的量。本申请的制剂、抗体或抗体片段或其缀合物或组合物的治疗有效量可以根据多种因素如疾病状态、个体的年龄、性别和重量和抗体或抗体部分在个体中激发所需反应的能力而变动。治疗有效量也是这样的一个量，其中制剂、抗体或抗体片段或其缀合物或组合物的任何有毒或有害作用不及治疗有益作用。
术语“约”在与数字数值联合使用时意为涵盖具有比指定数字数值小10％的下限和比指定数字数值大10％的上限的范围内的数字数值。
除非另有说明，如本文所用，术语“抗PD-1抗体”涵盖单克隆抗体、多克隆抗体或其抗原结合片段(该片段保留了相应的完整抗体所具有的特异性地结合至抗原的能力)，优选抗PD-1单克隆抗体或其抗原结合片段。
除非另有说明，在本文中，单数术语涵盖复数术语，反之亦然。
缩略语
Figure PCTCN2022118336-appb-000003
具体实施方式
下面将通过实施例对本申请进行更详细的说明，但是本领域技术人员将理解的是，本申请的保护范围不限于此。
①受试药物
抗PD-1抗体：信迪利单抗注射液，信达生物制药(苏州)有限公司，10mL:100mg。
安慰剂：甘露醇、组氨酸、枸橼酸钠(二水)、氯化钠、依地酸二钠、聚山梨酯80、枸橼酸(一水)、注射用水。
顺铂：10mg或20mg的多剂量瓶装，厂家：齐鲁制药有限公司/Intas Pharmaceuticals India Limited/Intas Pharma India BG不限。
紫杉醇：5mL:30mg、25mL:150mg，厂家：海口市制药厂有限公司/江苏奥赛康药业股份有限公司/EBEWE Pharma不限。
5-氟尿嘧啶：针剂：每只125mg(5mL)、250mg(10mL)，厂家：天津金耀药业有限公司/Accord Healthcare,Inc./Intas Pharma India BG不限。
②受试者入选标准
评估信迪利单抗或安慰剂联合化疗一线治疗不可切除的、局部晚期复发性或转移性食管鳞癌的有效性和安全性的随机、双盲、多中心、III期研究
1)年龄≥18周岁。
2)ECOG PS评分为0或1分。
3)受试者必须不适合接受根治性治疗方法，如根治性化放疗和/或手术；对于既往接受(新)辅助化疗/辅助(放)化疗/根治性放化疗的患者，末次治疗至疾病复发时间＞6个月。
4)能提供存档病理组织或新鲜病理组织用于PD-L1检测并能获得检测结果。
5)根据RECIST1.1版标准至少有一个可测量病灶。
6)具有充分的器官和骨髓功能。
③治疗方案
本研究中研究药物定义为信迪利单抗、安慰剂、紫杉醇、5-氟尿嘧啶和顺铂。研究药物的首次给药应在随机分组当日(第1周期，第1天)开始，但不能晚于随机分组日期48小时，超出48小时仍未用药需与申办方讨论。应尽所有努力在随机分组当日开始试验治疗。对于所有其它研究治疗周期，如遇节假日或者受试者因非安全性的其它原因无法前往中心，可顺延不超过一周给药。具体剂量及治疗方案见表1。
表1.剂量和治疗方案
Figure PCTCN2022118336-appb-000004
备注：
1.信迪利单抗/安慰剂应在化疗药物给药之前输注，信迪利单抗/安慰剂在体重＜60kg时均按照每次实际体重计算用量。信迪利单抗/安慰剂输注结束距化疗药物开始输注至少间隔1小时。
2.紫杉醇第一周期使用方法为：87.5mg/m 2IV D1,8 Q3W，第二周期开始每周期第1天给药：175mg/m 2IV D1 Q3W。
3.如果受试者的体重相对于基线(首剂研究治疗日)体重波动小于10％，则基线体重被用来计算体表面积，据此计算化疗药物给药量。反之，则按计划给药当日的实际体重计算化疗药物给药量。为了方便给药，方案允许计算的每次输注总剂量有±5％的偏差。
4. 5-氟尿嘧啶的单个周期累积剂量为4000mg/m 2，也可采用其它临床可接受的给药方式，如在第1-4天给予1000mg/(m 2·d)。单个周期累积给药时间可以允许有20％的调整范围(即持续给药4-6天)。如有必要，允许研究者根据受试者的耐受性，单个周期累积剂量在3200-4000mg/m 2之间进行调整。
④实验结果
Figure PCTCN2022118336-appb-000005
备注：
1.Sin指信迪利单抗；
2.Chemo指化疗药，具体为紫杉醇+顺铂或顺铂+5-氟尿嘧啶，临床上选择其中一种组合给药。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本文中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
本领域技术人员将认识到，本公开的范围并不限于上文描述的各种具体实施方式和实施例，而是能够在不脱离本公开的精神和构思的情况下，进行各种修改、替换、或重新组合，这都落入了本公开的保护范围内。

Claims (27)

  1. 一种药物组合，包括抗PD-1抗体和化疗药，抗PD-1抗体包含重链和轻链，其中所述重链包含HCDR1、HCDR2、HCDR3，所述HCDR1包含SEQ ID NO:1所示的氨基酸或由所示氨基酸序列组成；HCDR2包含SEQ ID NO:2所示的氨基酸或由所示氨基酸序列组成；HCDR3包含SEQ ID NO:3所示的氨基酸或由所示氨基酸序列组成；所述轻链包含LCDR1、LCDR2、LCDR3，所述LCDR1包含SEQ ID NO:4所示的氨基酸或由所示氨基酸序列组成；LCDR2包含SEQ ID NO:5所示的氨基酸或由所示氨基酸序列组成；LCDR3包含SEQ ID NO:6所示的氨基酸或由所示氨基酸序列组成。
  2. 根据权利要求1所述的药物组合，所述的抗PD-1抗体包含VH、VL，其中所述VH包含SEQ ID NO:7所示的氨基酸序列，所述VL包含SEQ ID NO:8所示的氨基酸序列。
  3. 根据权利要求1-2任一所述的药物组合，所述的抗PD-1抗体包含重链和轻链，其中所述重链包含SEQ ID NO:9所示的氨基酸序列或与其具有至少80％同源性的氨基酸序列，所述轻链包含SEQ ID NO:10所示的氨基酸序列或与其具有至少80％同源性的氨基酸序列。
  4. 根据权利要求1-3任一所述的药物组合，其中，所述的化疗药包含铂类药物、以及选自紫杉烷类抗肿瘤药物和氟嘧啶类抗肿瘤药物中的至少一种。
  5. 根据权利要求4所述的药物组合，其中，铂类药物为顺铂、卡铂、奈达铂、洛铂、奥沙利铂或环硫铂；所述紫杉烷类抗肿瘤药物为紫杉醇、多西他赛、或卡巴它赛；所述氟嘧啶类抗肿瘤药物为5-氟尿嘧啶、卡培他滨、替吉奥、替加氟、卡莫氟、吉西他滨、脱氧氟尿苷、或双呋氟尿嘧啶。
  6. 根据权利要求1-5任一所述的药物组合，所述的化疗药包含顺铂、以及选自紫杉醇和5-氟尿嘧啶中的至少一种，优选包含紫杉醇及顺铂的化疗组合或5-氟尿嘧啶及顺铂的化疗组合。
  7. 根据权利要求1-6任一所述的药物组合，其中，所述抗PD-1抗体包含重链和轻链，所述重链包含SEQ ID NO:9所示的氨基酸序列或与其具有至少80％同源性的氨基酸序列，所述轻链包含SEQ ID NO:10所示的氨基酸序列或与其具有至少80％同源性的氨基酸序列，并且
    所述化疗药包含顺铂、以及选自紫杉醇和5-氟尿嘧啶中的至少一种。
  8. 根据权利要求1-7任一所述的药物组合，所述抗PD-1抗体和化疗药分开、同时或依次使用。
  9. 根据权利要求1-8任一所述的药物组合，所述组合用于预防或治疗个体肿瘤疾病，所述肿瘤是食管癌，优选地，所述食管癌是食管鳞癌，更优选地，所述食管鳞癌是不可切除的、局部晚期复发性或转移性食管鳞癌。
  10. 根据权利要求9所述的药物组合，所述的个体是哺乳动物，优选人。
  11. 一种成套药盒，其中包含有效量的抗PD-1抗体和有效量的化疗药；优选地，还包含包装插页，其印有关于在个体中使用抗PD-1抗体和化疗药的组合预防或治疗癌症的说明书；优选地，所述化疗药包含铂类药物、以及选自紫杉烷类抗肿瘤药物和氟嘧啶类抗肿瘤药物中的至少一种，优选地，铂类药物为顺铂、卡铂、奈达铂、洛铂、奥沙利铂或环硫铂；所述紫杉烷类抗肿瘤药物为紫杉醇、多西他赛、或卡巴它赛；所述氟嘧啶类抗肿瘤药物为5-氟尿嘧啶、卡培他滨、替吉奥、替加氟、卡莫氟、吉西他滨、脱氧氟尿苷、或双呋氟尿嘧啶；更优选地，所述化疗药包含顺铂、以及选自紫杉醇和5-氟尿嘧啶中的至少一种，或者所述化疗药为紫杉醇和顺铂联合化疗组合或5-氟尿嘧啶和顺铂联合化疗组合。
  12. 根据权利要求1-10任一所述的药物组合或权利要求11所述的成套药盒在制备预防或治疗肿瘤疾病的药物中的用途；优选地，所述肿瘤是食管癌，更优选地，所述食管癌是食管鳞癌，更优选地，所述食管鳞癌为不可切除的、局部晚期复发性或转移性食管鳞癌。
  13. 用于预防或治疗肿瘤的权利要求1-10任一所述的药物组合或权利要求11所述的成套药盒；优选地，所述肿瘤是食管癌，更优选地，所述食管癌是食管鳞癌，更优选地，所述食管鳞癌为不可切除的、局部晚期复发性或转移性食管鳞癌。
  14. 一种预防或治疗肿瘤的方法，包括向所述个体施用有效治疗量的抗PD-1抗体及有效治疗量的化疗药，所述化疗药为紫杉醇和顺铂联合化疗组合或5-氟尿嘧啶和顺铂联合化疗组合；所述抗PD-1抗体单次给药100-300mg或1-5mg/kg，所述紫杉醇单次给药120-200mg/m 2，所述5-氟尿嘧啶单次给药3000-5000mg/m 2，所述顺铂单次给药60-90mg/m 2。
  15. 根据权利要求14所述的治疗方法，其中，所述抗PD-1抗体单次给药200mg或3mg/kg，所述紫杉醇单次给药175mg/m 2，所述5-氟尿嘧啶单次给药4000mg/m 2，所述顺铂单次给药75mg/m 2。
  16. 根据权利要求14或15所述的治疗方法，其中，所述抗PD-1抗体，每三周为一个周期，每周期给药一次，每周期第一天给药；所述紫杉醇，每三周为一个周期，第一周期给药两次，每周期第一天、第八天给 药，第二周期及之后周期，每周期给药一次，每周期第一天给药；所述5-氟尿嘧啶每三周为一个周期，每周期第一到五天每天24小时持续给药，所述顺铂，每三周为一个周期，每周期给药一次，每周期第一天给药。
  17. 根据权利要求14-16任一所述的治疗方法，其中，所述抗PD-1抗体每周期给药200mg或3mg/kg；所述紫杉醇第一周期给药两次，每次给药87.5mg/m 2，第二周期及之后周期，每周期给药一次，每周期给药175mg/m 2；所述5-氟尿嘧啶每周期给药4000mg/m 2，所述顺铂每周期给药75mg/m 2。
  18. 根据权利要求14-17任一所述的治疗方法，其中，所述肿瘤为食管癌，优选为食管鳞癌，更优选地，所述食管鳞癌为不可切除的、局部晚期复发性或转移性食管鳞癌。
  19. 一种预防或治疗肿瘤的方法，包括向有需要的个体给予有效治疗量的包含抗PD-1抗体和化疗药的药物组合。
  20. 根据权利要求19所述的方法，其中，所述化疗药包含铂类药物、以及选自紫杉烷类抗肿瘤药物和氟嘧啶类抗肿瘤药物中的至少一种；优选地，所述铂类药物为顺铂、卡铂、奈达铂、洛铂、奥沙利铂或环硫铂；所述紫杉烷类抗肿瘤药物为紫杉醇、多西他赛、或卡巴它赛；所述氟嘧啶类抗肿瘤药物为5-氟尿嘧啶、卡培他滨、替吉奥、替加氟、卡莫氟、吉西他滨、脱氧氟尿苷、或双呋氟尿嘧啶；更优选地，所述化疗药包含顺铂、以及选自紫杉醇和5-氟尿嘧啶中的至少一种，或者所述化疗药为紫杉醇和顺铂的组合、或者5-氟尿嘧啶和顺铂的组合。
  21. 根据权利要求19或20所述的方法，其中，所述抗PD-1抗体的单日给药剂量为10mg-300mg，或者1-5mg/kg；或者，在单个治疗周期中，所述抗PD-1抗体的给药剂量为10mg-300mg，或者1-5mg/kg，优选在单个治疗周期中，给予1-2次所述抗PD-1抗体。
  22. 根据权利要求20或21所述的方法，其中，所述紫杉醇的单日给药剂量为25mg-700mg，或者50-200mg/m 2；或者，在单个治疗周期中，所述紫杉醇的给药剂量为50mg-700mg，或者100-200mg/m 2，优选在第1个治疗周期中，给予1-4次所述紫杉醇，并且在第1个治疗周期之后的单个治疗周期中，给予1-2次所述紫杉醇。
  23. 根据权利要求20-22任一所述的方法，其中，所述5-氟尿嘧啶的单日给药剂量为250mg-4200mg，或者500-1200mg/m 2；或者，在单个治疗周期中，所述5-氟尿嘧啶的给药剂量为2500-6000mg/m 2，优选在单个治疗周期中，给予1-10次所述5-氟尿嘧啶。
  24. 根据权利要求20-23任一所述的方法，其中，所述顺铂的单日给药剂量为25mg-350mg，或者50-100mg/m 2；或者，在单个治疗周期中，所述顺铂的给药剂量为25mg-350mg，或者50-100mg/m 2，优选在单个治疗周期中，给予1-2次所述顺铂。
  25. 根据权利要求20-24任一所述的方法，所述抗PD-1抗体在每个治疗周期的第一天给药一次；所述紫杉醇在第一个治疗周期的第一天和第八天分别给药一次，并在第二治疗周期及之后的各治疗周期中的每个治疗周期的第一天给药一次；所述5-氟尿嘧啶在每个治疗周期的第一天到第五天每天一次持续给药24小时；所述顺铂在每个治疗周期的第一天给药一次。
  26. 根据权利要求20-25任一所述的方法，其中，所述抗PD-1抗体在每个治疗周期的第一天给药一次，给药剂量为20mg-250mg或者3mg/kg；
    所述紫杉醇在第一个治疗周期的第一天和第八天分别给药一次，每次的给药剂量为43.5mg-306.5mg或者87.5mg/m 2，并在第二治疗周期及之后的各治疗周期中的每个治疗周期的第一天给药一次，给药剂量为87.5mg-615mg或者175mg/m 2；
    所述5-氟尿嘧啶在每个治疗周期的第一天到第五天每天一次持续给药24小时，每次的给药剂量为400mg-2800mg或者800mg/(m 2·d)；
    所述顺铂在每个治疗周期的第一天给药一次，给药剂量为37.5mg-262.5mg或者75mg/m 2。
  27. 根据权利要求21-26任一所述的方法，其中，每个所述治疗周期为21天。
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