WO2020233723A1 - 用于治疗头颈癌的喹啉衍生物 - Google Patents

用于治疗头颈癌的喹啉衍生物 Download PDF

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WO2020233723A1
WO2020233723A1 PCT/CN2020/092125 CN2020092125W WO2020233723A1 WO 2020233723 A1 WO2020233723 A1 WO 2020233723A1 CN 2020092125 W CN2020092125 W CN 2020092125W WO 2020233723 A1 WO2020233723 A1 WO 2020233723A1
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cancer
head
carcinoma
drug
compound
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PCT/CN2020/092125
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English (en)
French (fr)
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王善春
张彬
王伟锋
徐萍
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正大天晴药业集团股份有限公司
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Priority to US17/613,332 priority Critical patent/US20220211694A1/en
Priority to CA3141174A priority patent/CA3141174A1/en
Priority to EP20808747.8A priority patent/EP3973963A4/en
Priority to AU2020278733A priority patent/AU2020278733A1/en
Priority to CN202080031678.XA priority patent/CN113766917A/zh
Publication of WO2020233723A1 publication Critical patent/WO2020233723A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152

Definitions

  • This application belongs to the field of medical technology, and this application relates to the use of quinoline derivatives for anti-tumor. Specifically, this application relates to a quinoline derivative for the treatment of head and neck cancer, a pharmaceutical composition thereof combined with a second therapeutic drug, and its use for the treatment of head and neck cancer.
  • Head and Neck Cancers refer to other malignant tumors located in the head and neck area except brain cancer.
  • Oral cancer and nasopharyngeal cancer are more common, in addition to oropharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, sinus cancer, salivary gland cancer and so on.
  • Common parts of head and neck cancer include the mouth, nose, throat, sinuses, salivary glands, and throat.
  • the symptoms of head and neck cancer include unhealed sores or lumps, persistent sore throat, difficulty swallowing, or changes in voice. If there is abnormal bleeding, facial swelling, or breathing difficulties, it may also be head and neck cancer.
  • head and neck cancer In 2015, 5.5 million people worldwide suffered from head and neck cancer (2.4 million in the oral cavity, 1.7 million in the throat, and 1.4 million in the throat), resulting in more than 379,000 deaths (146,000 of oral cavity, 127,400 of larynx, 105,900 of throat).
  • head and neck cancer is the seventh most common cancer and the ninth most common cause of cancer death.
  • About 1% of people in the United States have suffered from head and neck cancer.
  • the number of men suffering from head and neck cancer is twice that of women, and it is common in adults between 55 and 65. In developed countries, the average five-year survival rate after diagnosis is 42-64%.
  • Nasopharyngeal carcinoma is a malignant tumor that occurs on the top and side walls of the nasopharyngeal cavity. It is one of the most common malignant tumors in China, and the incidence is the first among malignant tumors of the ear, nose, and throat.
  • the WHO pathological classification of nasopharyngeal carcinoma mainly includes the following types: type I keratinizing squamous cell carcinoma and type II non-keratinizing squamous cell carcinoma. The second type is divided into differentiated and undifferentiated carcinoma. Epidemiological data show that 98% of patients with nasopharyngeal carcinoma in high-risk areas are type II, and only 2% are type I.
  • this application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of head and neck cancer.
  • the application also provides a method for treating head and neck cancer, which comprises administering Compound I or a pharmaceutically acceptable salt thereof to a subject.
  • the application also provides the use of Compound I or a pharmaceutically acceptable salt thereof for the treatment of head and neck cancer.
  • this application provides a combination pharmaceutical composition for the treatment of head and neck cancer, which comprises: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic drug.
  • this application also provides the use of the pharmaceutical composition in the preparation of drugs for the treatment of head and neck cancer.
  • the application also provides the use of the pharmaceutical composition for treating head and neck cancer.
  • the application also provides a method for treating head and neck cancer, which includes administering the pharmaceutical composition of the application to a subject.
  • the pharmaceutical composition includes: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic drug.
  • this application provides the use of therapeutic compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of head and neck cancer
  • the head and neck cancer is head and neck squamous cell carcinoma.
  • the head and neck cancer is head and neck adenocarcinoma.
  • the head and neck cancer includes, but is not limited to, neck tumors, ENT tumors, and oral and maxillofacial tumors.
  • the head and neck cancer includes, but is not limited to, oral cancer, laryngeal cancer, parotid gland cancer, nasal cavity cancer, paranasal sinus cancer, paranasal sinus cancer, oropharyngeal cancer, oral floor cancer, hypopharyngeal cancer, palate cancer, gums Cancer, tongue cancer, tongue mucosal squamous cell carcinoma, buccal mucosal cancer, lip cancer, salivary gland cancer, tonsil cancer, etc.
  • the head and neck adenocarcinoma includes but not limited to mucoepidermoid carcinoma, adenoid cystic carcinoma, lymphoepithelial carcinoma, pleomorphic adenocarcinoma, salivary duct carcinoma , Myoepithelial carcinoma, non-specific adenocarcinoma, non-specific clear cell carcinoma, cystadenocarcinoma, sebaceous adenocarcinoma, sebaceous lymphatic adenocarcinoma, mucinous adenocarcinoma, epithelial-myoepithelial carcinoma.
  • this application provides a combination pharmaceutical composition for the treatment of head and neck cancer, which includes (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic drug.
  • the combination pharmaceutical composition includes: (i) a pharmaceutical composition of Compound I or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutical combination of at least one second therapeutic drug Things.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one chemotherapeutic drug, And optionally combined with radiotherapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer is provided, which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one small molecule target To anti-tumor drugs, and optionally combined with radiation therapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one immunotherapy drug , And optionally combined with radiation therapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one macromolecular antibody Drugs, and optionally combined with radiation therapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) platinum-based drugs, and any Select the place to combine with radiotherapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) a platinum-based drug and At least one of a fluoropyrimidine derivative and an anti-PD-1 antibody, and optionally combined with radiotherapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) platinum drugs and cetyl Ciximab, and optionally in combination with radiation therapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) gemcitabine and platinum drugs, And optionally combined with radiotherapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) gemcitabine and cisplatin, and Optionally combined with radiotherapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) a fluoropyrimidine derivative and violet At least one of the firs, and optionally combined with radiotherapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) gemcitabine and paclitaxel, and any Select the place to combine with radiotherapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) cisplatin and 5-fluorouracil , And optionally combined with radiation therapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) sintilizumab, And optionally combined with radiotherapy.
  • a combination pharmaceutical composition for the treatment of head and neck cancer which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) capecitabine, and Optionally combined with radiotherapy.
  • this application provides the use of a pharmaceutical composition in the preparation of a medicament for the treatment of head and neck cancer, which comprises: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one The second therapeutic agent, and optionally combined with radiation therapy.
  • the application also provides a method for treating head and neck cancer, which includes administering the pharmaceutical composition of the application to a subject.
  • the pharmaceutical composition includes: (i) Compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one second therapeutic drug.
  • This application provides a method for treating patients suffering from head and neck cancer.
  • the patient has previously received surgery, chemotherapy, and/or radiation therapy.
  • the patient recurs disease progression after achieving complete remission after surgery, chemotherapy, and/or radiotherapy.
  • the patient fails to achieve complete or partial relief after surgery, chemotherapy, and/or radiation therapy.
  • This application provides a method for treating head and neck cancer, which comprises administering Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic drug to a patient in need of treatment.
  • the application provides a method for treating head and neck cancer that has not received chemotherapy drugs, the method comprising administering Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, and at least one second medicine.
  • the application provides a method for head and neck cancer that has previously received at least one chemotherapeutic agent, the method comprising administering Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, and at least one A second treatment drug.
  • the present application provides a method for treating head and neck cancer that has failed second-line and second-line treatment, the method comprising administering Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, and at least one 2.
  • Therapeutic drugs In one embodiment, the present application provides a method for treating refractory relapsed head and neck cancer, the method comprising administering Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, and at least one second treatment drug.
  • the compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic drug are used in combination to treat primary head and neck cancer or secondary head and neck cancer.
  • the head and neck cancer is a head and neck cancer that cannot tolerate chemotherapy.
  • the patient has not previously received systemic chemotherapy.
  • the patient has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • the patient has not previously received systemic chemotherapy, but has received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • the patient undergoes surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy, and disease progression occurs again after complete remission.
  • the patient fails to complete or partially relieve after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • the cancer metastasizes after the patient undergoes surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.
  • the second therapeutic drug may be daily (qd), every other day (qod), every 3 days (q3d), every 4 days (q4d) ), every 5 days (q5d), every week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) once, twice, three times or four times, such as daily Two times (bid), twice a week (biw), three times a day (tid), four times a day (qid), etc.
  • the second therapeutic drug in the use or treatment method, may also be administered in an interval administration manner.
  • the intermittent administration includes a dosing period and a drug withdrawal period.
  • the second therapeutic drug is given every day during the drug administration period, and then the drug administration is stopped for a period of time during the drug withdrawal period, followed by the dosing period, and then the drug withdrawal period. It can be repeated many times.
  • the compound I or a pharmaceutically acceptable salt thereof in the use or treatment method, including but not limited to, can be administered at a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for continuous administration 2 Weeks, one-week off regimen; and/or, two-week continuous medication, two-week off regimen.
  • the second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof have the same or different treatment cycles, respectively. In some specific embodiments, the second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle. In some specific embodiments, the second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof are treated every 3 weeks.
  • the present application provides a combination pharmaceutical composition, which is a formulation suitable for administration within a single treatment cycle (for example, a treatment cycle of 3 weeks), including 84-168 mg, preferably 112-168 mg Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic agent.
  • Compound I or a pharmaceutically acceptable salt thereof can be separately packaged in multiple equal parts (for example, 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts or more).
  • kits for the treatment of head and neck cancer includes Compound I or a pharmaceutically acceptable salt thereof and at least one second therapeutic drug in a separate package, and optional instructions.
  • the compound I or its pharmaceutically acceptable salt and the combination pharmaceutical composition containing compound I or its pharmaceutically acceptable salt in the present application are effective for head and neck in clinical trials.
  • the objective remission rate of human cancer patients reaches about 10% or more, preferably about 15% or more, more preferably about 20% or more, more preferably about 30% or more, especially 35% or more; disease control rate is more than 50% , Preferably up to about 60% or more, more preferably up to about 70% or more, more preferably up to about 80% or more, especially up to 90% or more.
  • the head and neck cancer is head and neck squamous cell carcinoma. In some embodiments, the head and neck cancer is head and neck adenocarcinoma. In some embodiments, the head and neck cancer includes, but is not limited to, neck tumors, ENT tumors, and oral and maxillofacial tumors.
  • the head and neck cancer includes, but is not limited to, oral cancer, laryngeal cancer, parotid gland cancer, thyroid cancer, nasopharyngeal cancer, nasal cavity cancer, sinus cancer, paranasal sinus cancer, oropharyngeal cancer, mouth floor cancer, lower Pharyngeal cancer, palate cancer, gum cancer, tongue cancer, tongue mucosal squamous cell carcinoma, buccal mucosa cancer, lip cancer, salivary gland cancer, tonsil cancer, etc.
  • Salivary gland cancer can originate from the major salivary glands (parotid, submandibular, and sublingual glands), or minor salivary glands, which are found throughout the oral cavity and the submucosa of the upper respiratory and digestive tract, including the oral cavity (especially the palate), sinuses, Throat and pharynx. Salivary gland cancer has a low incidence and is not common clinically. Its incidence is less than 5% of head and neck malignancies. The annual incidence rate reported worldwide varies from 0.3-4 new cases per 100,000 population. The experience of its treatment is mainly based on retrospective case series studies.
  • the most common malignant tumors of the salivary glands include: mucoepidermoid carcinoma, adenoid cystic carcinoma, and lymphoepithelial carcinoma.
  • Other head and neck adenocarcinomas also include pleomorphic adenocarcinoma (pleomorphic low-grade adenocarcinoma), salivary duct carcinoma, myoepithelial carcinoma (epithelial tumor), non-specific adenocarcinoma, non-specific clear cell carcinoma, cyst gland Carcinoma, sebaceous adenocarcinoma, sebaceous lymphatic adenocarcinoma, mucinous adenocarcinoma, epithelial-myoepithelial carcinoma (epithelial tumor).
  • Nasal cavity and paranasal sinus adenocarcinoma may be similar to ordinary salivary gland tumors, serous mucinous tumors, intestinal-type differentiated tumors and other rare variants.
  • the head and neck cancer is occult cancer or head and neck cancer with unknown primary focus.
  • the clinical stages of the head and neck cancer include, but are not limited to, locally advanced and/or advanced (for example, stage IIIB/IV) head and neck cancer.
  • the head and neck cancer is metastatic head and neck cancer.
  • metastatic head and neck cancers include, but are not limited to, distant metastases, single lesions, disseminated metastases, and diffuse metastases; the metastatic lesions include, but are not limited to, lungs, lymph nodes, pleura, bone, brain, pericardium, and adrenal glands. ,liver.
  • the head and neck cancer is head and neck cancer with brain metastases.
  • the head and neck cancer is a head and neck cancer with lymph node metastasis.
  • the head and neck cancer is recurrent; in some embodiments, the head and neck cancer is refractory; in some embodiments, the head and neck cancer is intractable Excised. In some embodiments, the head and neck cancer is head and neck cancer that has failed treatment with chemotherapeutic drugs and/or targeted drugs. In some embodiments, the head and neck cancer is a head and neck cancer that has received at least two chemotherapy drugs. In some embodiments, the head and neck cancer is a head and neck cancer that has failed second-line and higher-line chemotherapy.
  • the head and neck cancer is a refractory and relapsed head and neck cancer
  • the "refractory and relapsed head and neck cancer” refers to a head and neck cancer that has not been remitted by chemotherapy, and chemotherapy is effective but is effective after chemotherapy. Head and neck cancer that progressed within months.
  • the nasopharyngeal carcinoma includes, but is not limited to, keratinizing squamous cell carcinoma and non-keratinizing carcinoma.
  • the non-keratinizing nasopharyngeal carcinoma may include differentiated or undifferentiated, such as nasopharyngeal apex Undifferentiated non-keratinizing carcinoma of the posterior wall.
  • the nasopharyngeal carcinoma includes but is not limited to nasopharyngeal carcinoma in situ and invasive nasopharyngeal carcinoma.
  • the invasive nasopharyngeal carcinoma includes but is not limited to squamous cell carcinoma (including high, medium, and poorly differentiated), adenocarcinoma (including high, medium, and poorly differentiated), microinvasive carcinoma, and alveolar cell nuclear carcinoma Or undifferentiated nasopharyngeal carcinoma.
  • the adenocarcinoma includes papillary adenocarcinoma or columnar cell adenocarcinoma.
  • the clinical stages of nasopharyngeal carcinoma include but are not limited to: stage I, stage II, stage III, stage IVa, stage IVb, such as T1N0M0, T2N0-1M0, T0-2N1M0, T3N0-2M0, T0 ⁇ 3N1M0, T4N0 ⁇ 3M0, T0 ⁇ 4N3M0, or any T, any N, M1.
  • the nasopharyngeal carcinoma is type I keratinizing squamous cell carcinoma. In some embodiments, the nasopharyngeal carcinoma is type II non-keratinizing squamous cell carcinoma. In some embodiments, the nasopharyngeal carcinoma is type II undifferentiated non-keratinizing squamous cell carcinoma. In some embodiments, the nasopharyngeal carcinoma is type II differentiated non-keratinizing squamous cell carcinoma.
  • the nasopharyngeal carcinoma is metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and/or refractory and/or advanced nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is unresectable nasopharyngeal carcinoma; in some embodiments, the nasopharyngeal carcinoma is nasopharyngeal carcinoma that has received at least two chemotherapy drugs.
  • the chemotherapy includes first-line chemotherapy and second-line chemotherapy; including but not limited to one or more of taxanes (such as paclitaxel, docetaxel), fluorouracil, cisplatin, and cyclophosphamide.
  • taxanes such as paclitaxel, docetaxel
  • fluorouracil such as paclitaxel, docetaxel
  • cisplatin such as paclitaxel, docetaxel
  • cyclophosphamide such as paclitaxel, docetaxel
  • the patient can also receive radiotherapy simultaneously or sequentially with the chemotherapy.
  • the second therapeutic drugs described in this application include, but are not limited to, chemotherapy drugs, small molecule targeted anti-tumor drugs, immunotherapy drugs, and macromolecular antibody drugs.
  • the second therapeutic drug is a chemotherapy drug, including but not limited to platinum drugs, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, One or more of podophyllum and antimetabolites, examples that can be cited include but are not limited to platinum drugs (such as oxaliplatin, cisplatin, carboplatin, miplatin, nedaplatin, bicycloplatin ( dicycloplatin), Lobaplatin, triplatin tetranitrate, phenanthroplatin, picoplatin, saplatin), fluoropyrimidine derivatives (e.g.
  • gemcitabine capecitabine, amcitabine, fluorouracil (5-fluorouracil), difuran Fluorouracil, deoxyfluridine, tegafur, carmofur, trifluorouridine), taxanes (such as paclitaxel, albumin-bound paclitaxel and docetaxel), camptothecins (such as camptotheca Alkali, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan), vinblastines (vinorelbine, vinblastine, vincristine, vindesine, Vinflunine (vinflunine, norvinblastine), anthracyclines (epirubicin, adriamycin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitot Anthraquinone, arubicin, valrubicin, zor
  • the second therapeutic drug is one or more of platinum drugs including but not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, Miplatin, triplatin tetranitrate, phenanthroplatin, picoplatin, satraplatin, Lebaplatin, etc.
  • the second therapeutic drug is used in conjunction with chemotherapy adjuvant drugs
  • the chemotherapy adjuvant drugs include but are not limited to calcium leucovorin (CF), folate, mesna, bisphosphonate, and ammonia Phospstin, hematopoietic cell colony stimulating factors (CSFs).
  • the chemotherapeutic adjuvant drug is calcium leucovorin (CF), mesna, and aldofolate.
  • the second therapeutic drug is an immunotherapeutic drug, including but not limited to interferon (interferon alpha, interferon alpha-1b, interferon alpha-2b), interleukin, temsirolimus (temsirolimus ), one or more of everolimus, ridaforolimus, and temsirolimus.
  • interferon interferon alpha, interferon alpha-1b, interferon alpha-2b
  • interleukin interleukin
  • temsirolimus temsirolimus
  • everolimus temsirolimus
  • ridaforolimus ridaforolimus
  • temsirolimus temsirolimus
  • the second therapeutic drug is a small molecule targeted anti-tumor drug, including but not limited to protein kinase inhibitors.
  • the protein kinase inhibitors include but are not limited to tyrosine kinase inhibitors, serine and/or threonine kinase inhibitors, poly ADP-ribose polymerase (PARP, poly ADP-ribose polymerase) inhibitors
  • PARP poly ADP-ribose polymerase
  • the targets targeted by inhibitors include but are not limited to Fascin-1 protein, HDAC (histone deacetylase), proteasome, CD38, SLAMF7 (CS1/CD319/CRACC), RANKL, EGFR (epidermal growth factor receptor).
  • anaplastic lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 (disc death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1 ), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene;
  • the targets of the small molecule targeted anti-tumor drugs also include COX-2 (cyclooxygenase-2), APE1 (depurinating Pyrimidine endonuclease), VEGFR (vascular endothelial growth factor receptor), CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor), Ezrin , PEDF (Pigment Epithelium Derived Factor), AS, ES, OPG (Bone Protective Factor), Src, IFN, ALCAM (Leukocyte Activated Adhesion
  • the small molecule targeted anti-tumor drugs that can be enumerated include, but are not limited to, Imatinib, Sunitinib, Nilotinib, Bosutinib, Secatinib (Saracatinib), Pazopanib (Pazopanib), Trabectedin (Trabectedin), Regorafenib (Regorafenib), Cediranib (Cediranib), Bortezomib (Bortezomib), Pabirestat (Panobinostat) , Carfilzomib (Carfilzomib), Ixazomib (Ixazomib), Apatinib (apatinib), Erlotinib (Erlotinib), Afatinib (Afatinib), Crizotinib (Crizotinib), color Ceritinib, Vemurafenib, Dabrafenib, Cabozantin
  • the small-molecule targeted anti-tumor drug is sorafenib, erlotinib, afatinib, crizotinib, ceritinib, velofenib, dalafi Ni, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, loratinib, trametinib, larotinib, icotinib Ni, Lapatinib, Vandetanib, Smeltinib, Omotinib, Volitinib, Fruquintinib, Entratinib, Dasatinib, Ensatinib, Levatinib Ni, itacitinib, pyrrotinib, bimetinib, erdatinib, axitinib, lenatinib, cobitinib, acatin
  • the second therapeutic drug is a macromolecular antibody drug.
  • the targets targeted by the macromolecular antibody drug include but are not limited to PD-1, PD-L1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), platelet-derived growth factor receptor ⁇ (PDGFR- ⁇ ), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor-2 (HER2), epidermal growth factor receptor (EGFR), ganglioside GD2, B cell surface protein CD20, B cells Any one or more of surface protein CD52, B cell surface protein CD38, B cell surface protein CD319, B cell surface protein CD30, and B cell surface protein CD19/CD3.
  • CTLA-4 cytotoxic T-lymphocyte antigen 4
  • PDGFR- ⁇ platelet-derived growth factor receptor ⁇
  • VEGF vascular endothelial growth factor
  • HER2 human epidermal growth factor receptor-2
  • EGFR epidermal growth factor receptor
  • ganglioside GD2 B cell surface protein CD20
  • the antibody drug is an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1; in some embodiments, the antibody drug is a cytotoxic T lymphocyte Antigen 4 (cytotoxic T-lymphocyte antigen 4, CTLA-4) inhibitor. In some embodiments, the antibody drug is a platelet-derived growth factor receptor alpha (PDGFR- ⁇ ) inhibitor. In some embodiments, the antibody drug is an epidermal growth factor receptor (EGFR) inhibitor.
  • cytotoxic T lymphocyte Antigen 4 cytotoxic T-lymphocyte antigen 4, CTLA-4
  • CTLA-4 cytotoxic T-lymphocyte antigen 4, CTLA-4
  • the antibody drug is a platelet-derived growth factor receptor alpha (PDGFR- ⁇ ) inhibitor. In some embodiments, the antibody drug is an epidermal growth factor receptor (EGFR) inhibitor.
  • EGFR epidermal growth factor receptor
  • the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody that binds to programmed death receptor 1 (PD-1) and/or inhibits the activity of PD-1 or its
  • the antigen-binding portion alternatively, is an antibody or antigen-binding portion thereof that binds to programmed death ligand 1 (PD-L1) and/or inhibits the activity of PD-L1, for example, an anti-PD-1 antibody or an anti-PD-L1 antibody.
  • the antibody or antigen-binding portion thereof is (a) an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof, which specifically binds to human PD-1 and blocks human PD-L1 and human PD -1; or (b) an anti-PD-L1 monoclonal antibody or an antigen-binding fragment thereof, which specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.
  • the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.
  • the anti-PD-1 or PD-L1 antibody is a human antibody or a murine antibody.
  • the anti-PD-1 antibody may be selected from the group consisting of Nivolumab, Pembrolizumab, Durvalumab, and Toripalimab , JS-001), Sintilizumab (IBI308), Camrelizumab (Camrelizumab), Tirelizumab (BGB-A317), Genozumab (GB226), Livizumab ( LZM009), HLX-10, BAT-1306, AK103 (HX008), AK104 (Kangfang Biological), CS1003, SCT-I10A, F520, SG001, GLS-010 any one or more.
  • the anti-PD-L1 antibody can be selected from Atezolizumab, Avelumab, Durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014 (ZKAB0011), KN035, MSB2311, HLX-20, Any one or more of CS-1001.
  • the anti-PD-1 antibody is teriprizumab.
  • the anti-PD-1 antibody is pembrolizumab.
  • the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor is an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.
  • the anti-CTLA-4 antibody may be selected from the group consisting of Ipilimumab, Tremelimumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI310 Any one or more.
  • the anti-CTLA-4 antibody is ipilimumab.
  • the platelet-derived growth factor receptor alpha (PDGFR- ⁇ ) inhibitor is an anti-PDGFR ⁇ antibody.
  • the anti-PDGFR ⁇ antibody is an anti-PDGFR ⁇ monoclonal antibody.
  • the anti-PDGFRa antibody is Olaratumab.
  • the antibody drug is an epidermal growth factor receptor (EGFR) inhibitor and an anti-EGFR antibody.
  • EGFR epidermal growth factor receptor
  • the anti-EGFR antibody is an anti-EGFR monoclonal antibody.
  • the anti-EGFR antibody is cetuximab (Cotuximab).
  • the antibody drug may also include, but is not limited to, Bevacizumab, Ramucirumab, Pertuzumab, Trastuzumab Anti-(Trastuzmab), Cetuximab (Cotuximab), Nimotuzumab (Nimotuzumab), Panitumumab (Panitumumab), Necitumumab (Necitumumab), Dinutuximab, Rituximab (Rituximab) ), Ibritumomab, Ofatumumab, Obinutuzumab, Alemtuzumab, Daratumumab, Gemtuzumab, Erotuzumab Any one or more of Elotuzumab, Brentuximab, Inotuzumab Ozogamicin, and Blinatumomab.
  • the second therapeutic drug is methotrexate, cisplatin, carboplatin, paclitaxel, docetaxel, fluorouracil, norvinblastine, bleomycin, ifosfamide, meth Sodium, aldhydrofolate, mitoxantrone, pirarubicin, daunorubicin, cytarabine, mercaptoguanine, etoposide, harringtonine, gemcitabine, cetuximab, One or more of epirubicin.
  • the second therapeutic agent is methotrexate.
  • the second therapeutic drug is specifically methotrexate 40 mg/m 2 IV on day 1, once every 7 days.
  • the second therapeutic agent is paclitaxel.
  • the second therapeutic drug is specifically paclitaxel 250 mg/m 2 CIV on the first day, repeated every 21 days.
  • the second therapeutic agent is carboplatin and 5-fluorouracil.
  • the second therapeutic agent is cisplatin and cetuximab.
  • the second therapeutic agent is carboplatin and cetuximab.
  • the second therapeutic agent is gemcitabine and vinorelbine.
  • the second therapeutic agent is gemcitabine and paclitaxel.
  • the second therapeutic agent is the DF regimen, specifically cisplatin and fluorouracil.
  • the second therapeutic drug is a PC regimen, specifically paclitaxel and carboplatin.
  • the second therapeutic agent is a DA regimen, specifically daunorubicin and cytarabine.
  • the second therapeutic drug is the ME regimen, specifically mitoxantrone and etoposide.
  • the second therapeutic agent is a GP regimen, specifically gemcitabine and cisplatin.
  • the second therapeutic agent is an FP regimen, specifically 5-fluorouracil and cisplatin.
  • the second therapeutic drug is AP regimen, specifically doxorubicin and cisplatin.
  • the second therapeutic drug is an IE regimen, specifically ifosfamide, mesna, and etoposide.
  • the second therapeutic agent is docetaxel, cisplatin and 5-fluorouracil.
  • the second therapeutic agent is cisplatin, epirubicin and paclitaxel.
  • the second therapeutic agent is cisplatin, 5-fluorouracil and cetuximab.
  • the second therapeutic agent is carboplatin, 5-fluorouracil and cetuximab.
  • the second therapeutic agent is cisplatin, docetaxel and paclitaxel.
  • the second therapeutic agent is carboplatin, docetaxel and paclitaxel.
  • the second therapeutic agent is carboplatin, paclitaxel and gemcitabine.
  • the second therapeutic drug is an NMB regimen, specifically vinblastine, methotrexate, and bleomycin.
  • the second therapeutic drug is a PIC regimen, specifically paclitaxel, ifosfamide, mesna, and cisplatin.
  • the second therapeutic drug is a DLF regimen, specifically cisplatin, fluorouracil, and aldohydrofolate.
  • the second therapeutic drug is a PBF regimen, specifically cisplatin, bleomycin, and fluorouracil.
  • the second therapeutic drug is an MFC regimen, specifically mitoxantrone, fluorouracil, and carboplatin.
  • the second therapeutic drug is a TPF regimen, specifically pirarubicin, cisplatin, and fluorouracil.
  • the second therapeutic drug is a DAT regimen, specifically daunorubicin, cytarabine, mercaptoguanine, and etoposide.
  • the second therapeutic drug is an HA regimen, specifically harringtonine, cytarabine, and mercaptoguanine.
  • the second therapeutic drug is a HOAP regimen, specifically harringtonine, vincristine, cytarabine, and prednisone.
  • the second therapeutic agent is Tiggio.
  • the second therapeutic agent is sintilimab.
  • the second therapeutic agent is capecitabine.
  • Compound I can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of Compound I in vivo.
  • the pharmaceutically acceptable salt of Compound I can be produced from different organic acids and inorganic acids according to methods well known in the art within the scope of this application.
  • the administration is in the form of Compound I hydrochloride. In some embodiments, the administration is in the form of Compound I monohydrochloride. In some embodiments, the administration is in the form of Compound I dihydrochloride. In some embodiments, the administration is in the crystalline form of Compound I hydrochloride. In a specific embodiment, it is administered in the crystal form of Compound I dihydrochloride.
  • Compound I, or a pharmaceutically acceptable salt thereof, and the second therapeutic drug can be administered by a variety of routes, including but not limited to routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, and transfusion. Skin, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vagina, intraocular, topical, subcutaneous, intra-fat, intra-articular, intraperitoneal and intrathecal. In a specific embodiment, it is administered orally.
  • the amount of compound I or its pharmaceutically acceptable salt and the second therapeutic agent administered can be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the subject.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 3 mg to 30 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg to 16 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 8 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 10 mg. In a specific embodiment, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 12 mg.
  • "contains 12 mg of Compound I or a pharmaceutically acceptable salt thereof on a unit dose basis" means that each tablet or capsule is finally made The preparation contains 12 mg of compound I.
  • Compound I or a pharmaceutically acceptable salt thereof, and the second therapeutic agent can be administered one or more times a day.
  • Compound I or a pharmaceutically acceptable salt thereof is administered once a day.
  • the oral solid formulation is administered once a day.
  • the method of administration can be comprehensively determined according to the activity, toxicity of the drug, and tolerance of the subject.
  • Compound I or a pharmaceutically acceptable salt thereof is administered at intervals.
  • the interval administration includes an administration period and a drug withdrawal period.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day.
  • Compound I or its pharmaceutically acceptable salt is administered every day during the administration period, and then the administration is stopped for a period of time during the withdrawal period, followed by the administration period, and then the withdrawal period, which can be repeated many times.
  • the ratio of the administration period to the drug withdrawal period in days is 2:(0.5-5), preferably 2:0.5-3, more preferably 2:0.5-2, more preferably 2:0.5-1.
  • the administration is continued for 2 weeks and the drug is stopped for 2 weeks.
  • the drug is administered once a day for 14 days, and then the drug is stopped for 14 days; then once a day, the drug is administered for 14 days, then the drug is stopped for 14 days, and the drug is continuously administered for 2 weeks.
  • the two-week interval dosing method can be repeated many times.
  • the administration is continued for 2 weeks and the drug is stopped for 1 week.
  • the drug is administered once a day for 14 days, and then the drug is stopped for 7 days; then once a day, the drug is administered for 14 days, then the drug is stopped for 7 days, and the drug is continuously administered for 2 weeks.
  • the one-week interval administration can be repeated many times.
  • Compound I or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each cycle, and every 21 days is a dosing cycle.
  • the drug is discontinued for 2 days for 5 consecutive days. In some embodiments, the drug is administered once a day for 5 days, and then the drug is stopped for 2 days; then once a day, the drug is administered for 5 days, then the drug is stopped for 2 days, and the drug is stopped for 5 consecutive days.
  • the two-day interval administration method can be repeated many times.
  • it is administered orally at a dose of 12 mg once a day for 2 consecutive weeks and a one-week stop for administration.
  • Compound I or a pharmaceutically acceptable salt thereof is combined with surgical resection and/or radiation therapy.
  • each component in the pharmaceutical composition described in the present application may optionally be used in combination with one or more pharmaceutically acceptable carriers, wherein the components may each independently, or part or all of them may contain pharmaceutically acceptable carriers. Accepted carriers and/or excipients.
  • the pharmaceutical compositions described in this application can be formulated separately, or part or all of them can be formulated together. Preferably, each component of the pharmaceutical composition is formulated separately, or each is formulated into a suitable pharmaceutical composition.
  • the pharmaceutical composition of the present application can be formulated as a pharmaceutical composition suitable for single or multiple administration.
  • the pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof may be selected from solid pharmaceutical compositions including but not limited to tablets or capsules.
  • the components in the pharmaceutical composition of the present application may be administered separately, or part or all of them may be administered together.
  • the components in the pharmaceutical composition of the present application may be administered at substantially different times, or some or all of them may be administered at substantially the same time.
  • the components in the pharmaceutical composition of the present application can be administered independently, or part or all of them can be administered together by a suitable route, including but not limited to oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes) .
  • the components of the pharmaceutical composition of the present application may be individually administered orally or by injection, such as intravenous injection or intraperitoneal injection, or part or all of them may be administered independently.
  • the components of the pharmaceutical composition of the present application can be independently, or some or all of them together are suitable dosage forms, including but not limited to tablets, troches, pills, capsules (such as hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • suitable dosage forms including but not limited to tablets, troches, pills, capsules (such as hard capsules, soft capsules, Enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration
  • suitable dosage forms including but not limited to tablets, troches, pills, capsules (such as hard capsules
  • the pharmaceutical composition is a fixed combination.
  • the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.
  • the pharmaceutical composition is a non-fixed combination.
  • the second therapeutic agent and Compound I or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition.
  • Compound I or a pharmaceutically acceptable salt thereof and one or more second therapeutic agents are administered simultaneously or sequentially.
  • one or more second therapeutic agents have been administered to the subject before administration of Compound I or a pharmaceutically acceptable salt thereof or before combination with Compound I or a pharmaceutically acceptable salt thereof.
  • one or more second therapeutic agents are administered to the subject after administration of Compound I or a pharmaceutically acceptable salt thereof or after combination with Compound I or a pharmaceutically acceptable salt thereof.
  • Compound I or a pharmaceutically acceptable salt thereof has been administered to the subject before the administration of one or more second therapeutic agents or before combination with one or more second therapeutic agents.
  • Compound I or a pharmaceutically acceptable salt thereof is administered to the subject after administration of one or more second therapeutic agents or after combination with one or more second therapeutic agents.
  • the subject when Compound I or a pharmaceutically acceptable salt thereof is administered to a subject in combination with one or more second therapeutic agents, the subject is sequentially administered Compound I or a pharmaceutically acceptable salt thereof and One or more second therapeutic drugs.
  • one or more second therapeutic agents are ineffective in treating cancer.
  • the second therapeutic agent is any anticancer agent described herein or known in the art.
  • kits of a pharmaceutical composition for the treatment of head and neck cancer which contains: (a) a first pharmaceutical composition containing a chemotherapeutic drug as an active ingredient; and (b) a second drug
  • the composition contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a kit of a pharmaceutical composition for the treatment of head and neck cancer which contains: (a) a first pharmaceutical composition containing a small molecule targeted anti-tumor drug as an active ingredient; and (b ) The second pharmaceutical composition, which contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • kits of a pharmaceutical composition for the treatment of head and neck cancer which contains: (a) a first pharmaceutical composition containing an immunotherapeutic drug as an active ingredient; and (b) a second A pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a kit for the treatment of head and neck cancer with a drug combination which contains (a) a first pharmaceutical composition containing a macromolecular antibody drug as an active ingredient; and (b) a second drug The composition contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • kits of a pharmaceutical composition for the treatment of head and neck cancer which contains: (a) a first pharmaceutical composition containing cetuximab and platinum-based drugs as active ingredients; and (b) The second pharmaceutical composition, which contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a kit of a pharmaceutical composition for the treatment of head and neck cancer which contains (a) the first pharmaceutical composition containing gemcitabine and platinum-based drugs as active ingredients; and (b) the second A pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • kits of a pharmaceutical composition for the treatment of head and neck cancer which contains (a) the first pharmaceutical composition, containing gemcitabine and cisplatin as active ingredients; and (b) the second A pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a kit of a pharmaceutical composition for the treatment of head and neck cancer which contains (a) a first pharmaceutical composition containing gemcitabine and paclitaxel as active ingredients; and (b) a second drug The composition contains Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect can be therapeutic based on partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a subject's disease, including: (a) inhibiting the symptoms of the disease, that is, preventing its development; or (b) alleviating the symptoms of the disease, that is, causing the disease or symptoms to degenerate.
  • treatment failure refers to intolerable side effects, disease progression during treatment, or relapse after treatment ends. Specifically, it refers to patients who have undergone surgery, radiotherapy, chemotherapy or comprehensive treatment, and have disease progression or distant metastasis. There is currently no other effective standard treatment.
  • Advanced refers to the clinical stage of metastatic adenocarcinoma or locally advanced cancer that cannot be treated with local radical surgery or radiotherapy.
  • the term "subject” means mammals, such as rodents, felines, canines, and primates. Preferably, the subject according to the present application is a human.
  • the term “patient” is human.
  • Administration refers to the physical introduction of a composition containing a therapeutic agent to a patient using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion.
  • parenteral administration refers to modes of administration other than enteral and local administration that are usually performed by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, and intralymphatic , Intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injections and infusions , And electroporation in vivo.
  • the drug is administered via a non-parenteral route, and in certain embodiments, it is administered orally.
  • Non-parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasal, vaginal, rectal, sublingual, or topical. Administration can also be performed, for example, once, multiple times, and/or over one or more extended periods of time.
  • anticancer drugs promote regression of cancer in patients or prevent further tumor growth.
  • the drug promotes cancer regression to the point where the cancer is eliminated.
  • Promote cancer regression refers to the administration of drugs alone or in combination with an antitumor agent, resulting in a reduction in tumor growth or size, tumor necrosis, reduction in the severity of at least one disease symptom, and frequency of disease-free stages And the increase in duration.
  • the terms "effective” and “effective” with respect to treatment include pharmacological effectiveness and physiological safety.
  • Pharmacological effectiveness refers to the ability of a drug to promote cancer regression in a subject.
  • Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cell, organ, and/or biological level caused by drug administration.
  • anticancer drugs can inhibit cell growth or tumor growth by at least about 10 relative to untreated patients, or, in certain embodiments, relative to subjects treated with standard-of-care therapies. %, at least about 20%, at least about 40%, at least about 60%, or at least about 80%. In other embodiments of the application, tumor regression can be observed for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these final measures of therapeutic effectiveness, drug evaluation must also consider "immune-related" response patterns.
  • Immunotherapeutic response pattern refers to a clinical response pattern frequently observed in cancer subjects treated with immunotherapeutic agents that produce anti-tumor effects by inducing cancer-specific immune responses or by altering innate immune processes effect. This response pattern is characterized by a beneficial therapeutic effect after the initial increase in tumor burden or the appearance of new lesions, which will be classified as disease progression in the evaluation of traditional chemotherapeutics and will be synonymous with drug failure. Therefore, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on target diseases.
  • the term "antibody” refers to a binding protein having at least one antigen binding domain.
  • the antibodies and fragments of the present application may be whole antibodies or any fragments thereof. Therefore, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, and 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 can also include recombinant polypeptides, fusion proteins and bispecific antibodies.
  • the anti-PD-L1 antibodies and fragments thereof disclosed herein may be of IgG1, IgG2, IgG3, or IgG4 isotype.
  • the term "isotype" refers to the antibody species encoded by the heavy chain constant region genes.
  • the anti-PD-1/PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype.
  • the anti-PD-1/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.
  • the PD-1/PD-L1 antibody and its fragments can be chimeric antibodies, humanized antibodies or whole human antibodies.
  • humanization means that the antigen binding site in the antibody is derived from a non-human species and the variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may contain substitutions in the framework regions so that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.
  • isolated antibody refers to an antibody that contains substantially no other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds PD-1/PD-L1 contains substantially no specific binding other Antibodies to antigens other than PD-1/PD-L1).
  • an isolated antibody that specifically binds PD-1/PD-L1 may have cross-reactivity with other antigens, such as PD-1/PD-L1 molecules from different species.
  • the isolated antibody may be substantially free of other cellular materials and/or chemical substances.
  • the term "monoclonal antibody”("mAb”) refers to an antibody molecule of single molecular composition.
  • the monoclonal antibody composition shows a single binding specificity and affinity for a specific epitope, or in the case of a bispecific monoclonal antibody, shows a dual binding specificity for two different epitopes.
  • mAb is an example of an isolated antibody.
  • the mAb can be produced by hybridoma technology, recombinant technology, transgenic technology, or other technologies known to those skilled in the art.
  • isolated monoclonal antibodies include but are not limited to Nivolumab (Nivolumab) Pembrolizumab (Pembrolizumab) Durvalumab, Avelumab, Tereprizumab (JS-001, Junshi Bio), Sintilimab (Sintilimab, IBI308, Xinda Biological), Carrelizumab (SHR-1210, Camrelizumab, Hengrui
  • CN105026428B or WO2015085847A1 tisleli strain monoclonal antibody
  • BGB-A317, BeiGene genozumab (GB226, Jiahe Biologics)
  • HLX- 10 Fuhong Henlius
  • BAT-1306 Biotech
  • HX008 AK103, Kangfang Biological/Hanzhong Biological
  • AK104 Zahongshan Kangfang
  • CS Chem
  • the "antigen-binding portion" (also referred to as “antigen-binding fragment”) of an antibody refers to one or more fragments of the antibody that retain the ability to specifically bind to the antigen bound by the intact antibody.
  • PD-1 Programmed death receptor-1
  • PD-1 is mainly expressed on previously activated T cells in the body and binds two ligands, PD-L1 and PD-L2.
  • the term "PD-1” as used herein includes human PD-1 (hPD-1), variants, homologs and species homologs of hPD-1, and analogs that have at least one common epitope with hPD-1.
  • P-L1 Programmed Death Ligand-1 (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2), which down-regulates T cells after binding to PD-1 Activation and cytokine secretion.
  • Recurrent cancer is cancer that regenerates at the original site or at a remote site after responding to an initial treatment (such as surgery).
  • "Locally recurrent” cancer is cancer that appears in the same place as the previously treated cancer after treatment.
  • Metalstatic cancer refers to cancer that has spread from one part of the body, such as the head and neck, to another part of the body.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • salts includes salts formed by alkali ions and free acids or salts formed by acid ions and free bases, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, Formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate, p-toluene Sulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate Acid salt, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.
  • the molar ratio of the free acid to the base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • the ratio of the molar amount of the free base to the acid radical ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1. :3, 1:4, 1:5, 1:6, 1:7 or 1:8.
  • fixed combination means that the active ingredients (for example, chemotherapeutics or Compound I) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or preparation.
  • non-fixed combination means that two or more active ingredients are administered to a subject simultaneously, concurrently, or sequentially without any specific time limit as separate entities (eg, pharmaceutical compositions, preparations), wherein The active ingredient reaches the therapeutically effective level.
  • An example of a non-fixed combination is cocktail therapy, for example, the administration of 3 or more active ingredients.
  • the respective active components can be packaged, sold or administered as completely independent pharmaceutical compositions.
  • the "non-fixed combination” also includes the combined use of the "fixed combination” or the "fixed combination” with any one or more independent entities of the active ingredient.
  • combined use or “combined use” means that two or more active substances can be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially as a single formulation in any order.
  • pharmaceutical composition refers to a mixture of one or more of the active ingredients of the application (for example, the second therapeutic drug or Compound I) or its drug combination and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the application or its pharmaceutical combination to a subject.
  • Chronic benefits in this application include but are not limited to: clinical patient progression-free survival (PFS) prolonged, overall survival (OS) prolonged, objective response rate (ORR) improved, disease control rate (DCR) ) Is improved, the number and/or degree of adverse reactions are reduced, the rate of distant metastasis and the rate of local control are reduced.
  • PFS clinical patient progression-free survival
  • OS overall survival
  • ORR objective response rate
  • DCR disease control rate
  • the objective remission rate for human patients with head and neck cancer in clinical trials reaches about 10% or more, preferably about 15% Above, it is more preferable to reach more than about 20%, more preferably more than about 30%, especially more than 35%; the disease control rate of the patient reaches more than 50%, preferably more than about 60%, and more preferably more than about 70%, More preferably, it is more than about 80%, especially more than 90%.
  • the drug of the present application shows clinical benefit.
  • Example 1 The effect of compound I dihydrochloride on the growth of human laryngeal cancer cells
  • the tested drugs were all dissolved in dimethyl sulfoxide, prepared into a 100mmol/L mother liquor, and stored at -20°C for later use. Use DMEM serum culture medium to make the required concentration.
  • the human laryngeal carcinoma Hep-2 cell line and the human laryngeal carcinoma TU212 cell line were cultured in DMEM containing 10% fetal bovine serum and 0.1g/L streptomycin and penicillin (final concentration 100U ⁇ mL -1 ) respectively. In the liquid, placed in a 5% CO 2 incubator at a constant temperature of 37°C. When the cell confluence reached about 85%, it was digested with 0.02% EDTA+0.25% trypsin, the cells were collected, centrifuged at 1000 r/min, and subcultured.
  • the IC 50 value can be determined according to the usual method in the art (such as the common MTT method), or the following method (MTT method):
  • Logarithmic phase cells were seeded in 96-well culture plate (180 L / well, 105 cells / well) and grown for 24 hours at 37 °C, 5% CO 2 conditions, the addition of compound I dihydrochloride (gradient For 0, 0.005, 0.1, 0.05, 0.1, 0.5, 1.5, 4, 12, 30 ⁇ g/ml concentration solution) for culture, each concentration set two multiple wells, each well add 20 ⁇ L, and set the corresponding concentration of physiological saline solvent Control and cell-free zeroing holes; culture the tumor cells for another 24 hours under the conditions of 37°C and 5% CO 2 (ie 48 hours in total); after the drug action is over, add MTT working solution to each hole, 4 hours later, triple solution Dissolve at 37°C overnight.
  • compound I dihydrochloride gradient For 0, 0.005, 0.1, 0.05, 0.1, 0.5, 1.5, 4, 12, 30 ⁇ g/ml concentration solution
  • Inhibition rate (OD value control hole-OD value administration hole)/OD value control hole ⁇ 100%
  • Example 2 The effect of compound I dihydrochloride on the growth of human oral squamous cell carcinoma cells
  • the tested drugs were all dissolved in dimethyl sulfoxide, prepared into a 100mmol/L mother liquor, and stored at -20°C for later use. Use DMEM serum culture medium to make the required concentration.
  • Human oral squamous cell carcinoma scc4 cell line, human oral squamous cell carcinoma CAL-27 cell line and human oral squamous cell carcinoma HSC-4 cell line were cultured with 10% fetal bovine serum and 0.1g/L streptomycin and penicillin respectively (final concentration is 100U ⁇ mL -1 ) DMEM complete culture solution, placed in a 5% CO 2 incubator at a constant temperature of 37°C. When the cell confluence reached about 85%, it was digested with 0.02% EDTA+0.25% trypsin, the cells were collected, centrifuged at 1000 r/min, and subcultured.
  • the IC50 value can be determined according to the usual method in the art (such as the common MTT method), or the following method (MTT method):
  • Logarithmic phase cells were seeded in 96-well culture plate (180 L / well, 105 cells / well) and grown for 24 hours at 37 °C, 5% CO 2 conditions, the addition of compound I dihydrochloride (gradient For 0, 0.005, 0.1, 0.05, 0.1, 0.5, 1.5, 4, 12, 30 ⁇ g/ml concentration solution) for culture, each concentration set two multiple wells, each well add 20 ⁇ L, and set the corresponding concentration of physiological saline solvent Control and cell-free zeroing holes; culture the tumor cells for another 24 hours under the conditions of 37°C and 5% CO 2 (ie 48 hours in total); after the drug action is over, add MTT working solution to each hole, 4 hours later, triple solution Dissolve at 37°C overnight.
  • compound I dihydrochloride gradient For 0, 0.005, 0.1, 0.05, 0.1, 0.5, 1.5, 4, 12, 30 ⁇ g/ml concentration solution
  • Inhibition rate (OD value control hole-OD value administration hole)/OD value control hole ⁇ 100%
  • Adenocarcinoma of the head and neck that was diagnosed by histopathology and failed conventional treatment including: mucoepidermoid carcinoma, adenoid cystic carcinoma, pleomorphic adenocarcinoma, salivary duct carcinoma, myoepithelial carcinoma, non-specific adenocarcinoma, Non-specific clear cell carcinoma, cystadenocarcinoma, sebaceous adenocarcinoma, sebaceous lymphatic adenocarcinoma, mucinous adenocarcinoma, epithelial-myoepithelial carcinoma, administer Anlotinib hydrochloride capsules to the above patients: once a day, orally before breakfast, each time 12mg, d1-14 administration in each cycle, continuous medication for 2 weeks, withdrawal for 1 week, 21 days as a treatment cycle.
  • Anlotinib Hydrochloride Capsules once a day, orally before breakfast, 12 mg each time, d1-14 administration in each cycle, continuous medication for 2 weeks, withdrawal for 1 week, 21 days as a treatment cycle;
  • Sintilimab 200 mg, intravenous infusion, d1 administration per cycle, 21 days as a treatment cycle.
  • the duration of treatment for all patients is up to 12, or until the disease progresses, an intolerable toxic reaction occurs, death or other circumstances that require termination of treatment in the case occur, whichever occurs first.
  • the drug was administered for 4 cycles, and the efficacy was evaluated as PR (partial remission).
  • the drug was administered for 8 cycles, and the efficacy was evaluated as SD (stable disease).
  • Anlotinib Start using it about a week before radiotherapy, 10mg/day, two weeks of continuous use, and one week off. A total of three cycles of medication plan will be completed during radiotherapy. You can decide whether to continue taking it depending on the tumor changes after radiotherapy.
  • the efficacy evaluation observation indicators include 3-year overall survival (OS), progression-free survival (DFS), 3-year distant metastasis rate and local control rate.
  • Radiotherapy time Radiotherapy dose (Gy) Efficacy evaluation Week 1 10.75 - Week 2 21.5 - Week 3 32.25 - Week 4 43.0 PR (partial remission) Week 5 53.75 - Week 6 Stop for a week - Week 7 64.5 -
  • Anlotinib Hydrochloride Capsules/Placebo Starting dose 12mg/0mg. Take orally on an empty stomach before breakfast, one pill a day for two consecutive weeks and stop for one week.
  • Gemcitabine Hydrochloride for Injection The initial dose is 1g/m 2 , which is administered on the 1st and 8th day of each cycle.
  • Cisplatin injection starting dose 75mg/m 2 , administered on the first day of each cycle.
  • Anlotinib Hydrochloride Capsules/Placebo 12mg, taken orally on an empty stomach before breakfast, one capsule per day, taking two consecutive weeks and stopping for one week, one cycle every 21 days, until the study termination criteria.
  • MDT Multidisciplinary Diagnosis and Treatment
  • Anlotinib Hydrochloride Capsules once a day, orally before breakfast, 12 mg each time, d1-14 for each cycle, continuous medication for 2 weeks, withdrawal for 1 week, 21 days as a treatment cycle, continuous medication until emergence PD, death, intolerable toxicity;
  • Capecitabine tablets oral total 1000mg/m 2 , oral, bid, d1-d14, continuous medication for 2 weeks, withdrawal for 1 week, 21 days as a treatment cycle, continuous medication until PD, death, intolerable The toxicity.
  • Efficacy evaluation observation indicators include objective response rate (ORR), progression-free survival (PFS), overall survival (OS), quality of life, and drug safety indicators.
  • the amount of anlotinib hydrochloride capsule is based on the weight of anlotinib free base contained therein.

Abstract

化合物1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺在制备用于治疗头颈癌的药物中的用途，以及其联合第二治疗药物的药物组合物在制备用于治疗头颈癌的药物中的用途，所述头颈癌可以是鼻咽癌。

Description

用于治疗头颈癌的喹啉衍生物 技术领域
本申请属于医药技术领域，本申请涉及喹啉衍生物用于抗肿瘤的用途。具体而言，本申请涉及用于治疗头颈癌的喹啉衍生物，以及其联合第二治疗药物的药物组合物及其用于治疗头颈癌的用途。
背景技术
头颈癌(Head and Neck Cancers)是指位于头颈部位，除了脑癌以外的其它恶性肿瘤。较常见有口腔癌、鼻咽癌，另外还有口咽癌、下咽癌、喉癌、鼻窦癌、唾液腺癌等。头颈癌的常见部分包括口腔、鼻、喉咙、鼻窦、唾液腺、喉头等。头颈癌的症状包括有无法医好的疮或是硬块，持续出现的喉咙痛，吞咽困难或是声音的变化，若是有异常出血、面部肿胀、呼吸困难，也有可能是头颈癌。
2015年全球有550万人罹患头颈癌(口腔的有240万，喉咙的有170万，喉头的有140万)，已造成超过379,000人死亡(口腔癌146000，喉癌127400，喉头癌105900)。头颈癌合并来看，是第七常见的癌症，也是第九常见的癌症死因。美国约有1％的人曾罹患头颈癌，男性罹患人数是女性的二倍，常见于55岁至65岁的成年人。在发达国家，在诊断后的平均五年存活率为42-64％。
鼻咽癌是发生于鼻咽腔顶部和侧壁的恶性肿瘤，是中国高发恶性肿瘤之一，发病率为耳鼻咽喉恶性肿瘤之首。鼻咽癌WHO病理分型(2005年版)主要有以下几种类型：I型角化性鳞癌和II型非角化鳞癌，第二种又被分为分化型与未分化型癌。流行病学资料显示：高发区鼻咽癌患者98％为II型，只有2％为I型。I和II型鼻咽癌患者5年生存状态差异显著，而II型当中的分化型与未分化型患者的5年生存状态差异不明显。鼻咽癌病理形态学表现出多样性，且与临床意义关联性不显著。
陈斯泽等在“NLK表达在鼻咽癌中的诊断意义及作用研究”一文中指出，鼻咽癌大多对放射治疗具有中度敏感性，放射治疗是鼻咽癌的首选治疗方法。但是对较高分化癌、病程较晚以及放疗后复发的病例，手术切除和化学药物治疗亦属于不可缺少的手段。由于鼻咽部构成复杂，发病部位较深且隐蔽，增加了治疗难度，同时缺乏个体化特异性治疗方式和药物，治疗方式较为单一，因此对鼻咽癌的治疗效果仍旧不佳，5年生存率始终不高。
发明概述
第一部分，本申请提供化合物I或其药学上可接受的盐在制备用于治疗头颈癌的药物中的用途。本申请还提供治疗头颈癌的方法，其包括向受试者给予化合物I或其药学上可接受的盐。本申请还提供化合物I或其药学上可接受的盐用于治疗头颈癌的用途。
第二部分，本申请提供用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物。
第三部分，本申请还提供药物组合物在制备用于治疗头颈癌的药物中的用途。本申请还提供药物组合物用于治疗头颈癌的用途。
第四部分，本申请还提供治疗头颈癌的方法，其包括向受试者给予本申请的药物组合物。所述药物组合物包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物。
发明内容
第一部分，本申请提供治疗化合物I或其药学上可接受的盐在制备用于治疗头颈癌的药物中的用途，
Figure PCTCN2020092125-appb-000001
在一些实施方案中，所述的头颈癌为头颈部鳞癌。
在一些实施方案中，所述的头颈癌为头颈部腺癌。
在一些实施方案中，所述的头颈癌包括但不限于颈部肿瘤、耳鼻喉科肿瘤以及口腔颌面部肿瘤。在一些实施方案中，所述的头颈癌包括但不限于口腔癌、喉癌、腮腺癌、鼻腔癌、鼻窦癌、副鼻窦癌、口咽癌、口底癌、下咽癌、腭癌、牙龈癌、舌癌、舌粘膜鳞癌、颊粘膜癌、唇癌、唾液腺癌、扁桃体癌等。
在一些实施方案中，所述的头颈部腺癌，根据其组织病理学分析，包括但不限于黏液表皮样癌、腺样囊性癌、淋巴上皮癌、多形性腺癌、涎腺导管癌、肌上皮癌、非特异性腺癌、非特异性透明细胞癌、囊腺癌、皮脂腺癌、皮脂淋巴腺癌、黏液腺癌、上皮-肌上皮癌。
第二部分，本申请提供用于治疗头颈癌的联用药物组合物，其包括(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物。
在本申请的一些实施方案中，所述联用药物组合物包括：(i)化合物I或其药学上可接受的盐的药物组合物；和(ii)至少一种第二治疗药物的药物组合物。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种化疗药物，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种小分子靶向抗肿瘤药物，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种免疫治疗药物，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种大分子抗体药物，以及任选地与放射治疗联合。
在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)铂类药物，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)铂类药物和选自氟嘧啶衍生物和抗PD-1抗体中的至少一种，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)铂类药物和西妥昔单抗，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)吉西他滨和铂类药物，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)吉西他滨和顺铂，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)氟嘧啶衍生物和紫杉类中的至少一种，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)吉西他滨和紫杉醇，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)顺铂和5-氟尿嘧啶，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)信迪利单抗，以及任选地与放射治疗联合。在一些的实施方案中，提供了一种用于治疗头颈癌的联用药物组合物，其包括：(i)化合物I或其药学上可接受的盐；和(ii)卡培他滨，以及任选地与放射治疗联合。
第三部分，本申请提供了一种药物组合物在制备用于治疗头颈癌的药物中的用途，其包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物，以及任选地与放射治疗联合。
第四部分，本申请还提供治疗头颈癌的方法，其包括向受试者给予本申请的药物组合物。所述药物组合物包括：(i)化合物I或其药学上可接受的盐；和(ii)至少一种第二治疗药物。
本申请提供了一种用于治疗患有头颈癌的患者的方法。在本申请的一些方案中，所述患者先前已接受手术、化疗和/或放射治疗。在一些具体实施方式中，所述患者经手术、化疗和/或放射治疗后获完全缓解后再次出现疾病进展。在一些具体实施方式中，所述患者经手术、化疗和/或放射治疗后未能完全缓解或未能部分缓解。
本申请提供了一种治疗头颈癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐和至少一种第二治疗药物。在一些实施方案中，本申请提供了一种治疗未接受过化疗药物的头颈癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐，和至少一种第二治疗药物。在一些实施方案中，本申请提供了一种在先接受过至少一种化疗药物的头颈癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐，和至少一种第二治疗药物。在一些实施方案中，本申请提供了一种治疗二线和二线以上治疗失败的头颈癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐，和至少一种第二治疗药物。在一个实施方案中，本申请提供了一种治疗难治性复发的头颈癌的方法，所述方法包括给予需要治疗的患者化合物I或其药学上可接受的盐，和至少一种第二治疗药物。在一些实验方案中，所述化合物I或其药学上可接受的盐和至少一种第二治疗药物联用用于治疗原发性头颈癌或继发性头颈癌。在一些实施方案中，所述的头颈癌为无法耐受化疗的头颈癌。
在本申请的一些方案中，患者先前未接受过***化疗。在一些方案中，患者先前已接受手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗。在一些具体实施方式中，患者先前未接受过***化疗，但是接受过手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗。在一些具体实施方式中，患者经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，获完全缓解后再次出现疾病进展。在一些具体实施方式中，患者经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后，未能完全缓解或未能部分缓解。在一些具体实施方式中，患者经手术治疗、放射治疗、诱导化疗、同期的化疗和/或辅助化疗后癌症发生转移。
给药的方法可根据药物的活性、毒性以及受试者的耐受性等来综合确定。在本申请的一些实施方案中，所述用途或治疗方法中，包括但不限于所述第二治疗药物可以每天(qd)、隔日(qod)、每3天(q3d)、每4天(q4d)、每5天(q5d)、每周(q1w)、每2周(q2w)、每3周(q3w)、或者每4周(q4w)施用一次、两次、三次或者四次，例如每天施用两次(bid)、每周施用两次(biw)、每天施用三次(tid)、每天施用四次(qid)等。在本申请的一些实施方案中，所述用途或治疗方法中，也可以以间隔给药的方式给予第二治疗药物。所述的间隔给药包括给药期和停药期，例如在给药期内每天给予第二治疗药物，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。
在本申请的一些实施方案中，所述用途或治疗方法中，包括但不限于所述化合物I或其药学上可接受的盐可以每日一次6mg、8mg、10mg或者12mg的剂量，连续用药2周，停1周的给药方案给药；和/或，以连续用药2周，停2周的给药方案给药。
在一些实施方案中，第二治疗药物和化合物I或其药学上可接受的盐分别具有相同或者不同的治疗周期。在一些具体的实施方案中，第二治疗药物和化合物I或其药学上可接受的盐具有相同的治疗周期，例如每1周、每2周、每3周或者每4周为一个治疗周期。在一些具体的实施方案中，第二治疗药物和化合物I或其药学上可接受的盐均为每3周一个治疗周期。
在一些实施方案中，本申请提供了一种联用药物组合物，其为适用于在单个治疗周期(例如3周的一个治疗周期)内施用的制剂，包括84～168mg、优选112～168mg的化合物I或其药学上可接受的盐和至少一种第二治疗药物。其中，化合物I或其药学上可接受的盐能够以多个等份(例如2等份、7等份、14等份、28等份或更多等份)分开包装。
另外，本申请提供用于治疗头颈癌的试剂盒，所述试剂盒包括各自独立包装的化合物I或其药学上可接受的盐和至少一种第二治疗药物，以及任选的说明书。
在本申请的一些具体的实施方案中，本申请中的化合物I或其药学上可接受的盐以及含有化合物I或其药学上可接受的盐的联用药物组合物，在临床试验中对于头颈癌人类患者的客观缓解率达到约10％以上，优选达到约15％以上，进一步优选达到约20％以上，更优选达到约30％以上，尤其是达到35％以上；疾病控制率达到50％以上，优选达到约60％以上，进一步优选达到约70％以上，更优选达到约80％以上，尤其达到90％以上。
头颈癌
在本申请的一些实施方案中，所述的头颈癌为头颈部鳞癌。在一些实施方案中，所述的头颈癌为头颈部腺癌。在一些实施方案中，所述的头颈癌包括但不限于颈部肿瘤、耳鼻喉科肿瘤以及口腔颌面部肿瘤。在一些实施方案中，所述的头颈癌包括但不限于口腔癌、喉癌、腮腺癌、甲状腺癌、鼻咽癌、鼻腔癌、鼻窦癌、副鼻窦癌、口咽癌、口底癌、下咽癌、腭癌、牙龈癌、舌癌、舌粘膜鳞癌、颊粘膜癌、唇癌、唾液腺癌、扁桃体癌等。
原发性头颈部腺癌可能发生于唾液腺或鼻腔鼻窦区域。唾液腺癌可起源于大唾液腺(腮腺、下颌下腺及舌下腺)，也可起源于小唾液腺，小唾液腺遍布于口腔及上呼吸消化道的黏膜下层，包括口腔(尤其是腭部)、鼻窦、喉及咽部。唾液腺癌发病率低，临床并不常见，它的发病率不到头颈部恶性肿瘤的5％。世界范围内报道的年发病率变化在0.3-4个新发病例/10万人口，关于其治疗的经验主要基于回顾性病例系列研究。最常见的唾液腺恶性肿瘤包括：黏液表皮样癌、腺样囊性癌、淋巴上皮癌。其它头颈部腺癌还包括多形性腺癌(多形性低度恶性腺癌)、涎腺导管癌、肌上皮癌(上皮性肿瘤)、非特异性腺癌、非特异性透明细胞癌、囊腺癌、皮脂腺癌、皮脂淋巴腺癌、黏液腺癌、上皮-肌上皮癌(上皮性肿瘤)。鼻腔鼻窦腺癌可能类似于普通涎腺肿瘤、浆液黏液性肿瘤、肠型分化的肿瘤及其它罕见变异型。
在一些实施方案中，所述的头颈癌为隐性癌或原发灶不明的头颈癌。在一些实施方案中，所述的头颈癌，其临床分期包括但不限于局部晚期、和/或晚期(例如IIIB/IV期)的头颈癌。在一些实施方案中，所述的头颈癌为转移性的头颈癌。其中转移性的头颈癌包括但不限于远处转移、病灶单个转移、播散性转移、弥漫性转移；所述转移的病灶包括但不限于肺部、***、胸膜、骨、脑、心包、肾上腺、肝脏。在一些实施方案中，所述的头颈癌为脑转移的头颈癌。在一些实施方案中，所述的头颈癌为***转移的头颈癌。
在本申请的一些实施方案中，所述的头颈癌为复发性的；在某些实施方案中，所述的头颈癌为难治性的；在某些实施方案中，所述的头颈癌为不可切除的。在一些实施方案中，所述的头颈癌为化疗药物和/或靶向药物治疗失败的头颈癌。在一些实施方案中，所述的头颈癌为接受过至少两种化疗药物的头颈癌。在一些实施方案中，所述的头颈癌为二线和二线以上化疗失败的头颈癌。在一个实施方案中，所述的头颈癌为难治性复发的头颈癌，其中所述的“难治性复发的头颈癌”是指化疗无缓解的头颈癌，和化疗有效但在化疗结束后3个月内出现病情进展的头颈癌。
在本申请的一些实施方案中，所述的鼻咽癌包括但不限于角化鳞癌、非角化癌，所述非角化鼻咽癌可以包括分化型或未分化型，如鼻咽顶后壁未分化型非角化癌。
在一些实施方案中，所述的鼻咽癌包括但不限于原位型鼻咽癌、浸润型鼻咽癌。在一些实施方案中，所述的浸润型鼻咽癌包括但不限于鳞癌(包括高、中、低分化)、腺癌(包括高、中、低分化)、微小***、泡状细胞核癌或未分化鼻咽癌。在一些具体的实施例中，所述的腺癌又包括***状腺癌或柱状细胞腺癌。
在一些实施方案中，所述的鼻咽癌的临床分期包括但不限于：I期、II期、III期、IVa期、IVb期，例如T1N0M0、T2N0～1M0、T0～2N1M0、T3N0～2M0、T0～3N1M0、T4N0～3M0、T0～4N3M0、或者任何T、任何N、M1。
在一些实施方案中，所述的鼻咽癌为I型角化鳞癌。在一些实施方案中，所述的鼻咽癌为II型非角化鳞癌。在一些实施方案中，所述的鼻咽癌为II型未分化型非角化鳞癌。在一些实施方案中，所述的鼻咽癌为II型分化型非角化鳞癌。
在一些实施方案中，所述的鼻咽癌为转移性的鼻咽癌。在一些实施方案中，所述的鼻咽癌为复发性和/或难治性和/或晚期的鼻咽癌。在一些实施方案中，所述的鼻咽癌为不可切除的鼻咽癌；在某些实施方案中，所述的鼻咽癌为接受过至少两种化疗药物的鼻咽癌。
在一些实施方案中，所述的化疗包括一线化疗和二线化疗；包括但不限于紫杉类(例如紫杉醇、多西他赛)、氟尿嘧啶、顺铂、环磷酰胺中的一种或多种。本领域技术人员可以理解的是，与所述的化疗同时或者先后，患者也可以接受放疗。
第二治疗药物
本申请所述的第二治疗药物包括但不限于化疗药物、小分子靶向抗肿瘤药物、免疫治疗药物、大分子抗体药物。
在一些实施方案中，所述的第二治疗药物为化疗药物，包括但不限于铂类药物、氟嘧啶衍生物、喜树碱类、紫杉类、长春碱类、蒽环类、抗生素类、鬼臼类、抗代谢类药物中的一种或多种，可以列举的实例包括但不限于铂类药物(例如奥沙利铂、顺铂、卡铂、米铂、奈达铂、双环铂(dicycloplatin)、乐铂(Lobaplatin)、四硝酸三铂、菲铂、吡铂、沙铂)、氟嘧啶衍生物(例如吉西他滨、卡培他滨、安西他滨、氟尿嘧啶(5-氟尿嘧啶)、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷)、紫杉烷类(例如紫杉醇、白蛋白结合的紫杉醇以及多西他赛)、喜树碱类(例如喜树碱、羟基喜树碱、9-氨基喜树碱、7-乙基喜树碱、伊立替康、拓扑替康)、长春碱类(长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁(vinflunine)、去甲长春花碱)、蒽环类(表柔比星、阿霉素、柔红霉素、吡柔比星、氨柔比星、伊达柔比星、米托蒽醌、阿柔比星、戊柔比星、佐柔比星、匹杉琼、吡喃阿霉素)、阿糖胞苷、巯鸟嘌呤、培美曲塞、卡氮芥、美法仑、依托泊苷(足叶乙苷)、替尼铂苷、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、甲氨蝶呤、苯达莫司汀、脂质体阿霉素、放线菌素D(更生霉素)、博来霉素、平阳霉素、替莫唑胺、氨烯咪胺、培洛霉素、艾日布林、普那布林(plinabulin)、Sapacitabine、曲奥舒凡(treosulfan)、153Sm-EDTMP、替吉奥和encequidar中的一种或多种。
在某些具体实施方案中，所述第二治疗药物是铂类药物中的一种或多种，所述铂类药物包括但不限于顺铂、卡铂、奈达铂、奥沙利铂、米铂、四硝酸三铂、菲铂、吡铂、沙铂、乐铂等。
视需要，所述的第二治疗药物配合化疗辅助药物使用，所述的化疗辅助药物包括但不限于甲酰四氢叶酸钙(CF)、醛氢叶酸、美司钠、双膦酸盐、氨磷汀、造血细胞集落刺激因子(CSFs)。在一些实施方案中，所述的化疗辅助药物为甲酰四氢叶酸钙(CF)、美司钠、醛氢叶酸。
在一些实施方案中，所述的第二治疗药物为免疫治疗药物，包括但不限于干扰素(干扰素α、干扰素α-1b、干扰素α-2b)、白介素、西罗莫司(temsirolimus)、依维莫司(everolimus)、地磷莫司(ridaforolimus)、替西罗莫司中的一种或多种。
在一些实施方案中，所述的第二治疗药物为小分子靶向抗肿瘤药物，包括但不限于蛋白激酶抑制剂。其中，所述的蛋白激酶抑制剂包括但不限于酪氨酸激酶抑制剂、丝氨酸和/或苏氨酸激酶抑制剂、聚ADP 核糖聚合酶(PARP，poly ADP-ribose polymerase)抑制剂，所述抑制剂针对的靶点包括但不限于Fascin-1蛋白、HDAC(组蛋白去乙酰化酶)、蛋白酶体(Proteasome)、CD38、SLAMF7(CS1/CD319/CRACC)、RANKL、EGFR(表皮生长因子受体)、间变性淋巴瘤(ALK)、MET基因、ROS1基因、HER2基因、RET基因、BRAF基因、PI3K信号通路、DDR2(盘状死亡受体2)基因、FGFR1(成纤维生长因子受体1)、NTRK1(神经营养酪氨酸激酶1型受体)基因、KRAS基因；所述小分子靶向抗肿瘤药物的靶点还包括COX-2(环氧酶-2)、APE1(脱嘌呤脱嘧啶核酸内切酶)、VEGFR(血管内皮生长因子受体)、CXCR-4(趋化因子受体-4)、MMP(基质金属蛋白酶)、IGF-1R(***受体)、Ezrin、PEDF(色素上皮衍生因子)、AS、ES、OPG(骨保护因子)、Src、IFN、ALCAM(白细胞活化黏附因子)、HSP、JIP1、GSK-3化(糖原合成激酶3糖)、CyclinD1(细胞周期调节蛋白)、CDK4(细胞周期素依赖性激酶)、TIMP1(组织金属蛋白酶抑制物)、THBS3、PTHR1(甲状旁腺素相关蛋白受体1)、TEM7(人肿瘤血管内皮标志物7)、COPS3、组织蛋白酶K。可以列举的小分子靶向抗肿瘤药物包括但不限于伊马替尼(Imatinib)、舒尼替尼(Sunitinib)、尼罗替尼(Nilotinib)、波舒替尼(bosutinib)、塞卡替尼(Saracatinib)、帕唑帕尼(Pazopanib)、曲贝替定(Trabectedin)、瑞格非尼(Regorafenib)、西地尼布(Cediranib)、硼替佐米(Bortezomib)、帕比司他(Panobinostat)、卡非佐米(Carfilzomib)、伊沙佐米(Ixazomib)、阿帕替尼(apatinib)、厄洛替尼(Erlotinib)、阿法替尼(Afatinib)、克唑替尼(Crizotinib)、色瑞替尼(Ceritinib)、威罗菲尼(Vemurafenib)、达拉菲尼(Dabrafenib)、卡博替尼(Cabozantinib)、吉非替尼(Gefitinib)、达可替尼(Dacomitinib)、奥希替尼(Osimertinib)、奥美替尼、艾乐替尼(Alectinib)、布格替尼(Brigatinib)、劳拉替尼(Lorlatinib)、曲美替尼(Trametinib)、拉罗替尼(Larotrectinib)、埃克替尼(icotinib)、拉帕替尼(Lapatinib)、凡德他尼(Vandetanib)、司美替尼(Selumetinib)、索拉非尼(Sorafenib)、奥莫替尼(Olmutinib)、沃利替尼(Savolitinib)、呋喹替尼(Fruquintinib)、恩曲替尼(Entrectinib)、达沙替尼(Dasatinib)、恩沙替尼(Ensartinib)、乐伐替尼(Lenvatinib)、itacitinib、吡咯替尼(Pyrotinib)、比美替尼(Binimetinib)、厄达替尼(Erdafitinib)、阿西替尼(Axitinib)、来那替尼(Neratinib)、考比替尼(Cobimetinib)、阿卡替尼(Acalabrutinib)、法米替尼(Famitinib)、马赛替尼(Masitinib)、伊布替尼(Ibrutinib)、rociletinib、尼达尼布(nintedanib)、来那度胺、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、帕博西尼(palbociclib)、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、poziotinib、DS-1205c、capivasertib、SH-1028、二甲双胍、seliciclib、OSE-2101、APL-101、berzosertib、idelalisib、lerociclib、ceralasertib、PLB-1003、tomivosertib、AST-2818、SKLB-1028、D-0316、LY-3023414、allitinib、MRTX-849、AP-32788、AZD-4205、lifirafenib、vactosertib、mivebresib、napabucasin、sitravatinib、TAS-114、molibresib、CC-223、rivoceranib、CK-101、LXH-254、simotinib、GSK-3368715、TAS-0728、masitinib、tepotinib、HS-10296、AZD-4547、merestinib、olaptesed pegol、galunisertib、ASN-003、gedatolisib、defactinib、lazertinib、CKI-27、S-49076、BPI-9016M、RF-A-089、RMC-4630、AZD-3759、antroquinonol、SAF-189s、AT-101、TTI-101、naputinib、LNP-3794、HH-SCC-244、ASK-120067、CT-707、epitinib succinate、tesevatinib、SPH-1188-11、BPI-15000、copanlisib、niraparib、olaparib、veliparib、talazoparib tosylate、DV-281、Siremadlin、Telaglenastat、MP-0250、GLG-801、ABTL-0812、bortezomib、tucidinostat、vorinostat、resminostat、epacadostat、tazemetostat、entinostat、mocetinostat、quisinostat、LCL-161、KML-001中的一种或者多种。在一些实施方案中，所述的小分子靶向抗肿瘤药物为索拉非尼、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、尼达尼布中的一种或者多种。
在一些实施方案中，所述的第二治疗药物为大分子抗体药物。其中，所述大分子抗体药物针对的靶点包括但不限于PD-1、PD-L1、细胞毒性T淋巴细胞抗原4(cytotoxic T-lymphocyte antigen 4,CTLA-4)、血小板衍生生长因子受体α(PDGFR-α)、血管内皮生长因子(VEGF)、人表皮生长因子受体-2(HER2)、表皮生长因子受体(EGFR)、神经节苷脂GD2、B细胞表面蛋白CD20、B细胞表面蛋白CD52、B细胞表面蛋白CD38、B细胞表面蛋白CD319、B细胞表面蛋白CD30、B细胞表面蛋白CD19/CD3中的任意一种或多种。
在一些实施方案中，所述的抗体药物为PD-1受体和其配体PD-L1之间的相互作用的抑制剂；在一些实施方案中，所述的抗体药物为细胞毒性T淋巴细胞抗原4(cytotoxic T-lymphocyte antigen 4,CTLA-4)抑制剂。在一些实施方案中，所述的抗体药物为血小板衍生生长因子受体α(PDGFR-α)抑制剂。一些实施方案中，所述的抗体药物为表皮生长因子受体(EGFR)抑制剂。
在一些方案中，PD-1受体和其配体PD-L1之间的相互作用的抑制剂是结合程序性死亡受体1(PD-1)和/或抑制PD-1活性的抗体或其抗原结合部分，或者，是结合程序性死亡配体1(PD-L1)和/或抑制PD-L1 活性的抗体或其抗原结合部分，例如是抗PD-1抗体或者抗PD-L1抗体。在一些具体实施方案中，所述抗体或其抗原结合部分是(a)抗PD-1单克隆抗体或其抗原结合片段，其特异地结合人PD-1且阻断人PD-L1与人PD-1的结合；或(b)抗PD-L1单克隆抗体或其抗原结合片段，其特异地结合人PD-L1且阻断人PD-L1与人PD-1的结合。
在一些方案中，所述抗PD-1或PD-L1抗体是抗PD-1或PD-L1单克隆抗体。
在一些方案中，所述抗PD-1或PD-L1抗体为人源性抗体或鼠源性抗体。
在一些方案中，所述抗PD-1抗体可以选自纳武利尤单抗(Nivolumab)、帕博利珠单抗(Pembrolizumab)、德瓦鲁单抗(Durvalumab)、特瑞普利单抗(toripalimab，JS-001)、信迪利单抗(IBI308)、卡瑞利株单抗(Camrelizumab)、替雷利株单抗(BGB-A317)、杰诺单抗(GB226)、丽珠单抗(LZM009)、HLX-10、BAT-1306、AK103(HX008)、AK104(康方生物)、CS1003、SCT-I10A、F520、SG001、GLS-010中的任意一种或多种。
在一些方案中，所述抗PD-L1抗体可以选自Atezolizumab、Avelumab、Durvalumab、KL-A167、SHR-1316、BGB-333、JS003、STI-A1014(ZKAB0011)、KN035、MSB2311、HLX-20、CS-1001中的任意一种或多种。
在一些具体的实施方案中，所述抗PD-1抗体为特瑞普利单抗。
在一些具体的实施方案中，所述抗PD-1抗体为帕博利珠单抗。
在一些方案中，所述细胞毒性T淋巴细胞抗原4(cytotoxic T-lymphocyte antigen 4，CTLA-4)抑制剂是抗CTLA-4抗体。在一些具体实施方案中，所述的抗CTLA-4抗体是抗CTLA-4单克隆抗体。
在一些方案中，所述抗CTLA-4抗体可以选自伊匹单抗(Ipilimumab)、替西木单抗(Tremelimumab)、AGEN-1884、BMS-986249、BMS-986218、AK-104、IBI310中的任意一种或多种。
在一些具体的实施方案中，所述抗CTLA-4抗体为伊匹单抗。
在一些方案中，所述血小板衍生生长因子受体α(PDGFR-α)抑制剂是抗-PDGFRα抗体。在一些具体实施方案中，所述的抗-PDGFRα抗体是抗-PDGFRα单克隆抗体。
在一些具体的实施方案中，所述抗-PDGFRα抗体为奥拉单抗(Olaratumab)。
在一些方案中，所述的抗体药物为表皮生长因子受体(EGFR)抑制剂是抗EGFR抗体。在一些具体实施方案中，所述的抗EGFR抗体是抗EGFR单克隆抗体。在一些具体的实施方案中，所述抗EGFR抗体为西妥昔单抗(Cotuximab)。
在一些具体的实施方案中，所述的抗体药物还可以包括但不限于贝伐珠单抗(Bevacizumab)、雷莫芦单抗(Ramucirumab)、帕妥珠单抗(Pertuzumab)、曲妥珠单抗(Trastuzmab)、西妥昔单抗(Cotuximab)、尼妥珠单抗(Nimotuzumab)、帕尼单抗(Panitumumab)、耐昔妥珠单抗(Necitumumab)、Dinutuximab、利妥昔单抗(Rituximab)、替依莫单抗(Ibritumomab)、奥法木单抗(Ofatumumab)、Obinutuzumab、阿仑单抗(Alemtuzumab)、达雷木单抗(Daratumumab)、吉妥单抗(Gemtuzumab)、埃罗妥珠单抗(Elotuzumab)、本妥昔单抗(Brentuximab)、奥英妥珠单抗(Inotuzumab Ozogamicin)、博纳吐单抗(Blinatumomab)中的任意一种或多种。
在一些实施方案中，所述的第二治疗药物为甲氨蝶呤、顺铂、卡铂、紫杉醇、多西他赛氟尿嘧啶、去甲长春花碱、博来霉素、异环磷酰胺、美司钠、醛氢叶酸、米托蒽醌、吡喃阿霉素、柔红霉素、阿糖胞苷、巯鸟嘌呤、依托泊苷、三尖杉酯碱、吉西他滨、西妥昔单抗、表柔比星中的一种或多种。
在一些实施方案中，所述的第二治疗药物为甲氨蝶呤。
在一些具体的实施方案中，所述的第二治疗药物具体为甲氨蝶呤40mg/m 2IV第1天，每7天一次。
在一些实施方案中，所述的第二治疗药物为紫杉醇。
在一些具体的实施方案中，所述的第二治疗药物具体为紫杉醇250mg/m 2CIV第1天，每21天重复。
在一些实施方案中，所述的第二治疗药物为卡铂和5-氟尿嘧啶。
在一些实施方案中，所述的第二治疗药物为顺铂和西妥昔单抗。
在一些实施方案中，所述的第二治疗药物为卡铂和西妥昔单抗。
在一些实施方案中，所述的第二治疗药物为吉西他滨和长春瑞滨。
在一些实施方案中，所述的第二治疗药物为吉西他滨和紫杉醇。
在一些实施方案中，所述的第二治疗药物为DF方案，具体为顺铂和氟尿嘧啶。
在一些实施方案中，所述的第二治疗药物为PC方案，具体为紫杉醇和卡铂。
在一些实施方案中，所述的第二治疗药物为DA方案，具体为柔红霉素和阿糖胞苷。
在一些实施方案中，所述的第二治疗药物为ME方案，具体为米托蒽醌、依托泊苷。
在一些实施方案中，所述的第二治疗药物为GP方案，具体为吉西他滨和顺铂。
在一些实施方案中，所述的第二治疗药物为FP方案，具体为5-氟尿嘧啶和顺铂。
在一些实施方案中，所述的第二治疗药物为AP方案，具体为阿霉素、顺铂。
在一些实施方案中，所述的第二治疗药物为IE方案，具体为异环磷酰胺、美司钠、依托泊苷。
在一些实施方案中，所述的第二治疗药物为多西他赛、顺铂和5-氟尿嘧啶。
在一些实施方案中，所述的第二治疗药物为顺铂、表柔比星和紫杉醇。
在一些实施方案中，所述的第二治疗药物为顺铂、5-氟尿嘧啶和西妥昔单抗。
在一些实施方案中，所述的第二治疗药物为卡铂、5-氟尿嘧啶和西妥昔单抗。
在一些实施方案中，所述的第二治疗药物为顺铂、多西他赛和紫杉醇。
在一些实施方案中，所述的第二治疗药物为卡铂、多西他赛和紫杉醇。
在一些实施方案中，所述的第二治疗药物为卡铂、紫杉醇和吉西他滨。
在一些实施方案中，所述的第二治疗药物为NMB方案，具体为去甲长春花碱、甲氨蝶呤、博来霉素。
在一些实施方案中，所述的第二治疗药物为PIC方案，具体为紫杉醇、异环磷酰胺、美司钠、顺铂。
在一些实施方案中，所述的第二治疗药物为DLF方案，具体为顺铂、氟尿嘧啶、醛氢叶酸。
在一些实施方案中，所述的第二治疗药物为PBF方案，具体为顺铂、博来霉素、氟尿嘧啶。
在一些实施方案中，所述的第二治疗药物为MFC方案，具体为米托蒽醌、氟尿嘧啶、卡铂。
在一些实施方案中，所述的第二治疗药物为TPF方案，具体为吡喃阿霉素、顺铂、氟尿嘧啶。
在一些实施方案中，所述的第二治疗药物为DAT方案，具体为柔红霉素、阿糖胞苷、巯鸟嘌呤、依托泊苷。
在一些实施方案中，所述的第二治疗药物为HA方案，具体为三尖杉酯碱、阿糖胞苷、巯鸟嘌呤。
在一些实施方案中，所述的第二治疗药物为HOAP方案，具体为三尖杉酯碱、长春新碱、阿糖胞苷、强地松。
在某些具体实施方案中，所述第二治疗药物是替吉奥。
在某些具体实施方案中，所述第二治疗药物是信迪利单抗。
在某些具体实施方案中，所述第二治疗药物是卡培他滨。
化合物I或其药学上可接受的盐
化合物I的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
Figure PCTCN2020092125-appb-000002
本申请中，凡是涉及安罗替尼，均是指化合物I。
化合物I可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成化合物I的游离碱形式。例如，化合物I药学上可接受的盐在本申请的范围内可按照本领域公知的方法由不同的有机酸和无机酸产生。
在一些实施方案中，以化合物I盐酸盐的形式给药。在一些实施方案中，以化合物I一盐酸盐的形式给药。在一些实施方案中，以化合物I二盐酸盐的形式给药。在一些实施方案中，以化合物I盐酸盐的晶体形式给药。在特定的实施方案中，以化合物I二盐酸盐的晶体形式给药。
化合物I或其药学上可接受的盐、第二治疗药物可通过多种途径给药，该途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、***、眼内、局部、皮下、脂肪内、关节内、腹膜内和鞘内。在一个特定的实施方案中，通过口服给药。
给予化合物I或其药学上可接受的盐、第二治疗药物的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、受试者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克至16毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克至14毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为8毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为10毫克。在一个特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为12毫克。在本申请中，例如，对于片剂或胶囊剂而言，“以单位剂量为基础含有12mg的化合物I或其药学上可接受的盐”意味着最终制成的每片片剂或每颗胶囊剂中含有12mg的化合物I。
化合物I或其药学上可接受的盐、第二治疗药物可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一个实施方案中，以口服固体制剂每天给药一次。
上述治疗方法中，给药的方法可根据药物的活性、毒性以及受试者的耐受性等来综合确定。优选地，以间隔给药的方式给予化合物I或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予化合物I或其药学上可接受的盐。例如在给药期内每天给予化合物I或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:(0.5～5)，优选2:0.5～3，较优选2:0.5～2，更优选2:0.5～1。
在一些实施方案中，连续给药2周停药2周。在一些实施方案中，每天给药1次，持续给药14天，然后停药14天；接着每天给药1次，持续给药14天，然后停药14天，如此连续给药2周停药2周的间隔给药方式可以反复进行多次。
在一些实施方案中，连续给药2周停药1周。在一些实施方案中，每天给药1次，持续给药14天，然后停药7天；接着每天给药1次，持续给药14天，然后停药7天，如此连续给药2周停药1周的间隔给药方式可以反复进行多次。在一个具体的实施方案中，化合物I或其药学上可接受的盐在每个周期的第1-14天给药，每21天为一个给药周期。
在一些实施方案中，连续给药5天停药2天。在一些实施方案中，每天给药1次，持续给药5天，然后停药2天；接着每天给药1次，持续给药5天，然后停药2天，如此连续给药5天停药2天的间隔给药方式可以反复进行多次。
在某些特定的实施方案中，以每日一次12mg的剂量口服给药，连续用药2周，停1周的给药方式给药。
药物组合
在某些实施方案中，化合物I或其药学上可接受的盐与手术切除和/或放射疗法组合。
本申请所述的药物组合物中的各组分可任选地与一种或者多种药学上可接受的载体并用，其中组分可以各自独立地、或者其中的部分或全部共同含有药学上可接受的载体和/或赋形剂。本申请所述的药物组合物可以各自分开配制，或者其中的部分或全部共同配制。优选的，所述药物组合物的各组分分开配制，或各自配制成合适的药物组合物。在一些实施方案中，本申请的药物组合物可以配制成适合于单次或多次施用的药物组合物。在一些特定的实施方案中，含有化合物I或其药学上可接受的盐的药物组合物可选自固体药物组合物，所述固体药物组合物包括但不限于片剂或胶囊。
本申请的药物组合物中的组分可以各自单独施用，或者其中的部分或全部共同施用。本申请的药物组合物中的组分可以基本上不同时施用，或者其中的部分或全部基本上同时施用。
本申请的药物组合物中的组分可以各自独立地，或者其中的部分或全部共同以适合的途径施用，包括但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)。在一些实施方案中，本申请的药物组合物的组分可以各自独立地，或者其中的部分或全部共同口服施用或注射施用，例如静脉注射或腹腔注射。
本申请的药物组合物中的组分可以各自独立地，或者其中的部分或全部共同是适合的剂型，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
在本申请的一些方案中，所述药物组合物是固定组合。在一些方案中，所述固定组合呈固体药物组合物形式或液体药物组合物形式。
在本申请的一些方案中，所述药物组合物是非固定组合。在一些方案中，所述非固定组合中的第二治疗药物和化合物I或其药学上可接受的盐各自呈药物组合物形式。
在本申请的一些实施方案中，化合物I或其药学上可接受的盐与一种或多种第二治疗药物同时或先后给予。在某些实施方案中，一种或多种第二治疗药物在给予化合物I或其药学上可接受的盐前或在与化合物I或其药学上可接受的盐组合前已给予受试者。在某些实施方案中，一种或多种第二治疗药物在给予化合物I或其药学上可接受的盐后或在与化合物I或其药学上可接受的盐组合后再给予受试者。在某些实施方案中，化合物I或其药学上可接受的盐在给予一种或多种第二治疗药物前或在与一种或多种第二治疗药物组合前已给予受试者。在某些实施方案中，化合物I或其药学上可接受的盐在给予一种或多种第二治疗药物后或在与一种或多种第二治疗药物组合后再给予受试者。在一些实施方案中，化合物I或其药学上可接受的盐与一种或多种第二治疗药物组合给予受试者时，序贯给予受试者化合物I或其药学上可接受的盐和一种或多种第二治疗药物。在某些实施方案中，一种或多种第二治疗药物在治疗癌症中无效。在一些实施方案中，所述第二治疗药物是本文描述或本领域已知的任何抗癌剂。
在一些方案中，还提供一种用于治疗头颈癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有化疗药物作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。在一些方案中，还提供一种用于治疗头颈癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有小分子靶向抗肿瘤药物作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。在一些方案中，还提供一种用于治疗头颈癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有免疫治疗药物作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。在一些方案中，还提供一种用于治疗头颈癌的药物组合的试剂盒，其中含有(a)第一种药物组合物，含有大分子抗体药物作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。
在一些方案中，还提供一种用于治疗头颈癌的药物组合物的试剂盒，其中含有：(a)第一种药物组合物，含有西妥昔单抗和铂类药物作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。在一些方案中，还提供一种用于治疗头颈癌的药物组合物的试剂盒，其中含有(a)第一种药物组合物，含有吉西他滨和铂类药物作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。在一些方案中，还提供一种用于治疗头颈癌的药物组合物的试剂盒，其中含有(a)第一种药物组合物，含有吉西他滨和顺铂作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。在一些方案中，还提供一种用于治疗头颈癌的药物组合物的试剂盒，其中含有(a)第一种药物组合物，含有吉西他滨和紫杉醇作为活性成分；和(b)第二种药物组合物，其中含有化合物I或其药学上可接受的盐作为活性成分。
定义和说明
本文中，除非另有说明，为本申请的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
如本文所用，术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对受试者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
如本文所用，术语“治疗失败”是指毒副作用不可耐受、治疗过程中疾病进展或治疗结束后复发。具体是指接受过手术、放疗、化疗或综合治疗的患者，出现疾病进展或远处转移，目前无其它有效标准治疗手段。
“晚期”是指转移性腺癌或局部晚期无法局部根治性手术或放疗的临床分期。
如本文所用，术语“受试者”表示哺乳动物，诸如啮齿动物、猫科动物、犬科动物和灵长类动物。优选地，根据本申请的受试者是人。术语“患者”是人。“施用”表示，使用本领域技术人员已知的多种方法和递送***中的任一种，向患者物理引入包含治疗剂的组合物。施用途径包括静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径，例如通过注射或输注。本文中使用的短语“胃肠外施用”是指，通常通过注射进行的除了肠内和局部施用以外的施用模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、***内、病灶内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。在某些实施方案中，药物通过非胃肠外途径施用，在某些实施方案中，口服施用。其它非胃肠外途径包括局部、表皮或粘膜施用途径，例如，鼻内地、***地、直肠地、舌下地或局部地。还可以执行施用，例如，一次、多次，和/或在一个或多个延长的时间段中。
作为例子，“抗癌药”促进患者中的癌症消退或阻止进一步的肿瘤生长。在某些实施方案中，药物将癌症消退促进至消除癌症的点。“促进癌症消退”是指单独地或与抗肿瘤剂联合施用药物，导致肿瘤生长 或大小的减小、肿瘤的坏死、至少一种疾病征状的严重程度的降低、无疾病征状阶段的频率和持续时间的增加。此外，关于治疗的术语“有效的”和“有效性”包括药理学有效性和生理学安全性。药理学有效性表示药物在受试者中促进癌症消退的能力。生理学安全性表示由药物施用引起的在细胞、器官和/或生物体水平的毒性水平或其它不利的生理效应(不良作用)。
作为用于***的例子，相对于未治疗的患者，或者，在某些实施方案中，相对于用护理标准疗法治疗的受试者，抗癌药可以将细胞生长或肿瘤生长抑制至少约10％、至少约20％、至少约40％、至少约60％或至少约80％。在本申请的其它实施方案中，可以观察到肿瘤消退并持续至少约20天、至少约40天或至少约60天的时间段。尽管存在治疗有效性的这些最终测量，药物的评价还必须考虑“免疫相关的”应答模式。
“免疫相关的”应答模式表示在用免疫治疗剂治疗的癌症受试者中经常观察到的临床应答模式，所述免疫治疗剂通过诱导癌症特异性免疫应答或通过改变天然免疫过程而产生抗肿瘤作用。该应答模式的特征在于在肿瘤负荷的初始增加或新病变出现之后的有益的治疗效果，其在传统化学治疗剂的评价中将被分类为疾病进展并且将与药物失效同义。因此，免疫治疗剂的适当评价可以需要长期监测这些药剂对靶疾病的影响。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的结合蛋白。本申请的抗体和其片段可以是整个抗体或其任何片段。因此，本申请的抗体和片段包括单克隆抗体或其片段和抗体变体或其片段，以及免疫缀合物。抗体片段的实例包括Fab片段、Fab'片段、F(ab)'2片段、Fv片段、分离的CDR区、单链Fv分子(scFv)、Fd片段和本领域已知的其它抗体片段。抗体和其片段还可以包括重组多肽、融合蛋白和双特异性抗体。本文公开的抗PD-L1抗体和其片段可以是IgG1、IgG2、IgG3或IgG4同种型。
术语“同种型”是指由重链恒定区基因编码的抗体种类。在一个实施方案中，本文公开的抗PD-1/PD-L1抗体和其片段是IgG1或IgG4同种型。本申请的抗PD-1/PD-L1抗体和其片段可以衍生自任何物种，其包括但不限于小鼠、大鼠、兔、灵长类动物、美洲驼和人。PD-1/PD-L1抗体和其片段可以是嵌合抗体、人源化抗体或完整的人抗体。
术语“人源化”是指抗体中抗原结合位点来源于非人物种且可变区框架来源于人免疫球蛋白序列。人源化抗体在框架区中可包含置换，使得该框架可能不是表达的人免疫球蛋白或种系基因序列的精确拷贝。
“分离的抗体”表示这样的抗体：其基本上不含有具有不同抗原特异性的其它抗体(例如，分离的特异性地结合PD-1/PD-L1的抗体基本上不含有特异性地结合除PD-1/PD-L1以外的抗原的抗体)。但是，分离的特异性地结合PD-1/PD-L1的抗体可以具有与其它抗原(诸如来自不同物种的PD-1/PD-L1分子)的交叉反应性。此外，分离的抗体可以基本上不含有其它细胞材料和/或化学物质。
术语“单克隆抗体”(“mAb”)是指单一分子组成的抗体分子。单克隆抗体组合物显示出对于特定表位的单一结合特异性和亲和力，或就双特异性单克隆抗体而言，显示出对于两种不同表位的双重结合特异性。mAb是分离的抗体的一个例子。通过本领域技术人员已知的杂交瘤技术、重组技术、转基因技术或其它技术，可以生产mAb。分离的单克隆抗体的例子包括但不限于纳武利尤单抗(Nivolumab)
Figure PCTCN2020092125-appb-000003
帕博利珠单抗(Pembrolizumab)
Figure PCTCN2020092125-appb-000004
Durvalumab、Avelumab、特瑞普利单抗(JS-001，君实生物)、信迪利单抗(Sintilimab，IBI308，信达生物)、卡瑞利株单抗(SHR-1210，Camrelizumab，恒瑞医药，可以参见CN105026428B或WO2015085847A1)、替雷利株单抗(BGB-A317，百济神州)、杰诺单抗(GB226，嘉和生物)、丽珠单抗(LZM009，丽珠制药)、HLX-10(复宏汉霖)、BAT-1306(百奥泰)、HX008(AK103，康方生物/翰中生物)、AK104(中山康方)、CS1003(基石药业)、SCT-I10A(神州细胞)、F520(山东新时代药业/鲁南制药)、SG001(尚健生物)、GLS-010(誉衡药业)、Atezolizumab(
Figure PCTCN2020092125-appb-000005
罗氏)、Avelumab(
Figure PCTCN2020092125-appb-000006
默克/辉瑞)、Durvalumab(
Figure PCTCN2020092125-appb-000007
阿斯利康)KL-A167(科伦药业)、SHR-1316(恒瑞医药)、BGB-333(百济神州)、JS003(君实生物)、STI-A1014(ZKAB0011，兆科药业)、KN035(康宁杰瑞/思路迪)、MSB2311(迈博斯生物)、HLX-20(复宏汉霖)、CS-1001(基石药业)等。
抗体的“抗原结合部分”(也称为“抗原结合片段”)表示抗体的一个或多个片段，其保留特异性地结合被完整抗体结合的抗原的能力。
“程序性死亡受体-1(PD-1)”表示属于CD28家族的免疫抑制性受体。PD-1主要在体内先前活化的T细胞上表达，并且结合两种配体PD-L1和PD-L2。本文使用的术语“PD-1”包括人PD-1(hPD-1)，hPD-1的变体、同种体和物种同系物，以及与hPD-1具有至少一个共同表位的类似物。
“程序性死亡配体-1(PD-L1)”是针对PD-1的两种细胞表面糖蛋白配体(另一种是PD-L2)之一，其在结合PD-1后下调T细胞活化和细胞因子分泌。
“复发性”癌症是在对初始治疗(例如手术)产生应答后，在初始部位或远处部位再生的癌症。“局部复发性”癌症是在治疗后，在与先前治疗的癌症相同的位置出现的癌症。
“不能切除的”癌症是无法通过手术去除的。
“转移性”癌症是指从身体的一部分(例如头颈部)扩散到身体的另一部分的癌症。
备选方案(例如，“或”)的应用应当被理解为是指备选方案中的任一个、两个或它们的任意组合。本文中使用的不定冠词“一个”或“一种”应当理解为表示任何列举或枚举的组分中的“一个或多个/一种或多种”。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”，包括碱根离子与自由酸形成的盐或酸根离子与自由碱形成的盐，例如包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、琥珀酸盐、甲磺酸盐、苯磺酸盐、对甲基苯磺酸盐、钠盐、钾盐、铵盐、氨基酸盐，优选盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐、对甲基苯磺酸盐、钠盐、钾盐、铵盐、氨基酸盐等。本申请中，当形成药学上可接受的盐时，所述自由酸与碱根离子的摩尔量之比为约1:0.5～1:5，优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。本申请中，当形成药学上可接受的盐时，所述自由碱与酸根离子的摩尔量之比为约1:0.5～1:5，优选1:0.5、1:1、1:2、1:3、1:4、1:5、1:6、1:7或1:8。
术语“固定组合”指活性组分(例如化疗药物或化合物I)以固定总剂量或剂量比例，或以单一实体、药物组合物或制剂的形式同时给予受试者。
术语“非固定组合”指两种以上活性组分作为独立的实体(例如药物组合物、制剂)同时、并行或依序且无具体时间限制地给予受试者，其中所述给予受试者的活性成分达到治疗有效量水平。非固定组合可列举的例子是鸡尾酒疗法，例如给予3种或以上之活性组分。在非固定组合中，所述各个活性组分可以作为完全独立的药物组合物进行包装、销售或给药。所述“非固定组合”也包括“固定组合”之间、或“固定组合”与任一或多种活性组分的独立实体的联合使用。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以在混合物中一起、作为单一制剂同时地或作为单一制剂以任何顺序依次地施用于受试者。
术语“药物组合物”是指一种或多种本申请的活性成分(例如第二治疗药物或化合物I)或其药物组合与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本申请的化合物或其药物组合。
本申请中的“临床有收益”，包括但不限于：临床患者无进展生存期(PFS)得到延长、总生存期(OS)得到延长、客观缓解率(ORR)得到提高、疾病控制率(DCR)得到提高、不良反应数量减少和/或程度降低、远处转移率以及局部控制率下降等。具体来说，在本申请的一些具体的实施方案中，尤其是在本申请的具体实施例中，在临床试验中对于头颈癌人类患者的客观缓解率达到约10％以上，优选达到约15％以上，进一步优选达到约20％以上，更优选达到约30％以上，尤其是达到35％以上；患者的疾病控制率达到50％以上，优选达到约60％以上，进一步优选达到约70％以上，更优选达到约80％以上，尤其达到90％以上，此时，本申请的药物表现出临床有收益。
本申请中的“约”是指在所给定的具体数值范围±5％范围内波动，优选在±2％范围内波动，更优选在±1％范围内波动。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
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，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
下面结合具体实施例对本申请进行进一步的描述，然而，本申请中这些实施例仅用于阐明而不限制本申请的范围。同样，本申请不限于本文描述的任何具体优选的实施方案。本领域技术人员应该理解，对本申请技术特征所作的等同替换，或相应的改进，仍属于本申请的保护范围之内。除特别说明的以外，以下 实施例采用的试剂均为市售产品，溶液的配制可以采用本领域常规技术。
实施例1化合物I的二盐酸盐对于人喉癌细胞生长的影响
配制方法：
受试药物均用二甲基亚砜溶解，配成100mmol/L的母液，于-20℃保存，备用。使用时用DMEM血清培养液配制成所需浓度。
细胞培养：
人喉癌鳞癌Hep-2细胞株和人喉癌TU212细胞株分别培养于含10％胎牛血清和0.1g/L链霉素与青霉素(终浓度为100U·mL -1)的DMEM完全培养液中，恒温37℃置于5％CO 2培养箱中培养。待细胞融合度达到85％左右时，用0.02％EDTA+0.25％胰蛋白酶混合消化，收集细胞，1000r/min离心，传代培养。
实验过程：
可按照本领域通常的方法(例如常见的MTT法)来测定IC 50值，也可按照如下的方法(MTT法)来测定：
接种的对数生长期细胞于96孔培养板(180μL/孔，10 5个细胞/孔)中，在37℃、5％CO 2条件下生长24小时，加入化合物I的二盐酸盐(梯度为0、0.005、0.1、0.05、0.1、0.5、1.5、4、12、30μg/ml浓度的溶液)进行培养，每个浓度设两复孔，每孔加20μL，同时设相应浓度的生理盐水溶媒对照及无细胞调零孔；将肿瘤细胞在37℃、5％CO 2条件下再培养24小时(即总共48小时)；药物作用结束后，每孔加入MTT工作液，4小时后，三联液溶解，37℃过夜。次日，用酶标仪(SPECTRA max 190)在570nm和630nm波长下测定OD值(所有在570nm波长下测得的OD值，减去对照波长630nm波长OD值后再计算)，以下列公式计算细胞生长抑制率：
抑制率＝(OD值对照孔-OD值给药孔)/OD值对照孔×100％
根据各浓度抑制率，采用GraphPad Prism 5软件计算半数抑制浓度IC 50。
实验结果：
化合物I的二盐酸盐对人喉癌鳞癌细胞Hep-2细胞株和人喉癌细胞TU212细胞株的体外药效学作用显示，化合物I的二盐酸盐对人喉癌鳞癌细胞和人喉癌细胞的增殖有明确的抑制作用。
实施例2化合物I的二盐酸盐对于人口腔鳞癌细胞生长的影响
配制方法：
受试药物均用二甲基亚砜溶解，配成100mmol/L的母液，于-20℃保存，备用。使用时用DMEM血清培养液配制成所需浓度。
细胞培养：
人口腔鳞癌scc4细胞株、人口腔鳞癌CAL-27细胞株和人口腔鳞癌HSC-4细胞株分别培养于含10％胎牛血清和0.1g/L链霉素与青霉素(终浓度为100U·mL -1)的DMEM完全培养液中，恒温37℃置于5％CO 2培养箱中培养。待细胞融合度达到85％左右时，用0.02％EDTA+0.25％胰蛋白酶混合消化，收集细胞，1000r/min离心，传代培养。
实验过程：
可按照本领域通常的方法(例如常见的MTT法)来测定IC50值，也可按照如下的方法(MTT法)来测定：
接种的对数生长期细胞于96孔培养板(180μL/孔，10 5个细胞/孔)中，在37℃、5％CO 2条件下生长24小时，加入化合物I的二盐酸盐(梯度为0、0.005、0.1、0.05、0.1、0.5、1.5、4、12、30μg/ml浓度的溶液)进行培养，每个浓度设两复孔，每孔加20μL，同时设相应浓度的生理盐水溶媒对照及无细胞调零孔；将肿瘤细胞在37℃、5％CO 2条件下再培养24小时(即总共48小时)；药物作用结束后，每孔加入MTT工作液，4小时后，三联液溶解，37℃过夜。次日，用酶标仪(SPECTRA max 190)在570nm和630nm波长下测定OD值(所有在570nm波长下测得的OD值，减去对照波长630nm波长OD值后再计算)，以下列公式计算细胞生长抑制率：
抑制率＝(OD值对照孔-OD值给药孔)/OD值对照孔×100％
根据各浓度抑制率，采用GraphPad Prism 5软件计算半数抑制浓度IC 50。
实验结果：
化合物I的二盐酸盐对人口腔鳞癌scc4细胞株、人口腔鳞癌CAL-27细胞株和人口腔鳞癌HSC-4细胞株的体外药效学作用显示，化合物I的二盐酸盐对人口腔鳞癌细胞的增殖有明确的抑制作用。
实施例3盐酸安罗替尼胶囊治疗复发/转移头颈部腺癌的临床研究
经组织病理学确诊，常规治疗失败的或晚期头颈部腺癌，包括：黏液表皮样癌、腺样囊性癌、多形性腺癌、涎腺导管癌、肌上皮癌、非特异性腺癌、非特异性透明细胞癌、囊腺癌、皮脂腺癌、皮脂淋巴腺癌、黏液腺癌、上皮-肌上皮癌，对上述患者给药盐酸安罗替尼胶囊：每日一次，早餐前口服，每次12mg，每个周期的d1-14给药，连续服药2周，停药1周，21天为一个治疗周期。
该研究表明，对于头颈部腺癌患者，安罗替尼的治疗方案临床有收益。
实施例4
经组织病理学确诊，既往接受或放疗和/或手术，以及铂治疗后、局部复发或远处转移不能耐受根治性治疗(包括放疗及手术)的头颈部鳞癌患者，具体为发生于口腔、口咽、喉和/或下咽的组织学和/或细胞学检查证实为鳞癌的患者，联合给药安罗替尼和信迪利单抗，具体给药方法如下：
盐酸安罗替尼胶囊：每日一次，早餐前口服，每次12mg，每个周期的d1-14给药，连续服药2周，停药1周，21天为一个治疗周期；
信迪利单抗：200mg，静脉输注，每个周期d1给药，21天为一个治疗周期。
所有患者持续治疗时间最多为12个，或直至疾病进展、发生不可耐受的毒性反应、死亡或发生其它案中规定需要终止治疗的情况，以先发生者为准。
疗效评估观察指标包括无进展生存期(PFS)、总生存期(OS)、客观缓解率(ORR＝CR+PR)、疾病控制率(DCR＝CR+PR+SD)、安全性指标。
该研究表明，对于头颈部鳞癌患者，安罗替尼联用信迪利单抗的治疗方案临床有收益。
患者病例1：
患者，男，55岁，喉癌术后复发(腮腺区复发)，肺转移。联合给药安罗替尼和信迪利单抗，具体给药方法，盐酸安罗替尼胶囊：每日一次，早餐前口服，每次12mg，每个周期的d1-14给药，连续服药2周，停药1周，21天为一个治疗周期；信迪利单抗：200mg，静脉输注，每个周期d1给药，21天为一个治疗周期。
给药4周期，疗效评估为PR(部分缓解)。
患者病例2：
患者，男，57岁，口底癌术后复发，联合给药安罗替尼和信迪利单抗，具体给药方法，盐酸安罗替尼胶囊：每日一次，早餐前口服，每次12mg，每个周期的d1-14给药，连续服药2周，停药1周，21天为一个治疗周期；信迪利单抗：200mg，静脉输注，每个周期d1给药，21天为一个治疗周期。
给药8周期，疗效评估为SD(病情稳定)。
实施例5
经病理学证实为头颈部癌初治患者；具体包括鼻咽癌、扁桃体癌、口底癌、口腔癌、喉癌及下咽癌患者，所有患者均使用调强放疗，并在放疗开始前使用安罗替尼，具体给药方法如下：
安罗替尼服用：放疗前约一周开始使用，10mg/天，连用两周后休息一周，放疗期间共完成三周期服药方案，视放疗后肿瘤变化情况决定是否继续服用。
疗效评估观察指标包括3年总体生存(OS)，无进展生存(DFS)，3年远处转移率以及局部控制率。
患者病例1：
患者，男，32岁，病理诊断为扁桃体癌，2018年10月10日开始服用盐酸安罗替尼胶囊：每日一次，早餐前口服，每次10mg，连用两周后休息一周；2018年10月15日开始放射治疗：
放疗时间 放疗剂量(Gy) 疗效评估
第1周 10.75 -
第2周 21.5 -
第3周 32.25 -
第4周 43.0 PR(部分缓解)
第5周 53.75 -
第6周 停一周 -
第7周 64.5 -
第8周 74.15 PR(部分缓解)
患者病例2：
患者，男，45岁，病理诊断为鼻咽癌，2018年11月05日开始服用盐酸安罗替尼胶囊：每日一次，早餐前口服，每次10mg，连用两周后休息一周；2018年11月10日开始放射治疗：
Figure PCTCN2020092125-appb-000008
该研究表明，对于头颈部癌患者，安罗替尼联用放疗的治疗方案临床有收益。
实施例6
经组织学或细胞学证实为鼻咽癌，且既往未接受过针对复发/转移性鼻咽癌的全身***性的抗肿瘤治疗的患者，联合给药安罗替尼、吉西他滨和顺铂，试验期间每21天为1个周期，具体给药方法如下：
联合化疗期间给药方案：
盐酸安罗替尼胶囊/安慰剂：起始剂量12mg/0mg。早餐前空腹口服，每天一粒，连续服用两周停一周。
注射用盐酸吉西他滨：起始剂量1g/m 2，在每周期第1天和第8天给药。
顺铂注射液：起始剂量75mg/m 2，在每周期第1天给药。
维持治疗期间给药方案：
盐酸安罗替尼胶囊/安慰剂；12mg，早餐前空腹口服，每天一粒，连续服用二周停一周，每21天1个周期，直至研究终止标准。
疗效评估观察指标包括无进展生存期(PFS)、总生存期(OS)、客观缓解率(ORR＝CR+PR)、疾病控制率(DCR＝CR+PR+SD)、安全性指标。
该研究表明，对于鼻咽癌患者，安罗替尼联用吉西他滨和顺铂的治疗方案临床有收益。
实施例7
经组织学证实，曾接受过含铂化疗或复发后至少接受过一线化疗的不可手术、不可放疗、复发和或转移的鼻咽癌；其中不可手术、不可放疗的鼻咽癌符合以下任意一项：1.放疗后复发2.转移3.经相关多学科诊疗模式(MDT)专家认为不适合手术和放疗的患者，联合给药安罗替尼和卡培他滨，具体给药方法如下：
盐酸安罗替尼胶囊：每日一次，早餐前口服，每次12mg，每个周期的d1-14给药，连续服药2周，停药1周，21天为一个治疗周期，连续服药直至出现PD、死亡、不可耐受的毒性；
卡培他滨片：口服总量1000mg/m 2，口服，bid，d1-d14，连续服药2周，停药1周，21天为一个治疗周期，连续服药直至出现PD、死亡、不可耐受的毒性。
疗效评估观察指标包括客观缓解率(ORR)、无进展生存期(PFS)、总生存期(OS)、生活质量、药物安全性指标。
该研究表明，对于鼻咽癌患者，安罗替尼联用卡培他滨的治疗方案临床有收益。
在本申请的上述实施例中，盐酸安罗替尼胶囊的量以其中包含的安罗替尼游离碱的重量计。
根据本申请所公开的内容，虽然根据优选实施方案对本申请的组合物和方法进行了描述，但对本领域技术人员而言，在不背离本申请的概念、精神和范围的情况下，可对在此所述的组合物和/或方法以及所述方法的步骤或步骤的顺序进行改变。
本文所引用的所有文献的公开内容通过引用结合于此，引用程度为，他们提供示例性的、程序上和其它的细节补充本文所述内容。

Claims (16)

  1. 化合物I或其药学上可接受的盐在制备用于治疗头颈癌的药物中的用途，
    Figure PCTCN2020092125-appb-100001
    其中，所述的头颈癌选自口腔癌、喉癌、腮腺癌、鼻腔癌、鼻窦癌、副鼻窦癌、口咽癌、口底癌、下咽癌、腭癌、牙龈癌、舌癌、舌粘膜鳞癌、颊粘膜癌、唇癌或唾液腺癌、扁桃体癌。
  2. 化合物I或其药学上可接受的盐与第二治疗药物的联用在制备用于治疗头颈癌的药物中的用途，所述的第二治疗药物为化疗药物、小分子靶向抗肿瘤药物、免疫治疗药物、大分子抗体药物中的一种或多种，
    Figure PCTCN2020092125-appb-100002
    其中，所述的头颈癌选自口腔癌、喉癌、腮腺癌、甲状腺癌、鼻咽癌、鼻腔癌、鼻窦癌、副鼻窦癌、口咽癌、口底癌、下咽癌、腭癌、牙龈癌、舌癌、舌粘膜鳞癌、颊粘膜癌、唇癌或唾液腺癌、扁桃体癌。
  3. 根据权利要求1或2所述的用途，其中，所述的头颈癌为头颈部鳞癌或头颈部腺癌。
  4. 根据权利要求3所述的用途，其中，所述的头颈部腺癌选自黏液表皮样癌、腺样囊性癌、淋巴上皮癌、多形性腺癌、涎腺导管癌、肌上皮癌、非特异性腺癌、非特异性透明细胞癌、囊腺癌、皮脂腺癌、皮脂淋巴腺癌、黏液腺癌或上皮-肌上皮癌。
  5. 根据权利要求2所述的用途，其中，所述的鼻咽癌为角化鳞癌、分化型非角化癌、未分化型非角化癌、原位型鼻咽癌、鳞癌、腺癌、微小***、泡状细胞核癌或未分化鼻咽癌。
  6. 根据权利要求1-5任一项所述的用途，其中，所述头颈癌为隐性癌或原发灶不明的头颈癌，或者为局部晚期、和/或晚期的头颈癌，或者为转移性的头颈癌，或者为复发性的、不可切除的、化疗药物和/或靶向药物治疗失败的头颈癌。
  7. 根据权利要求1或2所述的用途，其中，所述的头颈癌为喉癌、喉癌鳞癌或口腔鳞癌。
  8. 根据权利要求1-7任一项所述的用途，其中，所述的化合物I或其药学上可接受的盐进一步地与放射治疗联合。
  9. 根据权利要求2-7任一项所述的用途，其中，所述的化疗药物为奥沙利铂、顺铂、卡铂、奈达铂、双环铂、乐铂、四硝酸三铂、菲铂、吡铂、米铂、沙铂、吉西他滨、卡培他滨、安西他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷、紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇、喜树碱、羟基喜树碱、9-氨基喜树碱、7-乙基喜树碱、伊立替康、拓扑替康、长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁、表柔比星、阿霉素、柔红霉素、吡柔比星、氨柔比星、伊达柔比星、米托蒽醌、阿柔比星、戊柔比星、佐柔比星、匹杉琼、培美曲塞、卡氮芥、美法仑、依托泊苷、替尼铂苷、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、甲氨蝶呤、苯达莫司汀、脂质体阿霉素、放线菌素D、博来霉素、平阳霉素、替莫唑胺、氨烯咪胺、培洛霉素、艾日布林、普那布林、Sapacitabine、曲奥舒凡、153Sm-EDTMP、替吉奥和encequidar中的一种或多种。
  10. 根据权利要求2-7任一项所述的用途，其中，所述的免疫治疗药物为干扰素类、白介素、西罗莫司、依维莫司、地磷莫司、替西罗莫司的一种或多种。
  11. 根据权利要求2-7任一项所述的用途，其中，所述的小分子靶向抗肿瘤药物为伊马替尼、舒尼替尼、尼罗替尼、波舒替尼、塞卡替尼、帕唑帕尼、曲贝替定、瑞格非尼、西地尼布、硼替佐米、帕比司他、卡 非佐米、伊沙佐米、阿帕替尼、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、奥美替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、索拉非尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、rociletinib、尼达尼布、来那度胺、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、帕博西尼、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、poziotinib、DS-1205c、capivasertib、SH-1028、二甲双胍、seliciclib、OSE-2101、APL-101、berzosertib、idelalisib、lerociclib、ceralasertib、PLB-1003、tomivosertib、AST-2818、SKLB-1028、D-0316、LY-3023414、allitinib、MRTX-849、AP-32788、AZD-4205、lifirafenib、vactosertib、mivebresib、napabucasin、sitravatinib、TAS-114、molibresib、CC-223、rivoceranib、CK-101、LXH-254、simotinib、GSK-3368715、TAS-0728、masitinib、tepotinib、HS-10296、AZD-4547、merestinib、olaptesed pegol、galunisertib、ASN-003、gedatolisib、defactinib、lazertinib、CKI-27、S-49076、BPI-9016M、RF-A-089、RMC-4630、AZD-3759、antroquinonol、SAF-189s、AT-101、TTI-101、naputinib、LNP-3794、HH-SCC-244、ASK-120067、CT-707、epitinib succinate、tesevatinib、SPH-1188-11、BPI-15000、copanlisib、niraparib、olaparib、veliparib、talazoparib tosylate、DV-281、Siremadlin、Telaglenastat、MP-0250、GLG-801、ABTL-0812、bortezomib、、tucidinostat、vorinostat、resminostat、epacadostat、tazemetostat、entinostat、mocetinostat、quisinostat、LCL-161、KML-001中的一种或者多种。
  12. 根据权利要求2-7任一项所述的用途，其中，所述的大分子抗体药物是贝伐珠单抗、雷莫芦单抗、帕妥珠单抗、曲妥珠单抗、西妥昔单抗、尼妥珠单抗、帕尼单抗、耐昔妥珠单抗、Dinutuximab、利妥昔单抗、替依莫单抗、奥法木单抗、Obinutuzumab、阿仑单抗、达雷木单抗、吉妥单抗、埃罗妥珠单抗、本妥昔单抗、奥英妥珠单抗、博纳吐单抗、纳武利尤单抗、帕博利珠单抗、德瓦鲁单抗、特瑞普利单抗、信迪利单抗、卡瑞利株单抗、替雷利株单抗、杰诺单抗、丽珠单抗、HLX-10、BAT-1306、AK103、AK104、CS1003、SCT-I10A、F520、SG001、GLS-010、Atezolizumab、Avelumab、Durvalumab、KL-A167、SHR-1316、BGB-333、JS003、STI-A1014、KN035、MSB2311、HLX-20、CS-1001、伊匹单抗、替西木单抗、AGEN-1884、BMS-986249、BMS-986218、AK-104、IBI310中的任意一种或多种。
  13. 根据权利要求2-7任一项所述的用途，其中，所述第二治疗药物为氟嘧啶衍生物、铂类药物、抗PD-1抗体中的一种或多种。
  14. 根据权利要求2-7任一项所述的用途，其中，所述第二治疗药物为以下(1)～(28)中的任意一种或多种：
    (1)甲氨蝶呤、替吉奥、紫杉醇的一种、两种或三种；(2)铂类药物和5-氟尿嘧啶的一种或两种；(3)铂类药物和西妥昔单抗的一种或两种；(4)吉西他滨、长春瑞滨的一种或两种；(5)吉西他滨和紫杉醇的一种或两种；(6)紫杉醇和卡铂的一种或两种；(7)柔红霉素和阿糖胞苷的一种或两种；(8)米托蒽醌和依托泊苷的一种或两种；(9)吉西他滨和顺铂的一种或两种；(10)阿霉素、顺铂的一种或两种；(11)异环磷酰胺、美司钠、依托泊苷的一种、两种或三种；(12)多西他赛、顺铂和5-氟尿嘧啶的一种、两种或三种；(13)顺铂、表柔比星和紫杉醇的一种、两种或三种；(14)铂类药物、5-氟尿嘧啶和西妥昔单抗的一种、两种或三种；(15)铂类药物、多西他赛和紫杉醇的一种、两种或三种；(16)卡铂、紫杉醇和吉西他滨的一种、两种或三种；(17)去甲长春花碱、甲氨蝶呤和博来霉素的一种、两种或三种；(18)紫杉醇、异环磷酰胺、美司钠、顺铂的一种、两种、三种或四种；(19)顺铂、氟尿嘧啶、醛氢叶酸的一种、两种或三种；(20)顺铂、博来霉素、氟尿嘧啶的一种、两种或三种；(21)米托蒽醌、氟尿嘧啶、卡铂的一种、两种或三种；(22)吡喃阿霉素、顺铂、氟尿嘧啶的一种、两种或三种；(23)柔红霉素、阿糖胞苷、巯鸟嘌呤、依托泊苷的一种、两种、三种或四种；(24)三尖杉酯碱、阿糖胞苷、巯鸟嘌呤；(25)三尖杉酯碱、长春新碱、阿糖胞苷、强地松的一种、两种、三种或四种的一种、两种或三种；(26)顺铂和5-氟尿嘧啶；(27)信迪利单抗；(28)卡培他滨。
  15. 根据权利要求1-14任一项所述的用途，其特征在于，给予化合物I或其药学上可接受的盐的日剂量为3毫克至30毫克，优选为5毫克至20毫克，更优选为8毫克至16毫克，进一步优选为8毫克至14毫克，最优选为8毫克、10毫克或12毫克。
  16. 根据权利要求1-15任一项的药物组合物，其中化合物I或其药学上可接受的盐在每个周期的第1-14天给药，每21天为一个给药周期。
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