WO2024120520A1 - Utilisation d'un composé de quinoléine dans le traitement du cancer du poumon à petites cellules - Google Patents

Utilisation d'un composé de quinoléine dans le traitement du cancer du poumon à petites cellules Download PDF

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WO2024120520A1
WO2024120520A1 PCT/CN2023/137421 CN2023137421W WO2024120520A1 WO 2024120520 A1 WO2024120520 A1 WO 2024120520A1 CN 2023137421 W CN2023137421 W CN 2023137421W WO 2024120520 A1 WO2024120520 A1 WO 2024120520A1
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Prior art keywords
etoposide
lung cancer
small cell
treatment
extensive
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PCT/CN2023/137421
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English (en)
Chinese (zh)
Inventor
万晓婧
张喜全
王训强
于鼎
朱名洁
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正大天晴药业集团股份有限公司
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Publication of WO2024120520A1 publication Critical patent/WO2024120520A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of medical technology, and relates to the use of quinoline compounds in treating small cell lung cancer, and specifically to the use and method of N-(4-((7-((1-(cyclopentylamino)cyclopropane)methoxy)-6-methoxyquinoline-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in treating extensive-stage small cell lung cancer.
  • SCLC Small cell lung cancer
  • ES-SCLC extensive stage small cell lung cancer
  • WO2012034055 discloses N-(4-((7-((1-(cyclopentylamino)cyclopropanyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as the compound of formula (I)) as a c-Met kinase inhibitor and its use in inhibiting tyrosine kinase activity.
  • the compound of formula (I) is a new class of compounds with excellent pharmacological properties, which can inhibit the activity of multiple protein tyrosine kinases, such as c-Met, VEGFr, EGFr, c-kit, PDGF, FGF, SRC, Ron, Tie2, etc.
  • multiple protein tyrosine kinases such as c-Met, VEGFr, EGFr, c-kit, PDGF, FGF, SRC, Ron, Tie2, etc.
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating extensive small cell lung cancer.
  • the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating extensive-stage small cell lung cancer.
  • the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in treating extensive-stage small cell lung cancer.
  • the present disclosure provides a method for treating extensive-stage small cell lung cancer, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating extensive-stage small cell lung cancer.
  • the pharmaceutical composition further contains a pharmaceutically acceptable excipient.
  • the present disclosure provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating extensive small cell lung cancer.
  • the pharmaceutical composition is a pharmaceutical composition in a single-dose form, or a pharmaceutical composition in a multi-dose form.
  • the pharmaceutical composition further contains a pharmaceutically acceptable excipient.
  • the present disclosure provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of extensive-stage small cell lung cancer.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for treating extensive small cell lung cancer, the method comprising administering a therapeutically effective amount of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • the present disclosure provides a kit for treating extensive-stage small cell lung cancer, the kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; and b) instructions for use in treating extensive-stage small cell lung cancer.
  • the kit may contain a single dose or multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the patient with extensive-stage small cell lung cancer meets at least one of the following conditions:
  • the lesion is more than one side of the chest cavity and includes malignant pleural and pericardial effusion or hematogenous metastasis;
  • the extensive-stage small cell lung cancer is advanced extensive-stage small cell lung cancer.
  • the extensive-stage small cell lung cancer is recurrent extensive-stage small cell lung cancer.
  • the extensive-stage small cell lung cancer is inoperable extensive-stage small cell lung cancer.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer previously treated with radiation therapy.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one systemic therapy.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one systemic therapy and has failed treatment (eg, progressed or relapsed after treatment).
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received one or two systemic therapies.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received one or two systemic therapies and has failed treatment (eg, progressed or relapsed after treatment).
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two systemic therapies.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has been previously treated with at least two systemic therapies and has failed treatment (eg, progressed or relapsed after treatment).
  • the systemic therapy is selected from a combination of one or more of systemic chemotherapy or targeted therapy.
  • the targeted therapy is selected from immunotherapy.
  • the systemic therapy is selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received greater than or equal to first-line systemic treatment.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received or is equal to first-line systemic treatment and has failed treatment (eg, progressed or relapsed after treatment).
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received first-line, second-line, third-line, fourth-line, or fifth-line systemic treatment.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received first-line, second-line, third-line, fourth-line, or fifth-line systemic treatment and has failed treatment (eg, progressed or relapsed after treatment).
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received first-line systemic treatment.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one line of systemic treatment and has failed treatment (eg, progressed or relapsed after treatment).
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received second-line systemic treatment.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two lines of systemic treatment and has failed treatment (eg, progressed or relapsed after treatment).
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received three lines of systemic treatment.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic treatment and has failed treatment (eg, progressed or relapsed after treatment).
  • the first-line systemic treatment is selected from a combination of one or more of systemic chemotherapy or targeted therapy.
  • the targeted therapy is selected from immunotherapy.
  • the first-line systemic treatment is selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy.
  • the second-line systemic treatment is selected from a combination of one or more of systemic chemotherapy or immunotherapy.
  • the second-line systemic treatment is selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy.
  • the third-line systemic treatment is selected from a combination of one or more of systemic chemotherapy or immunotherapy.
  • the third-line systemic treatment is selected from systemic chemotherapy, or systemic chemotherapy plus immunotherapy.
  • the systemic chemotherapy drugs include but are not limited to one or more of the following: alkylating agents (including but not limited to bendamustine, carmustine, chlorambucil, nitrogen mustard, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin); antimetabolites (including but not limited to azacitidine, cytarabine, 5-fluorouracil, 6-mercaptopurine, capecitabine, decitabine, gemcitabine, floxuridine, fludarabine, nelarabine, hydroxyurea, methotrexate, pralatrexate, pemetrexed, pentostatin, hexamethylmelamine, trifluridine/decitabine); and combinations of vinorelbine); plant alkaloids (including but not limited to camptothecin and vinorel
  • the systemic chemotherapy drugs include but are not limited to one or more of platinum drugs, fluoropyrimidine derivatives, camptothecins, taxanes, vinca alkaloids, anthracyclines, antibiotics, podophyllums, other anti-tumor drugs, and anti-metabolites.
  • platinum drugs e.g., oxaliplatin, miplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin, triplatin tetranitrate, phenaplatin, picoplatin, satraplatin, lobaplatin
  • fluoropyrimidine derivatives e.g., gemcitabine, capecitabine, ancitabine, fluorouracil, bisfurouracil, doxifluridine, tegafur, carmofur, trifluridine
  • taxanes e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel
  • camptothecins e.g., camptothecin, hydroxycamptothecin, 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan
  • camptothecins e.g., camptothec
  • the systemic chemotherapy drug is selected from one or more of carboplatin, cisplatin, lobaplatin, doxorubicin, cyclophosphamide, etoposide, irinotecan (including polyethylene glycol irinotecan), topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.
  • the systemic chemotherapy drug is selected from one or more of carboplatin, cisplatin, lobaplatin, etoposide, irinotecan (including polyethylene glycol irinotecan), topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.
  • carboplatin cisplatin, lobaplatin, etoposide, irinotecan (including polyethylene glycol irinotecan), topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.
  • the systemic chemotherapy drug is selected from one or more of carboplatin, cisplatin, lobaplatin, doxorubicin + cyclophosphamide, etoposide, irinotecan (including polyethylene glycol irinotecan), topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.
  • the systemic chemotherapy drug is selected from a combination of a platinum drug and other chemotherapy drugs.
  • the platinum drug includes but is not limited to one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, bicycloplatin, picoplatin, satraplatin, phenaplatin, tetranitrotriplaplatin or lobaplatin.
  • the platinum drug is selected from cisplatin, carboplatin, or lobaplatin.
  • the other chemotherapy drugs include but are not limited to one or more of doxorubicin, cyclophosphamide, etoposide, irinotecan (including polyethylene glycol irinotecan), topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.
  • the other chemotherapy drugs include but are not limited to one or more of etoposide, irinotecan, topotecan, paclitaxel, docetaxel, gemcitabine, vinorelbine, temozolomide, rubicatin, and bendamustine.
  • the other chemotherapy drug is selected from doxorubicin, cyclophosphamide, rubicatin, etoposide and/or irinotecan.
  • the other chemotherapy drug is selected from doxorubicin, cyclophosphamide, rubicatin, etoposide, or irinotecan.
  • the systemic chemotherapy drug is selected from doxorubicin + cyclophosphamide, doxorubicin + platinum drugs, cyclophosphamide + platinum , paclitaxel + a platinum drug, paclitaxel + a platinum drug + rubicatin, etoposide + a platinum drug, irinotecan + a platinum drug, topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, rubicatin, or bendamustine.
  • the systemic chemotherapy drug is selected from etoposide + platinum drugs, irinotecan + platinum drugs, topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, rubicatin, or bendamustine.
  • the systemic chemotherapy drug is selected from etoposide + carboplatin, etoposide + cisplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, rubicatin, or bendamustine.
  • the immunotherapy drugs include but are not limited to immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors).
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors.
  • the immunotherapy drugs include but are not limited to anti-CTLA-4 antibodies (e.g., ipilimumab), anti-PD-1 antibodies (e.g., candurizumab, slulimab, sepalizumab, penampalimumab, dotalimumab, tislelizumab, carrelizumab, toripalimab, sintilimab, cemiprilimab, pembrolizumab, nivolumab, BMS-986213, palolizumab, gelolimab, rivallimumab, HX-008), anti-PD-L1 antibodies (e.g., sugemalimab, envolimab, durvalumab, avelumab, atezolizumab, sukemalimab, adebelimumab, TQB2450).
  • anti-CTLA-4 antibodies e.g., ipilimumab
  • the immunotherapy drug is selected from atezolizumab, durvalumab, slulizumab, adebelimumab, TQB2450, toripalizumab, tislelizumab, carrelizumab, nivolumab, or pembrolizumab.
  • the systemic therapy is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, durvalumab + paclitaxel + carboplatin or cisplatin, atezolizumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin + sintilimab, doxorubicin + cyclophosphamide + durvalumab, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide etoposide + lobaplatin, durvalumab + irinotecan + carboplatin or cisplatin, irinotecan + cisplatin, irinotecan + c
  • the systemic therapy is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, slulizumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalizumab + etopo
  • the first-line systemic treatment is selected from atezolizumab + etoposide + carboplatin or cisplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + cisplatin + sintilimab, doxorubicin + cyclophosphamide + durvalumab, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, slulizumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalizumab + etopo
  • the first-line systemic treatment is selected from atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, srulimumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalimab + etoposide + carboplatin, or toripalimab + etoposide + cisplatin.
  • the second-line systemic treatment is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, irinotecan + atezolizumab, atezolizumab + docetaxel, atezolizumab + paclitaxel, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, carboplatin or cisplatin + irinotecan + durvalumab Ulizumab, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, slulizumab + etoposide + carboplatin,
  • the second-line systemic treatment is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, srulizumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin, tislelizumab + etoposide + cisplatin, toripalizumab + e
  • the third-line systemic treatment is selected from one or more of the following: alkylating agents (including but not limited to bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin), mitotic inhibitors (including but not limited to paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel), anti-PD-L1 antibodies (e.g., sugemalimab, envolimab, durvalumab, avelumab, atezolizumab, sugelimumab, adebelimumab, TQB2450), etc.
  • alkylating agents including but not limited to bendamustine, carmustine, chlorambucil, mechlor
  • the third-line systemic treatment is selected from one or more of the following drugs: bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin, paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, sugemalimab, envolimab, durvalumab, avelumab, atezolizumab, sugemalimab, adebelimumab, or TQB2450.
  • drugs bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, if
  • the third-line systemic treatment is selected from durvalumab + paclitaxel + cisplatin or carboplatin, and/or rubicatin.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one systemic therapy and has failed treatment
  • the systemic therapy is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, slulizumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin,
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received one or two systemic therapies and has failed, and the systemic therapies are selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, slulizumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin,
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two systemic therapies and has failed treatment
  • the systemic therapies are selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, slulizumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carboplatin,
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one line of systemic treatment and has failed treatment
  • the first-line systemic treatment is selected from atezolizumab + etoposide + carboplatin or cisplatin, durvalumab + etoposide + carboplatin or cisplatin, etoposide + cisplatin, etoposide + cisplatin + sintilimab, doxorubicin + cyclophosphamide + durvalumab, etoposide + carboplatin, etoposide + lobaplatin, irinotecan + cisplatin, irinotecan + carboplatin, slulizumab + etoposide + carboplatin, adebelimumab + etoposide + carboplatin, tislelizumab + etoposide + carbop
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one line of systemic treatment and has failed treatment
  • the first-line systemic treatment is selected from doxorubicin + cyclophosphamide + durvalumab, etoposide + cisplatin + sintilimab, etoposide + cisplatin, atezolizumab + etoposide + carboplatin or cisplatin, durvalumab, or atezolizumab.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least one line of systemic treatment and has failed treatment
  • the first-line systemic treatment is doxorubicin + cyclophosphamide + durvalumab, and durvalumab maintenance treatment.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has received at least two-line systemic treatments and failed treatment
  • the second-line systemic treatment is selected from topotecan, irinotecan, paclitaxel, docetaxel, gemcitabine, etoposide, vinorelbine, temozolomide, bendamustine, irinotecan + atezolizumab, atezolizumab + docetaxel, atezolizumab + paclitaxel, atezolizumab + etoposide + carboplatin, durvalumab + etoposide + Carboplatin or cisplatin, carboplatin or cisplatin + irinotecan + durvalumab, etoposide + cisplatin, etoposide + carboplatin, etoposide + lovaplatin, irinotecan + cisplatin, irinote
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two lines of systemic treatment and failed treatment
  • the second-line systemic treatment is selected from irinotecan + atezolizumab, cisplatin + irinotecan + durvalumab, atezolizumab + docetaxel, atezolizumab + paclitaxel, atezolizumab, or irinotecan (including polyethylene glycol irinotecan).
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least two-line systemic treatments and failed treatment, and the second-line systemic treatment is selected from atezolizumab + docetaxel, atezolizumab + paclitaxel, or atezolizumab.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic treatment and has failed treatment.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has received at least three lines of systemic treatment and failed treatment
  • the third-line systemic treatment is selected from alkylating agents (including but not limited to bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin), mitotic inhibitors (including but not limited to paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel), anti-PD-L1 antibodies (such as sugemalimab, envolimab, durvalumab, avelumab, atezolizumab, sugelimumab, adebelimumab, TQB2450), etc.
  • alkylating agents including
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic treatment and failed treatment
  • the third-line systemic treatment is selected from one or more of the following drugs: bendamustine, carmustine, chlorambucil, mechlorethamine, lomustine, carboplatin, cisplatin, lobaplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide, rubicatin, paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, sugemalimab, envolimab, durvalumab, avelumab, atezolizumab, sugemalimab, adebelimumab, or TQB2450.
  • the extensive-stage small cell lung cancer is extensive-stage small cell lung cancer that has previously received at least three lines of systemic treatment and has failed treatment, and the third-line systemic treatment is selected from durvalumab + paclitaxel + cisplatin or carboplatin, or rubicatin.
  • the patient with extensive-stage small cell lung cancer has not received anti-angiogenic drug treatment.
  • the anti-angiogenic drug comprises pazopanib, sorafenib, erlotinib, apatinib, cabozantinib, anlotinib, recombinant human endostatin, or bevacizumab.
  • the patient with extensive-stage small cell lung cancer has not received anti-angiogenic drug treatment, and the anti-angiogenic drug includes cabozantinib, anlotinib, recombinant human endostatin, or bevacizumab.
  • the anti-angiogenic drug comprises apatinib or anlotinib.
  • the patient with extensive-stage small cell lung cancer has been treated with surgery.
  • the patient with extensive-stage small cell lung cancer has received radiation therapy.
  • the radiation therapy includes but is not limited to chest radiation therapy and head radiation therapy.
  • the patient with extensive-stage small cell lung cancer has previously received at least one systemic treatment but failed the treatment, and optionally has received treatment with immune checkpoint inhibitors (such as PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.
  • immune checkpoint inhibitors such as PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has previously received at least one systemic treatment but failed, has not received anti-angiogenic drug treatment, and optionally has received immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has previously received one or two systemic treatments but failed, and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatments.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has previously received one or two systemic treatments but failed, has not received anti-angiogenic drug treatment, and optionally has received immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has previously received at least two systemic treatments but failed, and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatments.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has previously received at least two systemic treatments but failed, has not received anti-angiogenic drug treatment, and optionally has received immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatments.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has previously received at least one line of systemic treatment but has failed the treatment (e.g., progression or recurrence after treatment), and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has previously received at least one line of systemic treatment but failed the treatment (e.g., progression or recurrence after treatment), has not received anti-angiogenic drug treatment, and optionally has received immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has previously received at least two lines of systemic treatment but has failed treatment (e.g., progression or recurrence after treatment), and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has previously received at least two lines of systemic therapy but failed treatment (e.g., The patients should have progressed or relapsed after previous treatment, have not received anti-angiogenic drugs, and optionally have received immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.
  • the patients should have progressed or relapsed after previous treatment, have not received anti-angiogenic drugs, and optionally have received immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer has undergone three consecutive chemotherapy combined with immune checkpoint inhibitor treatments but all treatments have failed.
  • the patient with extensive-stage small cell lung cancer has successively undergone treatment with doxorubicin + cyclophosphamide + durvalumab but failed, treatment with cisplatin + irinotecan + durvalumab but failed, and treatment with durvalumab + paclitaxel + cisplatin followed by treatment with rubicatin but failed.
  • the patient with extensive-stage small cell lung cancer has failed two consecutive systemic chemotherapy treatments.
  • the patient with extensive-stage small cell lung cancer has sequentially undergone etoposide + cisplatin treatment but failed, followed by polyethylene glycol irinotecan treatment but failed.
  • the patient with extensive-stage small cell lung cancer meets all of the following conditions:
  • the patient with extensive-stage small cell lung cancer meets all of the following conditions:
  • the patient with extensive-stage small cell lung cancer has previously received at least two lines of systemic treatment and has failed treatment (e.g., progression or recurrence after treatment), and optionally has received treatment with immune checkpoint inhibitors (such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.) in previous treatment, and has not received anti-angiogenic drug treatment.
  • immune checkpoint inhibitors such as CTLA-4 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, etc.
  • the patient with extensive-stage small cell lung cancer meets all of the following conditions:
  • the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 2-6 weeks. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or the range formed by any of the above values. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt is 3 weeks or 4 weeks.
  • the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt may be more than 1 cycle, including 1, 2, 3, 4, 5, 6 or more cycles. In some embodiments, the administration cycle of the compound of formula (I) or its pharmaceutically acceptable salt may preferably be 1-6 administration cycles.
  • the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt can be 3 times a day, 2 times a day, 1 time a day, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 3 times a week, 2 times a week, 1 time a week, 1 time every two weeks, or 1 time every three weeks.
  • the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is 3 times a day, 2 times a day, or 1 time a day.
  • the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is 1 time a day.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, or a range formed by any of the above values.
  • the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 20-180 mg. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 20-40 mg, 20-60 mg, 20-90 mg, 20-120 mg, 20-150 mg, 40-60 mg, 40-90 mg, 40-120 mg, 40-150 mg, 40-180 mg, 60-90 mg, 60-120 mg, 60-150 mg, 60-180 mg, 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg.
  • the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 20-40 mg, 20-60 mg, 20-90 mg, 20-120 mg, 20-150 mg, 40-150 mg, 40-180 mg or 150-180 mg.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 60-120 mg, 60-150 mg, 60-180 mg, 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg.
  • the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 60 mg, 90 mg, 120 mg, 150 mg or 180 mg. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 90 mg or 120 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered in a single dose or multiple doses. In some embodiments, it is administered in multiple doses.
  • the pharmaceutical composition is a pharmaceutical composition with a single dose of 30-60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a pharmaceutical composition with a single dose of 30 mg or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is a multiple-dose pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multiple doses may consist of a single dose of 30 mg or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is a pharmaceutical composition of multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be 60 mg, 90 mg, 120 mg, 150 mg or 180 mg. In some embodiments, the multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof are 90 mg or 120 mg.
  • the multiple doses of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof may consist of a single dose of 30 mg or 60 mg of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered for one or more dosing cycles.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered for one or more dosing cycles, and the frequency of administration may be 3 times a day, 2 times a day, once a day, once every two days, once every three days, once every four days, once every five days, once every six days, 3 times a week, 2 times a week, once a week, once every two weeks, or once every three weeks, preferably 3 times a day, 2 times a day or once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject for one or more dosing cycles, and the administration is continued every day (e.g., 3 times a day, 2 times a day or once a day).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered to the subject continuously every day (e.g., 3 times a day, 2 times a day or once a day).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: with a 28-day administration cycle, a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, administered once a day.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: one or more administration cycles are administered with 28 days as one administration cycle, and the daily dose is 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, administered once a day.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 60 mg, 90 mg, 120 mg, 150 mg or 180 mg.
  • the daily dose can be adjusted after administration (including but not limited to increasing or decreasing the daily dose).
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 90 mg or 120 mg, and optionally, the daily dose is adjusted after administration (including but not limited to upward or downward adjustment of the daily dose).
  • the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt may be 90 mg or 120 mg, and optionally, the daily dose is adjusted upward after administration. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt may be 90 mg or 120 mg, and optionally, the daily dose is adjusted upward after administration to a daily dose selected from 120 mg, 150 mg or 180 mg.
  • the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 90 mg or 120 mg, and optionally, the daily dose is adjusted downward after administration. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 90 mg, and optionally, the daily dose is adjusted downward after administration to 60 mg or less. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 120 mg, and optionally, the daily dose is adjusted downward after administration to 90 mg or 60 mg or less.
  • the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 90 mg, and optionally, the daily dose is adjusted down to 60 mg after administration. In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 120 mg, and optionally, the daily dose is adjusted down to 90 mg or 60 mg after administration.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition can be administered by various routes, including but not limited to oral administration.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition can be taken orally on an empty stomach (e.g., in the morning on an empty stomach).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered by oral administration on an empty stomach in the morning, once a day, for one or more dosing cycles (for example, 28 days can be one dosing cycle).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered by oral administration on an empty stomach in the morning, once a day, for one or more dosing cycles, wherein 28 days is one dosing cycle.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: oral administration on an empty stomach every day (e.g., once a day), with a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, for one or more consecutive administration cycles (e.g., 28 days as one administration cycle).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: with a dosing cycle of 28 days, it is orally administered once a day on an empty stomach, with a daily dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, for 28 consecutive days (i.e., one dosing cycle).
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is administered as follows: with a dosing cycle of 28 days, orally administered once a day on an empty stomach, with each dose of 60 mg, 90 mg, 120 mg, 150 mg or 180 mg, for 28 consecutive days (i.e., one dosing cycle).
  • the above dosing cycle is repeated as long as the disease remains under control and the regimen is clinically tolerated.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared in a single or multiple dose form suitable for each administration of 60 mg-180 mg, or 60 mg-150 mg, or 60 mg-120 mg, or 90 mg-180 mg, or 90 mg-150 mg, or 90 mg-120 mg, or 120 mg-150 mg, or 120 mg-180 mg, or 150 mg-180 mg, or 60 mg, or 90 mg, or 120 mg, or 150 mg, or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared in a single or multiple dose form suitable for once a day and administering 60mg-180mg, or 60mg-150mg, or 60mg-120mg, or 90mg-180mg, or 90mg-150mg, or 90mg-120mg, or 120mg-150mg, or 120mg-180mg, or 150mg-180mg, or 60mg, or 90mg, or 120mg, or 150mg, or 180mg of the compound of formula (I) or its pharmaceutically acceptable salt to the patient each time.
  • the compound of formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition is prepared in a single or multiple dose form suitable for administering 60 mg-180 mg, or 60 mg-150 mg, or 60 mg-120 mg, or 90 mg-180 mg, or 90 mg-150 mg, or 90 mg-120 mg, or 120 mg-150 mg, or 120 mg-180 mg, or 150 mg-180 mg, or 60 mg, or 90 mg, or 120 mg, or 150 mg, or 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt once a day for 28 consecutive days.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is used as a single active agent.
  • the disclosed compound of formula (I) can be administered in the form of its free base or in the form of its pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt of the compound of formula (I) is within the scope of the present disclosure, and can be produced from different organic acids and inorganic acids according to methods known in the art, such as the inorganic acid can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and the organic acid can be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthylsulfuric acid.
  • the compound of formula (I) is administered in the form of its free base.
  • the "compound of formula (I) or a pharmaceutically acceptable salt thereof” described in the present disclosure may be in the form of a “pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof".
  • the strength of the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is 30-60 mg (calculated as the compound of formula (I)). In some embodiments, the strength of the pharmaceutical composition may be 30 mg or 60 mg (calculated as the compound of formula (I)).
  • the method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be suitable for oral administration.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.
  • the solid pharmaceutical composition is a capsule.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule formulation with strengths of 30 mg and 60 mg.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule preparation, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule preparation comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, corn starch, carboxymethylcellulose calcium, hypromellose and magnesium stearate.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule preparation, which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose, sodium starch glycolate and magnesium stearate.
  • the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition disclosed herein has good safety and anti-tumor activity, shows good inhibitory activity against small cell lung cancer cells, and shows good tumor inhibition activity in a nude mouse subcutaneous transplant tumor model of human small cell lung cancer.
  • the treatment scheme disclosed herein has good efficacy and good safety in the treatment of extensive small cell lung cancer.
  • the compound of formula (I) or its pharmaceutically acceptable salt, or a pharmaceutical composition comprising the compound of formula (I) or its pharmaceutically acceptable salt at least in survival efficacy evaluation, such as overall survival (OS), median survival; in tumor response efficacy evaluation, such as disease-free survival (DFS), median DFS, progression-free survival (PFS), 6-month PFS rate, time to disease progression (TTP), objective response rate (ORR), disease control rate (DCR), duration of remission (DOR); and tolerability or safety evaluation, such as the incidence and severity of adverse events, etc., at least one aspect has excellent effect.
  • survival efficacy evaluation such as overall survival (OS), median survival
  • tumor response efficacy evaluation such as disease-free survival (DFS), median DFS, progression-free survival (PFS), 6-month PFS rate, time to disease progression (TTP), objective response rate (ORR), disease control rate (DCR), duration of remission
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof has a good objective response rate and/or disease control rate in the treatment of extensive-stage small cell lung cancer.
  • the dosages and ranges thereof provided herein relating to the compound of formula (I) or its pharmaceutically acceptable salt are calculated based on the molecular weight of the free base of the compound of formula (I).
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt includes salts formed by alkali ions and free acids (free acid) or salts formed by acid ions and free bases (free alkali).
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect, including partial or complete stabilization or cure of a disease and/or effects resulting from a disease.
  • treatment encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its development; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or symptoms.
  • first-line systemic therapy refers to the first treatment given to a disease. It is usually part of a group of standard treatments, such as surgery followed by chemotherapy and radiation therapy. When used alone, first-line therapy is generally considered the best treatment. If it does not cure the disease or causes serious side effects, other treatments may be added or used.
  • second-line systemic therapy refers to treatment given when the initial treatment (first-line treatment) is ineffective or stops working. The same applies to third-line treatment or more lines of treatment.
  • treatment failure refers to disease progression, recurrence, or intolerable toxic side effects during or after treatment (eg, within 3, 6, or 12 months after treatment).
  • the term "recurrent” cancer is a cancer that regenerates at the initial site or at a distant site after responding to an initial treatment (e.g., surgery).
  • effective amount means an amount of a compound of the disclosure that (i) treats a particular disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder.
  • the amount of active substance (e.g., a compound of the disclosure) that constitutes a "therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the subject (e.g., a mammal) to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • administering means physically introducing a composition comprising an active compound into a host or patient or subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral.
  • daily dose refers to the dose administered to a patient for one day.
  • patient or “subject” or “subject” are used interchangeably herein to refer to mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the patient, subject, or subject is a human.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; for example, if a box of medicine contains seven tablets, each tablet is a single dose.
  • multiple doses consists of a plurality of single doses.
  • composition refers to a mixture of one or more active ingredients of the present disclosure and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to a subject.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the pharmaceutical composition of the present disclosure can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into a solid preparation (e.g., granules, tablets, pills, capsules, etc.), or formulated into a liquid preparation (e.g., injection).
  • suitable pharmaceutically acceptable excipients for example, it can be formulated into a solid preparation (e.g., granules, tablets, pills, capsules, etc.), or formulated into a liquid preparation (e.g., injection).
  • the pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain the core of a capsule, tablet or dragee.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • day When referring to a dosing regimen, the terms "day,” “daily,” and the like refer to the times within a calendar day, beginning at midnight and ending at the following midnight.
  • the compounds of formula (I) disclosed in the present invention exhibit good inhibitory activity against small cell lung cancer cells.
  • NCI-H526 cells were subcutaneously inoculated in the right axilla of SPF female nude mice (source: Jiangsu Huachuang Xinnuo Pharmaceutical Technology Co., Ltd.), 5 ⁇ 10 6 cells/mouse. When the average tumor volume reached about 200 mm 3 , the animals were divided into groups.
  • the day of grouping was day 0. From day 0 onwards, drugs were administered by gavage once a day. Tumor volume was measured 2-3 times a week, and the mice were weighed and the data were recorded. The general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.
  • the detection indicators and calculation formula are as follows:
  • Tumor volume, TV (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ); where a is the long diameter of the tumor, and b is the short diameter of the tumor.
  • T/C (%) TRTV / CRTV ⁇ 100%, wherein TRTV is the RTV of the treatment group; CRTV is the RTV of the vehicle control group.
  • TGI (%) (1-TW/TW 0 ) ⁇ 100%; wherein, TW is the tumor weight of the treatment group, and TW 0 is the tumor weight of the vehicle control group.
  • Body weight change rate, WCR (%) (Wt t - Wt 0 )/Wt 0 ⁇ 100%; wherein Wt 0 is the body weight of mice on day 0, and Wt t is the body weight of mice at each measurement.
  • the compound of formula (I) disclosed in the present invention exhibits good tumor inhibition activity in a nude mouse subcutaneous transplant tumor model of human small cell lung cancer.
  • Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy test should be negative within 7 days before study entry, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.
  • contraceptive measures such as intrauterine devices, birth control pills or condoms
  • Test drug capsules of compound of formula (I), specifications: 30 mg or 60 mg.
  • Dosage method Oral administration on an empty stomach in the morning, once a day, for 28 consecutive days as a dosing cycle, until the study termination criteria are met.
  • Dosage 90mg or 120mg.
  • Effectiveness evaluation RECIST 1.1 standard was used for evaluation.
  • AEs adverse events
  • SAEs serious adverse events
  • TEAEs treatment-emergent adverse events
  • Objective response rate refers to the proportion of subjects whose tumor volume reduction reaches the predetermined value and can be maintained for the minimum time limit according to the RECIST 1.1 standard, that is, the proportion of subjects with complete remission (CR) and partial remission (PR).
  • Progression-free survival refers to the time from the first treatment to the first disease progression or death due to any cause, whichever occurs first, regardless of whether the subject has stopped the study treatment before disease progression, but re-acceptance of other approved systemic anticancer treatments is not included. If the subject has not been observed to have disease progression and has not died, lost to follow-up, or received other systemic anticancer treatments by the data analysis cutoff date, the data will be treated as censored data, and the censoring date will be the date of the last imaging examination of measurable lesions. If the subject has missed more than 3 RECIST assessment visits before disease progression or death, the censoring date will be the date of the last imaging examination of the last measurable lesion before that. PFS time is always based on the imaging examination date, not the assessment date or visit date.
  • DCR Disease control rate
  • Duration of response refers to the time from the first complete response or partial response of the tumor to the first disease progression or various causes. The time of death was not used if tumor response was not confirmed. If the patient did not have disease progression or died of various causes before the data analysis cutoff date, the data were treated as censored data, and the PFS censoring time was used to determine the duration of response.
  • OS Overall survival
  • the test results show that the compound of formula (I) disclosed in the present invention has good safety, can effectively control the progression of the disease, and shows certain clinical benefits.
  • the disease was effectively controlled by using the treatment regimen of the compound of formula (I) disclosed in the present invention; in a patient with extensive-stage small cell lung cancer who has experienced disease progression after treatment with etoposide + cisplatin and disease progression after treatment with polyethylene glycol irinotecan, the disease was effectively controlled by using the treatment regimen of the compound of formula (I) disclosed in the present invention.

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Abstract

La présente invention concerne l'utilisation d'un composé de quinoléine dans le traitement du cancer du poumon à petites cellules, et en particulier, l'utilisation et le procédé pour le N-(4-((7-((1-(cyclopentylamino) cyclopropyl) méthoxy)-6-méthoxyquinolin-4-yl) oxy)-3-fluorophényl)-N-(4-fluorophényl) cyclopropane-1,1-dicarboxamide pour le traitement du cancer du poumon à petites cellules en phase étendue.
PCT/CN2023/137421 2022-12-09 2023-12-08 Utilisation d'un composé de quinoléine dans le traitement du cancer du poumon à petites cellules WO2024120520A1 (fr)

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CN202211582933.7 2022-12-09

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Citations (2)

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CN103328447A (zh) * 2010-09-12 2013-09-25 南京爱德程医药科技有限公司 作为c-Met激酶抑制剂的化合物
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