Drug combinations to treat small cell lung cancer

Abstract

The present invention provides a drug combination for treating small cell lung cancer, comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent. It also provides a use of a drug combination or kit comprising an anti-PD-L1 antibody, anlotinib or a pharma-ceutical acceptable salt thereof, and a chemotherapeutic agent in the manufacture of a medicament for treating small cell lung cancer. It also provides a method for treating small cell lung cancer, comprising administering to a patient in need thereof therapeutically effective amounts of an anti-PD-L1 antibody, anlotinib or a pharma-ceutical acceptable salt thereof, and a chemotherapeutic agent.

Description

[Technical field]

[0001] The present application belongs to the field of biopharmaceuticals and relates to a drug combination, kit and use thereof for treating small cell lung cancer. [Background technology]

[0002] Tyrosine kinases are a series of enzymes that catalyze the phosphorylation of tyrosine residues in proteins, and play an important role in intracellular signal transduction, participating in the control, signal transduction and development of normal cells, as well as being closely related to the proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases are involved in the formation of tumors, and are classified according to the structure of their extracellular domains into epidermal growth factor receptors (EGFR), platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), etc.

[0003] PD-L1 (Programmed death-ligand 1), also known as CD247 and B7-H1, is a ligand of programmed cell death molecule 1 (PD-1). PD-L1 is highly expressed on the surface of several types of tumor cells, and the malignancy and poor prognosis of tumors are closely related to the expression level of PD-L1. In the tumor microenvironment, PD-L1 on the surface of cancer cells binds to PD-1 or CD80 on the surface of T cells, suppressing the activation and proliferation of T cells, promoting the exhaustion or unresponsiveness of effector T cells, inducing apoptosis of T cells, and stimulating the differentiation of helper T cells into regulatory T cells, thereby blocking the damaging effect of T cells on tumor cells. Anti-PD-L1 antibodies block the interaction of PD-L1 with PD-1 and CD80, preventing the initiation and transmission of related negative regulatory signals, thereby avoiding the suppression of effector T cell activity in the tumor microenvironment, and allowing T cells to exert their function of damaging or suppressing tumor cells. Anti-PD-L1 antibodies can act directly on tumor tissue, making them highly specific and safe.

[0004] Small cell lung cancer (SCLC) is the most malignant type of lung cancer, characterized by rapid progression, early metastasis, and a tendency to recur. It accounts for approximately 15-20% of new lung cancers, and its occurrence is closely related to long-term smoking. SCLC is highly invasive and has a poor prognosis, with a 5-year survival rate of less than 5% and an average survival time of only 2-4 months for untreated patients. Compared with other types of lung cancer, SCLC is sensitive to chemotherapy and radiotherapy, and the combination of etoposide and platinum-based antitumor drugs is the standard first-line treatment plan for extensive-stage SCLC, but many patients experience disease progression within 3 months, and the recurrence and drug resistance rates are high, so treatment still faces many challenges.

[0005] WO2016022630 discloses a PD-L1 antibody that has high affinity for PD-L1, significantly inhibits the interaction between PD-L1 on the cell surface and PD-1, and significantly promotes the secretion of IL-2 and INF-γ by T cells. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO2016022630 Summary of the Invention [Problem to be solved by the invention]

[0007] Although many options are available for the treatment of patients with proliferative diseases (cancer), there remains a clinical need for more effective therapeutic agents, especially combinations of one or more drugs. [Means for solving the problem]

[0008] One aspect of the present application provides a drug combination for treating small cell lung cancer comprising an anti-PD-L1 antibody and anlotinib, or a pharmaceutically acceptable salt thereof, and further comprising a chemotherapeutic agent.

[0009] Furthermore, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain CDR1 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:4; a heavy chain CDR2 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:5; a heavy chain CDR3 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:6; a light chain CDR1 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:10; a light chain CDR2 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:11; and a light chain CDR3 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:12. The anti-PD-L1 antibody further comprises the following amino acid sequences: a heavy chain CDR1 region selected from SEQ ID NO: 1 or SEQ ID NO: 4, a heavy chain CDR2 region selected from SEQ ID NO: 2 or SEQ ID NO: 5, a heavy chain CDR3 region selected from SEQ ID NO: 3 or SEQ ID NO: 6, a light chain CDR1 region selected from SEQ ID NO: 7 or SEQ ID NO: 10, a light chain CDR2 region selected from SEQ ID NO: 8 or SEQ ID NO: 11, and a light chain CDR3 region selected from SEQ ID NO: 9 or SEQ ID NO: 12. The anti-PD-L1 antibody further comprises a heavy chain CDR1 region having the amino acid sequence of SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR3 region having the amino acid sequence of SEQ ID NO: 3, a light chain CDR1 region having the amino acid sequence of SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence of SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence of SEQ ID NO: 9. Furthermore, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain variable region that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO:13 or SEQ ID NO:14, and a light chain variable region that has at least 80% identity to the amino acid sequence set forth in SEQ ID NO:15 or SEQ ID NO:16.Furthermore, the anti-PD-L1 antibody comprises a humanized antibody heavy chain variable domain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4, and a humanized antibody light chain variable domain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4.

[0010] Further, the chemotherapeutic agent is one or more selected from platinum-based antitumor agents and topoisomerase inhibitors. In some embodiments, the platinum-based antitumor agents include, but are not limited to, one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miriplatin, or lobaplatin. In some specific embodiments, the platinum-based antitumor agent is one or more selected from carboplatin, cisplatin, nedaplatin, picoplatin, miriplatin, or lobaplatin. In some specific embodiments, the platinum-based antitumor agent is selected from carboplatin. In some specific embodiments, the platinum-based antitumor agent is selected from cisplatin. In some embodiments, the topoisomerase inhibitor includes, but is not limited to, a topoisomerase I inhibitor, a topoisomerase II inhibitor, and a topoisomerase I / II dual inhibitor, and in some embodiments, the topoisomerase inhibitor is selected from a topoisomerase II inhibitor. In some embodiments, the topoisomerase inhibitor includes, but is not limited to, one or more of camptothecin, topotecan, adriamycin, daunorubicin, epirubicin, idarubicin, mitoxantrone, irinotecan, topotecan, etoposide, or teniposide. In some embodiments, the topoisomerase inhibitor is selected from one or more of topotecan, adriamycin, epirubicin, mitoxantrone, irinotecan, topotecan, or etoposide. In some specific embodiments, the topoisomerase inhibitor is selected from etoposide. In some embodiments, the chemotherapeutic agent is selected from platinum-based antitumor agents and etoposide. In some embodiments, the chemotherapeutic agent is selected from carboplatin and a topoisomerase inhibitor. In some embodiments, the chemotherapeutic agent includes one or more selected from carboplatin, cisplatin, nedaplatin, picoplatin, miriplatin, or lobaplatin, and one or more selected from topotecan, adriamycin, epirubicin, mitoxantrone, irinotecan, topotecan, or etoposide.In some embodiments, the chemotherapeutic agent is selected from carboplatin and etoposide.

[0011] In some embodiments, the drug combination further comprises a pharma- ceutically acceptable carrier.

[0012] Another aspect of the present application provides a drug combination for treating small cell lung cancer, comprising a first drug combination and, optionally, a second drug combination. In some embodiments, the drug combination comprises a first drug combination administered to a patient in need thereof in a first treatment phase, and, optionally, a second drug combination administered to a patient in need thereof in a second treatment phase. In some embodiments, the treatment periods of the first treatment phase are 1-10 treatment periods, preferably 2-8 treatment periods, and most preferably 4 treatment periods.

[0013] In some embodiments, the first drug combination comprises an anti-PD-L1 antibody, anlotinib, or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent.

[0014] In some embodiments, the second drug combination comprises an anti-PD-L1 antibody and anlotinib, or a pharma- ceutically acceptable salt thereof.

[0015] In a specific embodiment, the drug combination comprises a first drug combination administered to a patient in need thereof in a first treatment phase, and optionally a second drug combination administered to a patient in need thereof in a second treatment phase, wherein the first drug combination comprises an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent, and the second drug combination comprises an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the treatment periods in the first treatment phase are 1 to 10 treatment periods, preferably 2 to 8 treatment periods, and most preferably 4 treatment periods.

[0016] In some embodiments, the drug combination further comprises a pharma- ceutically acceptable carrier.

[0017] In some embodiments, in a drug combination comprising an anti-PD-L1 antibody described herein, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent, the anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and the chemotherapeutic agent are each in the form of a pharmaceutical composition, and may be administered simultaneously, sequentially, or sequentially. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-PD-L1 antibody, a pharmaceutical composition of anlotinib or a pharma- ceutical salt thereof, and a pharmaceutical composition of a chemotherapeutic agent.

[0018] Furthermore, the above drug combinations of the present application are packaged in the same kit, said kit further comprising instructions for treating small cell lung cancer.

[0019] In some embodiments, the present application provides a kit for treating small cell lung cancer comprising an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent. In some embodiments, the anti-PD-L1 antibody is comprised in a first compartment, anlotinib or a pharmaceutically acceptable salt thereof is comprised in a second compartment, and the chemotherapeutic agent is comprised in another compartment, which may be administered simultaneously, sequentially, or sequentially to a patient in need thereof, optionally increasing the number of compartments in the kit based on the type of chemotherapeutic agent. In some embodiments, the kit further comprises instructions for treating small cell lung cancer with a combination of an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent. In some embodiments, the kit comprises a pharmaceutical composition of an anti-PD-L1 antibody, a pharmaceutical composition of anlotinib or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition of a chemotherapeutic agent.

[0020] Furthermore, the above kit is suitable for administration within a single treatment period (e.g., one treatment period of 21 days), and comprises 600-2400 mg of a pharmaceutical composition comprising an anti-PD-L1 antibody and 84-168 mg of anlotinib. In some embodiments, one treatment period is 1 week, 2 weeks, 3 weeks, or 4 weeks.

[0021] The dosage of the anti-PD-L1 antibody may be determined based on the severity of the disease, the response of the disease, any treatment-related toxicities, and the age and health status of the patient. For example, the daily dosage of the anti-PD-L1 antibody may be 600-2400 mg, and in some embodiments, the daily dosage of the anti-PD-L1 antibody may be 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg. In some embodiments, the anti-PD-L1 antibody is administered in a parenteral manner. In some embodiments, the anti-PD-L1 antibody is administered in an intravenous manner. In some embodiments, the concentration of the pharmaceutical composition of the anti-PD-L1 antibody is 10-60 mg / mL. In some embodiments, the concentration of the anti-PD-L1 antibody pharmaceutical composition is 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL or 60 mg / mL.

[0022] The administration schedule of the anti-PD-L1 antibody may be determined comprehensively based on the activity, toxicity, and patient tolerability of the drug. In some embodiments, the anti-PD-L1 antibody is administered for 1 week, 2 weeks, 3 weeks, or 4 weeks in one treatment period. In some embodiments, the anti-PD-L1 antibody is administered once every week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the dose of the anti-PD-L1 antibody in each treatment period is 600-2400 mg. In some specific embodiments, the dose of the anti-PD-L1 antibody in each treatment period is 1200 mg. In some embodiments, the anti-PD-L1 antibody is administered once every 3 weeks, each time at a dose of 600-2400 mg. In some embodiments, the anlotinib or a pharma- ceutically acceptable salt thereof is administered at a daily dose of 6 mg, 8 mg, 10 mg, or 12 mg, in a dosing schedule of 2 weeks of continuous administration and 1 week of rest.

[0023] In some embodiments, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent described herein comprises a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, wherein the pharmaceutical composition of the anti-PD-L1 antibody is prepared so as to be suitable for administering to a patient a unit dose or multiple doses of 600-2400 mg of the anti-PD-L1 antibody upon a first administration, and the pharmaceutical composition of anlotinib or a pharma- ceutical acceptable salt thereof is prepared so as to be suitable for administering to a patient daily unit doses of 6 mg, 8 mg, 10 mg, and / or 12 mg of anlotinib or a pharma- ceutical acceptable salt thereof for 14 consecutive days.

[0024] In some embodiments, the drug combination comprising an anti-PD-L1 antibody described herein, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent comprises a pharmaceutical composition of an anti-PD-L1 antibody, wherein the concentration of the anti-PD-L1 antibody is 10-60 mg / mL, and a pharmaceutical composition of anlotinib or a pharma-ceutical acceptable salt thereof, wherein the unit dose is 6 mg, 8 mg, 10 mg, and / or 12 mg.

[0025] In some embodiments, the drug combination comprising an anti-PD-L1 antibody described herein, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent comprises a pharmaceutical composition in which 1200 mg of the anti-PD-L1 antibody is provided in a multiple dose form, and a pharmaceutical composition of anlotinib or a pharma- ceutical acceptable salt thereof in unit doses of 8 mg, 10 mg, and / or 12 mg.

[0026] Further, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and a chemotherapeutic agent described herein is a formulation suitable for administration within a single treatment period (e.g., a single treatment period of 21 days), and comprises a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody and a pharmaceutical composition comprising 84-168 mg of anlotinib. In some embodiments, the formulation suitable for administration within a single treatment period (e.g., a single treatment period of 21 days) described herein further comprises a pharmaceutical composition comprising 90-1800 mg, preferably 150-1800 mg, of etoposide. In some embodiments, the formulation suitable for administration within a single treatment period (e.g., a single treatment period of 21 days) described herein further comprises a pharmaceutical composition comprising 50-800 mg of carboplatin.

[0027] Furthermore, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and a chemotherapeutic agent described herein comprises an anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, and most preferably (7-14.5):1, with the proviso that the anti-PD-L1 antibody and anlotinib may be packaged separately or together, with the proviso that anlotinib may be packaged in multiple equal portions (e.g., 2 equal portions, 7 equal portions, 14 equal portions, 28 equal portions or more), and the anti-PD-L1 antibody may be packaged in a single equal portion or multiple equal portions (e.g., 2 equal portions, 4 equal portions or more). In some embodiments, the drug combination described herein comprises an anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, carboplatin, and etoposide, wherein the weight ratio of the anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, carboplatin, and etoposide is (300-1200):(42-84):(25-400):(45-900), for example, (300-1200):(42-84):(25-400):(75-900).Preferably, the carboplatin and etoposide may be packaged in a single aliquot or multiple aliquots (e.g., 3 aliquots, 6 aliquots, or more aliquots).

[0028] Another aspect of the present application also provides the use of the drug combination of the present application or the kit of the present application in the manufacture of a medicament for treating small cell lung cancer in a patient. Alternatively, the present application also provides a method for treating small cell lung cancer comprising administering to a patient in need thereof an effective amount of the drug combination of the present application or the kit of the present application. Alternatively, the present application also provides the use of the drug combination of the present application or the kit of the present application for treating small cell lung cancer in a patient. Alternatively, the present application also provides the drug combination of the present application or the kit of the present application for treating small cell lung cancer in a patient.

[0029] In some embodiments, the method of treating small cell lung cancer provided herein comprises administering to a patient in need thereof a therapeutically effective amount of an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent. In some embodiments, the method of treatment comprises administering to a patient in need thereof a first drug combination in a first treatment phase, and optionally administering to a patient in need thereof a second drug combination in a second treatment phase. In some embodiments, the first drug combination comprises an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent. In some embodiments, the second drug combination comprises an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the first treatment phase comprises between 1 and 10 treatment periods, preferably between 2 and 8 treatment periods, and most preferably 4 treatment periods.

[0031] In some embodiments, the chemotherapeutic agent is one or more selected from a platinum-based antitumor agent and a topoisomerase inhibitor. In some embodiments, the chemotherapeutic agent is selected from a platinum-based antitumor agent and etoposide. In some embodiments, the chemotherapeutic agent is selected from carboplatin and etoposide.

[0032] Furthermore, the anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and chemotherapeutic agent are each in the form of a pharmaceutical composition, and may be administered simultaneously, sequentially, or at intervals. Furthermore, the anti-PD-L1 antibody is administered once every week, every two weeks, every three weeks, or every four weeks, and preferably, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time. Furthermore, the anlotinib is administered at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily, with a dosing schedule of two weeks of continuous administration and one week of rest.

[0033] Anlotinib: As used herein, the chemical name of the free base of anlotinib is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine and has the following structural formula: [ka]

[0034] Pharmaceutically acceptable salts of anlotinib include those of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, caproic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorosulfonic acid, and 1,2-hexanediol. In some embodiments, the pharmaceutically acceptable salts include, but are not limited to, salts formed by anlotinib with an acid selected from the group consisting of aryl benzoate, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, and stearic acid, and in some embodiments, the pharmaceutically acceptable salts are the hydrochloride and maleate salts, and in some embodiments, the pharmaceutically acceptable salt is the dihydrochloride salt.

[0035] All doses of anlotinib or a pharma- ceutically acceptable salt thereof in this application are based on the molecular weight of the free base of anlotinib, unless otherwise specified.

[0036] Anlotinib or a pharmaceutically acceptable salt thereof may be administered by various routes, including oral and parenteral routes, including but not limited to oral, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, subcutaneous, intraadipose, intraarticular, intraperitoneal, and intrathecal. In some particular embodiments, it is administered orally. The dosage of anlotinib or a pharmaceutically acceptable salt thereof may be determined based on the severity of the disease, the response of the disease, any treatment-related toxicities, and the age and health of the patient. For example, the daily dose of anlotinib or a pharma- ceutically acceptable salt thereof may be 2-20 mg, and in some embodiments, the daily dose of anlotinib or a pharma- ceutically acceptable salt thereof may be 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg. Anlotinib or a pharma- ceutically acceptable salt thereof may be administered once or multiple times daily. In some embodiments, anlotinib or a pharma- ceutically acceptable salt thereof is administered once daily as an oral solid formulation.

[0037] The dosing schedule of anlotinib or a pharma- ceutically acceptable salt thereof may be determined comprehensively based on the activity, toxicity, and tolerability of the drug. Preferably, anlotinib or a pharma- ceutically acceptable salt thereof is administered in an interval dosing manner. The interval dosing includes an administration period and a withdrawal period, and anlotinib or a pharma- ceutical acceptable salt thereof may be administered once or multiple times daily during the administration period. For example, the ratio of the number of days of the administration period to the withdrawal period is 2: (0.5 to 5), 2: (0.5 to 3), 2: (0.5 to 2), or 2: (0.5 to 1). In some embodiments, the administration period is 2 weeks of continuous administration and 2 weeks of withdrawal. In some embodiments, the administration period is 2 weeks of continuous administration and 1 week of withdrawal. In some embodiments, the administration period is 5 days of continuous administration and 2 days of withdrawal. For example, anlotinib or a pharma- ceutically acceptable salt thereof may be administered orally at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily, administered on a regimen of two weeks on continuous therapy followed by one week off.

[0038] Pharmaceutical compositions of anlotinib or a pharma- ceutical acceptable salt thereof: In some embodiments of the present application, the unit dose of the pharmaceutical composition of anlotinib or a pharma- ceutically acceptable salt thereof contains 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib.

[0039] In some embodiments of the present application, the total dose of the pharmaceutical composition of anlotinib or a pharma- ceutically acceptable salt thereof administered during each treatment period of 2 weeks of administration and 1 week of rest is 84 to 168 mg. In some embodiments, the total dose of the pharmaceutical composition of anlotinib or a pharma- ceutically acceptable salt thereof is selected from 84 mg, 112 mg, 140 mg, 168 mg, or a range formed by any of the above values. In some embodiments, the total dose of the pharmaceutical composition of anlotinib or a pharma- ceutically acceptable salt thereof is 112 to 168 mg.

[0040] In some embodiments, the pharmaceutical composition includes, but is not limited to, a formulation suitable for oral, parenteral, or topical administration, in some embodiments, the pharmaceutical composition is a formulation suitable for oral administration, in some embodiments, the pharmaceutical composition is a solid formulation suitable for oral administration, in some embodiments, the pharmaceutical composition includes, but is not limited to, a tablet, a capsule.

[0041] Chemotherapy drugs: In some embodiments of the present application, the chemotherapeutic agent is one or more selected from platinum-based antitumor agents and topoisomerase inhibitors.

[0042] In the present application, the platinum-based antitumor drug includes, but is not limited to, one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miriplatin, or lobaplatin. In some embodiments of the present application, the platinum-based antitumor drug is selected from carboplatin.

[0043] In the present application, the topoisomerase inhibitor includes, but is not limited to, a topoisomerase I inhibitor, a topoisomerase II inhibitor, and a topoisomerase I / II dual inhibitor, and in some embodiments, the topoisomerase inhibitor is selected from a topoisomerase II inhibitor. In some embodiments, the topoisomerase inhibitor includes, but is not limited to, one or more of camptothecin, topotecan, adriamycin, daunorubicin, epirubicin, idarubicin, mitoxantrone, irinotecan, topotecan, etoposide, or teniposide. In some embodiments, the topoisomerase inhibitor is selected from etoposide.

[0044] In some embodiments of the present application, the chemotherapeutic agent is selected from a platinum-based antitumor agent and etoposide. In some embodiments, the chemotherapeutic agent is selected from carboplatin and a topoisomerase inhibitor. In some embodiments of the present application, the chemotherapeutic agent is selected from carboplatin and / or etoposide. In some embodiments of the present application, the chemotherapeutic agent is selected from carboplatin and etoposide.

[0045] In some embodiments, carboplatin is administered at a dose that provides an AUC (area under the blood concentration-time curve) of 4-7 mg / mL / min, preferably at a dose that provides an AUC of 5-7 mg / mL / min, and more preferably at a dose that provides an AUC of 5 mg / mL / min.

[0046] In some embodiments, etoposide is administered at a dose of 60 to 120 mg / m 2 is administered at a dose of 60 to 100 mg / m 2 and more preferably at a dose of 100 mg / m 2 However, as will be appreciated by those skilled in the art, the dosage may be in the range of mg / m 2 refers to the dose of drug used per square meter of the subject's body surface area.

[0047] Anti-PD-L1 antibody: In some embodiments of the application, the anti-PD-L1 antibody is an antibody described in WO2016022630 or CN107001463A.

[0048] In some embodiments of the application, the anti-PD-L1 antibody comprises a heavy chain CDR1 region that has at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:4, and a heavy chain CDR1 region that has at least 80% (e.g., 81% , 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6, and a heavy chain CDR3 region having homology thereto, and a light chain CDR1 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:10, and a light chain CDR1 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:11; and a light chain CDR3 region having at least 80% homology (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:12.

[0049] In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain CDR1 region selected from SEQ ID NO:1 or SEQ ID NO:4, a heavy chain CDR2 region selected from SEQ ID NO:2 or SEQ ID NO:5, a heavy chain CDR3 region selected from SEQ ID NO:3 or SEQ ID NO:6, a light chain CDR1 region selected from SEQ ID NO:7 or SEQ ID NO:10, a light chain CDR2 region selected from SEQ ID NO:8 or SEQ ID NO:11, and a light chain CDR3 region selected from SEQ ID NO:9 or SEQ ID NO:12.

[0050] In some embodiments of the application, the isolated anti-PD-L1 antibodies described herein comprise a heavy chain CDR1 region having the amino acid sequence set forth in SEQ ID NO:1, a heavy chain CDR2 region having the amino acid sequence set forth in SEQ ID NO:2, a heavy chain CDR3 region having the amino acid sequence set forth in SEQ ID NO:3, and a light chain CDR1 region having the amino acid sequence set forth in SEQ ID NO:7, a light chain CDR2 region having the amino acid sequence set forth in SEQ ID NO:8, and a light chain CDR3 region having the amino acid sequence set forth in SEQ ID NO:9.

[0051] Each of the CDR regions described herein and its various variants described above can specifically recognize and bind to PD-L1, thereby effectively blocking the signal transduction between PD-L1 and PD-1.

[0052] In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:13 or SEQ ID NO:14; and a light chain variable region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to the amino acid sequence set forth in SEQ ID NO:15 or SEQ ID NO:16.

[0053] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain variable region set forth in SEQ ID NO:13 and a light chain variable region set forth in SEQ ID NO:15.

[0054] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain variable region set forth in SEQ ID NO:14 and a light chain variable region set forth in SEQ ID NO:16.

[0055] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain amino acid sequence set forth in SEQ ID NO:17 and a light chain amino acid sequence set forth in SEQ ID NO:18.

[0056] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain amino acid sequence set forth in SEQ ID NO:19 and a light chain amino acid sequence set forth in SEQ ID NO:20.

[0057] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain amino acid sequence set forth in SEQ ID NO:21, and a light chain amino acid sequence set forth in SEQ ID NO:18.

[0058] In a specific embodiment, the anti-PD-L1 humanized monoclonal antibodies provided by the present application contain one or more conservatively substituted variants selected from SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21. Anti-PD-L1 humanized monoclonal antibodies containing such conservatively substituted variants retain the ability to specifically recognize and bind to PD-L1.

[0059] In some embodiments of the application, the anti-PD-L1 antibody may be an IgG1 or IgG4 antibody.

[0060] In some embodiments of the present application, the anti-PD-L1 antibody is an IgG1 antibody, hi some embodiments, the anti-PD-L1 antibody is a glycosylated IgG1 antibody.

[0061] In some embodiments of the application, the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) of an antibody chosen from 13C5 or 5G11, and a light chain complementarity determining region of an antibody chosen from 13C5 or 5G11. In one embodiment, the anti-PD-L1 antibody described in the application comprises a heavy chain variable region of a chimeric antibody chosen from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, or ch13C5-hIgG4, and a light chain variable region of a chimeric antibody chosen from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, or ch13C5-hIgG4. In one embodiment, the anti-PD-L1 antibodies described in the present application comprise a heavy chain variable region of a humanized antibody selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4, and a light chain variable region of a humanized antibody selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4. According to the description in patent document WO2016022630 or CN107001463A, that is, the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID NO: 5), the HCDR3 sequence is GYDSGFAY (SEQ ID NO: 6), the LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO: 10), the LCDR2 sequence is YASNLES (SEQ ID NO: 11), and the LCDR3 sequence is QHSW EIPYT (SEQ ID NO: 12), and the HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 is TYGVH (SEQ ID NO: 1), the HCDR2 sequence is VIWRGVTTDYNAAFMS (SEQ ID NO: 2), the HCDR3 sequence is LGFYAMDY (SEQ ID NO: 3), the LCDR1 sequence is KASQSVSNDVA (SEQ ID NO: 7), the LCDR2 sequence is YAANRYT (SEQ ID NO: 8) and the LCDR3 sequence is QQDYTSPYT (SEQ ID NO: 9).

[0062] In some embodiments of the present application, the anti-PD-L1 antibody in the drug combination is selected from one or more types. As used herein, the term "multiple types" can mean one or more types, for example, two, three, four, five or more types. For example, in some embodiments of the present application, the anti-PD-L1 antibody is selected from those comprising a heavy chain variable region set forth in SEQ ID NO: 13 and a light chain variable region set forth in SEQ ID NO: 15, or from those comprising a heavy chain variable region set forth in SEQ ID NO: 14 and a light chain variable region set forth in SEQ ID NO: 16, or from any combination of the above. Also, for example, the anti-PD-L1 antibody is selected from the heavy chain amino acid sequence set forth in SEQ ID NO: 17 and the light chain amino acid sequence set forth in SEQ ID NO: 18, or from the heavy chain amino acid sequence set forth in SEQ ID NO: 19 and the light chain amino acid sequence set forth in SEQ ID NO: 20, or from the heavy chain amino acid sequence set forth in SEQ ID NO: 21 and the light chain amino acid sequence set forth in SEQ ID NO: 18, or from any combination of the above.

[0063] In some embodiments, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain CDR1 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:4; a heavy chain CDR2 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:5; a heavy chain CDR3 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:6; a light chain CDR1 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:10; a light chain CDR2 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:11; and a light chain CDR3 region that has at least 80% homology to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:12.

[0064] Pharmaceutical compositions of anti-PD-L1 antibodies: In some embodiments of the present application, the pharmaceutical composition of an anti-PD-L1 antibody contains 600-2400 mg of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition of an anti-PD-L1 antibody contains 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2100 mg, 2400 mg, or a range formed by any of the preceding values. In some embodiments, the pharmaceutical composition of an anti-PD-L1 antibody contains 600-2100 mg, or 900-1500 mg of anti-PD-L1 antibody, provided that the pharmaceutical composition of an anti-PD-L1 antibody may be present in the form of multiple doses or unit doses.

[0065] In some embodiments of the application, the anti-PD-L1 antibody pharmaceutical composition comprises 300 mg, 600 mg, or 1200 mg of anti-PD-L1 antibody, and some embodiments of the application provide an anti-PD-L1 antibody pharmaceutical composition manufactured as a unit dose containing 300 mg, 600 mg, or 1200 mg of anti-PD-L1 antibody.

[0066] In some embodiments, the anti-PD-L1 antibody pharmaceutical composition is an injectable solution. In some embodiments, the anti-PD-L1 antibody pharmaceutical composition is an injectable aqueous solution. In some embodiments of the present application, the anti-PD-L1 antibody pharmaceutical composition comprises one or more of a buffer, a tonicity adjusting agent, a stabilizer, and / or a surfactant. In particular, the anti-PD-L1 antibody pharmaceutical composition comprises 1-150 mg / mL anti-PD-L1 antibody (e.g., monoclonal), 3-50 mM buffer, 2-150 mg / mL tonicity adjusting agent / stabilizer, 0.01-0.8 mg / mL surfactant, and has a pH of 4.5-6.8.

[0067] In some embodiments of the present application, the anti-PD-L1 antibody pharmaceutical composition has an anti-PD-L1 monoclonal concentration of 5-150 mg / mL, in some embodiments the concentration is 10-60 mg / mL, and in some embodiments the concentration is 10-30 mg / mL, hi some specific embodiments, the anti-PD-L1 monoclonal mass volume concentration is 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, or 120 mg / mL, in some embodiments the concentration is 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, or 60 mg / mL, and in some embodiments the concentration is 10 mg / mL, 20 mg / mL, or 30 mg / mL. In some embodiments, the mass volume concentration of the anti-PD-L1 monoclonal is 10 mg / mL, and in some embodiments, the mass volume concentration of the anti-PD-L1 monoclonal is 30 mg / mL, and in some embodiments, the mass volume concentration of the anti-PD-L1 monoclonal is 60 mg / mL.

[0068] In some embodiments of the present application, the buffer is a histidine salt buffer. The histidine salt buffer has a concentration of 5-30 mM, in some embodiments, the concentration is 10-25 mM, in some embodiments, the concentration is 10-20 mM, and in some embodiments, the concentration is 10-15 mM. In some specific embodiments, the histidine salt buffer has a concentration of 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, or 30 mM. In some embodiments, the histidine salt buffer has a concentration of 10 mM. In some embodiments, the histidine salt buffer has a concentration of 15 mM. In some embodiments, the histidine salt buffer has a concentration of 20 mM, provided that the histidine salt buffer contains histidine and hydrochloric acid.

[0069] In some embodiments of the present application, the tonicity adjusting / stabilizing agent is 20-150 mg / mL sucrose, in some embodiments, the tonicity adjusting / stabilizing agent is 40-100 mg / mL sucrose, in some embodiments, the tonicity adjusting / stabilizing agent is 60-80 mg / mL sucrose, calculated on a w / v basis. In some specific embodiments, the concentration of the sucrose is 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, or 100 mg / mL. In some specific embodiments, the concentration of the sucrose is 60 mg / mL. In some specific embodiments, the concentration of the sucrose is 70 mg / mL. In some specific embodiments, the concentration of the sucrose is 80 mg / mL. In some specific embodiments, the concentration of the sucrose is 90 mg / mL.

[0070] In some embodiments of the present application, the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188, in some embodiments the surfactant is selected from polysorbate 80 or polysorbate 20, in some embodiments the surfactant is selected from polysorbate 80. In some embodiments, calculated on a w / v basis, the concentration of the surfactant is 0.05-0.6 mg / mL, in some embodiments the concentration is 0.1-0.4 mg / mL, and in some embodiments the concentration is 0.2-0.3 mg / mL.

[0071] In some embodiments of the present application, calculated on a w / v basis, the surfactant is 0.01-0.8 mg / mL polysorbate 80 or polysorbate 20. In some specific embodiments, the surfactant is 0.05-0.6 mg / mL polysorbate 80, in some embodiments, the surfactant is 0.1-0.4 mg / mL polysorbate 80, in some embodiments, the surfactant is 0.2-0.3 mg / mL polysorbate 80, and in some embodiments, the surfactant is 0.2 mg / mL polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, or 0.6 mg / mL; in some embodiments, the pharmaceutical composition contains 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, or 0.5 mg / mL; in some embodiments, the pharmaceutical composition contains 0.2 mg / mL, 0.3 mg / mL, or 0.4 mg / mL; in some embodiments, the pharmaceutical composition contains 0.2 mg / mL, 0.3 mg / mL, or 0.4 mg / mL; in some embodiments, the pharmaceutical composition contains 0.2 mg / mL. In some embodiments, the pharmaceutical composition contains 0.1 mg / mL polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.2 mg / mL polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.3 mg / mL polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.4 mg / mL polysorbate 80. In some embodiments, the pharmaceutical composition contains 0.5 mg / mL polysorbate 80.

[0072] In some embodiments of the present application, the pH of the aqueous solution of the pharmaceutical composition is selected from 4.0 to 6.8, in some embodiments, the pH is 4.5 to 6.5, in some embodiments, the pH is 5.5 to 6.0, and in some embodiments, the pH is 5.5. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 4.5, 4.8, 5.0, 5.2, 5.4, 5.5, 5.6, 5.8, or 6.0, in some embodiments, the pH is 5.0, 5.2, 5.4, 5.5, or 5.6, and in some embodiments, the pH is 5.5. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.0. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.2. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.4. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.5. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.6. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is 5.8. In some embodiments, the aqueous solution of the pharmaceutical composition has a pH of 6.0.

[0073] In some specific embodiments of the present application, the pharmaceutical composition comprises (a) an anti-PD-L1 antibody having a mass volume concentration of 20 mg / mL, (b) sucrose having a mass volume concentration of 70 mg / mL, (c) polysorbate 80 having a mass volume concentration of 0.1 mg / mL, (d) histidine having a molar concentration of 20 mM, and (e) optionally a suitable amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.0. In a specific embodiment of the present application, the pharmaceutical composition comprises (a) an anti-PD-L1 monoclonal having a mass volume concentration of 20 mg / mL, (b) sucrose having a mass volume concentration of 70 mg / mL, (c) polysorbate 80 having a mass volume concentration of 0.1 mg / mL, (d) histidine having a molar concentration of 20 mM, and (e) optionally a suitable amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.0.

[0074] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody at a mass / volume concentration of 10 mg / mL; (b) sucrose at a mass / volume concentration of 80 mg / mL; (c) polysorbate 80 at a mass / volume concentration of 0.2 mg / mL; (d) histidine at a molar concentration of 10 mM; and (e) optionally, a suitable amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0075] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody at a mass / volume concentration of 50 mg / mL; (b) sucrose at a mass / volume concentration of 80 mg / mL; (c) polysorbate 80 at a mass / volume concentration of 0.3 mg / mL; (d) histidine at a molar concentration of 10 mM; and (e) optionally, a suitable amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0076] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody having a mass / volume concentration of 100 mg / mL; (b) sucrose having a mass / volume concentration of 80 mg / mL; (c) polysorbate 80 having a mass / volume concentration of 0.5 mg / mL; (d) histidine having a molar concentration of 10 mM; and (e) optionally, a suitable amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0077] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody at a mass / volume concentration of 30 mg / mL; (b) sucrose at a mass / volume concentration of 80 mg / mL; (c) polysorbate 80 at a mass / volume concentration of 0.2 mg / mL; (d) histidine at a molar concentration of 10 mM; and (e) optionally, a suitable amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0078] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody having a mass / volume concentration of 60 mg / mL; (b) sucrose having a mass / volume concentration of 80 mg / mL; (c) polysorbate 80 having a mass / volume concentration of 0.2 mg / mL; (d) histidine having a molar concentration of 10 mM; and (e) optionally, a suitable amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0079] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody having a mass / volume concentration of 10 mg / mL; (b) sucrose having a mass / volume concentration of 70 mg / mL; (c) polysorbate 80 having a mass / volume concentration of 0.4 mg / mL; (d) histidine having a molar concentration of 20 mM; and (e) optionally, a suitable amount of acetic acid, wherein the pH of the composition is adjusted to 6.5.

[0080] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) the anti-PD-L1 monoclonal having a mass / volume concentration of 10 mg / mL; (b) sucrose having a mass / volume concentration of 80 mg / mL; (c) polysorbate 80 having a mass / volume concentration of 0.2 mg / mL; (d) histidine having a molar concentration of 20 mM; and (e) optionally, a suitable amount of hydrochloric acid, wherein the pH of the composition is adjusted to 5.5.

[0081] In another specific embodiment of the present application, the pharmaceutical composition is an aqueous injection solution, and in some embodiments, the aqueous injection solution includes, but is not limited to, an aqueous formulation that has not been lyophilized or an aqueous formulation that has been reconstituted from a lyophilized powder. In some embodiments, the pharmaceutical composition is a lyophilized formulation. The lyophilized formulation refers to a formulation produced by performing a lyophilization process on an aqueous solution, in which the material is first frozen, then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent is at a level that does not correspond to biological activity or chemical reaction. The lyophilized formulation of the present application may be dried by other methods known in the art, for example, spray drying, bubble drying.

[0082] Drug Combinations: One aspect of the application provides a drug combination for treating small cell lung cancer comprising an anti-PD-L1 antibody, anlotinib or a pharmaceutical salt thereof, and a chemotherapeutic agent.

[0083] In some embodiments of the present application, the drug combination comprises an anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and a chemotherapeutic agent. In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and a chemotherapeutic agent is a defined combination. In some embodiments, the defined combination is in the form of a solid pharmaceutical composition or in the form of a liquid pharmaceutical composition. In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and a chemotherapeutic agent is an undefined combination. In some embodiments, the anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and the chemotherapeutic agent in the undefined combination are each in the form of a pharmaceutical composition. In some embodiments, each of the active ingredients of the anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and the chemotherapeutic agent in the undefined combination are each in the form of a pharmaceutical composition.

[0084] In some embodiments, there is provided a drug combination comprising an anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, and most preferably (7-14.5):1, with the proviso that the anti-PD-L1 antibody and anlotinib may be packaged separately or together, and with the proviso that anlotinib may be packaged in multiple equal portions (e.g., 2 equal portions, 7 equal portions, 14 equal portions, 28 equal portions or more).

[0085] In some embodiments of the application, the drug combination comprising the anti-PD-L1 antibody, anlotinib, or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent includes: i) An anti-PD-L1 antibody, in one embodiment, the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) of an antibody selected from 13C5 or 5G11, and a light chain complementarity determining region of an antibody selected from 13C5 or 5G11; in one embodiment, the anti-PD-L1 antibody comprises a heavy chain CDR of a chimeric antibody selected from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4, and a light chain CDR of an antibody selected from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4; and a chimeric antibody light chain variable region selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4; in one embodiment, the anti-PD-L1 antibody comprises a heavy chain variable region of a humanized antibody selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4, and a humanized antibody light chain variable region selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4; In one embodiment, the anti-PD-L1 antibody comprises the following complementarity determining regions: 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, or hu13C5-hIgG4 as described in patent document WO2016022630 or CN107001463A, in which the HCDR1 sequence is SYGMS, the HCDR2 sequence is SISSGGSTYYPDSVKG, the HCDR3 sequence is GYDSGFAY, the LCDR1 sequence is ASQSVSTSSSSFMH, and the LCDR the HCDR1 sequence is TYGVH, the HCDR2 sequence is VIWRGVTTDYNAAFMS, the HCDR3 sequence is LGFYAMDY, the LCDR1 sequence is KASQSVSNDVA, the LCDR2 sequence is YAANRYT, and the LCDR3 sequence is QQDYTSPYT of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4; ii) anlotinib or a pharma- ceutically acceptable salt thereof; iii) Platinum-based antineoplastic agents, and / or etoposide.

[0086] In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody and a chemotherapeutic agent comprises 600-2400 mg of a pharmaceutical composition comprising an anti-PD-L1 antibody, 50-700 mg of a carboplatin pharmaceutical composition, and 20-200 mg of an etoposide pharmaceutical composition, wherein the anti-PD-L1 antibody pharmaceutical composition, the carboplatin pharmaceutical composition, and the etoposide pharmaceutical composition are in a single dose or multiple doses.

[0087] In some embodiments of the application, the drug combination comprises an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent, or a pharmaceutical composition of the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent, as described above.

[0088] In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent comprises a pharmaceutical composition of an anti-PD-L1 antibody, a pharmaceutical composition of anlotinib or a pharma- ceutical salt thereof, and a pharmaceutical composition of a chemotherapeutic agent. In some embodiments of the present application, the drug combination is packaged in the same kit, and the kit further comprises instructions for treating small cell lung cancer with the combination of a PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent.

[0089] In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic drug comprises a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof in a single dose of 6 mg, 8 mg, 10 mg, and / or 12 mg, a carboplatin pharmaceutical composition in a single dose of 50-800 mg (e.g., 50-500 mg), and an etoposide pharmaceutical composition in a single dose of 20-200 mg, of which the anti-PD-L1 antibody pharmaceutical composition, the anlotinib or a pharma- ceutical salt thereof pharmaceutical composition, the carboplatin pharmaceutical composition, and the etoposide pharmaceutical composition are in a single dose or multiple doses.

[0090] In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent comprises a pharmaceutical composition provided in the form of multiple doses comprising 1200 mg of an anti-PD-L1 antibody, a single dose of anlotinib of 6 mg, 8 mg, 10 mg, and / or 12 mg, a pharmaceutical composition of carboplatin in the range of 200-400 mg, and a pharmaceutical composition of etoposide in the range of 50-150 mg.

[0091] In some embodiments of the application, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent comprises a pharmaceutical composition of an anti-PD-L1 antibody having a concentration of 10-60 mg / mL of the anti-PD-L1 antibody, anlotinib at a single dose of 6 mg, 8 mg, 10 mg, and / or 12 mg, a pharmaceutical composition of carboplatin at 50-500 mg, and a pharmaceutical composition of etoposide at 20-200 mg.

[0092] In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and a chemotherapeutic agent comprises a pharmaceutical composition of an anti-PD-L1 antibody, wherein the concentration of the anti-PD-L1 antibody is 10 mg / mL, anlotinib, wherein the single dose is 8 mg, 10 mg, and / or 12 mg, a pharmaceutical composition of carboplatin in the range of 200-400 mg, and a pharmaceutical composition of etoposide in the range of 50-150 mg.

[0093] In some embodiments, the drug combination comprises an anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, and most preferably (7-14.5):1, with the proviso that the anti-PD-L1 antibody and anlotinib may be packaged separately or together, and with the proviso that anlotinib may be packaged in multiple equal portions (e.g., 2 equal portions, 7 equal portions, 14 equal portions, 28 equal portions or more).

[0094] Another aspect of the present application provides a drug combination for treating small cell lung cancer, comprising a first drug combination administered to a patient in need thereof in a first treatment step, and optionally a second drug combination administered to a patient in need thereof in a second treatment step, and in some embodiments of the present application, the first drug combination may be selected from one or more of the drug combinations listed above.

[0095] In some embodiments, the first drug combination comprises an anti-PD-L1 antibody, anlotinib, or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent.

[0096] In some embodiments, the second drug combination comprises an anti-PD-L1 antibody and anlotinib, or a pharma- ceutically acceptable salt thereof.

[0097] In some embodiments, the first treatment phase comprises between 1 and 10 treatment periods, preferably between 2 and 8 treatment periods, and most preferably 4 treatment periods.

[0098] In some embodiments, the drug combination further comprises a pharma- ceutically acceptable carrier.

[0099] In some embodiments, the anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and the chemotherapeutic agent in the drug combination are each in the form of a pharmaceutical composition.In some embodiments, each of the active ingredients in the drug combination, the anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and the chemotherapeutic agent, are each in the form of a pharmaceutical composition.

[0100] kit: A further aspect of the application provides a kit for treating small cell lung cancer, the kit comprising a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of anlotinib or a pharmaceutical acceptable salt thereof, and further comprising a chemotherapeutic agent and instructions for the combination treatment of small cell lung cancer; in some embodiments, a kit for treating small cell lung cancer is provided, the kit comprising a pharmaceutical composition of an anti-PD-L1 antibody, a pharmaceutical composition of anlotinib or a pharmaceutical acceptable salt thereof, and / or a carboplatin pharmaceutical composition and / or an etoposide pharmaceutical composition, and instructions for the combination treatment of small cell lung cancer; or the kit comprising a drug combination of the application and instructions for the combination treatment of small cell lung cancer.

[0101] Usage: A further aspect of the present application also provides the use of a pharmaceutical combination of the present application, or a kit of the present application, in the manufacture of a medicament for treating small cell lung cancer in a patient. The present application also provides a method of treating small cell lung cancer in a patient, comprising administering to a patient in need thereof an effective amount of a pharmaceutical combination of the present application, or a kit of the present application. The present application also provides the use of a pharmaceutical combination of the present application, or a kit of the present application, for treating small cell lung cancer in a patient. The pharmaceutical combination or kit is as described above.

[0102] In some embodiments of the present application, in the above uses or methods of treatment, the anti-PD-L1 antibody, anlotinib or a pharma- ceutical acceptable salt thereof, and the chemotherapeutic agent are each a pharmaceutical composition, and may be administered simultaneously, sequentially, or at intervals.

[0103] In some embodiments of the present application, in the above uses or methods of treatment, the anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and the chemotherapeutic agent are each administered in an interval dosing manner. In some embodiments, the anti-PD-L1 antibody, anlotinib or a pharma-ceutically acceptable salt thereof, and the chemotherapeutic agent are each administered in the same or different dosing regimens. In some embodiments, the anti-PD-L1 antibody, anlotinib or a pharma-ceutically acceptable salt thereof, and the chemotherapeutic agent are each administered in different dosing regimens.

[0104] In some embodiments of the present application, in the uses or methods of treatment, the anti-PD-L1 antibody may be administered once every week (q1w), every two weeks (q2w), every three weeks (q3w), or every four weeks (q4w). In a specific embodiment, the anti-PD-L1 antibody is administered once every three weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time.

[0105] In some embodiments of the present application, the anlotinib or a pharma- ceutically acceptable salt thereof may be administered at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily in a dosing regimen of 2 weeks on and 1 week off, where 3 weeks is one dosing period.

[0106] In some embodiments of the present application, the chemotherapeutic agents may be administered according to known dosing regimens.

[0107] In some embodiments of the present application, the anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and the chemotherapeutic agent each have the same or different dosing periods. In some specific embodiments, the anti-PD-L1 antibody, anlotinib or a pharma- ceutically acceptable salt thereof, and the chemotherapeutic agent each have the same dosing period, e.g., one dosing period is 1 week, 2 weeks, 3 weeks, or 4 weeks.

[0108] In some embodiments of the present application, the dosing schedule of the drug combination or the use or method of treatment comprises a 21 day dosing period, with the PD-L1 antibody being administered on the first day of each dosing period, and anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent being administered daily on days 1-14 of each period, where the chemotherapeutic agent may be administered according to known dosing schedules. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each period, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily on days 1-14 of each period, and / or carboplatin is administered on day 1 of each period, and / or etoposide is administered on days 1, 2, and 3 of each period.

[0109] In some embodiments of the application, in the uses or treatment methods, the anti-PD-L1 antibody may be administered to a patient at a dose selected from 0.01 to 40 mg / kg, 0.1 to 30 mg / kg, 0.1 to 20 mg / kg, 0.1 to 15 mg / kg, 0.1 to 10 mg / kg, 1 to 15 mg / kg, 1 to 20 mg / kg, 1 to 3 mg / kg, 3 to 10 mg / kg, 3 to 15 mg / kg, 3 to 20 mg / kg, 3 to 30 mg / kg, 10 to 20 mg / kg, or 15 to 20 mg / kg, or at a dose of 60 to 2400 mg, 90 to about 1800 mg, 120 to 1500 mg, 300 to 900 mg, 600 to 900 mg, 300 to 1200 mg, 600 to 1200 mg, or 900 to 1200 mg.

[0110] In some embodiments of said uses or methods of treatment, one dosing period is 21 days, with 1200 mg of the PD-L1 antibody administered on the first day of each period, and 6 mg, 8 mg, 10 mg and / or 12 mg of anlotinib administered daily on days 1-14 of each period.

[0111] In some embodiments of the present application, the anti-PD-L1 antibody and anlotinib are administered to a subject in a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, and most preferably (7-14.5):1, per 3 week treatment period, where the anti-PD-L1 antibody and anlotinib are administered in a single dose and multiple doses, respectively.

[0112] In some embodiments of the present application, the drug combination dosing regimen or the use or method of treatment comprises administering an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent during overlapping time periods to perform a first treatment phase, followed by, optionally, administering an anti-PD-L1 antibody, and anlotinib or a pharmaceutically acceptable salt thereof, during a second treatment phase during overlapping time periods. In some embodiments, the first treatment phase and the second treatment phase each have a 21-day dosing period. In some embodiments, the first treatment phase comprises administering a PD-L1 antibody on the first day of each dosing period, and administering anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent daily on days 1-14 of each period, where the chemotherapeutic agent may be administered according to known dosing regimens. In some embodiments, the chemotherapeutic agent is one or more selected from platinum-based antitumor agents and / or topoisomerase inhibitors. In some embodiments, the chemotherapeutic agent is selected from carboplatin and etoposide. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each period, anlotinib or a pharma- ceutically acceptable salt thereof is administered once daily on days 1-14 of each period, and / or carboplatin is administered on day 1 of each period, and / or etoposide is administered on days 1, 2, and 3 of each period. In some embodiments, the treatment periods of the first treatment phase are 1 to 10 treatment periods, preferably 2 to 8 treatment periods, and most preferably 4 treatment periods.

[0113] In some embodiments, carboplatin is administered at a dose that has an AUC of 4-7 mg / mL / min, preferably at a dose that has an AUC of 5-7 mg / mL / min, and more preferably at a dose that has an AUC of 5 mg / mL / min.

[0114] In some embodiments, etoposide is administered at a dose of 60 to 120 mg / m 2 is administered at a dose of 60 to 100 mg / m 2 and more preferably at a dose of 100 mg / m 2 is administered at a dose of

[0115] In some embodiments, during the second treatment phase, the PD-L1 antibody is administered on the first day of each dosing period, and anlotinib, or a pharma- ceutically acceptable salt thereof, is administered daily on days 1-14 of each period.

[0116] Small cell lung cancer: In some embodiments, the small cell lung cancer includes limited-stage and extensive-stage small cell lung cancer. As will be understood by those skilled in the art based on common knowledge, the term "extensive-stage small cell lung cancer" includes, but is not limited to, first-time treated (i.e., first-time treatment) extensive-stage small cell lung cancer.

[0117] In some embodiments, the small cell lung cancer is late stage and / or refractory and / or recurrent and / or metastatic small cell lung cancer. In some embodiments, the small cell lung cancer comprises sensitive recurrent and / or refractory recurrent small cell lung cancer. In some embodiments, the small cell lung cancer is brain metastatic small cell lung cancer.

[0118] In some embodiments of the present application, the small cell lung cancer patient is a small cell lung cancer patient who has undergone surgery, chemotherapy and / or radiation therapy. In some embodiments, the chemotherapy is selected from chemotherapy including platinum-based antineoplastic drugs. In some embodiments, the platinum-based antineoplastic drugs include, but are not limited to, cisplatin and carboplatin.

[0119] In some embodiments, the small cell lung cancer is a small cell lung cancer that has not previously received systemic treatment. In some embodiments, the small cell lung cancer is a small cell lung cancer that has not previously received systemic treatment for extensive-stage small cell lung cancer. In some embodiments, the small cell lung cancer is an extensive-stage small cell lung cancer that has not previously received systemic treatment.

[0120] In some embodiments, the small cell lung cancer patient has previously undergone radiation therapy and / or chemotherapy for limited-stage small cell lung cancer.

[0121] The chemotherapeutic agents include, but are not limited to, one or more of platinum-based antineoplastic agents, podophyllums, alkylating agents, camptothecins, taxanes, antimetabolites, and antibiotic antineoplastic agents, examples of which include, but are not limited to, one or more of platinum-based antineoplastic agents (e.g., cisplatin, carboplatin, nedaplatin, miriplatin, and oxaliplatin), etoposide, irinotecan, topotecan, paclitaxel, docetaxel, temozolomide, vinorelbine, gemcitabine, cyclophosphamide, adriamycin, vincristine, bendamustine, epirubicin, methotrexate, and amrubicin.

[0122] Administration Method: The following is not intended to limit the administration regimen of the drug combinations of the present application.

[0123] The components of the pharmaceutical compositions of the present application, each independently or in part or in whole, may be administered by a variety of suitable routes, including but not limited to oral or parenteral (intravenous, intramuscular, topical or subcutaneous). In some embodiments of the present application, the components of the pharmaceutical combinations of the present application, each independently or in part or in whole, may be administered orally or by injection (e.g., intravenous or intraperitoneal injection).

[0124] The components of the pharmaceutical compositions of the present application, each independently or in part or in whole, may be in any suitable dosage form, including, but not limited to, dosage forms that are tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions, sustained release formulations for oral or parenteral administration.

[0125] The components of the pharmaceutical combinations of the present application may each, independently or in part or in whole, contain a pharma- ceutically acceptable carrier and / or excipient.

[0126] The drug combinations of the present application may further comprise another therapeutic agent, hi one embodiment, the other therapeutic agent may be a small cell lung cancer treatment known in the art.

[0127] Dosage regimen: For any dosing regimen of the pharmaceutical combinations herein, or the kits herein, the dosing regimen comprises a first treatment phase and, optionally, a second treatment phase.

[0128] The dosing regimens described herein are also suitable for use in the manufacture of a medicament for treating small cell lung cancer in a patient, in a method of treating small cell lung cancer in a patient, and for use in treating small cell lung cancer in a patient, as described herein.

[0129] In some embodiments of the present application, the first treatment phase comprises 1-10 treatment periods, preferably 2-8 treatment periods, and most preferably 4 treatment periods.

[0130] In some embodiments of the present application, the second treatment phase comprises 2 to 20 treatment periods. In some embodiments, the second treatment phase continues until clinical benefit is lost, toxicity is unacceptable, efficacy assessment is PD, or the investigator deems continued dosing inappropriate.

[0131] In some embodiments of the present application, the treatment period is 14 to 42 days, in some embodiments, the treatment period is 14 days, 21 days, 28 days, 35 days, or 42 days, and in some embodiments, the treatment period is 21 days. In some specific embodiments, the treatment period of the first treatment phase and the second treatment phase are the same. In some specific embodiments, the treatment period of both the first treatment phase and the second treatment phase (e.g., a single treatment period) is 21 days.

[0132] In some embodiments of the present application, the dosing regimen for the first treatment phase comprises: 1) the anti-PD-L1 antibody is administered once per day on days 1-7 of each treatment period; and 2) the anlotinib, or a pharma- ceutically acceptable salt thereof, is administered continuously on days 1-28 of each treatment period; and, optionally, 3) the platinum-based antineoplastic agent is administered once per day on days 1-7 of each treatment period; and, optionally, 4) the topoisomerase inhibitor is administered continuously on days 1-7 of each treatment period.

[0133] In some embodiments, 21 days is one treatment period, and the dosing regimen for the first treatment phase includes: 1) the anti-PD-L1 antibody is administered once on day 1 of each treatment period; and 2) the anlotinib, or a pharma- ceutically acceptable salt thereof, is administered consecutively on days 1-14 of each treatment period, and, optionally, 3) the platinum-based antineoplastic agent is administered once on day 1 of each treatment period, and, optionally, 4) the topoisomerase inhibitor is administered consecutively on days 1-3 of each period.

[0134] In some specific embodiments, the dosing regimen for the first treatment phase comprises: 1) the anti-PD-L1 antibody is administered once per day on days 1-7 of each treatment period; and 2) the anlotinib, or a pharma- ceutically acceptable salt thereof, is administered continuously on days 1-28 of each treatment period; and 3) the platinum-based antineoplastic agent is administered once per day on days 1-7 of each treatment period; and 4) the topoisomerase inhibitor is administered continuously on days 1-7 of each treatment period.

[0135] In some embodiments of the application, 21 days is one treatment period, and the dosing regimen for the first treatment phase includes: 1) the anti-PD-L1 antibody is administered once on day 1 of each treatment period, and 2) the anlotinib or a pharmaceutically acceptable salt thereof is administered continuously on days 1-14 of each treatment period, and 3) the platinum-based antineoplastic agent is administered once on day 1 of each treatment period, and 4) the topoisomerase inhibitor is administered continuously on days 1-3 of each period.

[0136] In some embodiments of the application, the dosing regimen for the first treatment phase comprises: 1) the anti-PD-L1 antibody hu5G11-hIgG1 is administered once on day 1 of each treatment period; and 2) anlotinib dihydrochloride is administered continuously on days 1-14 of each treatment period; and 3) the platinum-based antineoplastic agent is administered once on day 1 of each treatment period; and 4) the topoisomerase inhibitor is administered continuously on days 1-3 of each period.

[0137] In some embodiments of the application, the dosing regimen for the first treatment phase includes: 1) the anti-PD-L1 antibody hu5G11-hIgG1 is administered once on day 1 of each treatment period; and 2) anlotinib dihydrochloride is administered continuously on days 1-14 of each treatment period; and 3) carboplatin is administered once on day 1 of each treatment period; and 4) etoposide is administered continuously on days 1-3 of each period.

[0138] In some embodiments of the present application, the dosing regimen for the second treatment phase includes: 1) the anti-PD-L1 antibody is administered once daily on days 1 through 7 of each treatment period; and, optionally, 2) the anlotinib, or a pharma- ceutically acceptable salt thereof, is administered continuously on days 1 through 28 of each treatment period.

[0139] In some embodiments of the present application, the dosing regimen for the second treatment phase comprises: 1) the anti-PD-L1 antibody is administered once on day 1 of each treatment period; and 2) the anlotinib, or a pharma- ceutically acceptable salt thereof, is administered consecutively on days 1 through 14 of each treatment period.

[0140] In some embodiments of the application, the dosing regimen for the second treatment phase comprises: 1) the anti-PD-L1 antibody hu5G11-hIgG1 is administered once on day 1 of each treatment period; and 2) anlotinib dihydrochloride is administered continuously on days 1-14 of each treatment period.

[0141] In some embodiments of the present application, the anti-PD-L1 antibody is administered once on day 1, 2, 3, 4, 5, 6, or 7 of each treatment period, preferably once on day 1 of each treatment period.

[0142] In some embodiments of the present application, the anlotinib or a pharma- ceutically acceptable salt thereof is administered continuously on days 1-7, days 7-14, days 1-14, or days 7-21 of each treatment period, preferably on days 1-14 of each treatment period.

[0143] In some embodiments of the present application, the platinum-based anti-tumor drug is administered once on day 1, 2, 3, 4, 5, 6, or 7 of each treatment period, preferably once on day 1 of each treatment period.

[0144] In some embodiments of the present application, the topoisomerase inhibitor is administered continuously on days 1-3, 1-4, 1-5, 1-6, 1-7, 2-4, 2-5, 2-6, 2-7, 3-5, 3-6, 3-7, 4-6, 4-7, or 5-7 of each treatment period, preferably on days 1-3 of each treatment period. Effect of the Invention

[0145] The drug combinations of the present application can safely and effectively treat small cell lung cancer. In some embodiments, the drug combinations of the present application can safely and effectively treat extensive-stage small cell lung cancer. In some embodiments, the drug combinations of the present application can provide patients with a more tolerable treatment, with better anti-tumor effects and / or fewer treatment-related adverse events and / or complications than any one or any two drugs of the combination administered alone. In some embodiments, the drug combinations of the present application show better anti-tumor synergistic effects in the treatment of small cell lung cancer.

[0146] After receiving treatment with the drug combinations of the present application, patients with small cell lung cancer, particularly those with extensive stage small cell lung cancer, experience a significant increase in their median PFS (progression free survival) and / or median OS and / or OS (overall survival). In some embodiments, after receiving treatment, patients achieve a median PFS of 5-10 months, and in some specific embodiments, patients achieve a median PFS of more than 10 months. In some embodiments, after receiving treatment, patients achieve a median OS of 13-20 months, and in some specific embodiments, patients achieve a median OS of more than 20 months.

[0147] After patients with small cell lung cancer are treated with the drug combination of the present application, the patients' objective response rate (ORR) and disease control rate (DCR) are significantly improved.

[0148] In one embodiment of the present application, a 57-year-old patient is clinically diagnosed with right lower lung extensive-stage small cell lung cancer with metastases to bilateral hilar, mediastinal, bilateral supraclavicular lymph nodes, and right middle lobe, and after receiving two periods (42 days, 3 weeks is one treatment period) of treatment with the study regimen of anti-PD-L1 antibody hu5G11-hIgG1 injection, anlotinib hydrochloride capsule, carboplatin injection, and etoposide injection described in the present application, the sum of the target lesions (right lower lobe tumor lesion, middle lobe tumor lesion, and left hilar lymph node) is 21 mm, shrinking by 65%, and the overall efficacy evaluation is partial response (PR).The patient then continues to receive two periods of treatment with the above regimen, and then receives maintenance therapy with anti-PD-L1 antibody hu5G11-hIgG1 injection and anlotinib hydrochloride capsule, after which the target lesions further shrink or disappear, and the efficacy evaluation is persistent partial response (PR). As of the data collection date, progression-free survival (PFS) was greater than 27 months and the patient remains on treatment.

[0149] In another embodiment of the present application, a 69-year-old patient is clinically diagnosed with left lower lung small cell lung cancer with metastasis to the left lower hilum and left lower lobe, and after receiving two periods (42 days, 3 weeks is one treatment period) of treatment with the study plan described in the present application, which is anti-PD-L1 antibody hu5G11-hIgG1 injection, anlotinib hydrochloride capsule, carboplatin injection and etoposide injection, the sum of the target lesions (including left lower hilar tumor lesions, mediastinal lymph nodes, and left lower lung nodule lesions) is 21 mm, shrinking by 79.4%, and the overall efficacy evaluation is partial response (PR).The patient then continues to receive two periods of treatment with the above plan, and then receives maintenance therapy with anti-PD-L1 antibody hu5G11-hIgG1 injection and anlotinib hydrochloride capsule, after which the target lesions further shrink or disappear, the efficacy evaluation is persistent partial response (PR), and the patient's progression-free survival (PFS) is more than 20 months.

[0150] In another embodiment of the present application, a 55-year-old patient was clinically diagnosed with left hilar small cell lung cancer with mediastinal lymph node and bone metastasis. After receiving two periods (42 days, 3 weeks is one treatment period) of treatment with the study plan described in the present application, which is anti-PD-L1 antibody hu5G11-hIgG1 injection, anlotinib hydrochloride capsule, carboplatin injection and etoposide injection, the sum of the target lesions (including left hilar tumor lesions and mediastinal lymph nodes) is 41 mm, shrinking by 39.7%, and the overall efficacy evaluation is partial response (PR). After that, the patient continues to receive two periods of treatment with the above plan, and then receives maintenance therapy with anti-PD-L1 antibody hu5G11-hIgG1 injection and anlotinib hydrochloride capsule, the target lesions further shrink or disappear, and the efficacy evaluation is persistent partial response (PR). By the date of data statistics, the progression-free survival (PFS) is more than 26 months, and the patient continues to receive treatment.

[0151] Definitions and Explanations: Unless otherwise specified, the following terms used in this application have the following meanings: Certain terms are to be understood in their ordinary sense in the art and not as being indefinite or unclear unless otherwise defined: When trade names are mentioned in this application, it refers to the corresponding product or its active ingredients.

[0152] In this specification, unless otherwise specified, when the amount of anlotinib or a pharma- ceutically acceptable salt thereof is mentioned, it refers to the amount of the free base of anlotinib, which is the active ingredient.

[0153] Unless otherwise specified, the term "dose" refers to the dose administered to a patient without regard to the patient's weight or body surface area (BSA). For example, a 60 kg human and a 100 kg human receive the same dose of antibody (e.g., 240 mg of an anti-PD-1 antibody).

[0154] As used herein, the term "drug combination" refers to a combination of two or more active ingredients (each administered in the form of the active ingredient itself or in the form of a pharma- ceutically acceptable derivative, such as a salt or ester, prodrug, or composition thereof) administered simultaneously or sequentially, each of said active ingredients being administered simultaneously in a single formulation or sequentially in any order to a subject in a single formulation.

[0155] As used herein, the term "antibody" refers to a binding protein having at least one antigen-binding domain. The antibodies and fragments thereof of the present application may be whole antibodies or any fragments thereof. Thus, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof, antibody variants or fragments thereof, and immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)' fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv), Fd fragments, and other antibody fragments known in the art. Antibodies and fragments thereof may further include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be of the IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the antibody species encoded by the heavy chain constant region genes. In one embodiment, the anti-PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype. The PD-L1 antibodies and fragments thereof of the present application may be derived from any species, including, but not limited to, mouse, rat, rabbit, primate, llama, and human. The PD-L1 antibodies and fragments thereof may be chimeric, humanized, or fully human. In one embodiment, the anti-PD-L1 antibody is an antibody produced from a hybridoma cell line derived from a mouse. Thus, in one embodiment, the anti-PD-L1 antibody is a murine antibody. In another embodiment, the anti-PD-L1 antibody is a chimeric antibody. In another embodiment, the chimeric antibody is a mouse-human chimeric antibody. In another embodiment, the antibody is a humanized antibody. In another embodiment, the antibody is derived from a murine antibody and humanized.

[0156] A "humanized antibody" is an antibody that contains complementarity determining regions (CDRs) derived from a non-human antibody and framework and constant regions derived from a human antibody. For example, an anti-PD-L1 antibody provided herein may contain CDRs derived from one or more murine antibodies and human framework and constant regions. Thus, in one embodiment, a humanized antibody provided herein and the murine antibody from which the CDRs of the antibody are derived bind to the same epitope of PD-L1. This specification provides exemplary humanized antibodies. Other anti-PD-L1 antibodies or variants thereof that contain the heavy and light chain CDRs provided herein may be produced using any human framework sequence and are included herein. In one embodiment, framework sequences suitable for use in this specification include framework sequences that are structurally similar to the framework sequences provided herein. Other modifications in the framework regions may be made to improve the properties of the antibodies provided herein. Such other framework modifications include chemical modifications, point mutations to reduce immunogenicity or eliminate T-cell epitopes, and back mutations to residues in the original germline sequence. In some embodiments, such modifications include modifications corresponding to the exemplary mutations herein, including backmutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of the VH and / or VL of the humanized antibodies provided herein are backmutated to the corresponding amino acids of the parent mouse antibody. For example, in the case of the VH and VL of humanized 5G11 and humanized 13C5, several sites of the framework amino acids of the template human antibody are backmutated to the corresponding amino acid sequences of the mouse 5G11 and 13C5 antibodies. In one embodiment, the amino acids at positions 53 and / or 60 and / or 67 of the light chain variable region are backmutated to the corresponding amino acids found at said positions in the mouse 5G11 or 13C5 light chain variable region. In another embodiment, the amino acids at positions 24 and / or 28 and / or 30 and / or 49 and / or 73 and / or 83 and / or 94 of the heavy chain variable region are backmutated to the corresponding amino acids found at said positions in the murine 5G11 or 13C5 heavy chain variable region.In one embodiment, the humanized 5G11 antibody comprises a light chain variable region in which the amino acid at position 60 has been mutated from Ser (S) to Asp (D) and the amino acid at position 67 has been mutated from Ser (S) to Tyr (Y), and a heavy chain variable region in which the amino acid at position 24 has been mutated from Phe (F) to Val (V), the amino acid at position 49 has been mutated from Ala (A) to Gly (G), the amino acid at position 73 has been mutated from Thr (T) to Asn (N), and the amino acid at position 83 has been mutated from Thr (T) to Asn (N). In one embodiment, the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 has been mutated from Tyr (Y) to Lys (K), and a heavy chain variable region in which the amino acid at position 28 has been mutated from Thr (T) to Ile (I), the amino acid at position 30 has been mutated from Ser (S) to Arg (R), the amino acid at position 49 has been mutated from Ser (S) to Ala (A), and the amino acid at position 94 has been mutated from Tyr (Y) to Asp (D). The framework regions of the humanized antibodies provided herein may be subjected to other or any back mutations to improve the properties of the antibody. The present application further includes humanized antibodies that bind PD-L1 and have framework modifications that correspond to any of the exemplary modifications of suitable framework sequences described herein, as well as other framework modifications to improve the properties of the antibody in other ways.

[0157] The present application provides an isolated antibody or fragment thereof that binds to PD-L1, wherein the antibody may be produced by a hybridoma, wherein the hybridoma is selected from the group consisting of hybridomas designated herein as 13C5 and 5G11. Accordingly, the present application further includes hybridomas 13C5, 5G11, and any hybridoma that produces an antibody disclosed herein. The present application further provides an isolated polynucleotide encoding the antibody or fragment thereof provided herein. The present application further includes an expression vector comprising the isolated polynucleotide, and a host cell comprising the expression vector.

[0158] An "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic specificity (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind to antigens other than PD-1). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity with other antigens (e.g., PD-1 molecules from different species). An isolated antibody may also be substantially free of other cellular material and / or chemicals.

[0159] The term "monoclonal antibody (mAb)" refers to a non-naturally occurring composition of antibody molecules consisting of a single molecule (i.e., antibody molecules which have substantially the same basic sequence and which display a single binding specificity and affinity for a particular epitope). A mAb is an example of an isolated antibody. mAbs can be produced by hybridoma, recombinant, genetic engineering, or other techniques known to those of skill in the art.

[0160] The antibodies and antigen-binding fragments thereof disclosed herein are specific for PD-L1. In one embodiment, the antibodies and / or fragments thereof are specific for PD-L1. In one embodiment, the antibodies and fragments thereof provided herein bind to human or primate PD-L1 but do not bind to PD-L1 from other mammals. In another embodiment, the antibodies and / or fragments thereof do not bind to mouse PD-L1. The terms "human PD-L1," "hPD-L1," "huPD-L1," and the like, are used interchangeably herein to refer to human PD-L1 and variants or isotypes of human PD-L1. "Specific for" means that the antibodies and fragments thereof bind to PD-L1 with greater affinity than to other targets.

[0161] The term "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect. The effect is therapeutic if it is to partially or completely stabilize or cure a disease and / or side effects caused by the disease. As used herein, the term "treatment" includes any treatment of a disease in a patient, (a) suppressing the symptoms of the disease, i.e., preventing its progression, or (b) ameliorating the symptoms of the disease, i.e., eliminating the disease or symptoms.

[0162] The term "effective amount" refers to a dose of a compound of the present application that (i) treats a particular disease, condition, or disorder, (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of an active agent (e.g., an antibody or compound of the present application) in a "therapeutically effective amount" varies depending on several factors, such as the individual's condition, age, sex, weight, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. An effective amount may generally be determined by one of ordinary skill in the art based on their knowledge or the contents of this disclosure.

[0163] The term "administration" or terms that may be used interchangeably therewith, refers to the physical introduction of a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Routes of administration of immune checkpoint inhibitors (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies) include intravenous, intramuscular, subcutaneous, intraperitoneal, intrathecal, or other parenteral routes of administration (e.g., injection or infusion). The term "parenteral administration" as used herein refers to a form of administration other than enteral and topical administration, which is typically performed by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intrasternal injection and infusion, and in vivo electroporation. In some embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered parenterally, and in some embodiments, orally. Other parenteral routes include topical, transepidermal, or transmucosal routes of administration, such as intranasal, intravaginal, rectal, sublingual, and topical. Administration may be single or multiple times and / or over one or more extended periods of time.

[0164] The term "pharmacologically acceptable" is used to describe compounds, materials, compositions, and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissue, not toxic or irritating, and not likely to cause an allergic reaction or other problem or complication, and that are commensurate with a reasonable benefit-to-risk ratio.

[0165] The term "pharmaceutically acceptable salt" includes salts formed between base ions and free acids, or salts formed between acid ions and free bases, such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free acid to the base ion is about 1:0.5 to 1:5, and preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8. In the present application, when forming a pharma- ceutically acceptable salt, the molar ratio of the free base to the acid ion is about 1:0.5 to 1:5, and preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.

[0166] As used herein, the terms "subject" and "patient" are used interchangeably. In some embodiments, the term "subject" or "patient" is a mammal. In some embodiments, the subject or patient is a mouse. In some embodiments, the subject or patient is a human.

[0167] The term "about" should be understood to include up to three standard deviations of the mean, or up to the standard tolerance in a particular field. In some embodiments, "about" is understood to mean a difference of not more than 0.5. "About" modifies the value that follows it. For example, "about 1, 2, 3" means "about 1," "about 2," or "about 3."

[0168] As used herein, "combination" means that two or more active agents may be administered to a patient simultaneously, each in a single formulation, or sequentially, each in a single formulation, in any order.

[0169] The term "unit dose" refers to an indivisible packaged unit containing a predetermined amount of drug, e.g., each capsule in a medicine box containing seven capsules is a dose, or a bottle of injection solution is a dose.

[0170] The term "multiple doses" consists of a plurality of single doses.

[0171] The term "defined combination" refers to the fact that the active ingredients (e.g., an anti-PD-1 antibody and anlotinib) are administered simultaneously to a patient in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

[0172] The term "indefinite combination" refers to the administration of two or more active ingredients to a patient as independent entities (e.g., pharmaceutical compositions, formulations) simultaneously, in parallel or sequentially and without specific time limitations, provided that the active ingredients administered to the patient reach a therapeutically effective level. An example of an indefinite combination is cocktail therapy, for example, in which three or more active ingredients are administered. In an indefinite combination, each active ingredient may be packaged, sold or administered as a completely independent pharmaceutical composition. The "indefinite combination" includes the use of "definite combinations" together or "definite combinations" together with any one or more independent entities of the active ingredients.

[0173] The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application or pharmaceutical combinations thereof and pharma- ceutical acceptable excipients to facilitate administration of the compounds of the present application or pharmaceutical combinations thereof to a patient.

[0174] As used herein, unless otherwise indicated, the terms "comprise," "comprises," "comprising," or equivalent terms are used in an open-ended manner and mean that the invention may include unspecified elements, ingredients, and steps in addition to the listed elements, ingredients, and steps.

[0175] Unless the context clearly dictates otherwise, singular terms cover plural referents and vice versa. Similarly, unless the context clearly dictates otherwise, the word "or" includes "and" and vice versa.

[0176] All patents, patent applications, and other publications are expressly incorporated herein by reference for purposes of description and disclosure. Such publications may be provided because they were published prior to the filing date of this application. Any statement as to the disclosure date of such documents or representations of their contents is based on the information known to the applicants and does not constitute an admission that the disclosure date of such documents or the contents thereof are correct, nor does the incorporation of such publications into this specification constitute common general knowledge in the art in any country. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0177] For clarity, the present application is further described in the following examples, which are not intended to limit the scope of the present application. All reagents used in the present application are commercially available products and can be used without further purification. In the examples, the anti-PD-L1 antibodies are prepared according to the methods described in WO2016022630, and after affinity chromatography, an eluate containing the antibodies is obtained by conventional antibody purification methods.

[0178] Example 1: Clinical Trials Subjects who meet the criteria will be randomly assigned to study group 1, study group 2 or control group. Treatment will be divided into induction and maintenance phases. Efficacy assessment will be performed once every two periods. Patients with disease control (CR+PR+SD) and tolerable treatment-related adverse events may continue treatment, and the study will be terminated when clinical benefit is lost, toxicity is unacceptable, efficacy assessment is PD, or the investigator deems it inappropriate to continue treatment.

[0179] 1.1 Main inclusion criteria 1) Recruiting patients with pathologically confirmed extensive-stage small cell lung cancer (based on the staging classification of the Veterans Administration Lung Study Group (VALG)) to enroll in the clinical study; 2) the patient had not previously received systemic treatment for extensive-stage small cell lung cancer; 3) For patients who have previously received chemoradiotherapy for limited-stage SCLC, they must have received definitive treatment and have had at least 6 months of treatment-free time between the end of chemotherapy, radiotherapy, or chemoradiotherapy and the diagnosis of extensive-stage SCLC. 4) Measurable disease area as defined by RECIST 1.1 criteria; 5) Age 18-75 years, ECOG performance status score 0-1, and expected survival time greater than 3 months.

[0180] 1.2 Test Drug Anti-PD-L1 antibody injection hu5G11-hIgG1 or anti-PD-L1 antibody blank injection, 1200mg or 0mg anti-PD-L1 antibody injection diluted with normal saline to 250mL, injection time 60±10 minutes, flushed with normal saline after injection is completed as a routine medical procedure, administered once per 21-day treatment period on the first day of each period, specifications 100mg / 10mL, 300mg / 10mL.

[0181] Anlotinib hydrochloride capsules (active ingredient is anlotinib dihydrochloride) or anlotinib hydrochloride blank capsules. Take anlotinib hydrochloride capsules (12 mg) or blank capsules (0 mg) once a day on an empty stomach, one capsule each time. Each treatment period is 21 days, with 2 consecutive weeks of oral administration and 1 week of rest, and is administered on days 1 to 14 of each period. The specifications are 12 mg, 10 mg, and 8 mg.

[0182] Carboplatin injection is prepared by dissolving the drug in 5% glucose injection at a concentration of 10 mg / mL. This solution is added to 250-500 mL of 5% glucose injection and administered intravenously. Each treatment period is 21 days, and the drug is administered on the first day of each period. [Number 1] Dose (mg) = 5 (AUC) (mg / mL / min) × [creatinine clearance within 7 days prior to administration (mL / min) + 25]

[0183] Creatinine clearance Ccr (unit: mL / min) was calculated based on the creatinine Scr value, and the formula was as follows: [Number 2] Ccr = (140-age) x weight (kg) / [72 x Scr (mg / dL)] or Ccr = [(140-age) x weight (kg)] / [0.818 x Scr (μmol / L)] When calculating creatinine clearance, attention must be paid to the units of creatinine; in the case of female patients, the calculation result is multiplied by 0.85.

[0184] Etoposide injection is diluted with sodium chloride injection after calculating the dosage by formula, and the concentration is 0.25 mg / mL or less. Each treatment period is 21 days, and the drug is administered continuously on the 1st, 2nd, and 3rd days of each period. The dosage is 100 mg / m 2 It is.

[0185] 1.3 Dosing regimen Treatment is divided into an induction phase (ie, the first treatment phase) and a maintenance phase (ie, the second treatment phase).

[0186] The first treatment phase consisted of four treatment periods. Study group 1: 21 days is one treatment period.

[0187] Anti-PD-L1 antibody injection: 1200 mg once every 21 days, administered intravenously. Anlotinib hydrochloride capsules: 12 mg / dose, administered orally for 2 weeks consecutively followed by 1 week of rest. Injectable Carboplatin: Administer on day 1, AUC 5 mg / mL / min IV (maximum dose 800 mg). Etoposide injection: 100 mg / m2, given consecutively on days 1, 2, and 3 2 , administered intravenously.

[0188] Study group 2: 21 days is one treatment period.

[0189] Anti-PD-L1 antibody blank injection: 0 mg / injection, administered once every 21 days, intravenous infusion. Anlotinib hydrochloride capsules: 12 mg / dose, administered orally for 2 weeks consecutively followed by 1 week of rest. Injectable Carboplatin: Administer on day 1, AUC 5 mg / mL / min IV (maximum dose 800 mg). Etoposide injection: 100 mg / m2, given consecutively on days 1, 2, and 3 2 , administered intravenously.

[0190] Control group: 21 days is one treatment period.

[0191] Anti-PD-L1 antibody blank injection: 0 mg / injection, administered once every 21 days, intravenous infusion. Anlotinib hydrochloride blank capsule: 0 mg / dose, administered orally for 2 weeks continuously followed by 1 week of rest. Injectable Carboplatin: Administer on day 1, AUC 5 mg / mL / min IV (maximum dose 800 mg). Etoposide injection: 100 mg / m2, given consecutively on days 1, 2, and 3 2 , administered intravenously.

[0192] Second Treatment Phase (continues until clinical benefit is lost, toxicity is unacceptable, efficacy assessment is PD, or investigator deems continued treatment not appropriate): Study group 1: 21 days is one treatment period.

[0193] Anti-PD-L1 antibody injection: 1200 mg once every 21 days, administered intravenously. Anlotinib hydrochloride capsules: 12 mg / dose, administered orally for 2 weeks consecutively followed by 1 week of rest.

[0194] Study group 2: 21 days is one treatment period.

[0195] Anti-PD-L1 antibody blank injection: 0 mg / injection, administered once every 21 days, intravenous infusion. Anlotinib hydrochloride capsules: 12 mg / dose, administered orally for 2 weeks consecutively followed by 1 week of rest.

[0196] Control group: 21 days is one treatment period.

[0197] Anti-PD-L1 antibody blank injection: 0 mg / injection, administered once every 21 days, intravenous infusion. Anlotinib hydrochloride blank capsule: 0 mg / dose, administered orally for 2 weeks continuously followed by 1 week of rest.

[0198] 1.3 Evaluation Criteria 1) Safety will be assessed by evaluating drug treatment-related adverse events using the NCI-CTC AE 5.0 criteria.

[0199] 2) Efficacy will be evaluated by judging the disease status based on RECIST 1.1 / iRECIST, with RECIST 1.1 evaluation criteria as the main focus.

[0200] 1.4 Endpoint Indicators The primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints include objective response rate (ORR) = (complete remission (CR) + partial remission (PR)), disease control rate (DCR = CR + PR + stable disease (SD)), progression-free survival (PFS), overall survival (OS), duration of remission (DOR), as well as the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), and abnormal clinical test indicators.

[0201] 1.5 Test Results As of the date of data collection, more than 500 subjects have been enrolled in this study, and the overall research data to date shows that compared with the conventional first-line standard chemotherapy regimen (i.e., the control group), subjects receiving the regimens in study arm 1 and study arm 2 are expected to achieve significant clinical benefits. In addition, the current improvement in overall efficacy data suggests that the median PFS of subjects receiving the regimen in study arm 1 will be significantly improved, and the median OS is expected to exceed 14 months. It has been revealed that the combination of anti-PD-L1 antibody and anlotinib or a pharmacologic acceptable salt thereof with chemotherapy drugs can be a more effective first-line treatment regimen for small cell lung cancer, especially extensive small cell lung cancer.

[0202] Those skilled in the art will appreciate that the scope of the present disclosure is not limited to the various specific embodiments and examples described above, and that various amendments, substitutions, or recombinations may be made without departing from the spirit of the present disclosure, all of which fall within the scope of protection of the present application.

Claims

1. Use of an anti-PD-L1 antibody in the manufacture of a medicament for treating small cell lung cancer in combination with anlotinib or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent, comprising: the anti-PD-L1 antibody comprises a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 9; The above-mentioned use, wherein the chemotherapeutic agent is one or more selected from the group consisting of platinum-based antitumor agents and topoisomerase inhibitors.

2. 1. Use of an anti-PD-L1 antibody in the manufacture of a medicament for use in combination therapy for treating small cell lung cancer, comprising: the agent is administered in combination with anlotinib or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent; the anti-PD-L1 antibody comprises a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 9; The above-mentioned use, wherein the chemotherapeutic agent is one or more selected from the group consisting of platinum-based antitumor agents and topoisomerase inhibitors.

3. A use of an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent in the manufacture of a medicament for treating small cell lung cancer, comprising: the anti-PD-L1 antibody comprises a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 9; The above-mentioned use, wherein the chemotherapeutic agent is one or more selected from the group consisting of platinum-based antitumor agents and topoisomerase inhibitors.

4. The platinum-based antitumor drug is one or more selected from the group consisting of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miriplatin, or lobaplatin, and / or The use according to any one of claims 1 to 3, wherein the topoisomerase inhibitor is one or more selected from the group consisting of camptothecin, topotecan, adriamycin, daunorubicin, epirubicin, idarubicin, mitoxantrone, irinotecan, topotecan, etoposide, and teniposide.

5. The use according to any one of claims 1 to 3, wherein the chemotherapeutic agent is selected from a platinum-based antitumor agent and etoposide, or the chemotherapeutic agent is selected from carboplatin and etoposide.

6. The use according to any one of claims 1 to 3, wherein the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the chemotherapeutic agent are each in the form of a pharmaceutical composition, and may be administered simultaneously, sequentially, or sequentially.

7. The use according to any one of claims 1 to 3, wherein the daily dose of the anti-PD-L1 antibody or pharmaceutical composition thereof is 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg, and the daily dose of anlotinib or a pharmaceutically acceptable salt thereof is 6 to 12 mg, or 6 mg, 8 mg, 10 mg, or 12 mg.

8. The use according to any one of claims 1 to 3, wherein one treatment cycle is every 3 weeks, the anti-PD-L1 antibody is administered on day 1 of each cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered on days 1 to 14 of each cycle.

9. 6. The use of claim 5, wherein every three weeks is one treatment cycle, etoposide is administered on days 1 to 3 of each cycle, and carboplatin is administered on day 1 of each cycle.

10. The small cell lung cancer includes limited-stage and extensive-stage small cell lung cancer, or The small cell lung cancer is a small cell lung cancer that has not received prior systemic treatment; or The use according to any one of claims 1 to 3, wherein the small cell lung cancer is advanced and / or refractory and / or recurrent and / or metastatic small cell lung cancer.

11. The use according to claim 10, wherein the small cell lung cancer is extensive-stage small cell lung cancer, or the small cell lung cancer is extensive-stage small cell lung cancer that is being treated for the first time.

12. The use according to any one of claims 1 to 3, wherein the anti-PD-L1 antibody comprises a heavy chain variable region having at least 90% homology to the amino acid sequence shown in SEQ ID NO: 13 and a light chain variable region having at least 90% homology to the amino acid sequence shown in SEQ ID NO:

15.

13. The use of any one of claims 1 to 3, wherein the anti-PD-L1 antibody comprises a heavy chain variable region of a humanized antibody selected from hu5G11-hIgG1 or hu5G11-hIgG4, and a light chain variable region of a humanized antibody selected from hu5G11-hIgG1 or hu5G11-hIgG4.

14. The anti-PD-L1 antibody a heavy chain amino acid sequence set forth in SEQ ID NO: 17 and a light chain amino acid sequence set forth in SEQ ID NO: 18; or The use according to any one of claims 1 to 3, comprising a heavy chain amino acid sequence shown in SEQ ID NO: 21 and a light chain amino acid sequence shown in SEQ ID NO:

18.

15. comprising an anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent; the anti-PD-L1 antibody comprises a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 9; The combination drug for treating small cell lung cancer, wherein the chemotherapeutic drug is one or more selected from the group consisting of platinum-based antitumor drugs and topoisomerase inhibitors.

16. The platinum-based antitumor drug is one or more selected from the group consisting of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miriplatin, or lobaplatin, and / or The combination drug of claim 15, wherein the topoisomerase inhibitor is one or more selected from the group consisting of camptothecin, topotecan, adriamycin, daunorubicin, epirubicin, idarubicin, mitoxantrone, irinotecan, topotecan, etoposide, and teniposide.

17. The drug combination of claim 15 or 16, wherein the chemotherapeutic agent is selected from a platinum-based antitumor agent and etoposide, or the chemotherapeutic agent is selected from carboplatin and etoposide.

18. The combination drug according to claim 15 or 16, wherein the anti-PD-L1 antibody, anlotinib or a pharmaceutically acceptable salt thereof, and the chemotherapeutic agent are each in the form of a pharmaceutical composition.

19. The small cell lung cancer includes limited-stage and extensive-stage small cell lung cancer, or The small cell lung cancer is a small cell lung cancer that has not received prior systemic treatment; or The combination drug according to claim 15 or 16, wherein the small cell lung cancer is advanced and / or refractory and / or recurrent and / or metastatic small cell lung cancer.

20. The combination drug of claim 19, wherein the small cell lung cancer is extensive-stage small cell lung cancer, or the small cell lung cancer is extensive-stage small cell lung cancer that is being treated for the first time.

21. The combination drug of claim 15 or 16, wherein the anti-PD-L1 antibody comprises a heavy chain variable region having at least 90% homology to the amino acid sequence shown in SEQ ID NO: 13, and a light chain variable region having at least 90% homology to the amino acid sequence shown in SEQ ID NO:

15.

22. The anti-PD-L1 antibody a heavy chain amino acid sequence set forth in SEQ ID NO: 17 and a light chain amino acid sequence set forth in SEQ ID NO: 18; or The combination drug of claim 15 or 16, comprising a heavy chain amino acid sequence shown in SEQ ID NO: 21 and a light chain amino acid sequence shown in SEQ ID NO:

18.

23. A drug used in combination with anlotinib or a pharmaceutically acceptable salt thereof and a chemotherapy drug, The drug is for treating small cell lung cancer and comprises an anti-PD-L1 antibody; the anti-PD-L1 antibody comprises a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 9; The chemotherapeutic drug is one or more selected from the group consisting of platinum-based antitumor drugs and topoisomerase inhibitors.

24. A drug for treating small cell lung cancer, comprising: the drug comprises an anti-PD-L1 antibody in combination with anlotinib or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent; the anti-PD-L1 antibody comprises a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 9; The chemotherapeutic drug is one or more selected from the group consisting of platinum-based antitumor drugs and topoisomerase inhibitors.

25. A drug for treating small cell lung cancer in combination with anlotinib or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent, comprising: the drug comprises an anti-PD-L1 antibody; the anti-PD-L1 antibody comprises a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 3, and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 9; The chemotherapeutic drug is one or more selected from the group consisting of platinum-based antitumor drugs and topoisomerase inhibitors.

26. The drug according to any one of claims 23 to 25, wherein the chemotherapeutic drug is selected from a platinum-based antitumor drug and etoposide, or the chemotherapeutic drug is selected from carboplatin and etoposide.

27. The small cell lung cancer includes limited-stage and extensive-stage small cell lung cancer, or The small cell lung cancer is a small cell lung cancer that has not received prior systemic treatment; or The drug according to any one of claims 23 to 25, wherein the small cell lung cancer is advanced and / or refractory and / or recurrent and / or metastatic small cell lung cancer.

28. The drug of claim 27, wherein the small cell lung cancer is extensive-stage small cell lung cancer, or the small cell lung cancer is extensive-stage small cell lung cancer that is being treated for the first time.

29. The drug according to any one of claims 23 to 25, wherein the anti-PD-L1 antibody comprises a heavy chain variable region having at least 90% homology to the amino acid sequence shown in SEQ ID NO: 13, and a light chain variable region having at least 90% homology to the amino acid sequence shown in SEQ ID NO:

15.

30. The anti-PD-L1 antibody a heavy chain amino acid sequence set forth in SEQ ID NO: 17 and a light chain amino acid sequence set forth in SEQ ID NO: 18; or The drug according to any one of claims 23 to 25, comprising a heavy chain amino acid sequence shown in SEQ ID NO: 21 and a light chain amino acid sequence shown in SEQ ID NO: 18.