WO2022111618A1 - Combined pharmaceutical composition of anti-pd-l1 antibody and c-met kinase inhibitor for treating lung cancer - Google Patents

Abstract

The present invention relates to a combined pharmaceutical composition of an anti-PD-L1 antibody and a c-Met kinase inhibitor for treating lung cancer, and specifically to a combined pharmaceutical composition of an anti-PD-L1 antibody and N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1, 1-dimethylamide for treating lung cancer, and a use of the combined pharmaceutical composition in the treatment of lung cancer.

Description

Combination pharmaceutical composition of anti-PD-L1 antibody and c-Met kinase inhibitor for the treatment of lung cancer

This disclosure requires that the Chinese Patent Office with the application number 202011350770.0 and the invention titled "Combination Pharmaceutical Composition of Anti-PD-L1 Antibody and c-Met Kinase Inhibitor for the Treatment of Lung Cancer" filed with the China Patent Office on November 26, 2020 Priority to the patent application, the entire contents of which are incorporated by reference in this disclosure.

technical field

The present disclosure belongs to the technical field of medicine, and in particular relates to anti-PD-L1 antibodies and N-(4-((7-((1-(cyclopentylamino)cyclopropanyl)methoxy)-6-methoxyquinoline Norrin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide combined pharmaceutical composition, and its use in the treatment of lung cancer the use of.

Background technique

c-Met kinase is a prototypical member of the subfamily of heterodimeric receptor tyrosine kinases (RTKs), which includes Met, Ron, and Sea. The antiangiogenic and antiproliferative activities of c-Met make it an attractive target. The endogenous ligand of c-Met is hepatocyte growth factor (HGF), also known as scatter factor (SF) because of its ability to interfere with colony formation in vitro. HGF is a derivatized cytokine that induces receptor activation by autophosphorylation leading to increased receptor-dependent signaling in normal and tumor cells (Sonnenberg et al., J. Cell Biol. 123:223-235, 1993; Matsumato et al. , Crit. Rev. Oncog. 3:27-54, 1992; Stoker et al., Nature 327:239-242, 1987). Anti-HGF antibodies or HGF antagonists have also been shown to inhibit tumor metastasis.

WO2012034055 discloses N-(4-((7-((1-(cyclopentylamino)cyclopropanyl)methoxy)-6-methoxyquinoline-4 as c-Met kinase inhibitors -yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as the compound of formula (I)) and its tyrosine kinase inhibitory activity the use of,

The PD-1 immune checkpoint is an inhibitory cell surface receptor, and its corresponding ligand PD-L1 can be up-regulated on the surface of tumor cells and immune cells in the tumor environment, allowing tumor cells to escape immune cell attack. The use of anti-PD-1 or PD-L1 antibodies can block this response, resulting in an anti-tumor effect. Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have significantly improved the prognosis of patients with non-small cell lung cancer, but most patients have poor treatment outcomes due to primary drug resistance. In a study using the PD-1/PD-L1 pathway inhibitor Nivolumab (Gettinger S et al (2018) ClinOncol. 36(17):1675-1684), low PD-L1 expression and no The patients with high expression of PD-L1 accounted for 80.1% (55/68), and the survival rate of these patients was also significantly lower than that of patients with high PD-L1 expression. Therefore, there is an urgent need to find other therapeutic approaches to overcome the problem of immunotherapy resistance.

SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides a combined pharmaceutical composition for treating lung cancer, the combined pharmaceutical composition comprising an anti-PD-L1 antibody and a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the anti-PD-L1 antibody The L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:4; The amino acid sequence shown has at least 80% homology in the heavy chain CDR2 region; the heavy chain CDR3 region with at least 80% homology with the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6; and SEQ ID NO: 6 The amino acid sequence shown in NO:7 or SEQ ID NO:10 has at least 80% homology to the light chain CDR1 region; and the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:11 has at least 80% homology and a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO: 12;

In some embodiments, the combination pharmaceutical composition is packaged in the same kit, and the kit further comprises an anti-PD-L1 antibody in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof to treat lung cancer in a patient. illustrate.

In some embodiments, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof are packaged separately in separate kits, the kit further comprising an anti-PD-L1 antibody. Description of the use of a PD-L1 antibody in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof to treat lung cancer in a patient.

In some embodiments, the combination pharmaceutical composition includes a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some aspects of the present disclosure, in the combined pharmaceutical composition, wherein the anti-PD-L1 antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be simultaneously, sequentially or at intervals Dosing.

In some aspects of the present disclosure, the combination pharmaceutical composition is a fixed combination. In some aspects, the fixed composition is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

In some aspects of the present disclosure, the combination pharmaceutical composition is a non-fixed combination. In some aspects, the anti-PD-L1 antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition. In some aspects, in the non-fixed combination, the anti-PD-L1 antibody is in the form of a liquid pharmaceutical composition and the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a solid pharmaceutical composition.

In some embodiments, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4 (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 heavy chain CDR1 region; with the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 5 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 heavy chain CDR2 region; at least 80% (eg 81%, 82%, 83%, 84%, 85%, 86%) with the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6 %, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the heavy chain CDR3 region; at least 80% (eg 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the light chain CDR1 region; with SEQ ID NO: 8 or the amino acid sequence shown in SEQ ID NO: 11 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 light chain CDR2 region; and with SEQ ID NO:9 or SEQ ID NO:12 The indicated amino acid sequence 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 light chain CDR3 regions.

In some specific embodiments, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody comprises: the heavy chain CDR1 region shown in SEQ ID NO: 1 or SEQ ID NO: 4, SEQ ID NO: 2 or The heavy chain CDR2 region shown in SEQ ID NO:5, the heavy chain CDR3 region shown in SEQ ID NO:3 or SEQ ID NO:6, the light chain CDR1 region shown in SEQ ID NO:7 or SEQ ID NO:10 , the light chain CDR2 region shown in SEQ ID NO: 8 or SEQ ID NO: 11, and the light chain CDR3 region shown in SEQ ID NO: 9 or SEQ ID NO: 12.

In some specific embodiments, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO:1, having a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO:2 The heavy chain CDR2 region of the amino acid sequence shown has the heavy chain CDR3 region of the amino acid sequence shown in SEQ ID NO: 3, and the light chain CDR1 region of the amino acid sequence shown in SEQ ID NO: 7 has the SEQ ID NO: 7 region. The light chain CDR2 region of the amino acid sequence shown in ID NO:8, and the light chain CDR3 region having the amino acid sequence shown in SEQ ID NO:9.

In some embodiments, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is 13C5, 5G11, ch13C5-hIgG1, ch13C5-hIgG4, ch5G11-hIgG1, ch5G11-hIgG4, hu13C5 - hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 monoclonal antibodies or antigen-binding fragments thereof (see WO2016022630 or CN107001463A; incorporated herein by reference).

In some specific embodiments, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody comprises a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a heavy chain complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody Light chain complementarity determining regions. In one embodiment, the present disclosure provides an anti-PD-L1 antibody comprising a heavy chain variable region selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and selected from ch5G11- Light chain variable regions of hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies. In one embodiment, the present disclosure provides an anti-PD-L1 antibody comprising a heavy chain variable region selected from the group consisting of hu13C5-hlgG1, hu13C5-hlgG4, hu5G11-hlgG1 or hu5G11-hlgG4 humanized antibody, and selected from hu13C5 - the light chain variable region of a hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody. Reference can be made to the description of patent document WO2016022630 or CN107001463A: the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), and the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID 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 QHSWEIPYT (SEQ ID NO: 12); 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), and the HCDR3 sequence is LGFYAMDY (SEQ ID NO: 2) :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).

Preferably, the anti-PD-L1 antibody described in the present disclosure comprises the following amino acid sequence: at least 80% (eg 81%, 82%, 83%, 84%) of the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) Homologous heavy chain variable region; at least 80% (e.g. 81%, 82%, 83%, 84%, 85%, 86%) with the amino acid sequence shown in SEQ ID NO: 15 or SEQ ID NO: 16 , 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology of light chains can be variable area.

In a specific embodiment, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody comprises the following amino acid sequence: the heavy chain variable region as shown in SEQ ID NO: 13; and as shown in SEQ ID NO: Light chain variable region shown in 15.

In a specific embodiment, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody comprises the following amino acid sequence: the heavy chain variable region shown in SEQ ID NO: 14; and the heavy chain variable region shown in SEQ ID NO: Light chain variable region shown in 16.

Preferably, the anti-PD-L1 antibody described in the present disclosure comprises the following amino acid sequence: at least 80% (eg, 81%, 82%, 82%, 82%, 82%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 80%, 2, 1, 1, 2, and 8% back apart) to %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, A heavy chain of 99% or 100% homology; at least 80% (e.g. 81%, 82%, 83%, 84%, 85%) with the amino acid sequence shown in SEQ ID NO: 18 or SEQ ID NO: 20 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology light chain.

In a specific embodiment, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO: 17, and the light chain shown in SEQ ID NO: 18 amino acid sequence.

In a specific embodiment, the combined pharmaceutical composition, wherein the anti-PD-L1 antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO: 19 and the light chain shown in SEQ ID NO: 20 amino acid sequence.

In a specific embodiment, the combined pharmaceutical composition, wherein the anti-PD-L1 antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO: 21 and the light chain shown in SEQ ID NO: 18 amino acid sequence.

In a preferred embodiment of the present disclosure, the combined pharmaceutical composition, wherein the anti-PD-L1 antibody is hu5G11-hIgG1, which comprises the heavy chain amino acid sequence shown in SEQ ID NO: 17, and SEQ ID NO : the light chain amino acid sequence shown in 18.

In some embodiments, the combination pharmaceutical composition comprises about 20 mg to about 2400 mg of anti-PD-L1 antibody. In some embodiments, the combination pharmaceutical composition comprises about 600 mg to about 2400 mg of anti-PD-L1 antibody. In some embodiments, the combination pharmaceutical composition comprises about 1000 mg to about 1500 mg of anti-PD-L1 antibody.

In some embodiments, the combination pharmaceutical composition comprises about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg of anti-PD-L1 Antibody. In some specific embodiments, the combination pharmaceutical composition comprises about 1200 mg of anti-PD-L1 antibody.

In some embodiments, the combination pharmaceutical composition, wherein the pharmaceutical composition of the anti-PD-L1 antibody is a single dose or multiple doses, in some embodiments, multiple doses.

In some embodiments, the combined pharmaceutical composition comprises a pharmaceutical composition of an anti-PD-L1 antibody in a single dose of 100 mg-2000 mg, 100 mg-1200 mg, 1000 mg-2000 mg, 100 mg-600 mg, or 600 mg-1200 mg. In some embodiments, the combination pharmaceutical composition comprises a pharmaceutical composition of an anti-PD-L1 antibody in a single dose of 100 mg or 600 mg.

In some embodiments, the combination pharmaceutical composition, wherein the pharmaceutical composition of the anti-PD-L1 antibody is a multi-dose, and the multi-dose consists of a single dose of 100 mg or 600 mg of the pharmaceutical composition of the anti-PD-L1 antibody .

In some embodiments, the combination pharmaceutical composition, wherein the mass volume concentration of the pharmaceutical composition of the anti-PD-L1 antibody is about 1-150 mg/mL, or about 10-60 mg/mL, or about 10 mg/mL, or about 30 mg/mL.

In some embodiments, the combination pharmaceutical composition, wherein the anti-PD-L1 antibody is formulated to be suitable for 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg/kg, 6 mg/kg, 9 mg/kg The pharmaceutical composition administered in doses of kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 30 mg/kg body weight.

In certain embodiments, the combination pharmaceutical composition, wherein the dose of the anti-PD-L1 antibody is a fixed dose in the pharmaceutical composition.

In some embodiments, the combined pharmaceutical composition, wherein the content of anti-PD-L1 antibody is a daily dose.

In some embodiments, the combined pharmaceutical composition, wherein the content of anti-PD-L1 antibody is a unified dose.

In some embodiments, the combined pharmaceutical composition, wherein the content of the anti-PD-L1 antibody is a dose of one cycle, and each cycle is 21 days. In a specific embodiment of the present disclosure, the combined pharmaceutical composition, wherein the anti-PD-L1 antibody exists in the form of a pharmaceutical composition, the pharmaceutical composition comprises an anti-PD concentration of about 1-150 mg/mL by mass and volume -L1 antibody, 3-50 mM buffer, 2-150 mg/mL isotonicity modifier/stabilizer and 0.01-0.8 mg/mL surfactant, and pH about 4.5-6.8.

In another specific embodiment of the present disclosure, the combined pharmaceutical composition, wherein the pharmaceutical composition of the anti-PD-L1 antibody comprises: (a) a mass-volume concentration of about 10 mg/mL or about 30 mg/ml Anti-PD-L1 antibody, (b) sucrose at a concentration of about 80 mg/mL by volume, (c) polysorbate 80 at a concentration of about 0.2 mg/mL by volume, (d) histidine at a molar concentration of about 10 mM , (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to about 5.5.

In yet another specific embodiment of the present disclosure, the combined pharmaceutical composition, wherein the pharmaceutical composition of the anti-PD-L1 antibody comprises: (a) a mass-volume concentration of about 10 mg/mL or about 30 mg/mL hu5G11-hIgG1, (b) sucrose at a concentration of about 80 mg/mL by volume, (c) polysorbate 80 at a concentration of about 0.2 mg/mL by volume, (d) histidine at a molar concentration of about 10 mM, ( e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to about 5.5.

In some embodiments, the combined pharmaceutical composition, wherein the pharmaceutical composition of the anti-PD-L1 antibody is a water-soluble injection, the water-soluble injection includes, but is not limited to, a water-soluble preparation that is not lyophilized or frozen Dry powder reconstituted water-soluble formulation. In other embodiments, the combined pharmaceutical composition, wherein the pharmaceutical composition of the anti-PD-L1 antibody is a lyophilized preparation. The lyophilized preparation refers to the preparation of an aqueous solution through a freeze-drying process, a stabilization process in which the substance is first frozen, and then the amount of solvent is first 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 value that no longer supports biological activity or chemical reaction.

In some embodiments, the combined pharmaceutical composition, wherein the pharmaceutical composition of the anti-PD-L1 antibody is hu5G11-hIgG1 injection, with a specification of 100 mg/10 mL or 600 mg/20 mL.

The present disclosure provides a pharmaceutical composition preparation of an anti-PD-L1 antibody, the polymer is not more than 1.1%, preferably not more than 0.9%, more preferably not more than 1.1% when stored at 2-8°C or 25°C for at least 6 months more than 0.5%.

In some specific embodiments, the combination pharmaceutical composition contains a pharmaceutical composition of an anti-PD-L1 antibody in multiple doses of about 20 mg to about 2400 mg, about 600 mg to about 2400 mg, or about 1000 mg to about 1500 mg, wherein The content of the anti-PD-L1 antibody is a unified dose, and the multiple doses consist of a single dose of 100 mg or 600 mg of the pharmaceutical composition of the anti-PD-L1 antibody.

In some specific embodiments, the combination pharmaceutical composition contains multiple doses of about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg A pharmaceutical composition of an anti-PD-L1 antibody, wherein the content of the anti-PD-L1 antibody is a uniform dose, and the multiple doses are composed of a single dose of the pharmaceutical composition of an anti-PD-L1 antibody of 100 mg or 600 mg.

In some specific embodiments, the combination pharmaceutical composition contains a pharmaceutical composition of about 1200 mg of anti-PD-L1 antibody in multiple doses, wherein the content of the anti-PD-L1 antibody is a uniform dose, and the multiple doses are composed of A single dose of 100 mg or 600 mg of a pharmaceutical composition of an anti-PD-L1 antibody.

In some embodiments, the combined pharmaceutical composition contains 90 mg-180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the combined pharmaceutical composition contains 90 mg-120 mg, 90 mg-150 mg, 120 mg-150 mg, 120 mg-180 mg, or 150 mg-180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the combined pharmaceutical composition contains 90 mg, 120 mg, 150 mg, or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the combined pharmaceutical composition contains 120 mg or 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the combination pharmaceutical composition, wherein the pharmaceutical composition of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a single dose or multiple doses; in some embodiments, multiple doses.

In some embodiments, the combination pharmaceutical composition contains a single dose of 30 mg or 60 mg of the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the combination pharmaceutical composition, wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, is in multiple doses consisting of a single dose of 30 mg or 60 mg of formula (I) A pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the combined pharmaceutical composition, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a daily dose.

In some embodiments, the combined pharmaceutical composition, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in a once-daily dose.

In some embodiments, the combined pharmaceutical composition, wherein the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a once-a-day dose, and the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is Single or multiple doses.

In some specific embodiments, the combined pharmaceutical composition contains multiple doses of 90mg-180mg, 90mg-120mg, 90mg-150mg, 120mg-150mg, 120mg-180mg or 150mg-180mg of the compound of formula (I) or its A pharmaceutical composition of a pharmaceutically acceptable salt, wherein the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a once-a-day dose, and the multiple doses are composed of a single dose of 30 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions with salts.

In some specific embodiments, the combination pharmaceutical composition contains multiple doses of 90 mg, 120 mg, 150 mg, or 180 mg of a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) The content of a pharmaceutically acceptable salt thereof is a once-a-day dose, and the multiple doses consist of a single dose of 30 mg or 60 mg of the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some preferred embodiments, the combined pharmaceutical composition contains multiple doses of 120 mg or 150 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof The salt is present in a once-daily dose, and the multiple doses consist of a single dose of 30 mg or 60 mg of the pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) of the present disclosure can be administered in their free base form, as well as in the form of their pharmaceutically acceptable salts, hydrates and prodrugs, which are converted in vivo to the free form of compounds of formula (I) base form. For example, pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the present disclosure, and the salts can be generated from various organic and inorganic acids according to methods well known in the art, for example, the inorganic acids can be selected from the group consisting of hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid or phosphoric acid, the organic acid may be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid or naphthalene sulfuric acid. In some embodiments of the present disclosure, the compound of formula (I) is administered in its free base form.

Dosages or amounts of compounds of formula (I) or pharmaceutically acceptable salts thereof referred to in this disclosure, unless otherwise stated, are based on the molecular weight of compounds of formula (I).

The "compound of formula (I)" described in the present disclosure may be a "pharmaceutical composition of the compound of formula (I)".

The "compound of formula (I) or a pharmaceutically acceptable salt thereof" described in the present disclosure may be a "pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof".

The method of administration can be comprehensively determined according to the activity of the drug, the toxicity and the patient's tolerance.

In some embodiments, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure further contains a pharmaceutically acceptable adjuvant.

In some embodiments, a pharmaceutical composition of a compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered orally.

In some embodiments, the pharmaceutical composition of the compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, is a solid pharmaceutical composition.

In some embodiments, the formulation form of a solid pharmaceutical composition of a compound of formula (I) of the present disclosure, or a pharmaceutically acceptable salt thereof, is a capsule.

In some embodiments, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule of the compound of formula (I) or a pharmaceutically acceptable salt thereof in 30 mg and 60 mg strengths.

The pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pilling method, grinding method, emulsifying method method, freeze-drying method, etc.

Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to give tablets or icing core. Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

In some embodiments, the pharmaceutical composition of the compound of formula (I) can be a capsule of the compound of formula (I) containing the compound of formula (I), cornstarch, calcium carboxymethylcellulose, hypromellose, and hard Magnesium Fatty Acid.

In other embodiments, the pharmaceutical composition of the compound of formula (I) can be a capsule of the compound of formula (I) containing the compound of formula (I), lactose, microcrystalline cellulose, sodium starch glycolate, and magnesium stearate .

In a specific embodiment of the present disclosure, the pharmaceutical composition of the compound of formula (I) is a capsule of the compound of formula (I) containing: (a) about 30 mg or about 60 mg of the compound of formula (I), (b) about 93 mg or about 63 mg of corn starch, (c) about 22.5 mg of calcium carboxymethylcellulose, (d) about 3 mg of hypromellose, and (e) about 1.5 mg of magnesium stearate; total weight of 150mg.

In a specific embodiment of the present disclosure, the pharmaceutical composition of the compound of formula (I) is a capsule of the compound of formula (I) containing: (a) about 30 mg or about 60 mg of the compound of formula (I), (b) about 40 mg of lactose, (c) about 72.5 mg or about 42.5 mg of microcrystalline cellulose, (d) about 6 mg of sodium starch glycolate, and (e) about 1.5 mg of magnesium stearate; total weight 150 mg.

On the other hand, the present disclosure also provides a kit for a pharmaceutical composition for treating lung cancer, which contains (a) a first pharmaceutical composition comprising the anti-PD-L1 antibody described in the present disclosure as an active ingredient; and ( b) A second pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

In another aspect, the present disclosure also provides a method of treating lung cancer comprising administering to a subject suffering from lung cancer a therapeutically effective amount of the combination pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure also provides the use of the combined pharmaceutical composition in the preparation of a medicament for the treatment of lung cancer, and the combined pharmaceutical composition is the combined pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure also provides the use of a combined pharmaceutical composition for treating lung cancer, and the combined pharmaceutical composition is the combined pharmaceutical composition of the present disclosure.

In another aspect, the present disclosure also provides a combination therapy for treating a subject suffering from lung cancer, the combination therapy comprising administering to the subject alone a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and A therapeutically effective amount of an anti-PD-L1 antibody described in the present disclosure is administered alone.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use or combination therapy, the anti-PD-L1 antibody is administered at 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg /kg, 6 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 30 mg/kg of body weight, continuous administration. In some embodiments, the anti-PD-L1 antibody is administered in one or more uniform doses effective to treat the cancer. In some embodiments, wherein the uniform dose is in the range of about 20 mg to about 2400 mg, or about 600 mg to about 2400 mg, or about 1000 mg to about 1500 mg of anti-PD-L1 antibody. In some embodiments, wherein the unitary dose is selected from about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg of anti-PD-L1 antibody. In some embodiments, the unitary dose is selected from about 1200 mg of anti-PD-L1 antibody.

In some embodiments of the combination pharmaceutical compositions, or in some embodiments of the methods, uses, or combination therapy, a uniform dose (the dose administered to the patient regardless of the patient's weight) may be used. For example, a unified dose of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 mAbs can be about 1200 mg. In certain embodiments, the anti-PD-L1 antibody is administered at a dose of about 1800 mg. In certain embodiments, the anti-PD-L1 antibody is administered at a dose of about 1200 mg. In certain embodiments, the anti-PD-L1 antibody is administered at a dose of about 900 mg. In certain embodiments, the anti-PD-L1 antibody is administered at a dose of about 600 mg. In one embodiment, 900 mg of the anti-PD-L1 antibody is administered once every 3 weeks. In another embodiment, 1200 mg of the anti-PD-L1 antibody is administered once every 4 weeks. In another embodiment, 1200 mg of the anti-PD-L1 antibody is administered once every 3 weeks. In some embodiments of the combination pharmaceutical composition, or some embodiments of the method, use, or combination therapy, about every week (q1w), about every 2 weeks (q1w), about every 3 weeks (q1w) ), or anti-PD-L1 antibodies were administered approximately every 4 weeks (q1w). In some embodiments, the patient is administered a uniform dose of anti-PD-L1 antibody approximately every 3 weeks (21 days). In some embodiments, the anti-PD-L1 antibody is administered at a dose of 1200 mg per patient approximately every 3 weeks (21 days) for continuous administration.

In some embodiments of the combination pharmaceutical composition, or some embodiments of the method, use, or combination therapy, the anti-PD-L1 antibody is administered as an intravenous infusion. In some embodiments, the anti-PD-L1 antibody is administered as an intravenous infusion over about 1-2 hours, preferably as an intravenous infusion over about 1 hour (±5 minutes).

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use or combination therapy, the anti-PD-L1 antibody is hu5G11-hIgG1 injection, the hu5G11-hIgG1 injection The packaging specification is 100mg: 10mL or 600mg: 20mL; the dosing plan is an intravenous infusion of 1200mg of hu5G11-hIgG1 (diluted to 250mL with normal saline), and the infusion time is 60±5 minutes. Dosing every 21 days.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use or combination therapy, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is The amount is a daily dose, which is administered by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof once a day.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use or combination therapy, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is The amount is a daily dose, which is administered by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof once a day for 21 consecutive days.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use or combination therapy, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is The amount is a daily dose wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a single dose or in multiple doses. In some embodiments, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in multiple doses.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use, or combination therapy, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered by administering to a subject The subjects received daily doses of 90 mg, 120 mg, 150 mg or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, administered continuously daily.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use, or combination therapy, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered for 21 days For a treatment cycle, the daily dose is 90 mg, 120 mg, 150 mg or 180 mg, once a day.

In some embodiments of the combination pharmaceutical composition, or some embodiments of the method, use, or combination therapy, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally; in some embodiments Among them, the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered within ±5 minutes of administration of the pharmaceutical composition of the anti-PD-L1 antibody.

In some embodiments of the combination pharmaceutical composition, or some embodiments of the method, use, or combination therapy, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a fixed time each day.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use, or combination therapy, administration is by administering the anti-PD-L1 antibody within ± 5 minutes of administration of formula (I ) compound or a pharmaceutically acceptable salt thereof.

In some embodiments of the combination pharmaceutical composition, or some embodiments of the method, use, or combination therapy, administration is by: within ±5 minutes of administration of the pharmaceutical composition of the anti-PD-L1 antibody A pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use, or combination therapy, administration is by fasting within ±5 minutes of administration of the anti-PD-L1 antibody injection Capsules of a compound of formula (I) or a pharmaceutically acceptable salt thereof are administered.

In some embodiments of the combination pharmaceutical compositions, or in some embodiments of the methods, uses, or combination therapy, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-PD- L1 antibody administration, every 21 days is a treatment cycle, and the administration is as follows: 1200 mg of anti-PD-L1 antibody is infused on the first day, and the infusion time is 60 ± 5 minutes; the compound of formula (I) or its compound is administered once a day. 120 mg or 150 mg of a pharmaceutically acceptable salt for 21 days.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use, or combination therapy, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with hu5G11-hIgG1 Administration, every 21 days is a treatment cycle, and the administration is as follows: 1200 mg of hu5G11-hIgG1 antibody is infused on the first day, the infusion time is 60 ± 5 minutes; the compound of formula (I) or a pharmaceutically acceptable compound thereof is administered once a day Salt 120 mg for 21 days.

In some embodiments of the combination pharmaceutical composition, or in some embodiments of the method, use, or combination therapy, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with hu5G11-hIgG1 Administration, every 21 days is a treatment cycle, and the administration is as follows: 1200 mg of hu5G11-hIgG1 antibody is infused on the first day, the infusion time is 60 ± 5 minutes; the compound of formula (I) or a pharmaceutically acceptable compound thereof is administered once a day Salt 150 mg for 21 days.

In some embodiments of the combination pharmaceutical composition, or some embodiments of the method, use, or combination therapy, 1200 mg of the hu5G11-hlgG1 antibody is administered diluted to 250 mL with normal saline. In some regimens of the present disclosure, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered on day one, and is administered on an empty stomach within ± 5 minutes of the start of the hu5G11-hIgG1 antibody infusion.

In some embodiments of the present disclosure, the lung cancer is refractory, relapsed or metastatic lung cancer.

In some aspects of the present disclosure, the lung cancer is advanced lung cancer. In some aspects of the present disclosure, the lung cancer is locally advanced lung cancer.

In some embodiments of the present disclosure, the lung cancer is metastatic lung cancer. In other embodiments, the metastatic lung cancer is metastatic cancer metastasized from kidney cancer, liver cancer, gastric cancer, rectal cancer, colon cancer, colorectal cancer, prostate cancer, pancreatic cancer, or breast cancer.

In some aspects of the present disclosure, the lung cancer is advanced, recurrent and/or metastatic lung cancer. In some aspects of the present disclosure, the lung cancer is locally advanced, recurrent and/or metastatic lung cancer.

In some embodiments of the present disclosure, the lung cancer is small cell lung cancer or non-small cell lung cancer. In some specific embodiments, the lung cancer is squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma). In some specific embodiments, the lung cancer is lung adenocarcinoma, lung squamous cell carcinoma, or lung large cell carcinoma. In some specific embodiments, the lung cancer is non-small cell lung cancer with histologically predominant squamous cell carcinoma.

In some embodiments, the lung cancer is recurrent and/or metastatic non-small cell lung cancer. In some embodiments, the lung cancer is recurrent and/or metastatic small cell lung cancer.

In some embodiments of the present disclosure, the lung cancer is advanced non-small cell lung cancer. In some specific schemes, the lung cancer is advanced small cell lung cancer.

In some embodiments of the present disclosure, the lung cancer is advanced (or locally advanced), recurrent and/or metastatic non-small cell lung cancer or small cell lung cancer.

In some embodiments of the present disclosure, the lung cancer is advanced, recurrent and/or metastatic non-small cell lung cancer. . In some embodiments of the present disclosure, the lung cancer is advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma).

In some embodiments of the present disclosure, the lung cancer is locally advanced, recurrent and/or metastatic non-small cell lung cancer. In some embodiments of the present disclosure, the lung cancer is locally advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg, lung adenocarcinoma).

In some embodiments of the present disclosure, the subject of lung cancer has not previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments of the present disclosure, the subject of lung cancer has previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject of lung cancer has relapsed after achieving a complete remission following surgery, chemotherapy and/or radiation therapy. In some embodiments, the subject of lung cancer is not in complete remission or in partial remission after surgery, chemotherapy and/or radiation therapy. In some embodiments, the subject of lung cancer has metastasized cancer following surgery, chemotherapy and/or radiation therapy. In some aspects of the present disclosure, the subject of lung cancer has not previously received systemic chemotherapy. In some aspects of the present disclosure, the subject of lung cancer has previously received systemic chemotherapy. In some embodiments, the subject of lung cancer has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject of lung cancer has not previously received systemic chemotherapy, but has received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy. In some specific embodiments, the subject of lung cancer relapses after achieving complete remission after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy. In some specific embodiments, the subject of lung cancer fails to achieve complete remission or partial remission after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy. In some embodiments, the subject of lung cancer develops cancer metastasis after surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy.

In some embodiments of the present disclosure, the subject of lung cancer is the subject of non-small cell lung cancer (NSCLC) of UICC/AJCC 8th edition lung cancer TNM stage, conforming to stage IIIB/IIIC/IV.

In some embodiments of the present disclosure, the subject of lung cancer is a subject who has previously received PD-1 or PD-L1 inhibitor therapy alone or in combination with platinum-based chemotherapy (eg, treatment failure). In some embodiments of the present disclosure, the subject of lung cancer is non-small cell lung cancer that has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). main body.

In some embodiments of the present disclosure, the subject of lung cancer is an advanced, relapsed patient who has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). and/or subjects with metastatic non-small cell lung cancer. In some embodiments of the present disclosure, the subject of lung cancer is locally advanced, recurrent, and previously treated with PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). Subjects with sexual and/or metastatic non-small cell lung cancer.

In some embodiments of the present disclosure, the subject of lung cancer is an advanced, relapsed patient who has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). and/or metastatic squamous cell non-small cell lung cancer subjects. In some embodiments of the present disclosure, the subject of lung cancer is an advanced, relapsed patient who has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). and/or metastatic and histologically predominant squamous cell carcinoma of the body of non-small cell lung cancer. In some embodiments of the present disclosure, the subject of lung cancer is an advanced, relapsed patient who has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). and/or metastatic non-squamous non-small cell lung cancer subjects.

In some embodiments of the present disclosure, the subject of lung cancer is locally advanced, recurrent, and previously treated with PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). Primary and/or metastatic squamous cell non-small cell lung cancer. In some embodiments of the present disclosure, the subject of lung cancer is locally advanced, recurrent, and previously treated with PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). Primary and/or metastatic non-small cell lung cancer with predominantly squamous cell carcinoma histology. In some embodiments of the present disclosure, the subject of lung cancer is locally advanced, recurrent, and previously treated with PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). subjects with non-squamous and/or metastatic non-squamous non-small cell lung cancer.

In some embodiments of the present disclosure, in the previously received PD-1 or PD-L1 inhibitor therapy, the PD-1 inhibitor is an anti-PD-1 antibody, such as Nivolumab, Pembrolizumab (Pembrolizumab), Toripalizumab (JS-001), Sintilimab (IBI308), Camrelizumab (Camrelizumab), Tislelizumab (BGB-A317) ), balstilimab, AK105, genusumab (GB226), LZM009, HLX10, AK103 (HX008), CS1003, SCT-I10A, F520, SG001, or sepalimumab (GLS-010) .

In some embodiments of the present disclosure, in the previously treated PD-1 or PD-L1 inhibitor, the PD-L1 inhibitor is an anti-PD-L1 antibody, such as Atezolizumab , Durvalumab (Durvalumab), Avelumab (Avelumab), Envolumab (KN035), Sugelimab (CS1001), , TQB2450, SHR-1316, Socazolimab (ZKAB001), HS636 , LP002, JS003, MSB2311, KL-A167 or STI-A1014.

In some aspects of the present disclosure, the lung cancer is driver gene-negative lung cancer. In some embodiments, the lung cancer is driver gene-negative non-small cell lung cancer. The driver gene negative includes, but is not limited to, EGFR mutation negative, ALK mutation negative, ROS1 mutation negative, BRAF mutation negative, NTRK mutation negative, MET mutation negative, and/or KRAS mutation negative. In some specific embodiments, the lung cancer is selected from i) EGFR, ALK and/or ROS1 wild type squamous cell non-small cell lung cancer, and ii) EGFR, ALK and/or ROS1 wild type non-squamous non-small cell lung cancer Small cell lung cancer (eg lung adenocarcinoma).

In some embodiments of the present disclosure, the lung cancer is non-small cell lung cancer (eg, advanced non-small cell lung cancer) that has failed previous PD-1 or PD-L1 inhibitor therapy alone or in combination with platinum-based chemotherapy lung cancer). In some embodiments, the cancer therapy is first-line therapy for relapsed or refractory non-small cell lung cancer. In some embodiments, the lung cancer is metastatic non-small cell lung cancer, eg, non-small cell lung cancer that is lymphatic, brain, and/or bone metastases.

In some aspects of the present disclosure, the subject is a driver gene-negative (including EGFR, ALK, and ROS1 mutation-negative) patient with advanced, metastatic, or recurrent non-small cell lung cancer. In some aspects of the present disclosure, the subject is a driver gene-negative (including EGFR, ALK, and ROS1 mutation-negative) locally advanced (IIIB), metastatic, or recurrent (stage IV) non-small cell lung cancer patient. In some aspects of the present disclosure, the subject is driver gene-negative (including EGFR, ALK, and ROS1 mutation-negative) advanced, metastatic, or recurrent squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer ( such as lung adenocarcinoma). In some aspects of the present disclosure, the subject is driver gene-negative (including EGFR, ALK, and ROS1 mutation-negative) locally advanced, metastatic, or recurrent squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer (eg lung adenocarcinoma). In some instances, the patient is treated with a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy (eg, treatment failure). In some instances, the patient is histologically or cytologically inoperable and ineligible for curative concurrent chemoradiotherapy.

In some non-limiting examples, the EGFR mutation includes, but is not limited to, exon 19 or 21 mutations.

Generally, the combined pharmaceutical composition of the present application has one or more of the following effects:

(1) produce better efficacy in reducing tumor growth or even eliminating tumors compared to administration of either drug in the combination alone;

(2) provide a smaller amount of administration than either drug in the combination administered alone;

(3) Provide a treatment that is well tolerated in patients with fewer adverse reactions and/or complications than either drug administered alone;

(4) provide better disease control rates among treated patients;

(5) Provide longer survival (eg, median survival, progression-free survival, or overall survival) in the treated patient;

(6) Provide that the treated patient has a longer survival (eg, median survival, progression-free survival, or overall survival) compared to standard chemotherapy;

(7) Provide a longer duration of disease remission (DOR); and/or

(8) Compared with the single administration of any drug in the combination, it has a good activity for treating tumors or proliferative diseases, and exhibits a more excellent anti-tumor synergistic effect.

The combined pharmaceutical composition and its treatment scheme of the present disclosure have a good curative effect in the treatment of lung cancer, especially non-small cell lung cancer. wherein there is a beneficial effect on at least one of ORR, DCR, DoR, PFS, OS, tolerability and side effects.

Definition and Explanation

Unless otherwise specified, the following terms used in this disclosure have the following meanings. A particular term should not be considered indeterminate or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this disclosure, it is intended to refer to its corresponding commercial product, composition, or active ingredient thereof.

The words "comprise", "comprise" or "comprise" and their English variants such as comprises or comprising are to be understood in an open, non-exclusive sense, ie, "including but not limited to".

As used herein, the term "antibody" refers to an antigen-binding protein having at least one antigen-binding domain. The antibodies and fragments thereof of the present disclosure can be whole antibodies or any fragments thereof. Accordingly, the antibodies and fragments thereof of the present disclosure include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv) and other antibody fragments known in the art. Antibodies and fragments thereof can also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein can be of the IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the species of antibody encoded by the heavy chain constant region genes.

The term "treatment" generally refers to an operation to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms; and/or therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. "Treatment" as used herein encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.

As used herein, the term "systemic therapy" refers to a therapy in which a drug substance is transported through the bloodstream to reach and affect cells throughout the body.

As used herein, the term, "systemic therapy" refers to systemic chemotherapy, systemic or local radiation therapy.

As used herein, the term, "first-line treatment" refers to treatment with a drug that may be first or standardly selected according to the patient's condition.

"Administering" means physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, eg, by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic , intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion , and electroporation in vivo. In certain embodiments, administration is by non-parenteral routes, in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, eg, intranasal, vaginal, rectal, sublingual, or topical. Administration can also be performed, eg, once, multiple times, and/or over one or more extended periods of time.

As used herein, an "adverse event" (AE) is any unfavorable and often unintended or undesired sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. For example, adverse events can be associated with activation of the immune system or expansion of immune system cells (eg, T cells) in response to treatment. A medical treatment may have one or more associated AEs, and each AE may be of the same or a different level of severity. Reference to a method capable of "modifying an adverse event" refers to a treatment regimen that reduces the incidence and/or severity of one or more AEs associated with the use of a different treatment regimen.

As used herein, "dosing interval" refers to the amount of time that elapses between multiple doses of a formulation disclosed herein administered to a subject. The dosing interval can thus be indicated as a range.

The term "dosing frequency" as used herein refers to how often a dose of a formulation disclosed herein is administered at a given time. Dosing frequency can be indicated as the number of administrations per given time, eg, once a week or once every two weeks.

Use of the term "flat dose" refers to a dose administered to a patient regardless of the patient's weight or body surface area (BSA). The uniform dose is therefore specified as an absolute amount of an agent (eg, anti-PD-L1 antibody) rather than as a mg/kg dose. For example, a 60kg person and a 100kg person will receive the same dose of antibody (eg, 240mg anti-PD-L1 antibody).

Use of the term "fixed dose" with respect to the compositions of the present disclosure means that two or more different antibodies in a single composition are present in the composition in a specific (fixed) ratio to each other. In certain embodiments, the fixed dose is based on the weight (eg, mg) of the antibody. In certain embodiments, the fixed dose is based on the concentration of the antibody (eg, mg/ml).

Reference herein to a "body weight-based dose" refers to a dose administered to a patient calculated based on the patient's weight. For example, when a patient with a body weight of 60 kg requires 3 mg/kg of anti-PD-L1 antibody and 1 mg/kg of anti-CTLA-4 antibody, one can fix from a 3:1 ratio of anti-PD-L1 antibody and anti-CTLA-4 antibody Appropriate amounts of anti-PD-L1 antibody (ie, 180 mg) and anti-CTLA-4 antibody (ie, 60 mg) were withdrawn in one dose formulation.

The term "daily dose" refers to the dose administered to a patient for one day.

The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine, for example, a box of medicine contains seven capsules, each capsule is a single dose; for example, a box of medicine contains seven tablets, each medicine is a single dose; Or each vial of injection is a single dose.

The term "multi-dose" consists of multiple single doses.

When referring to dosing regimens, the terms "day", "every day" and the like refer to the time within a calendar day, beginning at midnight and ending at the next midnight.

The term "immunotherapy" refers to the treatment of a subject afflicted with or at risk of infection or relapse of a disease by a method that includes inducing, enhancing, suppressing or otherwise altering an immune response. "Treatment" or "therapy" of a subject means any type of intervention or procedure performed on the subject, or administration of an active agent to the subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, slowing or preventing a symptom, complication or disorder onset, progression, progression, severity, or recurrence of disease, or disease-related biochemical markers.

"Programmed Death Ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2), which downregulates T cells upon binding to PD-1 activation and cytokine secretion.

"Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In certain embodiments, the subject is a human. "Subject" means mammals such as rodents, felines, canines, and primates. Preferably, the subject of the present disclosure is a human. The terms "subject", "subject" and "patient" are used interchangeably in certain contexts herein.

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of a drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of disease or promotes regression of disease, said Disease regression is evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of injury or disability caused by disease affliction. The ability of therapeutic agents to promote disease regression can be assessed using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predicting efficacy in humans, or by in vitro assays The activity of the agent was determined.

As an example for use in the treatment of tumors, a therapeutically effective amount of an anticancer drug can inhibit cell growth or tumor growth by at least a About 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80%. In other embodiments of the present disclosure, tumor regression can be observed for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these ultimate measures of therapeutic efficacy, the evaluation of immunotherapeutic drugs must also take into account "immune-related" response patterns.

A "recurrent" cancer is one that regenerates at the initial site or at a distant site in response to initial treatment (eg, surgery). A "locally recurrent" cancer is one that, after treatment, develops in the same location as the previously treated cancer.

"Unresectable" cancer is one that cannot be removed by surgery.

"Metastatic" cancer refers to cancer that has spread from one part of the body (eg, the lungs) to another part of the body.

"Treatment failure" means disease progression or intolerable toxicity during or after treatment.

"Treatment failure with platinum-based chemotherapy" refers to disease progression or intolerable toxicity during or after treatment with platinum-based first-line chemotherapy or chemoradiotherapy.

"Failure of one systemic standard chemotherapy" was defined as disease progression during or after the last treatment, or intolerable toxicity during treatment.

"First-line or more chemotherapy failure" was defined as: disease progression during or after the last treatment; or intolerable toxicity during treatment.

The use of alternatives (eg, "or") should be understood to refer to either, both, or any combination of the alternatives. Although the disclosure supports the definition of the term "or" as only an alternative and "and/or", the term "or" in the claims means that unless expressly stated to be only an alternative or mutually exclusive between alternatives "and / or".

As used herein, the indefinite articles "a" or "an" should be understood to mean "one or more/one or more" of any listed or enumerated component. In the claims and/or specification of the present disclosure, unless the context dictates otherwise, referents such as "a, an", "said" or "the" etc. Intended to support both singular and/or plural cases.

The terms "about", "approximately" or "consisting essentially of" mean a value or composition within an acceptable error range of the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined. composition, that is, the limits of the measurement system. For example, "about", "approximately" or "substantially comprising" can mean within 1 or more than 1 standard deviation, as practiced in the art. Alternatively, "about" or "substantially comprising" may refer to a range that differs by up to 10% or 20% (ie, ±10% or ±20%) from the parameter or value modified by it. For example, about 3 mg can include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%). Furthermore, particularly in relation to biological systems or processes, the term may refer to up to an order of magnitude or up to 5 times the value. When a particular value or composition is provided in this disclosure and in the claims, unless stated otherwise, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that particular value or composition.

As used herein, the terms "about weekly," "about every two weeks," or any other similar dosing interval term refer to approximations. "About once a week" can include every 7 days ± 1 day, ie, every 6 days to every 8 days. "About every two weeks" can include every 14 days ± 3 days, ie, every 11 days to every 17 days. Similar approximations apply, for example, about once every 3 weeks, about once every 4 weeks, about once every 5 weeks, about once every 6 weeks, and about once every 12 weeks. In certain embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose may be administered on any day of the first week, followed by the administration of the first dose on the sixth or twelfth week, respectively. A second dose is administered on any day. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks means that the first dose is administered on a particular day of the first week (eg, Monday) and then on the sixth or fourth week, respectively. The second dose was administered on the same day (ie, Monday) for twelve weeks. Similar principles apply to phrases including, but not limited to, "about once every 2 weeks," "about once a month," etc. . . .

As described herein, any concentration range, percentage range, ratio range or integer range should be understood to include any integer value within the recited range and, where appropriate, fractions thereof (such as one-tenths of an integer and one percent) unless otherwise indicated.

Unless otherwise stated, "about" or "approximately" in this disclosure means within ±5% of the specified numerical range given, preferably within ±2%, more preferably within ±1% fluctuation. For example a pH of about 5.5 means a pH of 5.5±5%, preferably a pH of 5.5±2%, more preferably a pH of 5.5±1%.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of sound medical judgment, suitable for use in contact with human and animal tissue without excessive of toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.

The term "fixed combination" refers to the active components (eg, an anti-PD-L1 antibody or a compound of formula (I) or a pharmaceutically acceptable salt thereof) in a fixed total dose or dose ratio, or simultaneously in the form of a single entity, pharmaceutical composition or formulation given to the subject.

The term "non-fixed combination" refers to the simultaneous, concurrent or sequential administration of two or more active components as separate entities (eg, pharmaceutical compositions, formulations) to a subject without a specific time limit, wherein said administration to a subject of the active ingredient to a therapeutically effective level. An example of a non-fixed combination is a cocktail therapy, eg the administration of 3 or more active ingredients. In non-fixed combinations, the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions. The "non-fixed combination" also includes the use of a combination between "fixed combination" or "fixed combination" with any one or more separate entities of the active ingredient.

As used herein, "combination" or "combination" means that two or more active substances may be administered to a subject together in a mixture, each simultaneously as a single formulation, or each as a single formulation sequentially in any order to a subject By.

The term "pharmaceutical composition" refers to one or more active ingredients of the present disclosure (eg, an anti-PD-L1 antibody or a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical combination thereof and a pharmaceutically acceptable excipient. mixture. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof, to a subject. As used herein, the terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably.

way of administration

The following does not limit the mode of administration of the disclosed pharmaceutical combinations.

The components of the pharmaceutical combinations of the present disclosure may each be formulated separately, or some or all of them may be co-formulated. In one embodiment, the pharmaceutical combinations of the present disclosure can be formulated as pharmaceutical compositions suitable for single or multiple administration.

The components of the pharmaceutical combinations of the present disclosure may each be administered alone, or some or all of them may be co-administered. The components of the pharmaceutical combinations of the present disclosure may not be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.

The components of the pharmaceutical combinations of the present disclosure can be administered individually, or some or all of them together, by various routes as appropriate, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical, or subcutaneous routes). ). In some embodiments, the components of the pharmaceutical combinations of the present disclosure may each be administered independently, or some or all of them may be administered orally or by injection, eg, intravenously or intraperitoneally.

The components of the pharmaceutical combinations of the present disclosure may each independently, or some or all of them together be in a suitable dosage form including, but not limited to, tablets, troches, pills, capsules (eg, hard capsules, soft capsules, enteric capsules) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non-oral administration The dosage form of the sustained-release preparation.

The components of the pharmaceutical combination of the present disclosure may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient.

The pharmaceutical combinations of the present disclosure may also contain additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art.

Detailed ways

The present disclosure will be further described below in conjunction with specific embodiments, however, these embodiments in the present disclosure are only used for illustration and do not limit the scope of the present disclosure. Likewise, the present disclosure is not limited to any specific preferred embodiments described herein. Those skilled in the art should understand that equivalent replacements or corresponding improvements made to the technical features of the present disclosure still fall within the protection scope of the present disclosure. Unless otherwise specified, the reagents used in the following examples are all commercially available products, and conventional techniques in the art can be used for the preparation of solutions.

Table 1 List of Abbreviations

Example 1 Clinical trial

1.1 Inclusion criteria:

1) Age 18 to 75 years old; ECOG PS score: 0 to 1 point; expected survival period of more than 3 months;

2) Patients with non-small cell lung cancer diagnosed by histopathology or cytology;

3) Non-small cell lung cancer patients must meet the following criteria at the same time:

(1) UICC/AJCC 8th edition lung cancer TNM staging, non-small cell lung cancer (NSCLC) subjects who meet stage IIIB/IIIC/IV; (Note: If there are small cell components, the subjects are not eligible for enrollment );

(2) Failure to receive PD-1 (PD-L1) inhibitor monotherapy or in combination with platinum-based chemotherapy in the past;

4) The central nervous system metastasis has no clinical symptoms or is accompanied by clinical symptoms, and the condition is controlled and stable for ≥4 weeks after treatment;

5) HBVDNA quantification must be <500IU/ml or 2500 copies/ml. Patients who need treatment should receive anti-HBV treatment for at least 2 weeks before the start of the study in accordance with the "Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2019 Edition)" and are willing to receive it throughout the study period Antiviral therapy; patients with positive HCV RNA quantification must complete antiviral therapy at least 1 month before the start of the study;

5) At least one measurable lesion (RECIST 1.1);

6) The function of major organs is normal, that is, the following criteria are met:

(1) The blood routine examination standards must meet: a) hemoglobin ≥ 90g/L; b) absolute neutrophil count ≥ 1.5×10 ⁹ /L; c) platelet count ≥ 75×10 ⁹ /L; blood transfusion or blood products, not using granulocyte colony-stimulating factor, not using drug correction)

(2) Biochemical examinations must meet the following criteria: a) Albumin ≥ 30g/L (no albumin or blood products transfused within 14 days); b) ALT and AST < 3.0 × upper limit of the normal range (ULN), HCC or tumor associated with Patients with liver metastases <5.0×ULN; total bilirubin≤2×ULN; c) Serum creatinine≤1.5×ULN or creatinine clearance (Ccr)>50ml/min (Cockcroft-Gault formula: Ccr=(140-age)× Body weight (Kg)/72×Scr (mg/dl) or Ccr=(140-age)×body weight (Kg)/0.818×Scr (umol/L), women are calculated according to the result×0.85);

(3) Prothrombin time (PT) prolongation is less than or equal to 3 seconds higher than the upper limit of normal;

7) Radiotherapy for bone metastases with clinical symptoms must be completed at least 2 weeks before the start of the study;

8) Females of childbearing age should agree to use contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study period and within 6 months after the end of the study; serum pregnancy test negative within 7 days before study enrollment, and Must be non-breastfeeding; men should agree to use contraception during the study period and for 6 months after the end of the study period;

9) The patients voluntarily joined the study, signed the informed consent, and had good compliance.

1.2 Test Drugs

Compound capsules of formula (I): Specifications: 30mg/capsule and 60mg/capsule, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

hu5G11-hIgG1 injection: Specifications: 100mg/10mL and 600mg/20mL, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

1.3 Dosing regimen

Scheme A: Formula (I) compound capsule 120mg/qd+hu5G11-hIgG1 1200mg (first day)

Scheme B: Formula (I) compound capsule 150mg/qd+hu5G11-hIgG1 1200mg (first day)

1.4 Method of administration

hu5G11-hIgG1 injection: diluted with normal saline to 250mL, the infusion time is 60±5min, administered once every 21 days, and 21 days is a medication cycle.

Capsules of the compound of formula (I): once a day (the hu5G11-hIgG1 injection is administered on an empty stomach within ±5min after the infusion), and it is taken continuously. Without special circumstances, it is recommended to take it at a fixed time every day. 21 days is a cycle.

1.5 Dosage Adjustment

Dose down-regulation (150 mg-120 mg, 120 mg-90 mg) was allowed for adverse events related to compound capsules of formula (I) during the study, but cross-dose down-regulation was not allowed.

1.6 Evaluation Criteria

The main efficacy indicators were evaluated according to the RECIST 1.1 criteria, and the iRECIST evaluation criteria were referred to when pseudo-progression occurred.

1.7 Efficacy evaluation

PFS (Progression Free Survival): First dose until disease progression or death, whichever occurs first.

ORR (Objective Response Rate): The proportion of subjects with confirmed disease assessed as CR+PR.

DCR (disease control rate): The proportion of patients whose tumors shrank or remained stable for a certain period of time, including the sum of cases with CR, PR and SD.

DoR (Duration of Response): For patients whose best response was a complete or partial response, defined as the time from the first CR or PR to disease progression or relapse or death from all causes; for achieving a response, before analysis Subjects without disease progression, relapse, or death from all causes were terminated at the time of the last disease assessment.

CR (complete remission): All target lesions disappeared.

PR (Partial Remission): The total diameter of the target lesion is reduced by more than 30%.

PD (disease progression): The total diameter of the target lesion increased by 20% or more compared with the minimum total diameter in the study, and the absolute value of the total diameter increased by more than 5 mm; or one or more new lesions appeared.

SD (stable disease): The target lesion shrinks and does not meet the PR criteria; or the target lesion enlarges and does not meet the PD criteria.

Among them, the total diameter of the target lesions is the sum of the diameters of the target lesions (including the long diameter of the lesions and the short diameter of the lymph nodes).

2. Therapeutic effect

After treatment with compound of formula (I) capsules 120 mg/qd + hu5G11-hIgG1 1200 mg (day 1), in 8 subjects diagnosed with non-small cell lung cancer (including lung adenocarcinoma and lung squamous cell carcinoma) , 3 subjects achieved partial remission PR (37.5%), and the disease control rate DCR reached 100%. Preliminary results show the advantages of the compound of formula (I) in combination with hu5G11-hIgG1 in the treatment of patients with non-small cell lung cancer. Specific results for 3 PR patients (Patient A, Patient B, and Patient C as described below) are shown below.

2.1 Pre-treatment diagnosis and treatment history

Patient A:

(1) Diagnosis of squamous cell non-small cell lung cancer with lymph node metastasis.

(2) Past treatment history: right upper lobectomy + mediastinal lymph node dissection; 4 cycles of paclitaxel liposome + carboplatin chemotherapy, 4 cycles of gemcitabine + carboplatin + pembrolizumab, and then Disease progression, received nab-paclitaxel + cisplatin chemotherapy.

Patient B:

(1) Diagnosed as squamous cell non-small cell lung cancer with lymph node metastasis;

(2) Past treatment history: received nab-paclitaxel + carboplatin + sintilimab for 6 cycles, sintilimab for 3 cycles, and then the disease progressed.

Patient C:

(1) Diagnosed with squamous cell non-small cell lung cancer;

(2) History of previous treatment: received sintilimab + nab-paclitaxel + lobaplatin for 6 cycles, sintilimab for 11 cycles, and then received docetaxel (albumin-bound type) after disease progression. )treat.

2.2 Treatment plan:

For patients A, B, and C, the treatment regimen shown below was used:

Formula (I) compound capsule 120mg/qd+hu5G11-hIgG1 1200mg (first day)

2.3 Treatment effect and evaluation

For patient A, the treatment effect and evaluation are as follows:

Screening period: target lesions: 60.53mm; non-target lesions: mediastinal lymph nodes;

2 cycles of treatment: target lesions: 36.87mm; non-target lesions: mediastinal lymph nodes;

According to the efficacy evaluation criteria, the best treatment effect of patient A was PR (partial response).

For patient B, the treatment effect and evaluation are as follows:

Screening period: target lesions: 29mm; non-target lesions: hilar and mediastinal pathological lymph nodes, bilateral lung nodules;

2 cycles of treatment: target lesions: 13mm; non-target lesions: Non-CR/Non-PD (non-complete remission/non-disease progression);

According to the efficacy evaluation criteria, the best treatment effect of patient B was PR (partial response).

For patient C, the treatment effect and evaluation are as follows:

Screening period: target lesions: 55.9mm; non-target lesions: mediastinal lymph nodes, left lower lobe nodules, spleen nodules;

4 cycles of treatment: target lesions: 39mm; non-target lesions: Non-CR/Non-PD;

According to the efficacy evaluation criteria, the best treatment effect of patient C was PR (partial response).

Claims (15)

1. A combined pharmaceutical composition for treating lung cancer, comprising an anti-PD-L1 antibody and a compound of formula (I) or a pharmaceutically acceptable salt thereof, the anti-PD-L1 antibody comprising the following amino acid sequence: with SEQ ID NO: 1 or The amino acid sequence shown in SEQ ID NO:4 has a heavy chain CDR1 region with at least 80% homology; the heavy chain has at least 80% homology with the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:5 CDR2 region; heavy chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6; with the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:10 A light chain CDR1 region having at least 80% homology; a light chain CDR2 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:11; and a light chain CDR2 region having at least 80% homology with SEQ ID NO:9 Or a light chain CDR3 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 12;

   
2. The combined pharmaceutical composition according to claim 1, wherein the anti-PD-L1 antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
3. The combination pharmaceutical composition according to any one of claims 1-2, wherein the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having an amino acid sequence shown in SEQ ID NO: 1, having a heavy chain CDR1 region having an amino acid sequence shown in SEQ ID NO: 1 The heavy chain CDR2 region of the amino acid sequence shown in NO:2 has the heavy chain CDR3 region of the amino acid sequence shown in SEQ ID NO:3; the light chain CDR1 region has 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;

   Optionally, the anti-PD-L1 antibody comprises the heavy chain variable region shown in SEQ ID NO:13 and the light chain variable region shown in SEQ ID NO:15; or comprises the variable region shown in SEQ ID NO:14 Heavy chain variable region and light chain variable region shown in SEQ ID NO: 16;

   Optionally, wherein the anti-PD-L1 antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO: 17 and the light chain amino acid sequence shown in SEQ ID NO: 18; or comprises the amino acid sequence shown in SEQ ID NO: 19 The heavy chain amino acid sequence and the light chain amino acid sequence shown in SEQ ID NO:20; or the heavy chain amino acid sequence shown in SEQ ID NO:21 and the light chain amino acid sequence shown in SEQ ID NO:18;

   Optionally, the anti-PD-L1 antibody is hu5G11-hIgG1;

   Preferably, the anti-PD-L1 antibody is used in the form of a pharmaceutical composition, and the pharmaceutical composition is hu5G11-hIgG1 injection.
4. The combination pharmaceutical composition of any one of claims 1-3, comprising from about 20 mg to about 2400 mg of anti-PD-L1 antibody, or from about 600 mg to about 2400 mg of anti-PD-L1 antibody, or from about 1000 mg to about 1500 mg of anti-PD-L1 antibody, or containing about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg of anti-PD-L1 antibody, or containing about 1200 mg of anti-PD-L1 antibody -L1 antibody;

   Optionally, the pharmaceutical composition of the anti-PD-L1 antibody is a single dose or multiple doses;

   Optionally, the mass volume concentration of the pharmaceutical composition of the anti-PD-L1 antibody is about 1-150 mg/mL, or about 10-60 mg/mL, or about 10 mg/mL, or about 30 mg/mL;

   Optionally, the content of the anti-PD-L1 antibody is a uniform dose.
5. The combined pharmaceutical composition according to any one of claims 1-4, which contains 90mg-180mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or 90mg-120mg, 90mg-150mg, 120mg-150mg, 120mg-180mg or 150mg-180mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or containing 90mg, 120mg, 150mg or 180mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or containing 120mg or 150mg of a compound of formula ( I) a compound or a pharmaceutically acceptable salt thereof;

   Optionally, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a single dose or multiple doses;

   Optionally, the combined pharmaceutical composition is a pharmaceutical composition containing a single dose of 30 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof;

   Optionally, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combined pharmaceutical composition is a daily dose, or a daily dose.
6. A kit of pharmaceutical compositions for the treatment of lung cancer, comprising (a) a first pharmaceutical composition comprising an anti-PD-L1 antibody as an active ingredient; and (b) a second pharmaceutical composition comprising a compound of formula (I) or Its pharmaceutically acceptable salt is used as active ingredient; wherein the definition of anti-PD-L1 antibody is as described in any one of claims 1-4; wherein the definition of the compound of formula (I) or its pharmaceutically acceptable salt is the same as that of claim 1, 2 or any of 5;

   Optionally, the kit also includes instructions for using the anti-PD-L1 antibody in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof to treat lung cancer in a patient.
7. A method for treating lung cancer, comprising administering to a subject suffering from lung cancer a therapeutically effective amount of the combined pharmaceutical composition of any one of claims 1-5.
8. Combination therapy for the treatment of a subject suffering from lung cancer, the method comprising administering to the subject alone a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and alone administering a therapeutically effective amount of any one of claims 1-4 Anti-PD-L1 antibodies as defined.
9. Use of the combined pharmaceutical composition of any one of claims 1-5 in the treatment of lung cancer, or in the preparation of a medicament for the treatment of lung cancer.
10. The method of claim 7, the combination therapy of claim 8, or the use of claim 9, wherein the anti-PD-L1 antibody is at about 20 mg to about 2400 mg, or at about 600 mg to about 2400 mg, or At about 1000 mg to about 1500 mg, or at about 100 mg, about 300 mg, about 600 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1500 mg, about 1800 mg, about 2100 mg, or about 2400 mg, or at about 1200 mg in one or more unified doses administration, continuous administration;

    Optionally, the anti-PD-L1 antibody is intravenously infused at a time of 1200 mg;

    Optionally, one infusion time of the anti-PD-L1 antibody is about 1 hour;

    Optionally, the anti-PD-L1 antibody is administered once every 21 days;

    Optionally, the anti-PD-L1 antibody is intravenously infused at a time of 1200 mg, and the infusion time is about 1 hour, and it is administered once every 21 days.
11. The method of claim 7, the combination therapy of claim 8, or the use of claim 9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is 90 mg to 180 mg per administration, or 90 mg - 120mg, 90mg-150mg, 120mg-150mg, 120mg-180mg or 150mg-180mg, or 90mg, 120mg, 150mg or 180mg, or 120mg or 150mg;

    Optionally, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: once a day;

    Optionally, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: once a day for 21 consecutive days.
12. The method of claim 7, the combination therapy of claim 8, the use of claim 9, administered by administering a compound of formula (I) within ± 5 minutes of administration of an anti-PD-L1 antibody or Its pharmaceutically acceptable salt.
13. The method of claim 7, the combination therapy of claim 8, or the use of claim 9, wherein the combination pharmaceutical composition is a non-fixed combination;

    Optionally, the anti-PD-L1 antibody in the non-fixed combination is in the form of an injection, and/or the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a capsule.
14. The method of claim 7, the combination therapy of claim 8, or the use of claim 9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with hu5G11-hIgG1 every 21 days for One treatment cycle, administered as follows: 1200 mg of hu5G11-hIgG1 antibody was infused on the first day, infusion time of 60 ± 5 minutes; 120 mg or 150 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof was administered once a day for continuous Administered for 21 days.
15. The combination pharmaceutical composition of any one of claims 1-5, the kit of claim 6, the method of claim 7, the combination therapy of claim 8 or the use of claim 9, It is characterized in that, the lung cancer is refractory, recurrent or metastatic lung cancer; or the lung cancer is advanced lung cancer; or the lung cancer is advanced, recurrent and/or metastatic lung cancer; or the lung cancer is locally advanced, recurrent and/or metastatic lung cancer; or the lung cancer is metastatic cancer metastasized from kidney cancer, liver cancer, gastric cancer, rectal cancer, colon cancer, colorectal cancer, prostate cancer, pancreatic cancer, or breast cancer; or the Lung cancer is small cell lung cancer or non-small cell lung cancer; or the lung cancer is squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer; or the lung cancer is advanced, recurrent and/or metastatic non-small cell lung cancer Lung cancer; or the lung cancer is advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer; or the lung cancer is locally advanced, recurrent and/or metastatic non-small cell lung cancer cell lung cancer; or the lung cancer is locally advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer or non-squamous cell non-small cell lung cancer; or the subject of the lung cancer has previously undergone surgery, chemotherapy and/or Radiation therapy; or the subject of the lung cancer is UICC/AJCC 8th edition TNM staging of lung cancer, and the subject of non-small cell lung cancer conforming to stage IIIB/IIIC/IV; or the lung cancer has received PD-1 or PD-L1 inhibition in the past Lung cancer treated with a single agent or in combination with platinum-based chemotherapy; or the lung cancer is a non-cancer patient who has previously received a PD-1 or PD-L1 inhibitor alone or in combination with platinum-based chemotherapy. Small cell lung cancer; or the lung cancer is advanced, recurrent and/or metastatic non-small cell lung cancer that has previously failed PD-1 or PD-L1 inhibitor single-agent or combined platinum-based chemotherapy; Or the lung cancer is locally advanced, recurrent and/or metastatic non-small cell lung cancer that has previously failed PD-1 or PD-L1 inhibitor single-agent or combined platinum-based chemotherapy; or Lung cancer is advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer that has previously failed PD-1 or PD-L1 inhibitor single-agent or combined platinum-based chemotherapy; or the lung cancer Advanced, recurrent and/or metastatic non-squamous non-small cell lung cancer that has previously failed PD-1 or PD-L1 inhibitor monotherapy or in combination with platinum-based chemotherapy; or the lung cancer Locally advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer that has previously failed PD-1 or PD-L1 inhibitor monotherapy or in combination with platinum-based chemotherapy; or the lung cancer Locally advanced, recurrent and/or metastatic non-squamous non-small cell lung cancer that has previously failed PD-1 or PD-L1 inhibitor monotherapy or in combination with platinum-based chemotherapy; or Lung cancer is a driver gene-negative non-small cell or the lung cancer is advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer selected from i) EGFR, ALK and/or ROS1 wild-type, and ii) EGFR, ALK and/or ROS1 wild-type non-squamous cell non-small cell lung cancer; or the lung cancer is locally advanced, recurrent and/or metastatic squamous cell non-small cell lung cancer selected from i) EGFR, ALK and/or ROS1 wild-type, and ii) EGFR, ALK and/or ROS1 wild-type non-squamous non-small cell lung cancer.