CN111617243A

CN111617243A - Pharmaceutical combination of quinoline derivatives and antibodies

Info

Publication number: CN111617243A
Application number: CN202010119051.1A
Authority: CN
Inventors: 韩宝惠; 储天晴; 钟华; 李榕
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2019-02-28
Filing date: 2020-02-26
Publication date: 2020-09-04
Anticipated expiration: 2040-02-26
Also published as: CN111617243B

Abstract

The invention provides a pharmaceutical composition of a quinoline derivative and an antibody, and relates to application of the pharmaceutical composition of an anti-PD-1 antibody and a tyrosine kinase inhibitor in preparing a medicament for treating or preventing lung cancer, wherein the tyrosine kinase inhibitor is a compound shown in a formula I or a pharmaceutically acceptable salt thereof. The clinical research result of the pharmaceutical composition for treating the first-line treatment of the advanced non-small cell lung cancer shows excellent curative effect.

Description

Pharmaceutical combination of quinoline derivatives and antibodies

Technical Field

The invention belongs to the technical field of medicines, and relates to a combined therapy for resisting tumors. In particular, the invention relates to a combination based on quinoline derivatives and antibodies and their use against tumors.

Background

Tyrosine kinases are a group of enzymes catalyzing phosphorylation of tyrosine residues of proteins, play important roles in signal transduction in cells, participate in regulation, signal transmission and development of normal cells, and are closely related to proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases are involved in tumor formation and are classified into Epidermal Growth Factor Receptor (EGFR), platelet-derived growth factor receptor (PDGFR), Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor (FGFR), and the like according to their extracellular domain structures.

The erlotinib (Anlotinib) is a quinoline derivative tyrosine kinase inhibitor which plays a role in influencing tumor angiogenesis and proliferation signal transduction as a multi-target Tyrosine Kinase Inhibitor (TKI), and main targets comprise receptor tyrosine kinase Vascular Endothelial Growth Factor Receptors (VEGFR)1 to 3, Epidermal Growth Factor Receptor (EGFR), Fibroblast Growth Factor Receptors (FGFR)1 to 4, platelet-derived growth factor receptors (PDGFR) alpha and beta and Stem Cell Factor Receptors (SCFR)7,8 and 9. A phase 2 trial showed that erlotinib improved progression-free survival with potential benefits for overall survival (Han B, et al Br J cancer.2018; 118(5): 654-661.). A multicenter, double-blind, phase 3 randomized clinical trial showed that anlotinib resulted in prolonged overall and progression-free survival in Chinese patients, indicating that nilotinib is well tolerated and is a potential three-line or further treatment for advanced NSCLC patients (Han B, et al, JAMAOncol.2018Nov; 4(11): 1569-1575.).

Document WO2008112407 discloses in example 24 a quinoline derivative tyrosine kinase inhibitor 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine and a process for its preparation, which has the formula shown in formula i:

the innate immune system, which contains T lymphocytes, has a powerful anti-cancer capacity with a wide range of abilities and precise specificity to respond to a variety of tumor antigens. Emerging cancersSymptomatic immunotherapy enhances anti-tumor immune responses by adoptive transfer of activated effector cells, immunization against relevant antigens, or provision of non-specific immunostimulants. In the last 20 years, researchers have struggled to develop specific immune checkpoint inhibitors and expect to provide new immunotherapeutic protocols for the treatment of cancer, including the development of antibodies (antibodies) Ipilimumab (Ipilimumab) that bind to and inhibit CTLA-4

For treating patients with advanced melanoma (Hodi et al (2010) N Engl J Med 363:711-23), and for developing antibodies such as Nivolumab (Nivolumab,

and pabollizumab (Pembrolizumab,

) They specifically bind to programmed death receptor-1 (PD-1) and block the inhibitory PD-1/PD-1 ligand pathway (Topalian et al (2012a) N Engl J Med 366: 2443-54). Among them, PD-1(programmed death-1) is a key immune checkpoint receptor expressed by activated T lymphocytes and B lymphocytes and mediates immunosuppression, and its ligands include at least PD-L1 and PD-L2. PD-L1(Programmed death-ligand1), also known as CD274 or B7-H1, is a 40kDa type 1 transmembrane protein encoded by the CD274 gene and is a ligand for PD-1. Both PD-L1 and PD-1 belong to the immunoglobulin superfamily and both consist of two extracellular Ig domains, an N-terminal V domain and a C-terminal constant domain. The binding interface of PD-L1 to programmed death receptor-1 (PD-1) and B7-1(CD80) is on an IgV-like domain (Lin et al (2008) PNAS105: 3011-3016). PD-L1 contains a conserved short intracellular tail region (about 30 amino acids), and PD-1 contains two cytoplasmic tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switching motif (ITSM). Following T cell stimulation, PD-1 recruits the tyrosine phosphatase SHP-2 to the ITSM motif in its cytoplasmic tail, resulting in involvement in the CD 3T cell signaling cascadeDephosphorylation of effector molecules (such as CD3, PKC θ and ZAP70) (Freeman et al (2000) J Exp Med 192: 1027-34; Latchman et al (2001) Nat Immunol 2: 261-8; Carter et al (2002) Eur J Immunol32: 634-43). PD-L1 is widely distributed not only on leukocytes and nonhematopoietic cells in lymphoid and non-lymphoid tissues, but also in various cancer cells, is highly expressed on the surface of various tumor cells, and the degree of malignancy and poor prognosis of tumors are closely related to the expression level of PD-L1. There are clinical data indicating that high tumor expression of PD-L1 is associated with increased tumor invasiveness and poor prognosis. The formation of the PD-1/PD-L1 complex transmits inhibitory signals and negatively regulates T cell immune responses; it inhibits TCR-mediated T cell activation, cytokine production and T cell proliferation (Fife et al (2011) Nature Immunology 10: 1185-1193); induction of depletion or anergy in cognate antigen-specific T cells (Hofmeyer et al (2011) Journal of biomedicine and Biotechnology 2011: 1-9); promote the differentiation of Th1 cells into Foxp3+ regulatory T cells (Armanath et al (2011) Science TransMed 3: 1-13; Francisco et al (2009) J. exp. Med.206: 3015-; and inducing apoptosis of effector T cells. Disruption of the PD-L1 gene resulted in an upregulated T cell response and the generation of autoreactive T cells (Latchman et al (2004) PNAS 101: 10691-10696). Antibody blockade of PD-1 or PD-L1 resulted in increased anti-tumor immunity (Iwai et al (2002) PNAS99: 12293-12297).

The biggest challenge in the course of tumor immunotherapy in foreigners is poor treatment due to tumor immune tolerance and escape. Therefore, the small-molecule anti-tumor compound and the anti-PD-1/PD-L1 antibody are used in combination to break the immune tolerance established by the body to the tumor cells, and the method has important theoretical significance and application value.

Disclosure of Invention

The object of the present invention is at least to provide a pharmaceutical combination comprising a tyrosine kinase inhibitor and an inhibitor of the interaction between PD-1 and its ligand PD-L1. In some embodiments, the tyrosine kinase inhibitor is a compound of formula i or a pharmaceutically acceptable salt thereof, and in some embodiments, the tyrosine kinase inhibitor is a hydrochloride salt of a compound of formula i, i.e., angutinib hydrochloride.

In some embodiments, the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody or antigen-binding portion thereof that binds programmed death receptor 1(PD-1) and/or inhibits PD-1 activity, or an antibody or antigen-binding portion thereof that binds programmed death receptor 1(PD-L1) and/or inhibits PD-L1 activity, such as an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, the antibody or antigen-binding portion thereof is (a) a monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; or (b) a monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.

In some embodiments, the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.

In some embodiments, the anti-PD-1 or PD-L1 antibody is a human or murine antibody.

In some embodiments, the anti-PD-1 antibody can be selected from any one or more of Nivolumab, bebolizumab (Pembrolizumab), Durvalumab, terilisimab (JS-001), sildenumab (IBI308), caproleizumab (Camrelizumab), tirelinumab (BGB-A317), AK105 (Combo), Jenazumab (GB226), lizumab (LZM009), HLX-10, BAT-1306, AK103(HX008), AK104 (Combo), CS1003, SCT-I10A, F520, SG001, and GLS-010.

In some embodiments, the anti-PD-L1 antibody can be selected from any one or more of Atezolizumab, Avelumab, Durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014(ZKAB0011), KN035, MSB2311, HLX-20, CS-1001.

In some embodiments, the compound of formula i may be present as a pharmaceutically acceptable salt or a pharmaceutically acceptable carrier thereof, preferably as its hydrochloride salt.

In some embodiments, the compound is the hydrochloride salt of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, namely, nilotinib hydrochloride.

It is also an object of the present invention at least to provide an anti-tumor use of a pharmaceutical combination comprising a tyrosine kinase inhibitor and an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1. In some embodiments, the tyrosine kinase inhibitor is a compound of formula i or a hydrochloride salt thereof, and the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an anti-PD-1 antibody or an anti-PD-L1 antibody.

The invention also provides a method for treating a subject having a cancer or tumor comprising administering to the subject a therapeutically effective amount of a tyrosine kinase inhibitor and a therapeutically effective amount of an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1. In some embodiments, the tyrosine kinase inhibitor is a compound of formula i. In some embodiments, the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody or antigen-binding portion thereof that binds programmed death receptor 1(PD-1) and/or inhibits PD-1 activity, e.g., is an anti-PD-1 antibody or an anti-PD-L1 antibody.

The present invention also provides a combination therapy for treating a subject having a cancer or tumor, the method comprising administering to the subject a therapeutically effective amount of: binding to an antibody or antigen-binding portion thereof that inhibits the activity of PD-L1 and/or PD-L1.

The present invention also provides a method of treating a subject having a cancer or tumor that is lung cancer, comprising: (i) measuring the level of PD-1 and/or PD-L1 in a sample of the subject, wherein the subject is PD-1 and/or PD-L1 positive, and (ii) administering to the subject a therapeutically effective amount of an anti-PD-1 and/or PD-L1 antibody or antigen-binding portion thereof.

The present invention provides a method for treating a subject having a cancer or tumor. In certain embodiments, the subject is a patient diagnosed with lung cancer, e.g., a patient diagnosed with non-small cell lung cancer, or a patient diagnosed with small cell lung cancer, whose cancer may be refractory, recurrent, or metastatic lung cancer. For example, in some patients, their lung cancer is recurrent; in certain patients, the lung cancer is metastatic; in some patients, lung cancer is refractory. In some embodiments, the non-small cell lung cancer of the present invention is squamous, and in other embodiments, the non-small cell lung cancer of the present invention is non-squamous. In some embodiments, the non-small cell lung cancer of the present invention is lung adenocarcinoma, lung squamous cell carcinoma, or lung large cell carcinoma.

In some versions of the invention, the subject has previously undergone surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject has re-developed disease progression after achieving complete remission following surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject has failed to complete remission or failed to partial remission following surgery, chemotherapy, and/or radiation therapy.

In some embodiments of the invention, the subject has not previously received systemic chemotherapy. In some embodiments, the subject has previously received surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject has not previously received systemic chemotherapy, but has received surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject has complete remission following surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy before disease progression occurs again. In some embodiments, the subject has failed to complete remission or failed to partial remission following surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the subject undergoes metastasis following surgical treatment, radiation treatment, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.

In some embodiments of the invention, the Cancer or tumor is Lung Cancer (Lung Cancer) or a Lung malignancy. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In other specific embodiments, the cancer is Small Cell Lung Cancer (SCLC). In some embodiments, the cancer is relapsed or refractory lung cancer. In some embodiments, the lung cancer is recurrent. In some embodiments, the lung cancer is refractory. In some embodiments, the lung cancer is metastatic. In some embodiments, the cancer therapy is first-line therapy for relapsed or refractory non-small cell lung cancer. In some embodiments, the cancer therapy is a first line therapy of metastatic non-small cell lung cancer, for example, a first line therapy of non-small cell lung cancer that is a lymphatic metastasis, a brain metastasis, and/or a bone metastasis.

In some embodiments of the invention, the lung cancer is selected from non-small cell lung cancer. In some embodiments, the lung cancer comprises squamous lung cancer or adenocarcinoma of the lung. In some embodiments, the lung cancer is advanced lung cancer. In some embodiments, the lung cancer is EGFR, ALK and/or ROS1 wild-type non-small cell lung cancer. In some embodiments, the lung cancer is selected from advanced squamous cell lung cancer, advanced adenocarcinoma non-small cell lung cancer. In some embodiments, the lung cancer is selected from the group consisting of i) a squamous cell lung cancer of EGFR, ALK and/or ROS1 wild-type, and ii) an adenocarcinoma non-small cell lung cancer of EGFR, ALK and/or ROS1 wild-type. In some embodiments, the lung cancer is advanced (stage IIIB/IV) lung cancer that has failed or failed to tolerate first-line standard chemotherapy.

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

In some embodiments of the invention, the pharmaceutical combination is used for treating or preventing a lung malignancy, which may be a primary lung neoplasm or a secondary lung neoplasm.

In some embodiments of the invention, the lung malignancy is metastatic lung cancer. In other embodiments, the metastatic lung cancer is a metastatic cancer that is metastasized from lung cancer, gastric cancer, rectal cancer, colon cancer, colorectal cancer, pancreatic cancer, or breast cancer.

In some embodiments of the invention, the subject is a locally advanced (iiib), metastatic, or recurrent (stage IV) NSCLC patient that is drive gene negative (i.e., EGFR, ALK, and ROS1 mutation negative), and in some instances, the patient is histologically or cytologically confirmed to be inoperable and unable to receive radical concurrent chemotherapy. In some non-limiting examples, the EGFR mutation includes, but is not limited to, a 19 or 21 exon mutation.

In some embodiments of the invention, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

In some embodiments of the invention, the pharmaceutical combination is a non-fixed combination. In some embodiments, the anti-PD-1/PD-L1 antibody and the compound of formula i in the non-fixed combination are each in the form of a pharmaceutical composition.

In some embodiments, a kit of pharmaceutical combinations for treating lung tumor is also provided, which comprises (a) a first pharmaceutical composition comprising an anti-PD-1/PD-L1 antibody as an active ingredient; and (b) a second pharmaceutical composition comprising as an active ingredient a compound of formula I.

It is also an object of the invention at least to provide the use of an antagonist of PD-1 or PD-L1 for the treatment of cancer, in combination with a compound of formula I or a pharmaceutically acceptable salt thereof.

It is also an object of the invention at least to provide the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of cancer, in combination with an antagonist of PD-1 or PD-L1. In some embodiments, the PD-1 antagonist is a PD-1 monoclonal antibody or antigen-binding fragment thereof that specifically binds to human PD-1 and blocks binding of human PD-L1 to human PD-1, and/or the PD-L1 antagonist is a PD-L1 monoclonal antibody or antigen-binding fragment thereof that specifically binds to human PD-1 and blocks binding of human PD-L1 to human PD-1.

It is also an object of the present invention to provide a pharmaceutical pack comprising in separate containers a single package of a pharmaceutical composition comprising in one container a pharmaceutical composition comprising a compound of formula i or a pharmaceutically acceptable salt thereof and in a second container a pharmaceutical composition comprising a PD-1 antagonist or a PD-L1 antagonist.

Arotinib pharmaceutical composition

In some embodiments of the present application, a single dose of the pharmaceutical composition of angutinib comprises 6mg, 8mg, 10mg, or 12mg of angutinib.

In some embodiments of the present application, the total dose of the aritinib pharmaceutical composition administered per cycle comprises 84-168 mg, as a treatment cycle of 2 weeks to 1 week of administration. In some embodiments, the total dose of the anitinib pharmaceutical composition comprises 84mg, 112mg, 140mg, 168mg, or a range formed by any of the foregoing values. In some embodiments, the total dose of the anitinib pharmaceutical composition preferably comprises 112mg to 168 mg.

Arotinib

As used herein, the arotinib chemical name is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, having the following structural formula:

as used herein, the nilotinib includes its non-salt forms (e.g., free acid or free base), as well as its pharmaceutically acceptable salts, which are all included within the scope of the present application. For example, the pharmaceutically acceptable salt of the nilotinib can be the hydrochloride salt or the dihydrochloride salt. The dosage of the nilotinib or salt thereof referred to herein is based on the molecular weight of the free base of the nilotinib, unless otherwise indicated.

Xindilizumab

As used herein, the Nedilizumab (Sintilimab, IBI308, IBI-308) is an anti-PD-1 monoclonal antibody, the sequence and structure of which can be found in antibody D of the reference CN 108473977A. In 2018, 12 and 27 days, a PD-1 antibody drug of a creditant organism, namely 'Xindilizumab injection', is approved by the Chinese national drug administration (NMPA) to be listed on the market, and is used for treating recurrent or refractory classical Hodgkin lymphoma which is subjected to at least second-line system chemotherapy.

Full-length heavy chain sequence of the sillimumab:

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGLIIPMFDTAGYAQKFQGRVAITVDESTSTAYMELSSLRSEDTAVYYCARAEHSSTGTFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK。

full-length sequence of the light chain of the sillimumab:

DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLISAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANHLPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC。

definitions and explanations

The following terms used in the present invention have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears in the present invention, it is intended to refer to its corresponding commodity, composition, or active ingredient thereof.

As used herein, the term "antibody" refers to a binding protein having at least one antigen binding domain. The antibodies and fragments thereof of the present invention may be whole antibodies or any fragment thereof. Thus, the antibodies and fragments of the invention 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)' 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 may be of the IgG1, IgG2, IgG3, or IgG4 isotype.

The term "isotype" refers to the class of antibodies encoded by the heavy chain constant region gene. In one embodiment, the anti-PD-1/PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype. The anti-PD-1/PD-L1 antibodies and fragments thereof of the present invention can be derived from any species, including but not limited to mouse, rat, rabbit, primate, llama, and human. The PD-1/PD-L1 antibody and fragments thereof may be chimeric, humanized or fully human.

The term "humanized antibody" refers to antibodies in which the antigen binding site is derived from a non-human species and the variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may comprise substitutions in the framework regions such that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.

By "isolated antibody" is meant an antibody that: it is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds PD-1/PD-L1 is substantially free of antibodies that specifically bind antigens other than PD-1/PD-L1). However, an isolated antibody that specifically binds PD-1/PD-L1 may have cross-reactivity with other antigens (such as PD-1/PD-L1 molecules from different species). Furthermore, the isolated antibody may be substantially free of other cellular material and/or chemicals.

The term "monoclonal antibody" ("mAb") refers to an antibody molecule of a single molecular composition. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope or, in the case of bispecific monoclonal antibodies, dual binding specificities for two different epitopes. mabs are an example of an isolated antibody. Mabs can be produced by hybridoma techniques, recombinant techniques, transgenic techniques, or other techniques known to those of skill in the art. Examples of isolated anti-PD-1/PD-L1 monoclonal antibodies include, but are not limited to, Nivolumab

Pabolizumab (Pembrolizumab)

Durvalumab, Avelumab, Terepriamab (JS-001, Juniperus organism), Xindilizumab (Sintilimab, IBI308, Nedarabin), Cereli monoclonal antibody (SHR-1210, Camrelizumab, Henry medicine, see CN105026428B or WO2015085847A1), Tereli monoclonal antibody (BGB-A317, Baiji Shenzhou), AK105 (Zhongshan Kangfang), Jennuomab (GB226, Jia and Bio), Lizhuzumab (LZM009, Lizhu pharmaceutical), HLX-10 (Rehong Han), BAT-1306 (Baiotai), HX008(AK103, Kangfang Bio/Hanzhong Bio), AK104 (Zhongshan Kangfang Square), CS1003 (Kishiyashiyao pharmaceutical industry), SCTP-I10A (Shenzhou cell), F520 (Shandong Xinluyu pharmaceutical industry/Luzu SG), GLIcGzhu biological (GLizu S-010), Atlizumab (Atuzumab), Tanzojin pharmaceutical industry III (Atuzu pharmaceutical industry, Tanzojin Si-K)

Roche), Avelumab (

Merck/fevere), Durvalumab (

Aslicarban) KL-A167 (Konlun pharmaceutical industry), SHR-1316 (Henry medicine), BGB-333 (Baiji Shenzhou), JS003 (Junshi organism), STI-A1014(ZKAB0011, Megaku pharmaceutical industry), KN035 (kang Ning Jie Rui/Cidi), MSB2311 (Meubo Si organism), HLX-20 (Fuhong Hanlin), CS-1001 (Kishi pharmaceutical industry), and the like.

An "antigen-binding portion" (also referred to as an "antigen-binding fragment") of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen bound by an intact antibody.

As used herein, the term "derived" when used in reference to a molecule or polypeptide relative to a reference antibody or other binding protein means a molecule or polypeptide that is capable of specifically binding the same epitope as the reference antibody or other binding protein.

As used herein, the term "EC 50" refers to the effective concentration, 50% of the maximal response of an antibody. As used herein, the term "IC 50" refers to the inhibitory concentration, 50% of the maximal response of an antibody. Both EC50 and IC50 may be measured by ELISA or FACS analysis or any other method known in the art.

The term "treating" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic, in terms of preventing the disease or its symptoms, in whole or in part; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) preventing a disease or condition in a patient susceptible to the disease or condition but not yet diagnosed as having the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

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

As used herein, the term "systemic chemotherapy" refers to systemic chemotherapy that does not include chemotherapy for locally advanced disease as one of the links of multimodal treatment, wherein chemotherapy for locally advanced disease includes induction chemotherapy, concurrent chemotherapy with radiotherapy, and adjuvant chemotherapy.

As used herein, the term "subject" means a mammal, such as a rodent, feline, canine, and primate. Preferably, the subject according to the invention is a human.

By "administering" is meant 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 of the immune checkpoint inhibitor (e.g., anti-PD-1 antibody or anti-PD-L1 antibody) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, e.g., by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered by a non-parenteral route, and in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, e.g., intranasally, vaginally, rectally, sublingually or topically. Administration may also be performed, for example, once, multiple times, and/or over one or more extended periods of time.

As used herein, an "adverse effect" (AE) is any adverse and often unintended or undesirable sign (including abnormal laboratory findings), symptom or disease associated with the use of medical treatment. For example, an adverse event can be associated with activation of the immune system or expansion of cells of the immune system (e.g., T cells) in response to a treatment. The medical treatment may have one or more related AEs, and each AE may have the same or different severity level. Reference to a method capable of "altering 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 may thus be indicated as a range.

The term "dosing frequency" as used herein means the frequency of doses administered of a formulation disclosed herein over a given time. The frequency of administration may be indicated as the number of doses per given time, e.g. 1 time per week or 1 time per 2 weeks.

The use of the term "flat dose" refers to a dose that is administered to a patient without regard to the weight or Body Surface Area (BSA) of the patient. Thus, a uniform dose is provided as a mg/kg dose, rather than as an absolute amount of agent (e.g., anti-PD-1 antibody). For example, a 60kg human and a 100kg human will receive the same dose of antibody (e.g., 240mg anti-PD-1 antibody).

The use of the term "fixed dose" in relation to the compositions of the invention 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 of the antibody (e.g., mg). In certain embodiments, the fixed dose is based on the concentration of the antibody (e.g., mg/ml). In certain embodiments, the ratio of mg of the first antibody to mg of the second antibody is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 1: 8:1, about 1:1, about 5: 7, about 1:1, about 1: 6:1, about 1:1, about, About 4:1, about 3:1, or about 2: 1. For example, a 3:1 ratio of primary and secondary antibodies may mean that the vial may contain about 240mg of primary and 80mg of secondary antibody, or about 3mg/ml of primary and 1mg/ml of secondary antibody.

The term "weight-based dose" as referred to herein refers to a dose administered to a patient that is calculated based on the weight of the patient. For example, when a patient with a weight of 60kg requires 3mg/kg of anti-PD-1 antibody and 1mg/kg of anti-CTLA-4 antibody, one can extract appropriate amounts of anti-PD-1 antibody (i.e., 180mg) and anti-CTLA-4 antibody (i.e., 60mg) at a time from a 3:1 ratio fixed dose formulation of anti-PD-1 antibody and anti-CTLA-4 antibody.

The term "immunotherapy" means the treatment of a subject having a disease or at risk of infection or of suffering from a relapse of a disease by a method that includes inducing, enhancing, suppressing or otherwise altering an immune response. By "treatment" or "therapy" of a subject is meant any type of intervention or process performed on the subject, or the administration of an active agent to a subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the onset, progression, severity, or recurrence of a symptom, complication, or condition, or biochemical indicator associated with the disease.

As used herein, "PD 1/PD-L1 positive" may be used interchangeably with "at least about 1% PD-1/PD-L1 expression". In one embodiment, PD-1/PD-L1 expression may be used by any method known in the art. In another embodiment, PD-1/PD-L1 expression is measured by automated IHC. In certain embodiments, "PD-1/PD-L1 positive" means that there are at least 100 cells expressing PD-1/PD-L1 on the cell surface.

"programmed death receptor-1 (PD-1)" means an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo and binds to both ligands PD-L1 and PD-L2. The term "PD-1" as used herein includes variants, homologs, and species homologs of human PD-1(hPD-1), hPD-1, and analogs having at least one common epitope with hPD-1.

"programmed death ligand-1 (PD-L1)" is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that down-regulates T cell activation and cytokine secretion upon binding to PD-1.

"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. The terms "subject" and "patient" are used interchangeably herein in certain contexts.

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

As used herein, a "sub-therapeutic dose" refers to a dose of a therapeutic compound (e.g., an antibody) that is lower than the usual or typical dose of the therapeutic compound when administered alone for the treatment of a hyperproliferative disease (e.g., cancer).

As an example, an "anti-cancer drug" promotes cancer regression in a subject or prevents further tumor growth. In certain embodiments, the therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer. By "promoting cancer regression" is meant that an effective amount of a drug, administered alone or in combination with an anti-neoplastic agent, results in the reduction of tumor growth or size, necrosis of the tumor, a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of disease symptom-free stages, or the prevention of injury or disability resulting from the affliction of the disease. Furthermore, the terms "effective" and "effectiveness" with respect to treatment include pharmacological effectiveness and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression in a patient. Physiological safety means the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ and/or organism level resulting from drug administration.

As an example for treating a tumor, a therapeutically effective amount of an anti-cancer agent can inhibit cell growth or tumor growth by at least about 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80% relative to an untreated subject, or, in certain embodiments, relative to a patient treated with standard of care therapy. In other embodiments of the invention, tumor regression may be observed for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these final measures of therapeutic effectiveness, the evaluation of immunotherapeutic drugs must also take into account "immune-related" response patterns.

By "immune-related" response pattern is meant the clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that produce an anti-tumor effect by inducing a cancer-specific immune response or by altering the innate immune process. This response pattern is characterized by beneficial therapeutic effects following an initial increase in tumor burden or the appearance of new lesions, which would be classified as disease progression and would be synonymous with drug failure in the evaluation of traditional chemotherapeutic agents. Thus, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effect of these agents on the target disease.

A therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of drug that inhibits the occurrence or recurrence of cancer when administered, alone or in combination with an anti-neoplastic agent, to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of cancer recurrence. In certain embodiments, the prophylactically effective amount completely prevents the occurrence or recurrence of cancer. By "inhibiting" the occurrence or recurrence of cancer is meant reducing the likelihood of occurrence or recurrence of cancer, or completely preventing the occurrence or recurrence of cancer.

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

A "non-resectable" cancer is one that cannot be removed by surgery.

"metastatic" cancer refers to cancer that spreads from one part of the body (e.g., the lungs) to another part of the body.

The use of alternatives (e.g., "or") should be understood to refer to either, both, or any combination of alternatives. The indefinite articles "a" or "an" as used herein shall be understood to mean "one or more" of any listed or enumerated component.

The terms "about," about, "or" consisting essentially of mean a value or composition within an acceptable error range for 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, i.e., the limitations of the measurement system. For example, "about," about, "or" consisting essentially of 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 of up to 10% or 20% (i.e., ± 10% or ± 20%). For example, about 3mg may include any number between 2.7mg to 3.3mg (for 10%) or between 2.4mg to 3.6mg (for 20%). Furthermore, particularly with respect to biological systems or processes, the term may refer to up to an order of magnitude or up to at most 5 times the numerical value. Where particular values or compositions are provided herein, unless otherwise stated, the meaning of "about" or "consisting essentially of" should be assumed to be within an acceptable error range for the particular value or composition.

As used herein, the terms "about once per week", "about once per two weeks" or any other similar dosing interval term refer to approximations. "about once per week" may include every 7 days ± 1 day, i.e., every 6 days to every 8 days. "about once every two weeks" may include every 14 days ± 3 days, i.e., 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 a first dose may be administered on any day of the first week, and then a second dose may be administered on any day of the sixth or twelfth week, respectively. In other embodiments, a dosing interval of about once every 6 weeks or about once every 12 weeks refers to administration of a first dose on a particular day of the first week (e.g., monday) followed by administration of a second dose on the same day of the sixth or twelfth week (i.e., monday), respectively. Similar principles apply to phrases including, but not limited to, "about 1 every 2 weeks," "about 1 every month," etc. … ….

As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the recited range, and when appropriate, to include fractions thereof (such as tenths and hundredths of integers), unless otherwise indicated.

Unless otherwise stated, "about" or "approximately" in the context of the present invention means within + -5%, preferably within + -2%, more preferably within + -1% of the specified numerical range given. 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" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" includes salts of the base ion with the free acid or salts of the acid ion with the free base, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-methylbenzenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt and the like. In the present application, when forming a pharmaceutically acceptable salt, the molar amount of free acid to base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1: 8. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free base to the acid ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1: 8.

The term "fixed combination" means that the active ingredients (e.g. an anti-PD-1 antibody or a compound of formula i) are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

The term "non-fixed combination" means that two or more active ingredients are administered to a subject as separate entities (e.g. pharmaceutical compositions, formulations) simultaneously, concurrently or sequentially and without specific time constraints, wherein the active ingredients are administered to the subject to a therapeutically effective amount level. An example of an unfixed combination is cocktail therapy, e.g. 3 or more active ingredients are administered. In a non-fixed combination, the individual active ingredients may be packaged, sold or administered as a completely separate pharmaceutical composition. The term "non-fixed combination" also includes the use of "fixed combinations" in between, or "fixed combinations" in combination with, any one or more of the individual entities of the active ingredients.

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

The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application (e.g., an anti-PD-1 antibody or a compound of formula i) or a pharmaceutical combination thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application, or a pharmaceutical combination thereof, to a subject.

The term "synergistic effect" refers to a simple addition of two or more components (e.g., an anti-PD-1 antibody or a compound of formula I) that produces an effect (e.g., inhibiting the growth of colon cancer, or ameliorating the symptoms of colon cancer) that is greater than the effect of the components when administered alone.

Mode of administration

The following is not intended to limit the mode of administration of the pharmaceutical combinations of the present application.

The components of the pharmaceutical combination of the present application may be formulated separately from each other or some or all of them may be co-formulated. In one embodiment, the pharmaceutical combination of the present application may be formulated as a pharmaceutical composition suitable for single or multiple administration.

The components of the pharmaceutical combination of the present application may each be administered separately, or some or all of them may be co-administered. The components of the pharmaceutical combination of the present application may be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.

The components of the pharmaceutical combination of the present application may be administered independently of each other, or some or all of them together in a variety of 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 combination of the present application may be administered orally or parenterally, each independently, or some or all of them together, for example intravenously or intraperitoneally.

The components of the pharmaceutical combination of the present application 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 (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and sustained release formulations for oral or non-oral administration.

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

The pharmaceutical combination of the present application may also comprise additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a lung cancer therapeutic agent.

In some embodiments, the present invention contemplates the therapeutic effects of erlotinib hydrochloride, an anti-PD-1 antibody, alone or in combination, on lung tumors. The experimental result surprisingly discovers that the erlotinib hydrochloride and the anti-PD-1 antibody have obvious synergistic effect, and the immune tolerance of the body to the tumor cells is broken.

Drawings

Figure 1 an erlotinib in combination with first line treatment PFS of advanced non-small cell lung cancer with sillizumab; the initial number of cases was 22, with a PFS probability of 93.8% at 6 months.

Detailed Description

The present invention is further described below with reference to specific examples, which, however, are only illustrative and not intended to limit the scope of the present invention. Likewise, the present invention is not limited to any particular preferred embodiment described herein. It will be appreciated by those skilled in the art that equivalent substitutions for the features of the invention, or corresponding modifications, may be made without departing from the scope of the invention. The reagents used in the following examples are commercially available products, and the solutions can be prepared by techniques conventional in the art, except where otherwise specified.

TABLE 1 abbreviation table

Example combination of erlotinib hydrochloride for treatment of advanced non-small cell lung cancer

This example discloses the results of an exploratory study of the combination of nilotinib hydrochloride for the treatment of advanced non-small cell lung cancer. The main target population is patients with locally advanced (iiib), metastatic or recurrent (stage IV) NSCLC who are histologically or cytologically confirmed to be drive gene negative (i.e., EGFR, ALK, and ROS1 mutation negative) who are not surgically treatable and are not amenable to radical concurrent chemotherapy.

The primary study endpoint: security, ORR.

Secondary study endpoint: DCR, PFS, OS.

Progression Free Survival (PFS): defined as the time from the first dose until objective tumor progression or death.

Overall Survival (OS): defined as the time from the start of the first dose to death due to any cause. In days, the time of the last follow-up is usually calculated as the time of death for an unsuccessfully visited subject.

The key inclusion criteria are as follows: chinese stage IIIB/IV NSCLC; has not received systemic treatment; the molecular typing is definite; 18-75 years old; PS scoring: 0-1 min; the expected life span exceeds 3 months; has sufficient organ reserve function; there was no symptomatic brain metastasis.

Key exclusion criteria: prior receipt of systemic anti-cancer therapy; has a plurality of factors affecting oral drugs; those with symptomatic brain metastases, spinal cord compression, cancerous meningitis, or diseases of the brain or pia mater found by CT or MRI examination at screening; central cavity squamous carcinoma or bleeding tendency; there are patients with any severe and/or uncontrolled disease.

Arotinib hydrochloride: pale yellow crystalline powder with a content of 98.9%, lot No. 17316007, protected from light at 2-8 deg.C, and preserved. The erlotinib hydrochloride is provided by Ningda Nintenberg pharmaceutical industry group GmbH. The erlotinib hydrochloride was formulated with distilled water and diluted to the desired concentration.

Administration dose:

anti-PD-1 antibody: the first day (D1) of each cycle (total 21 days) was administered an injection of fiducizumab, 200mg, by intravenous infusion, once every 21 days.

An aritinib hydrochloride capsule (active ingredient is aritinib dihydrochloride): the anti-PD-1 antibody injection is infused into the oral cavity within +/-5 min, and then the oral cavity takes 12mg of the Anrotinib hydrochloride capsule, and the Anrotinib hydrochloride capsule is continuously taken orally for 2 weeks and stops for 1 week, namely 21 days is a treatment period.

The experimental protocol, duplicate electronic case report form, and written informed consent form of the experiment were submitted to the ethical committees of the clinical research responsible department and each research department before the experiment began, and clinical experiments could be performed only after obtaining the ethical committee approval agreed to the clinical experiments. Before the clinical trial began, researchers presented all subjects with details of the purpose, risk and benefit of the trial, ensured that all subjects had informed consent prior to the trial, signed an informed consent, and fully ensured the benefit of the subjects during the trial. Researchers strictly comply with ethical guidelines of human medical research announced by helsinki (2013) and regulations of related legal regulations, such as "clinical trial quality management of drugs code (2003)", and the like, perform the duties of researchers.

11 patients had the condition for evaluating the therapeutic effect by 1 month and 25 days in 2019. The 11 patients enrolled in the study had the basic and efficacy assessment shown in table 1, with efficacy assessment times for the second (about 42 days) and fourth (about 84 days) cycles, respectively; the statistics of the efficacy evaluations are given in table 2.

TABLE 1 basic condition and efficacy assessment results for the patients enrolled in the study

The results of the exploratory data study on the first-line treatment of advanced non-small cell lung cancer by the combination of aniotinib and the combination of ori: 63.6%, DCR: 100% (see Table 2), PFS and OS are expected. At the same time, the first-line combination mode of antratinib showed a high degree of patient tolerance (detailed results not shown).

TABLE 2 evaluation of efficacy of Arotinib in combination with Cedilizumab

22 patients had the condition for evaluating the therapeutic effect by 7 months and 3 days in 2019. The statistics of the efficacy evaluations are given in table 3.

TABLE 3 evaluation of efficacy of Arotinib in combination with Cedilizumab

The results of exploratory data studies on first-line treatment of advanced non-small cell lung cancer with anrolitinib in combination with sillizumab suggested a surprising efficacy, with 16 out of 22 patients reaching PR. Furthermore, the ORR was 72.7% and the DCR was 100% (83.33% for erlotinib), with a primary PFS of 93.8% for 6 months (shown in figure 1) and a PFS of 4.83 months for erlotinib alone, showing that the effect of the combination of the two drugs is better than that of erlotinib alone.

Exemplary embodiments described herein may be described by the following numbered paragraphs:

1. use of a pharmaceutical combination for the manufacture of a medicament for the treatment or prevention of lung cancer, the pharmaceutical combination comprising:

a) an anti-PD-1 or anti-PD-L1 antibody, or an antigen-binding fragment thereof, and

b) a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof,

wherein the anti-PD-1 or anti-PD-L1 antibody can be selected from any one or more of nivaletuzumab, Pabolizumab, Terepritumomab, Cedilizumab, Cerililizumab, Tirelizumab, AK105, Jennuzumab, Lilizumab, HLX-10, BAT-1306, AK103, AK104, CS1003, SCT-I10A, F520, SG001, GLS-010, Atezolizumab, Avelumab, Durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014(ZKAB0011), KN035, MSB2311, HLX-20, and CS-1001.

2. The use according to item 1, wherein the compound of formula i or a pharmaceutically acceptable salt thereof is hydrochloride of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine.

3. The use according to any one of claims 1-2, wherein the pharmaceutical combination is a non-fixed combination.

4. The use according to any one of claims 1-3, wherein the anti-PD-1 or anti-PD-L1 antibody, and the compound of formula I or a pharmaceutically acceptable salt thereof, in said non-fixed combination are each in the form of a pharmaceutical composition.

5. The use of any one of claims 1-4, wherein the anti-PD-1 or anti-PD-L1 antibody is Tradilizumab.

6. The use of any one of claims 1-5, wherein the EGFR, ALK, and/or ROS1 gene in said lung cancer is wild-type gene or is mutation negative.

7. The use of any one of claims 1-6, wherein the lung cancer is a relapsed, refractory, metastatic, or advanced lung cancer.

8. The use of any one of claims 1-7, wherein the lung cancer is small cell lung cancer or non-small cell lung cancer.

9. The use of any one of claims 1-8, wherein the lung cancer is advanced non-small cell lung cancer.

10. The use according to any one of claims 1-9, wherein the cancer treatment is first line treatment for recurrent, refractory, metastatic, or advanced non-small cell lung cancer.

11. The use of any one of claims 1-10, wherein the non-small cell lung cancer is lung adenocarcinoma, lung squamous cell carcinoma, or lung large cell carcinoma.

12. The use according to any one of claims 1 to 11, wherein the compound of formula I hydrochloride in the pharmaceutical combination is administered at a uniform dose of about 8 mg/dose, 10 mg/dose or 12 mg/dose and the anti-PD-1 or anti-PD-L1 antibody is administered at a uniform dose of about 200 mg/dose.

13. The use according to any one of claims 1 to 11, wherein the hydrochloride salt of the compound of formula I in the pharmaceutical combination is administered 1 time daily, 8mg, 10mg or 12mg each time, 2 weeks for 1 week on continuous oral administration, and the anti-PD-1 or anti-PD-L1 antibody is administered 1 time every 3 weeks, 200 mg/time.

14. An article of manufacture comprising a container containing a fixed dose of a hydrochloride salt of a compound of formula I selected from about 8mg, about 10mg, and about 12mg and an anti-PD-1 or anti-PD-L1 antibody, wherein the fixed dose of the anti-PD-1 or anti-PD-L1 antibody is selected from about 100mg and about 200 mg.

15. A kit for treating lung cancer, comprising (a) a first pharmaceutical composition comprising an anti-PD-1 or anti-PD-L1 antibody, or an antigen-binding fragment thereof, as an active ingredient; and (b) a second pharmaceutical composition comprising as an active ingredient a compound of formula I.

While the compositions and methods of this invention have been described in terms of preferred embodiments in light of the present disclosure, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention.

The disclosures of all documents cited herein are incorporated by reference herein, to the extent that they provide exemplary, procedural and other details supplementary to those set forth herein.

Claims

2. The use according to claim 1, wherein the compound of formula i or a pharmaceutically acceptable salt thereof is the hydrochloride salt of 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine.

3. The use according to any one of claims 1-2, wherein the pharmaceutical combination is a non-fixed combination in which the anti-PD-1 or 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.

4. The use of any one of claims 1-3, wherein the anti-PD-1 or anti-PD-L1 antibody is Tradilizumab.

5. The use of any one of claims 1-4, wherein the EGFR, ALK, and/or ROS1 gene in said lung cancer is wild-type gene or is mutation negative.

6. The use of any one of claims 1-5, wherein the lung cancer is relapsed, refractory, metastatic, or advanced non-small cell lung cancer.

7. The use of any one of claims 1-6, wherein the cancer treatment is first line treatment for recurrent, refractory, metastatic, or advanced non-small cell lung cancer.

8. The use of any one of claims 1-7, wherein the non-small cell lung cancer is lung adenocarcinoma, lung squamous cell carcinoma, or lung large cell carcinoma.

9. The use according to any one of claims 1 to 8, wherein the compound of formula I hydrochloride is administered in a combined dose of about 8 mg/dose, 10 mg/dose or 12 mg/dose and the anti-PD-1 or anti-PD-L1 antibody is administered in a combined dose of about 200 mg/dose.

10. The use according to any one of claims 1 to 9, wherein the hydrochloride salt of the compound of formula I in the pharmaceutical combination is administered 1 time a day, 8mg, 10mg or 12mg each time, 2 weeks for 1 week on continuous oral administration, and the anti-PD-1 or anti-PD-L1 antibody is administered 1 time every 3 weeks, 200 mg/time.