WO2023138576A1 - Pharmaceutical combination of spirocyclic aryl phosphorus oxide and anti-egfr antibody - Google Patents

Abstract

Disclosed is a pharmaceutical combination of an ALK inhibitor and an antibody, which comprises a spirocyclic aryl phosphorus oxide and an anti-EGFR antibody, wherein the ALK inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical combination of the present invention is used for treating lung cancer and displays good anti-tumor activity.

Description

Drug Combination of Spiroaryl Phosphate Oxide and Anti-EGFR Antibody

This application claims the priority of the Chinese patent application with the application number 202210052633.1 filed on January 18, 2022, entitled "Drug Combination of Spiroaryl Phosphate Oxide and Anti-EGFR Antibody", the entire content of which is incorporated in this application by reference.

technical field

The invention belongs to the field of medicinal chemistry and relates to a combined pharmaceutical composition for treating tumors. Specifically, the present invention relates to the drug combination of spirocyclic aryl phosphorus oxide and antibody and its use in the preparation of antitumor drugs.

Background technique

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) and a member of the insulin receptor (IR) superfamily. In 1994, ALK was first discovered in 60-80% of anaplastic large cell lymphoma (ALCLS) cell lines in the form of fusion protein NPM (nucleophosmin)-ALK. NPM-ALK was caused by t(2;5) chromosome translocation. Although the physiological function of ALK in cancer is unclear, ALK fusion proteins have been identified in various human cancers such as breast cancer, colorectal cancer, inflammatory myofibroblastic tumor (IMT), diffuse large B-cell lymphoma (DLBCL), and most notably in non-small cell lung cancer (NSCLC). Therefore, the kinase activity associated with ALK fusion proteins is considered to play a very important role in the survival and proliferation of human cancer cells.

The ALK gene provides a signaling instruction for receptor tyrosine kinases to transmit signals from the cell surface into the cell. This process begins when a kinase is stimulated at the cell surface and then attaches to a similar kinase (dimerization). After dimerization, the kinase is tagged with a phosphate group, a process called phosphorylation. Phosphorylation-activated kinase, an activated kinase is another protein capable of transferring a phosphate group into the cell, activating a series of proteins that continue through the signaling pathway. These signaling pathways are important for many cellular processes, such as cell growth and division (proliferation) or maturation (differentiation).

Often ALK is rearranged such that the tyrosine kinase domain of ALK is fused to the 5′-terminal domain of another protein, such as echinoderm microtubule-associated protein-like 4 (EML4) in NSCLC or nucleophosphoprotein (NPM) in anaplastic large cell lymphoma. The breakpoint of all ALK fusion genes is very conserved, located in the upstream kinase domain of the exon-encoded intragenic region. Since the part of the rearrangement involved in ALK does not include the transmembrane domain, the resulting fusion protein re-migrates from the cell membrane to the cytoplasm. The 5'-end of the fusion protein usually contains a coiled-coil or leucine zipper domain, which oligomerizes the fusion protein and leads to ligand-dependent activation of the ALK tyrosine kinase. This in turn constitutively activates downstream signaling pathways such as Ras/MAPK, PI3K/AKT, and JAK/STAT. ALK-driven lung cancers respond and regress following treatment with ALK small-molecule tyrosine kinase inhibitors. This finding demonstrates "oncogene dependency," whereby cancer cells become dependent on oncogenic driver genes and are thus highly sensitive to suppressing oncogenes.

Crizotinib is the first ALK inhibitor approved by the FDA for the treatment of ALK-positive lung cancer. Although patients initially responded very well to crizotinib therapy, most patients relapsed during the first year of treatment due to the development of drug resistance. In April 2014, the FDA approved Ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), including patients who are effective and resistant to crizotinib. However, drug resistance always occurs with the prolongation of treatment time, so that the drug loses its effectiveness.

Spirocyclic aryl phosphine oxide, chemical name: (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, is a novel ALK/ROS1 inhibitor for the treatment of ALK/ROS1 positive non-small cell lung cancer. It has the following structural formula:

The compound of formula I inhibits the phosphorylation of ALK by inhibiting the activation of ALK kinase, thereby preventing the phosphorylation of downstream signaling molecules, such as ERK, STAT5 and AKT. In addition, the compound of formula I inhibits the activation of ROS1 by inhibiting the phosphorylation of ROS1 fusion kinase, This in turn prevents the phosphorylation of downstream signaling molecules such as ERK or AKT. Ultimately inhibits ALK or ROS1 kinase-driven tumor growth by inhibiting kinase phosphorylation. Related patent documents include: patent WO2016/000581 discloses spirocyclic aryl phosphorus oxides as ALK inhibitors; patent CN106928275 discloses the preparation method and intermediates of spirocyclic aryl phosphorus oxides; patent CN110407877 discloses polymorphic forms of spirocyclic aryl phosphorus oxides.

In recent years, more and more evidences have shown that epidermal growth factor receptor (EGFR) is related to the occurrence and development of many tumors. EGFR normally helps regulate the growth of cells in the body, but it can also stimulate the growth of cancer cells. EGFR is present on the surface of cancer cells and is activated when proteins present in the body that bind to EGFR, such as epidermal growth factor (EGF) or transforming growth factor alpha (TGF-alpha). Binding changes the morphology of EGFR, stimulating the growth of tumor cells. EGFR-positive tumors are characterized by high malignancy and strong invasion, and the level of EGFR expression is related to prognosis. Therefore, it has also become an important target of current tumor molecular targeted therapy. It has been proven that HER1/EGFR is abnormally expressed in solid tumors, and its clinical manifestations are metastasis, shortened survival time, poor prognosis, and resistance to chemotherapy and hormone therapy. Blocking HER1/EGFR can inhibit the formation of tumors and improve the above conditions at the same time.

The drugs currently used for EGFR-targeted tumor therapy are mainly divided into two categories: EGFR monoclonal antibodies and small molecule compound tyrosine kinase antagonists. EGFR monoclonal antibody competes with endogenous ligands for binding to EGFR, and produces anti-tumor effects by inhibiting the activation of tyrosine kinase and promoting the internalization of EGFR. At present, there are 3 kinds of anti-EGFR monoclonal antibodies on the market at home and abroad. Compared with other chemotherapeutic drugs, these antibodies have strong specificity and small side effects, and have achieved good clinical curative effect.

Common mutations of the EGFR gene occur in exons 18, 19, 20, and 21, of which non-frameshift deletion mutations in exon 19 account for about 45%, and L858R point mutations in exon 21 account for 40-45%. These two mutations are called common sensitive mutations, and other mutations are called rare mutations.

Panitumumab is the first fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Panitumumab can specifically bind to EGFR in normal and tumor cells and is a competitive inhibitor of EGFR ligands. Non-clinical studies have shown that the combination of panitumumab and EGFR can prevent ligand-induced receptor autophosphorylation and activation of receptor-associated kinases, inhibit cell growth and induce apoptosis, reduce the production of pro-inflammatory cytokines and angiogenesis factors and the internalization of EGFR.

The biggest challenge encountered in the process of tumor treatment is the poor efficacy of drugs due to tumor immune tolerance and escape. Therefore, the combination of small molecule anti-tumor compounds and anti-EGFR antibodies to treat tumors has important application value.

Contents of the invention

The purpose of the present invention is to provide a combination pharmaceutical composition, which comprises ALK inhibitor and anti-EGFR antibody. Specifically, the pharmaceutical composition of the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as an ALK inhibitor, and an anti-EGFR antibody.

In some aspects of the present invention, the anti-EGFR antibody in the above combined pharmaceutical composition is panitumumab.

In some aspects of the present invention, the above-mentioned combined pharmaceutical composition is a non-fixed combination. In some aspects, the anti-EGFR 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, there is also provided a kit of a pharmaceutical combination for treating lung tumors, which contains (a) a first pharmaceutical composition comprising an anti-EGFR antibody; and (b) a second pharmaceutical composition comprising a compound of formula I as an active ingredient.

The present invention also provides an application of a combined pharmaceutical composition in the preparation of a drug for treating and/or preventing lung cancer, the combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an ALK inhibitor, and an anti-EGFR antibody.

In some aspects of the invention, the anti-EGFR antibody in the above use is panitumumab.

In some aspects of the present invention, the panitumumab used in the above application can be selected from Vectibix or its biosimilars.

In some aspects of the present invention, the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above application are each in the form of a pharmaceutical composition.

In some aspects of the present invention, the lung cancer in the above application is positive for EGFR sensitive mutation.

In some aspects of the present invention, the lung cancer mentioned in the above application is early-middle stage, locally advanced, advanced metastatic non-small cell lung cancer.

In some schemes of the present invention, the lung cancer described in the above application is early-middle stage, locally advanced, and advanced metastatic non-small cell lung cancer that is positive for EGFR sensitive mutations.

In some aspects of the present invention, the lung cancer in the above application is non-small cell lung cancer that has not been treated with an EGFR inhibitor or failed to be treated with an EGFR inhibitor.

In some aspects of the present invention, the lung cancer in the above application is a non-small cell lung cancer with positive EGFR sensitive mutation, T790M mutation and C797S mutation that has failed treatment with irreversible EGFR inhibitors such as osimertinib.

In some aspects of the present invention, the lung cancer in the above application is non-small cell lung cancer with Del19 mutation, T790M mutation and C797S mutation.

In some aspects of the present invention, the lung cancer in the above application is non-small cell lung cancer with L858R mutation, T790M mutation and C797S mutation.

In some aspects of the present invention, the non-small cell lung cancer in the above application is adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma or large cell carcinoma.

In some aspects of the present invention, the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above application are each in the form of a pharmaceutical composition, and can be administered simultaneously, sequentially or at intervals.

The present invention also provides a method for treating a subject suffering from cancer or tumor comprising administering to said subject a therapeutically effective amount of an ALK inhibitor and a therapeutically effective amount of an anti-EGFR antibody.

In some aspects of the present invention, the ALK inhibitor in the above treatment method is a spirocyclic aryl phosphorus oxide represented by formula I.

In some aspects of the invention, the anti-EGFR antibody in the above treatment method is panitumumab.

In some aspects of the present invention, the panitumumab in the above treatment method can be selected from Vectibix or its biosimilars.

In some aspects of the present invention, the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above treatment method are each in the form of a pharmaceutical composition.

In some aspects of the present invention, the lung cancer in the above treatment method is positive for EGFR sensitive mutation.

In some schemes of the present invention, the lung cancer mentioned in the above treatment method is early-middle stage, locally advanced, advanced metastatic non-small cell lung cancer.

In some schemes of the present invention, the lung cancer described in the above treatment method is early-middle stage, locally advanced, and advanced metastatic non-small cell lung cancer that is positive for EGFR sensitive mutations.

In some aspects of the present invention, the lung cancer in the above treatment method is non-small cell lung cancer that has not been treated with an EGFR inhibitor or failed to be treated with an EGFR inhibitor.

In some schemes of the present invention, the lung cancer mentioned in the above treatment method is non-small cell lung cancer with EGFR sensitive mutation positive, T790M mutation and C797S mutation that failed to be treated with irreversible EGFR inhibitors such as osimertinib.

In some aspects of the present invention, the lung cancer in the above treatment method is non-small cell lung cancer with Del19 mutation, T790M mutation and C797S mutation.

In some aspects of the present invention, the lung cancer in the above treatment method is non-small cell lung cancer with L858R mutation, T790M mutation and C797S mutation.

In some aspects of the present invention, the non-small cell lung cancer in the above treatment method is adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma or large cell carcinoma.

In some aspects of the present invention, the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof in the above treatment method are each in the form of a pharmaceutical composition, and can be administered simultaneously, sequentially or at intervals.

The present invention also provides a use of a compound of formula I or a pharmaceutically acceptable salt thereof for treating lung cancer, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is used in combination with an anti-EGFR antibody.

The present invention also provides a use of an anti-EGFR antibody for treating lung cancer. The anti-EGFR antibody is used in combination with the compound of formula I or a pharmaceutically acceptable salt thereof.

In some aspects, the anti-EGFR antibody used above is selected from panitumumab.

In some aspects of the present invention, the panitumumab used in the above use can be selected from Vectibix or its biosimilars.

The present invention also provides a pharmaceutical pack, which comprises a single-packaged pharmaceutical composition in an independent container, which comprises a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof in one container, and a pharmaceutical composition containing an anti-EGFR antibody in a second container.

Pharmaceutical compositions of compounds of formula I

Pharmaceutical compositions of compounds of formula I can be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like. Oral administration is preferred, eg as a tablet.

In some embodiments of the present invention, the dosage of the pharmaceutical composition of the compound of formula I is about 60 mg/time to 180 mg/time; or the dosage is about 90 mg/time to 180 mg/time.

In some embodiments of the present invention, according to once-a-day administration, the pharmaceutical composition of the compound of formula I is administered about 60 mg-180 mg; or about 90 mg-180 mg each time.

Compound of formula I

As used in the present invention, the compound of formula I is a spirocyclic aryl phosphorus oxide with a chemical name of (2-((5-chloro-2-((2-methoxy-4-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, which is a newly developed highly selective anaplastic lymphoma kinase (ALK) inhibitor, which has the following structural formula:

Panitumumab

As used in the present invention, panitumumab, trade name Vectibix, developed by Amgen Corporation of the United States, is the first fully humanized monoclonal antibody, which targets the epidermal growth factor receptor (EGFR), and was approved by the FDA at the end of 2005 for the treatment of metastatic colorectal cancer after chemotherapy failure.

QL1203 (recombinant anti-EGFR fully human monoclonal antibody injection), is a biosimilar to panitumumab.

The sequences and structures of the above-mentioned Vectibix and QL1203 are referred to the document WO98/50433, and their amino acid sequences are as follows:

Heavy chain:

Light chain:

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. when appearing in this article When using a trade name, it is intended to refer to the corresponding trade product or its active ingredient.

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

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

The term "antibody" refers to a binding protein having at least one antigen binding domain. Antibodies and fragments thereof of the present invention may be whole antibodies or any fragments thereof. Accordingly, 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 may 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 "humanized antibody" refers to an antibody 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 contain substitutions in the framework regions such that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.

The term "monoclonal antibody" ("mAb") refers to an antibody molecule of 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. A mAb is an example of an isolated antibody. mAbs can be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.

The term "anti-EGFR antibody" refers to an antibody that binds EGFR with sufficient affinity and specificity. The selected antibody typically has a binding affinity for EGFR, for example, the antibody can bind EGFR with a Kd value from 1 pM to 100 nM. For example, antibody affinity can be determined by surface plasmon resonance-based assays such as the BIAcore assay described in PCT Publication WO2005/012359; by enzyme-linked immunosorbent assays (ELISA); and competition assays such as RIA's. In certain embodiments, the anti-EGFR antibodies of the invention can be used as therapeutic agents in targeting and interfering with diseases or disorders in which EGFR activity is implicated. In addition, the antibodies can be tested for other biological activities, eg, to assess their efficacy as therapeutic agents. Such assays are known in the art and depend on the target antigen and the intended application of the antibody. Examples include HUVEC inhibition assays; tumor cell growth inhibition assays (eg, as described in WO89/06692); antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) assays (eg, patent US 5,500,362); and agonist activity or hematopoietic assays (see WO95/27062).

The term "treatment" generally refers to obtaining 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) preventing the disease or symptom in a patient susceptible to the disease or symptom but not yet diagnosed with the disease; (b) inhibiting the symptom of the disease, i.e. preventing its development; or (c) relieving the symptom of the disease, i.e. causing regression of the disease or symptom.

As used herein, the term "subject" refers to mammals, such as rodents, felines, canines, and primates. Preferably, the subject of the invention is a human.

As used herein, the term "administering" means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration for anti-EGFR antibodies include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. As used herein, "parenteral administration" 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, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the anti-EGFR antibody is administered non-parenterally, and in certain embodiments, orally. Other non-parenteral routes include topical, epidermal, or mucosal The route of administration is, for example, 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.

The term "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 in certain contexts herein.

A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug which, when used alone or in combination with another therapeutic agent, protects a subject from disease onset or promotes regression of disease as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or prevention of impairment or disability resulting from disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated 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 measuring the activity of the agent in in vitro assays.

A therapeutically effective amount of a drug includes a "prophylactically effective amount," which is any amount of drug that inhibits the onset or recurrence of cancer when administered alone or in combination with an antineoplastic 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. "Inhibiting" the occurrence or recurrence of cancer means reducing the likelihood of the occurrence or recurrence of cancer, or preventing the occurrence or recurrence of cancer altogether.

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

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

"Metastatic" cancer is cancer that has spread from one part of the body, such as the lungs, to another part of the body.

The term "fixed combination" means that the active ingredients (eg, anti-EGFR antibody or 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 components are administered to a subject simultaneously, concurrently or sequentially as independent entities (eg, pharmaceutical composition, preparation) without specific time limit, wherein the active components administered to the subject reach a therapeutically effective level. Examples of non-fixed combinations are cocktail therapy, eg 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 combined use of "fixed combinations" or independent entities of any one or more active components.

The term "combination" or "combined use" means that two or more active substances can be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially as a single formulation in any order.

The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present application (such as anti-EGFR antibody or compound of formula I) or its pharmaceutical combination and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of a compound of the present application, or a pharmaceutical combination thereof, to a subject.

The term "synergistic effect" refers to the simple addition of two or more ingredients (eg, anti-EGFR antibody or compound of formula I) that produce an effect (eg, inhibition of lung cancer growth) that is greater than the effect of the ingredients administered alone.

Application method

The following content does not limit the administration mode of the pharmaceutical combination of the present invention.

The components in the combined drug combination of the present invention can be formulated separately. In one embodiment, the components in the combination pharmaceutical composition of the present invention can be formulated into a pharmaceutical composition suitable for single or multiple administration.

The components in the combined pharmaceutical composition of the present invention can be administered alone, or part or all of them can be administered together. The components in the combined pharmaceutical composition of the present invention may be administered substantially differently, or part or all of them may be administered substantially simultaneously.

The components in the combined pharmaceutical composition of the present invention can be administered independently, or part or all of them together, in various suitable routes, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the combined pharmaceutical composition of the present invention can be administered independently, or part or all of them can be administered together orally or by injection, such as intravenous injection or intraperitoneal injection.

The components in the combined pharmaceutical composition of the present invention can be each independently, or some or all of them can be suitable dosage forms together, including, but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and dosage forms of sustained release preparations for oral or parenteral administration.

The components in the combined pharmaceutical composition of the present invention may be each independently, or part or all of them together contain pharmaceutically acceptable carriers and/or excipients.

The combination pharmaceutical compositions of the present invention may also contain 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 specific schemes of the present invention, the curative effect of the compound of formula I and anti-EGFR antibody alone or in combination on lung tumors was investigated. As a result of the experiment, it was surprisingly found that the compound of formula I had an obvious synergistic effect with the anti-EGFR antibody, breaking the established immune tolerance of the body to tumor cells.

Description of drawings

The drawings described here are used to provide a further understanding of the application and constitute a part of the application. The schematic embodiments and descriptions of the application are used to explain the application and do not constitute an improper limitation to the application.

Fig. 1 is the tumor growth curve of human lung cancer cell line H1975 EGFR (Del19/T790M/C797S) xenograft tumor model tumor-bearing mice after administration of test drug formula I compound, QL1203, Vectibix, formula I compound and QL1203 combination and formula I compound and Vectibix combination;

Fig. 2 is the relative tumor growth curve of the human lung cancer cell line H1975 EGFR (Del19/T790M/C797S) xenograft tumor model tumor-bearing mice given the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203 and the combination of the compound of formula I and Vectibix;

Fig. 3 is the tumor growth curve of the Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model tumor-bearing mice given the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203 and the combination of the compound of formula I and Vectibix;

Figure 4 is the relative tumor growth curve of the Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model tumor-bearing mice administered with the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203, and the combination of the compound of formula I and Vectibix.

Detailed ways

The present invention will be described in detail through examples below, but these examples are only for illustration and do not limit any scope of the present invention. Likewise, the invention is not limited to any specific preferred embodiments described herein. Those skilled in the art should understand that equivalent replacements or corresponding improvements to the technical features of the present invention still fall within the protection scope of the present invention.

Table 1-1. List of abbreviations

Example 1 In vivo drug on H1975 EGFR (Del19/T790M/C797S) subcutaneous xenograft tumor BALB/c nude mouse model effect

The purpose of this experiment is to evaluate the in vivo efficacy of small molecular formula I compound combined with panitumumab on H1975 EGFR (Del19/T790M/C797S) subcutaneous xenograft tumor BALB/c nude mouse model.

Experimental program

Table 1-2. Animal groups and dosing regimens for in vivo efficacy experiments

Note:
1.N: the number of mice in each group.
2. Administration volume: the compound of formula I was administered according to the body weight of the mice at 10 μL/g; the fixed volume of QL1203 and Vectibix was 200 μL/mouse. Vehicle is a mixed solution of 5% absolute ethanol and polyoxyethylene 40 hydrogenated castor oil (1:1) + 95% sterile water for injection.
3. Frequency of preparation of all medicines: ready-to-use.

Panitumumab

As used in this example, panitumumab, trade name Vectibix, was developed by Amgen Corporation of the United States.

QL1203 (recombinant anti-EGFR fully human monoclonal antibody injection), is a biosimilar to Vectibix.

The sequence and structure of the Vectibix and QL1203 refer to the document WO98/50433, and their amino acid sequences are as follows:

Heavy chain:

Light chain:

Experimental sample

①Name: compound of formula I

Structural formula:

Provider: Qilu Pharmaceutical Co., Ltd.

Batch number: T9001L51N

Purity: 99.6%

Molecular weight: 569.08

Property description: off-white powder

Storage conditions: Store at room temperature and avoid light

②Name: QL1203

Provider: Qilu Pharmaceutical Co., Ltd.

Batch number: 201905001KJB

Concentration: 20mg/mL

Description of properties: colorless transparent liquid

Storage conditions: 4°C protected from light

③Name: Vectibix

Provider: Qilu Pharmaceutical Co., Ltd.

Batch number: 1100612

Concentration: 20mg/mL

Description of properties: colorless transparent liquid

Storage conditions: 4°C protected from light

Experimental method and steps

cell culture

The cell line H1975 EGFR (Del19/T790M/C797S) was cultured in vitro, and the culture conditions were RPMI1640 medium plus 10% fetal bovine serum, 1% double antibody (penicillin/streptomycin solution), 10 μg/ml blasticidin, and cultured at 37°C in 5% CO ₂ . Subculture by routine centrifugation twice a week. When the confluence of the cells is 80%-90% and the number reaches the requirement, the cells are collected, counted and inoculated.

tumor cell inoculation

PBS containing 5× ¹⁰⁶ H1975 EGFR (Del19/T790M/C797S) cells was mixed with Matrigel at a ratio of 1:1 (final volume: 100 μL) and inoculated subcutaneously in the axilla of the right forelimb of each mouse, and grouped administration began when the average tumor volume of the animals reached ^185mm3 . See Table 1-2 for experimental groups and dosing regimens.

Preparation of test substance

Table 1-3. Test substance preparation method


Note: The drug needs to be mixed gently before administration.

Daily observation of laboratory animals

The health status and death of the animals were monitored every day. Routine inspections included observing the effects of tumor growth and drug treatment on the daily behavior of the animals, such as behavioral activities, food and water intake (visual inspection only), changes in body weight (body weight was measured once a day), appearance signs or other abnormal conditions. Animal deaths and side effects within groups were recorded based on the number of animals in each group.

Tumor Measurements and Experimental Indicators

The experimental index is to investigate whether tumor growth is inhibited, delayed or cured. Tumor diameters were measured with vernier calipers three times a week. The formula for calculating the tumor volume is: V=0.5a×b ² , where a and b represent the long diameter and short diameter of the tumor, respectively.

The antitumor efficacy of compounds was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects tumor growth inhibition rate. Calculation of TGI(%):

TGI (%)=【(1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group))/(Average tumor volume at the end of treatment of the vehicle control group-Average tumor volume at the beginning of treatment of the vehicle control group)]×100%.

Relative tumor proliferation rate T/C (%): the calculation formula is as follows:

T/C%=TRTV/CRTV×100% (TRTV: RTV of treatment group; CRTV: RTV of negative control group).

The relative tumor volume (RTV) was calculated according to the results of tumor measurement, and the calculation formula was RTV=Vt/V0, where V0 was the average tumor volume measured during group administration (i.e. d0), Vt was the average tumor volume during a certain measurement, and TRTV and CRTV took the data on the same day.

Statistical Analysis

Statistical analysis, including mean and standard error (SEM) of tumor volume at each time point of each group (see Tables 1-5 for specific data). Since each treatment group showed a better therapeutic effect 21 days after administration, statistical analysis was performed based on this data to evaluate the differences between the groups. The comparison between the two groups was analyzed by T-test. All data analyzes were performed with SPSS 17.0. p<0.05 considered significant difference.

Sample Collection

On day 21 after the start of dosing, plasma collection was performed according to Tables 1-4, and all plasma was analyzed.

Table 1-4. Plasma Collection Form


Note: a.pre-dose is before the last administration.

Experimental results

Mortality, morbidity, and weight change

The body weight of experimental animals was used as a reference index for indirect determination of drug toxicity. During the experiment, the vehicle group, the compound of formula I 25mg/kg and 75mg/kg group, the QL1203 0.1mg/group, the Vectibix 0.1mg/group, the compound of formula I 25mg/kg+QL1203 0.1mg/combination group and the compound of formula I 25mg/kg+Vectibix 0.1mg/combination group, the animal body weight remained stable, and the compound of formula I 75mg/kg+Vectibix 0.1 mg/mouse and the compound of formula I 75mg/kg+QL1203 0.1mg/mouse combined group, the body weight of individual mice decreased in the later stage of administration. All mice had no disease and death.

tumor volume

H1975 EGFR (Del19/T790M/C797S) xenograft tumor female BALB/c nude mouse model The changes in tumor volume in each group given the compound of formula I are shown in Table 1-5.

Table 1-5. Tumor volume of each group at different time points

Note:
a. Mean ± SEM,
b. Days after administration.

tumor growth curve

The H1975 EGFR (Del19/T790M/C797S) xenograft tumor female BALB/c nude mouse model was administered with the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203, and the combination of compound of formula I and Vectibix. The tumor growth curves and relative tumor growth curves of each group are shown in Figure 1 and Figure 2.

Anti-tumor drug efficacy evaluation index

Table 1-6. Antitumor efficacy evaluation of human lung cancer cell line H1975 EGFR (Del19/T790M/C797S) xenograft tumor model (calculated based on the tumor volume on day 21 after administration)

Note:
a. Mean ± SEM;
b. Tumor growth inhibition is calculated by T/C and TGI (TGI (%)=[1-(T ₂₁ -T ₀ )/(V ₂₁ -V ₀ )]×100);
The cp value was calculated based on the relative tumor volume, and the Vehicle group was used as the control, and the T-test was used for analysis and comparison between the two groups;
The dp value is calculated according to the relative tumor volume, with the compound of formula I 25mg/kg group as the control, and the compound of formula I 25mg/kg+QL1203 0.1mg/only or the compound of formula I 25mg/kg+Vectibix 0.1mg/group for analysis and comparison between the two groups by T-test;
The ep value is calculated based on the relative tumor volume, with the compound of formula I 75 mg/kg group as the control, and the compound of formula I 75 mg/kg+QL1203 0.1 mg/only or the compound of formula I 75 mg/kg+Vectibix 0.1 mg/ group between the two groups using T-test for analysis and comparison between the two groups;
The fp value is calculated based on the relative tumor volume, with the QL1203 0.1mg/only group as the control, and the formula I compound 25mg/kg+QL1203 0.1mg/only or the formula I compound 75
The mg/kg+QL1203 0.1mg/only group was analyzed and compared by T-test between the two groups;
The gp value is calculated based on the relative tumor volume, with the Vectibix 0.1mg/only group as the control, and the formula I compound 25mg/kg+Vectibix 0.1mg/only or the formula I compound 75
The mg/kg+Vectibix 0.1mg/only group was analyzed and compared by T-test between the two groups;
The hp value is calculated according to the relative tumor volume, with the compound of formula I 25mg/kg+QL1203 0.1mg/group as the control group, and the compound of formula I 75mg/kg+QL1203 0.1
mg/only or formula I compound 25mg/kg+Vectibix 0.1mg/only group was analyzed and compared by T-test between the two groups;
The ip value is calculated based on the relative tumor volume, with the compound of formula I 75mg/kg+Vectibix 0.1mg/ group as the control, and the compound of formula I 25mg/kg+Vectibix 0.1
The analysis and comparison between the two groups were performed by T-test in the group of mg/bird or compound of formula I 75mg/kg+QL1203 0.1mg/bird.

Experimental results

In this experiment, we evaluated the in vivo efficacy of the test compound of formula I, QL1203, Vectibix, the combination of compound of formula I and QL1203 and the combination of compound of formula I and Vectibix in human lung cancer cell line H1975 EGFR (Del19/T790M/C797S) xenograft tumor model. The tumor volumes of each group at different time points are shown in Tables 1-5, 1-6 and Figures 1 and 2.

Twenty-one days after administration, the tumor volume of the tumor-bearing mice in the vehicle control group reached 1,683 mm ³ . Compared with the vehicle control group, QL120 30.1mg/mouse, Vectibix 0.1mg/mouse and Formula I compound 25mg/kg in the single-drug group did not have significant tumor inhibitory effects, and the tumor volumes were 1,955mm ³ (T/C=115.36%, TGI=-18.1%, p=0.487), 2,202mm ³ (T/C=130.78%, TGI= -34.6%, p=0.211) and 1,639 mm ³ (T/C=97.37%, TGI=2.9%, p=0.930). Combination of 25 mg/kg ^of compound of formula I and 0.1 mg of ^QL1203 or 25 mg/kg of compound of formula I and 0.1 mg of Vectibix can delay tumor growth. .7%, p=0.256).

In the combined administration group, the antitumor effects of the compound of formula I 75mg/kg+QL1203 0.1mg/body and the compound of formula I 75mg/kg+Vectibix 0.1mg/body were significantly better than those of the QL1203 0.1mg/one group (p=0.001), Vectibix 0.1mg/one group (p=0.004) and the compound of formula I 25mg/kg+QL1203 0.1mg/only (p=2.13E-4) or formula I compound 25mg/kg+Vectibix 0.1mg/low dose combined administration group (p=0.003) is also significantly better than formula I compound 75mg/kg single use group (p=2.76E-4 and p=1.32E-5).

There was no significant difference in the anti-tumor effect between QL1203 0.1mg/mouse and Vectibix 0.1mg/mouse single-use groups, or between QL1203+ formula I compound and Vectibix+ formula I compound combination groups (p>0.05).

To sum up, the compound of formula I 25 mg/kg, QL1203 0.1 mg/body and Vectibix 0.1 mg/body alone had no obvious tumor inhibitory effect, the compound of formula I at a dose of 25 mg/kg combined with QL1203 or Vectibix had a certain delay effect on tumor growth; the compound of formula I combined with QL1203 or Vectibix at a dose of 75 mg/kg had a significantly enhanced tumor inhibitory effect. This shows that the combination of the compound of formula I and QL1203 or Vectibix has a synergistic effect.

Example 2 In vivo efficacy of Baf3 EGFR (L858R/T790M/C797S) subcutaneous xenograft tumor BALB/c nude mouse model

The purpose of this experiment is to evaluate the in vivo efficacy of small molecular formula I compound combined with panitumumab on Baf3 EGFR (L858R/T790M/C797S) subcutaneous xenograft tumor BALB/c nude mouse model.

Experimental program

Table 2-1. Animal groups and dosing regimens for in vivo efficacy experiments

Note:
aN: number of mice in each group;
b. If the body weight drops by more than 15%, the mice will be treated with drug withdrawal and observed until their body weight returns to more than 10% before continuing to administer the drug;
c. The vehicle is a mixed solution of 5% absolute ethanol and polyoxyethylene 40 hydrogenated castor oil (1:1) + 95% sterile water for injection.

Experimental sample

The sample supply of the compound of formula I, QL1203 and Vectibix is the same as in Example 1.

Experimental method and steps

cell culture

The cell line Baf3 EGFR (L858R/T790M/C797S) was cultured in vitro, and the culture conditions were RPMI1640 medium plus 10% fetal bovine serum, 1% double antibody (penicillin/streptomycin solution), 37 ° C, 5% CO ₂ culture. Subculture by routine centrifugation twice a week. When the confluence of the cells is 80%-90% and the number reaches the requirement, the cells are collected, counted and inoculated.

tumor cell inoculation

PBS containing 5×10 ⁵ Baf3 EGFR (L858R/T790M/C797S) cells was mixed with Matrigel at a ratio of 1:1 (final volume 100 μL) and inoculated subcutaneously in the right forelimb armpit of each mouse. On the 10th day after cell inoculation, the average tumor volume of the enrolled animals reached 105 mm ^{3 and} began to be administered into groups. See Table 2-1 for experimental groups and dosing regimens.

Preparation of test substance

Table 2-2. Test substance preparation method

Note: The drug is prepared and used now, and the drug needs to be mixed gently before administration.

Daily observation of laboratory animals

The health status and death of the animals were monitored every day. Routine inspections included observing the effects of tumor growth and drug treatment on the daily behavior of the animals, such as behavioral activities, food and water intake (visual inspection only), changes in body weight (body weight was measured once a day), appearance signs or other abnormal conditions. Animal deaths and side effects within groups were recorded based on the number of animals in each group.

Tumor Measurements and Experimental Indicators

The experimental index is to investigate whether tumor growth is inhibited, delayed or cured. Tumor diameters were measured with vernier calipers three times a week. The formula for calculating the tumor volume is: V=0.5a×b ² , where a and b represent the long diameter and short diameter of the tumor, respectively.

The antitumor efficacy of compounds was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects tumor growth inhibition rate. Calculation of TGI (%): TGI (%)=[1-(average tumor volume at the end of administration of a treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment of the vehicle control group-average tumor volume at the beginning of treatment of the vehicle control group)]×100%.

Relative tumor proliferation rate T/C (%): the calculation formula is as follows: T/C%=TRTV/CRTV×100% (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). The relative tumor volume (RTV) was calculated according to the results of tumor measurement, and the calculation formula was RTV=Vt/V0, where V0 was the average tumor volume measured during group administration (i.e. d0), Vt was the average tumor volume during a certain measurement, and TRTV and CRTV took the data on the same day.

Statistical Analysis

Statistical analysis, including mean and standard error (SEM) of tumor volume at each time point of each group (see Table 2-3 for specific data). Since the mice in each group survived on the 10th day and each treatment group showed a better therapeutic effect, the experiment ended on the 14th day, so statistical analysis was performed based on the data on the 10th day and the 14th day to evaluate the differences between the groups. The comparison between the two groups was analyzed by T-test, and SPSS 17.0 was used for all data analysis. p<0.05 considered significant difference.

Experimental results

Mortality, morbidity, and weight change

In this model, the body weight of the animals in the vehicle group, QL1203 0.1mg/group and Vectibix 0.1mg/group remained stable, and some animals in the formula I compound 75mg/kg single drug group, the formula I compound 75mg/kg+QL1203 0.1mg/group and the formula I compound 75mg/kg+Vectibix 0.1mg/group group showed weight loss, but no animal became ill or died.

tumor volume

Baf3 EGFR (L858R/T790M/C797S) xenograft tumor female BALB/c nude mouse model was administered with the compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203, and the combination of compound of formula I and Vectibix. The changes in tumor volume in each group are shown in Table 2-3.

Table 2-3. Tumor volume of each group at different time points

Note: a. Mean ± SEM; b. Days after administration.

tumor growth curve

Baf3 EGFR (L858R/T790M/C797S) xenograft tumor female BALB/c nude mouse model was given the compound of formula I, QL1203, Vectibix, the combination of compound of formula I and QL1203 and the combination of compound of formula I and Vectibix. The tumor growth curves and relative tumor growth curves of each group are shown in Figure 3 and Figure 4.

Anti-tumor drug efficacy evaluation index

Table 2-4. Evaluation of antitumor efficacy of Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model (calculated based on the tumor volume on day 10 after administration)

Note:
a. Mean ± SEM;
b. For the specific calculation of tumor growth inhibition T/C and TGI, please refer to the statistical analysis section;
The cp value was analyzed by T-test according to the relative tumor volume of each mouse in different groups and the vehicle group as the control;
The dp value is analyzed using T-test according to the relative tumor volume of each mouse in different groups with formula I compound 75mg/kg group as a control;
The ep value was analyzed by T-test according to the relative tumor volume of each mouse in different groups, and the QL1203 0.1mg/mouse group was used as the control;
The fp value was analyzed by T-test according to the relative tumor volume of each mouse in different groups, and the compound of formula I 75mg/kg+Vectibix 0.1mg/group was used as the control group.

Table 2-5. Evaluation of antitumor efficacy of Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model (calculated based on the tumor volume on the 14th day after administration)

Note:
a. Mean ± SEM;
The bp value is analyzed by T-test according to the relative tumor volume of each mouse in different groups with the formula I compound 75mg/kg group as a control;
The cp value was analyzed by T-test according to the relative tumor volume of each mouse in different groups, and the QL1203 0.1 mg/mouse group was used as the control;
The dp value is analyzed by T-test according to the relative tumor volume of each mouse in different groups with formula I compound 75mg/kg+Vectibix 0.1mg/ group as a control;
e. At the end of the experiment, if the tumor volume is greater than 0 and less than the initial tumor volume, it is regarded as partial regression;
f. At the end of the experiment, a tumor volume of 0 is considered as complete regression.

Experimental Results and Discussion

Mortality, morbidity, and weight change

In this model, the body weight of the animals in the vehicle group, vehicle group, QL1203 single-drug group, and Vectibix single-drug group remained stable. Some animals in the formula I compound single use group, the formula I compound 75mg/kg+QL1203 0.1mg/only combination group, and the formula I compound 75mg/kg+Vectibix 0.1mg/only combination group had a certain degree of weight loss, but no animal became ill or died.

In this experiment, we evaluated the in vivo efficacy of the test drug compound of formula I, QL1203, Vectibix, the combination of the compound of formula I and QL1203 and the combination of the compound of formula I and Vectibix in the mouse original B cell Baf3 EGFR (L858R/T790M/C797S) xenograft tumor model. The tumor volume changes of each group at different time points are shown in Table 2-3, Table 2-4, Table 2-5 and Figure 3 and Figure 4.

On the 10th day after the start of administration, the tumor volume of the tumor-bearing mice in the vehicle control group reached 449 mm ³ .与溶媒对照组相比，受试药物式I化合物单药组、QL1203单药组、Vectibix单药组及式I化合物与QL1203或Vectibix联合组均具有显著的抗肿瘤作用，肿瘤体积分别为289mm ³ (T/C＝64.26％,TGI＝46.55％,p＝0.012)、123mm ³ (T/C＝27.27％,TGI＝95.01％,p＝0.015)、98mm ³ (T/C＝21.84％,TGI＝102.12％,p＝0.010)、58mm ³ (T/C＝12.86％,TGI＝113.86％,p＝0.008)和56mm ³ (T/C＝12.54％,TGI＝114.24％,p＝0.008)。 There was no significant difference in the antitumor effect between the QL1203 and Vectibix single drug group, or between the compound of formula I+QL1203 and the compound of formula I+Vectibix combination group (p>0.05). Moreover, the combination group of the compound of formula I and QL1203 or the combination group of the compound of formula I and Vectibix has significantly better antitumor effect than that of the compound of formula I, QL1203 or Vectibix alone (p<0.05).

给药后第14天，实验终点，式I化合物单药组、QL1203单药组、Vectibix单药组、式I化合物+QL1203联合给药组及式I化合物+Vectibix联合给药组的肿瘤体积分别为483mm ³ ，225mm ³ ，171mm ³ ，51mm ³和58mm ³ ，各组分别有0/8(0％)，0/8(0％)，2/8(25％)，6/8(75％)，5/8(62.5％)只动物肿瘤达到部分消退，分别有0/8(0％)，0/8(0％)，0/8(0％)，1/8(12.5％)，2/8(25％)只动物肿瘤达到完全消退。 It can be seen that the combined use of the compound of formula I and QL1203 or Vectibix has better antitumor effect than that of the compound of formula I, QL1203 or Vectibix alone.

general conclusion

After the compound of formula I of the present invention is used in combination with panitumumab, the antitumor effect is significantly enhanced, and has an obvious synergistic effect.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (10)

1. A combined pharmaceutical composition comprising an anti-EGFR antibody and a compound represented by formula I or a pharmaceutically acceptable salt thereof
2. The combined pharmaceutical composition according to claim 1, wherein the anti-EGFR antibody is panitumumab.
3. According to the combined pharmaceutical composition of claim 1 or 2, the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition.
4. Application of the combination pharmaceutical composition described in any one of claims 1-3 in the preparation of drugs for treating and/or preventing lung cancer.
5. The use according to claim 4, wherein the lung cancer is positive for sensitive mutation of EGFR.
6. The use according to any one of claims 4-5, wherein the lung cancer is early-middle stage, locally advanced, advanced metastatic non-small cell lung cancer.
7. The application according to any one of claims 4-6, wherein the lung cancer is early-middle stage, locally advanced, and advanced metastatic non-small cell lung cancer that is positive for EGFR sensitive mutations.
8. The use according to any one of claims 4-7, wherein the lung cancer is non-small cell lung cancer that has not been treated with an EGFR inhibitor or failed to be treated with an EGFR inhibitor.
9. The use according to any one of claims 6-8, wherein the non-small cell lung cancer is adenocarcinoma, squamous cell carcinoma, adenosquamous cell carcinoma or large cell carcinoma.
10. The use according to any one of claims 4-9, wherein the anti-EGFR antibody and the compound of formula I or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or at intervals.