Combination of antibody-drug conjugate and tyrosine kinase inhibitor

Abstract

Provided is a drug for combination therapy of a tumor, comprising an antibody-drug conjugate and osimertinib. Also provided is a method for treating a tumor, comprising administering to a patient or subject in need of treatment a therapeutically effective amount of an antibody-drug conjugate and osimertinib. Also provided is use of an antibody-drug conjugate in the preparation of a drug used in combination with osimertinib to treat a tumor.

Description

Combination of an antibody drug conjugate and a tyrosine kinase inhibitor TECHNICAL FIELD

[0001] The present application belongs to the field of biological medicine, and particularly relates to a combination of an antibody drug conjugate and a tyrosine kinase inhibitor. BACKGROUND

[0002] Lung cancer is the highest incidence and mortality of malignant tumor in China and worldwide, most of the patients are in later stage when diagnosed, the 5-year survival rate is low, the disease burden is heavy, and seriously threatens the health of the people. Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer according to histological characteristics. Among them, NSCLC accounts for about 85% of the total number of lung cancer. A variety of gene mutations and expression abnormalities have been confirmed to be associated with the pathogenesis of NSCLC, and epidermal growth factor receptor (EGFR) is one of the main driver genes.

[0003] EGFR is a transmembrane glycoprotein composed of 1186 amino acids, 170-kDa. It is composed of three parts: extracellular receptor region, transmembrane region and intracellular tyrosine kinase region. The ligands that can bind to EGFR have been confirmed: epidermal growth factor (EGF), transforming growth factor a (TGFa), bidirectional regulator, heparin-binding EGF, cell regulator, etc. In human tissues, EGF and TGFa are considered to be the two most important ligands of EGFR.

[0004] EGFR is a constitutive expression component of many normal epithelial tissues, such as skin and hair follicles. In addition, EGFR is highly expressed in a variety of human malignant tumor tissues, for example, 40% to 80% in lung cancer, 14% to 91% in breast cancer, 33% to 74% in gastric cancer, 25 to 77% in colon cancer, 30% to 50% in pancreatic cancer, 40% to 80% in prostate cancer, 50% to 90% in renal cancer, 35% to 70% in ovarian cancer, 36% to 100% in head and neck cancer. EGFR is highly expressed. Overexpression and / or mutation of EGFR in most tumors is associated with poor prognosis. In vitro studies and experimental animal model studies have shown that activation of EGFR is involved in regulating several important cell functions in cell transformation and tumor cell progression: proliferation / differentiation, survival, induction of angiogenesis, ability to form metastasis, resistance to chemotherapy and radiotherapy. Therefore, EGFR has become a hotspot for the development of anti-tumor drugs.

[0005] Tyrosine Kinase Inhibitors (TKIs) are a class of important anti-tumor drugs that block the proliferation and growth of tumor cells by inhibiting the activity of tyrosine kinases. These inhibitors can act as competitive inhibitors of adenosine triphosphate (ATP) binding to tyrosine kinases, or as analogs of tyrosine, thereby inhibiting the activity of tyrosine kinases.

[0006] The relationship between the efficacy of precise targeted therapy and molecular typing of EGFR-mutant positive advanced NSCLC has been fully confirmed in clinical practice. EGFR-TKIs have become the first-line standard treatment for EGFR-mutant positive advanced NSCLC, including gefitinib, erlotinib, icotinib, dacomitinib, afatinib or osimertinib. Other alternative treatment options include EGFR-TKI combined with chemotherapy or anti-angiogenic therapy. Osimertinib is the third-generation EGFR-TKI and is the preferred recommended drug for first-line treatment of EGFR-mutant positive advanced NSCLC in the NCCN guidelines. The drug has been approved in China: 1) for locally advanced or metastatic NSCLC adult patients who have previously been treated with EGFR-TKI or have developed disease progression after treatment, and have been confirmed to have EGFR T790M mutation; 2) for first-line treatment of NSCLC patients with ex19del or L858R point mutations; 3) for adjuvant therapy after tumor resection in EGFR-sensitivity mutation NSCLC adult patients. Although osimertinib solves the resistance of first and second generation TKIs caused by T790M mutation, drug resistance still cannot be avoided.

[0007] Antibody Drug Conjugate (ADC) targeting EGFR has become a hot spot in drug research to overcome EGFR-TKI resistance. ADC is coupled by specific monoclonal antibodies against tumor molecules and cytotoxic payloads. After the monoclonal antibody binds to its own target, the drug is internalized, the linker is degraded to release the cytotoxic payload, thereby producing an anti-tumor effect. The currently marketed EGFR-ADC product is Akalux (cetuximab sarotalocan) from Lianxing Medical, which was acceleratedly approved in Japan on September 25, 2020 for the treatment of unresectable locally advanced or recurrent head and neck cancer, becoming the first light immunotherapy drug approved globally. The domestic progress is faster, and Meiya Ke's MRG003 has entered the phase II clinical trial stage.

[0008] CN202211461614.0 discloses an antibody drug conjugate targeting EGFR:

[0009] wherein Ab is an antibody targeting EGFR. In vitro studies show that the ADC has a good inhibitory effect on a variety of tumor cells.

[0010] However, the prior art does not describe the combination of the antibody drug and the tyrosine kinase inhibitor, and whether the combination of the antibody drug and the tyrosine kinase inhibitor can provide more effective treatment for tumors needs further study.

[0011] SUMMARY

[0012] The present application provides a drug for treating tumors in combination, which comprises an antibody drug shown in formula (I) and Osimertinib (AZD9291). A method for treating tumors is also provided, which comprises administering a therapeutically effective amount of the antibody drug shown in formula (I) and Osimertinib to a patient or subject in need of treatment. The use of the antibody drug shown in formula (I) in the preparation of a drug for treating tumors in combination with Osimertinib is also provided. The present application combines the administration of the antibody drug shown in formula (I) and Osimertinib, which can further enhance the effect of the drug in treating tumors, exhibit synergistic effect, and is safe and tolerable, thereby providing a new way for more effective treatment of tumors.

[0013] The antibody drug shown in formula (I) described in the present application has the following structure:

[0014] wherein Ab is an antibody or antigen binding fragment thereof targeting EGFR, n is selected from an integer of 1-8 or a decimal number of 1-8, preferably an integer of 4-8 or a decimal number of 4-8, further preferably 1, 2, 3, 4, 5, 6, 7, 8, and more preferably 8.

[0015] Further, the antibody or antigen binding fragment thereof targeting EGFR comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2), and a heavy chain complementarity determining region 3 (HCDR3), and the light chain variable region comprises a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2), and a light chain complementarity determining region 3 (LCDR3), wherein the amino acid sequence of HCDR1 is shown in SEQ ID NO: 1, the amino acid sequence of HCDR2 is shown in SEQ ID NO: 2, the amino acid sequence of HCDR3 is shown in SEQ ID NO: 3, and / or the amino acid sequence of LCDR1 is shown in SEQ ID NO: 4, the amino acid sequence of LCDR2 is shown in SEQ ID NO: 5, and the amino acid sequence of LCDR3 is shown in SEQ ID NO: 6.

[0016] In some embodiments, when the Ab is an antibody or antigen-binding fragment thereof targeting EGFR, it comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises an amino acid sequence that is at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO. 7 or is the amino acid sequence set forth in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence that is at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO. 8 or is the amino acid sequence set forth in SEQ ID NO. 8.

[0017] In some embodiments, when the Ab is an antibody or antigen-binding fragment thereof targeting EGFR, it comprises a heavy chain (HC) and a light chain (LC), wherein the heavy chain comprises an amino acid sequence that is at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO. 9 or is the amino acid sequence set forth in SEQ ID NO. 9; and the light chain comprises an amino acid sequence that is at least about 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO. 10 or is the amino acid sequence set forth in SEQ ID NO. 10.

[0018] Further, the antibody conjugate drug represented by formula (I) is ADC-1

[0019] wherein SWY2110 is an antibody having two heavy chains with the amino acid sequence set forth in SEQ ID NO: 9 and two light chains with the amino acid sequence set forth in SEQ ID NO: 10.

[0020] In the present application, the amino acid sequences of the CDRs of the antibody are determined according to the Kabat numbering rule.

[0021] In one aspect, the present application provides a medicament for treating tumors in combination, comprising an antibody conjugate drug represented by formula (I) and osimertinib.

[0022] In another aspect, the present application provides the use of an antibody conjugate drug represented by formula (I) and osimertinib in combination in the preparation of a medicament for treating tumors.

[0023] In a third aspect, the present application provides a method for treating tumors, comprising administering to a patient or subject in need of treatment a therapeutically effective amount of an antibody conjugate drug represented by formula (I) and osimertinib.

[0024] In a fourth aspect, the present application provides use of the antibody-drug conjugate of formula (I) in the manufacture of a medicament for treating a tumor in combination with osimertinib.

[0025] In a fifth aspect, the present application provides the medicament for treating a tumor as described above for use in treating a tumor.

[0026] In some embodiments, the antibody-drug conjugate of formula (I) and osimertinib can be contained in one clinical acceptable pharmaceutical preparation (single preparation) simultaneously, or can be prepared into clinical acceptable dosage forms respectively and packaged into the medicament in combination. That is, the medicament described in the present application not only includes a compound pharmaceutical preparation (single preparation), but also includes a combination package or kit product. The compound pharmaceutical preparation contains the antibody-drug conjugate of formula (I) and osimertinib in one preparation unit and is prepared into a clinical acceptable dosage form. In the combination package or kit product, the antibody-drug conjugate of formula (I) and osimertinib are prepared into clinical acceptable pharmaceutical preparations respectively, that is, the antibody-drug conjugate of formula (I) and osimertinib are contained in different preparation units and presented in the form of combination packaging; the preparation forms of the antibody-drug conjugate of formula (I) and osimertinib can be the same or different.

[0027] In some embodiments, the antibody-drug conjugate of formula (I) and osimertinib are prepared into clinical acceptable dosage forms respectively and packaged into the medicament in combination. Preferably, the antibody-drug conjugate of formula (I) is a lyophilized powder or an injection solution, and the osimertinib is a solid oral preparation (such as a tablet or a capsule) or an injection solution.

[0028] In some embodiments, the antibody-drug conjugate of formula (I) and osimertinib can be administered simultaneously or separately. That is, the antibody-drug conjugate of formula (I) and osimertinib can be contained in the same compound preparation unit and administered simultaneously. Alternatively, the antibody-drug conjugate of formula (I) and osimertinib are contained in different preparation units and administered simultaneously or in parallel, or administered sequentially at different times within one day at a clinically acceptable time interval, or administered according to the respective dosing frequencies and cycles of the antibody-drug conjugate of formula (I) and osimertinib at a clinically acceptable time interval. The antibody-drug conjugate of formula (I) and osimertinib have no special restrictions on the order of administration and can be used as the first treatment or the second treatment according to clinical needs. The simultaneous administration or parallel administration means that the first treatment and the second treatment start at the same time, or when the delivery of the second treatment starts, the delivery of the first treatment is still in progress.

[0029] In some embodiments, the antibody drug conjugate of formula (I) and osimertinib are administered each at their respective frequency and cycle of administration, if administered on the same day, preferably, orally administering osimertinib first, followed by injection of the antibody drug conjugate of formula (I).

[0030] In some embodiments, the ratio of the amount of the antibody drug conjugate of formula (I) and osimertinib per cycle is selected from the group consisting of (1-100):(1-100), such as (1-50):(1-50), (1-10):(1-10), (5-15):(1-5), 1:(5-15), 1:15, 1:10, 1:8, 1:4, 1:2 and 3:10.

[0031] In some embodiments, the drug of the present application is a combination pack or kit product, wherein the mass ratio of the antibody drug conjugate of formula (I) and osimertinib is selected from the group consisting of (1-100):(1-100), such as (1-50):(1-50), (1-10):(1-10), (5-15):(1-5), 1:(5-15), 1:15, 1:10, 1:8, 1:4, 1:2 and 3:10.

[0032] In some embodiments, the therapeutically effective amount of the antibody drug conjugate of Formula (I) (in mg of antibody drug conjugate of Formula I per kg of patient body weight) is 1 mg / kg to 15 mg / kg, such as about 1.5 mg / kg, about 1.8 mg / kg, about 2.0 mg / kg, about 2.2 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.8 mg / kg, about 3 mg / kg, about 3.2 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.8 mg / kg, about 4.0 mg / kg, about 4.2 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.8 mg / kg, about 5.0 mg / kg, about 5.2 mg / kg, about 5.4 mg / kg, about 5.5 mg / kg, about 5.6 mg / kg, about 5.8 mg / kg, about 6.0 mg / kg, about 6.2 mg / kg, about 6.4 mg / kg, about 6.6 mg / kg, about 6.8 mg / kg, about 7.0 mg / kg, about 7.2 mg / kg, about 7.5 mg / kg, about 7.8 mg / kg, about 8.0 mg / kg, about 8.2 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.8 mg / kg, about 9.0 mg / kg, about 9.5 mg / kg, about 10.0 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 11.5 mg / kg, about 12.0 mg / kg, about 13 mg / kg, about 14 mg / kg.

[0033] In some embodiments, the therapeutically effective amount of osimertinib is a conventional amount of osimertinib.

[0034] In some embodiments, the therapeutically effective amount of osimertinib is 20 mg to 200 mg, such as about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 90 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, about 190 mg / day. Preferably about 40 mg / day, about 80 mg / day.

[0035] In some embodiments, the antibody drug conjugate of Formula (I) and / or osimertinib can be administered once a day (QD), and the above-mentioned therapeutically effective amount can be administered as a total daily dose in multiple doses within a day, for example, in two doses a day (BID) or three doses a day (TID). It can be administered once a week (QW), and the above-mentioned therapeutically effective amount can be administered as a total weekly dose in multiple doses within a week, for example, in two doses a week (BIW) or three doses a week (TIW). It can be administered once every two weeks (Q2W), and the above-mentioned therapeutically effective amount can be administered as a total weekly dose in multiple doses within two weeks, for example, in two doses every two weeks (BI2W) or three doses every two weeks (TI2W). It can be administered once every three weeks (Q3W), and the above-mentioned therapeutically effective amount can be administered as a total dose in multiple doses within three weeks, for example, in two doses every three weeks (BI3W, such as D1, D8 administration, one cycle every three weeks) or three doses every three weeks (TI3W). It can be administered once a month (QM), and the above-mentioned therapeutically effective amount can be administered as a total dose in multiple doses within a month, for example, in two doses a month (BI2M) or three doses a month (TIM). It can also be administered at intervals, such as once every 2-7 days, or once every 3 days, or once every 4 days, or once every 5 days, or once every 6 days, or once every 2-4 weeks, such as once every 2 weeks (once every 3 weeks, one cycle every 3 weeks), once every 1 week (once every 2 weeks, one cycle every 2 weeks or one cycle every 4 weeks), and once every 3 weeks (once every 4 weeks, one cycle every 4 weeks), or once every 1-3 months, such as once every month (once every 2 months); or continuous administration for 3 weeks, 1 week off, one cycle every 4 weeks, or continuous administration for 2 weeks, 1 week off, one cycle every 3 weeks, or continuous administration for 2 weeks, 2 weeks off, one cycle every 4 weeks, or once every 1 week (once every 2 weeks), one cycle every 4 weeks. An exemplary administration method includes 1 cycle every 3 weeks, and administration once a day on the first day of each cycle.

[0036] In some embodiments, the antibody drug conjugate of Formula (I) can be administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W).

[0037] In some embodiments, the osimertinib can be administered once a day (QD), and the above-mentioned therapeutically effective amount can be administered as a total daily dose in multiple doses within a day, for example, in two doses a day (BID) or three doses a day (TID).

[0038] In some embodiments, the antibody drug conjugate of Formula (I) can be administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W).

[0039] In some embodiments, the dosage regimen is preferably a therapeutically effective amount of the antibody conjugate drug of Formula (I) is: 1.8-4.5 mg / kg (such as about 1.8 mg / kg, about 3.2 mg / kg, about 3.6 mg / kg, about 4.2 mg / kg or about 4.5 mg / kg); once every 3 weeks (Q3W) or once every 2 weeks (Q2W); in combination with a therapeutically effective amount of osimertinib is: 20-200 mg / day (such as about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day, about 120 mg / day); once a day (QD).

[0040] In some embodiments, the antibody conjugate drug of Formula (I) can be a lyophilized powder or an injection solution, and the osimertinib can be a solid oral preparation (such as a tablet or a capsule) or an injection solution.

[0041] In some embodiments, the administration can be oral administration, injection administration. Preferably, the antibody conjugate drug of Formula (I) is administered by injection, and the osimertinib is administered orally.

[0042] In some embodiments, the tumor is lung cancer, such as non-small cell lung cancer (NSCLC). Preferably, the non-small cell lung cancer is EGFR mutant non-small cell lung cancer, such as EGFR mutant locally advanced or metastatic non-small cell lung cancer.

[0043] In some embodiments, the tumor is non-small cell lung cancer in stage ⅢB or ⅢC and is not suitable for surgical resection or to receive radical radiotherapy, or is advanced non-small cell lung cancer in stage IV, or is EGFR mutant locally advanced or metastatic non-small cell lung cancer that has failed previous standard treatment, or is EGFR mutant locally advanced or metastatic non-small cell lung cancer that has not received EGFR-TKIs or other systemic treatment, or is non-small cell lung cancer that has progressed after 6 months of treatment after receiving adjuvant / neoadjuvant chemotherapy, or is non-small cell lung cancer that carries at least one EGFR sensitive mutation (ex19del or L858R, which can be combined with other EGFR mutations).

[0044] The present application combines the administration of the antibody conjugate drug of Formula (I) and osimertinib, which can significantly inhibit the growth of tumors (especially lung cancer), and has a significant effect on tumor inhibition compared to single drug, and achieves a synergistic effect. Clinical studies have shown that the antibody conjugate drug of Formula (I) in combination with osimertinib can effectively treat advanced malignant tumors, especially EGFR mutant non-small cell lung cancer, overcome EGFR-TKI resistance, and bring clinical benefits superior to existing treatments for patients with advanced solid tumors such as non-small cell lung cancer, and the disease can be controlled or relieved.

[0045] It should be understood that aspects and embodiments of the application described herein include aspects and embodiments that are "comprising", "consisting of, and "consisting essentially of. The foregoing detailed description of the application has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the application to the precise form disclosed. Many modifications and variations are possible in light of the above teaching. It is intended that the scope of the application encompass these and all other modifications and variations as come within the scope of the claims and their equivalents.

[0046] DETAILED DESCRIPTION

[0047] TERMINOLOGY

[0048] "Combination" administration or "combined" administration as used herein means that a patient or subject is administered two (or more) different treatments during the time the patient or subject is afflicted with the condition. For example, a patient or subject is administered two or more drugs after the patient or subject has been diagnosed with the condition and before the condition has been cured or eliminated or treatment has stopped for other reasons. In some embodiments, the delivery of the first treatment is still ongoing when the delivery of the second treatment begins, so there is overlap in terms of administration. This situation is sometimes referred to herein as "simultaneous" or "concurrent delivery." In other embodiments, the delivery of one treatment has ended before the delivery of the other treatment begins. In some embodiments of either of these situations, both treatments are more effective because of the combination administration. For example, the second treatment is more effective, e.g., an equivalent effect is observed with less of the second treatment than would be observed if the second treatment were administered in the absence of the first treatment, or the second treatment can reduce symptoms to a greater extent, or a similar situation is observed with the first treatment. In some embodiments, the delivery results in a greater reduction in symptoms or other parameter related to the condition than would be observed if the other treatment were delivered in the absence of one of the treatments. The effect of the two (or more) treatments can be a partially additive effect, a fully additive effect, or more than an additive effect. The delivery can be such that the effect of the first treatment delivered is still detectable when the second treatment is delivered.

[0049] The term "treatment" means to alleviate, abate, or ameliorate at least one symptom of a disease in a subject. For example, with respect to a malignant disease, the term "treatment" can mean preventing, delaying the onset of the disease (i.e., the period prior to the clinical manifestation of the disease or symptoms of the disease), and / or reducing the risk of developing or worsening of symptoms of the disease. The term, when used in connection with a disease such as cancer, includes, but is not limited to, one or more of: preventing the growth of a cancer; causing a cancer to shrink in weight or volume; prolonging the expected survival time of a patient or subject; inhibiting tumor growth; reducing tumor mass; reducing the size or number of metastatic lesions; inhibiting the development of new metastatic lesions; prolonging survival; prolonging progression-free survival; prolonging time to progression; and / or improving quality of life.

[0050] The terms "treatment," "treating," and "amelioration" are used interchangeably herein. These terms mean an approach for obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also contemplated by therapeutic benefit is eradication or amelioration of one or more of the symptoms associated with the disorder, such that the patient or subject experiences an improvement in quality of life, even though the patient or subject can still be afflicted with the disorder. With respect to prophylactic benefit, the pharmaceutical composition can be administered to a patient or subject at risk of developing a particular disease, or to a patient or subject reporting one or more of the physiological symptoms of a disease, even though the patient or subject can not yet be diagnosed with the disease. In one embodiment, the terms also mean partially or completely inhibiting or reducing a condition from which the individual suffers. In one embodiment, the terms mean an action taken to reduce the severity of a condition, or delay or slow the progression of a condition, while the patient or subject is suffering from or diagnosed with the condition. Treatment need not result in complete cure of the condition; the term includes partial inhibition or reduction of the condition. Treatment is intended to include prevention or prophylaxis.

[0051] The term "subject" or "patient" is intended to include animals, which have or are afflicted with a malignant disease. Examples of subjects or patients include mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the subject or patient is a human, such as a human afflicted with, at risk of, or potentially capable of being afflicted with a malignant disease.

[0052] The term "therapeutic effect" refers to a beneficial local or systemic effect in an animal, e.g., a mammal (e.g., a human), caused by administration of a compound or composition of the present disclosure. The phrase "therapeutically effective amount" refers to the amount of a compound or composition of the present disclosure that is effective to treat a disease or condition at a reasonable risk to benefit ratio. The therapeutically effective amount of the compound or composition will vary depending on the subject being treated, and the disease or condition, the subject's body weight and age, the severity of the disease or condition, the mode of administration and like factors, which can readily be determined by one of skill in the art.

[0053] The term "combination therapy" or "co-administration" refers to a dosing regimen in which a patient or subject is in need of administration of at least two different compounds. The at least two different compounds can be administered simultaneously or concurrently, or sequentially in overlapping or non-overlapping time intervals within a day, or according to the respective dosing frequency and period of each of the at least two different compounds, at a clinically acceptable time interval. The dosing regimen of the at least two compounds can, but need not, overlap.

[0054] The term "co-administration" means exposing a subject to two or more treatment regimens (e.g., two or more compounds). In some embodiments, the two or more compounds can be administered simultaneously; in some embodiments, the two or more compounds can be administered in sequence (in completely non-overlapping dosing regimens); in some embodiments, the two or more compounds can be administered in partially overlapping dosing regimens. In some embodiments, "administration" of a combination therapy can involve administering one or more compounds to a subject who has already received other compound(s). For clarity, combination therapy does not require that the compounds be dosed together in a single composition (or even administered at the same time), but in some embodiments, the two or more compounds can be administered together in a single composition. In some embodiments, the compounds to be co-administered are separate dosage forms, but are packaged together to facilitate their co-administration.

[0055] In this context, when referring to "A in combination with B for treating a tumor", "A and B in combination / combination for treating a tumor", or "A in combination with B for preparing a medicament for treating a tumor", etc., it generally means that A and B can produce a synergistic effect in treating a tumor, i.e., the combined therapeutic effect of A and B is better than the separate therapeutic effect of A or B, or the combined side effect / adverse reaction of A and B is lower than the separate side effect / adverse reaction of A or B, including but not limited to, A can enhance the therapeutic effect of an equivalent dose of B, so that the combined therapeutic effect of A and B can be better than the sum of the separate therapeutic effects of A and B; A can reduce the dose of B under the premise of producing equivalent efficacy, thereby reducing the side effects / adverse reactions that can be produced by using a high dose of B; A can directly reduce or avoid the side effects / adverse reactions that can be produced by B, etc.

[0056] Some quantitative data in this context do not use the term "about". It should be understood that, whether or not the term "about" is explicitly used, each numerical value given herein includes not only the actual value given, but also an approximation of the given value based on reasonable extrapolation by one of ordinary skill in the art, including equivalents and approximations of the given value due to experimental and / or measurement conditions. The approximation is preferably ±20%, ±15%, ±10%, ±8%, ±6%, ±5%, ±4%, ±3%, 2%, ±1% based on the given value.

[0057] It should be understood that the present application includes various aspects, embodiments, and combinations of the aspects and / or embodiments described herein. The above description and the following examples are intended to be illustrative but not limiting of the scope of the present application. Other aspects, improvements, and modifications within the scope of the present application will be apparent to those skilled in the art. Therefore, those of ordinary skill in the art should recognize that the scope of the present application also includes the described improvements and modifications to the described aspects and embodiments. Examples

[0058] Example 1: Pharmacodynamic study of ADC-1 in combination with osimertinib on Balb / c nude mice EGFR V769_D770insASV-BAF3 xenograft tumor model

[0059] 1. Test animals

[0060] Balb / c nude mice, 6-7 weeks old, 24, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0061] 2. Purpose of the test

[0062] The efficacy of ADC-1 combined with osimertinib on ex20ins mutant tumors was investigated using a Balb / c nude mouse EGFR V769_D770insASV-BAF3 cell transplanted tumor model.

[0063] 3. Test drug

[0064] 1) ADC1:

[0065] wherein SWY2110 is an antibody having two heavy chains of the amino acid sequence shown in SEQ ID NO: 9 and two light chains of the amino acid sequence shown in SEQ ID NO: 10.

[0066] Drug source: Prepared by Shijiazhuang Yabao Jujia Biopharmaceutical Co., Ltd., according to PCT / CN2024 / 093528.

[0067] 2) Osimertinib mesylate

[0068] Drug source: commercially available

[0069] 4. Drug dose and grouping

[0070] Table 1 Animal grouping and dose table Note: i.v.: intravenous injection; p.o.: oral administration.

[0071] 5. Test method

[0072] Twenty-four Balb / c nude female mice were subcutaneously inoculated with EGFR V769_D770insASV-BAF3 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) at 5×10 6 mL per mouse in the right front limb axillary. When the tumors grew to about 120 mm 3 The mice were divided into 4 groups, namely: vehicle (5% glucose injection) control group (Vehicle), ADC-1 3 mg / kg group, osimertinib 10 mg / kg group, and ADC-1 + osimertinib 3 + 10 mg / kg group. The first administration was performed on the day of grouping (D0). ADC-1 was administered by tail vein injection once a week, for a total of 2 times (qw×2, D0, D7 administration). Osimertinib was administered orally once a day, for a total of 14 times (qd×14).

[0073] 6. Observation index

[0074] 6.1 Observation index

[0075] (1) General state observation: All animals were observed twice a week during the test period, and the abnormality of each part of the body and the change of behavior were recorded.

[0076] (2) Death and Moribundity: Death animals record the time of death, and moribund animals are observed more frequently to determine the time of death.

[0077] 6.2 Evaluation index

[0078] (1) Tumor volume: V = 1 / 2 x A x B

[0079] (2) Tumor inhibition rate:

[0080] Note: V: tumor volume

[0081] A: tumor length

[0082] B: tumor width

[0083] TV Xn : average tumor volume of the administration group on the nth day

[0084] TV X0 : average tumor volume of the administration group on the 0th day

[0085] TV Mn : average tumor volume of the vehicle group on the nth day

[0086] TV M0 : average tumor volume of the vehicle group on the 0th day

[0087] 7 Results

[0088] 7.1 Effect on mouse survival

[0089] The median survival time of the vehicle group, the ADC-1 group, the osimertinib group, and the ADC-1 + osimertinib group was 15 days, 26 days, 15 days, and > 26 days, respectively. At the end of the experiment D26, the number of surviving animals and the survival rate of each group were 0 / 6 (0%), 3 / 6 (50%), 0 / 6 (0%), and 6 / 6 (100%), respectively. ADC-1 combined with osimertinib can significantly prolong the survival time of EGFR V769_D770insASV-BAF3 tumor-bearing mice.

[0090] Table 2 Survival of tumor-bearing mice (Mean ± SD) (n = 6)

[0091] 7.2 Tumor volume

[0092] Compared with the vehicle, the mice in the ADC-1 group, the osimertinib group, and the ADC-1 + osimertinib group could significantly inhibit the growth of tumor volume and relative tumor volume (P < 0.01); compared with the ADC-1 and osimertinib single-drug groups, the efficacy of the combined administration group was significantly better than that of the single drug (P < 0.05), showing a synergistic effect. See Table 3 for details.

[0093] Table 3 Tumor parameters of each group on day 12 of administration Note: *P<0.05, **P<0.01 compared with the vehicle group; #P<0.05, compared with the ADC-1 group; △△△P<0.001 compared with the osimertinib group.

[0094] Example 2 Randomized, open, multi-center, phase lb / III clinical trial of ADC-1 combined with osimertinib in patients with EGFR-mutated locally advanced or metastatic non-small cell lung cancer

[0095] 1. Test drug

[0096] 1) ADC1:

[0097] Among them, SWY2110 is an antibody with two heavy chains with the amino acid sequence as shown in SEQ ID NO: 9 and two light chains with the amino acid sequence as shown in SEQ ID NO: 10.

[0098] Drug dosage form: lyophilized powder for injection;

[0099] Specification: 100 mg / bottle;

[0100] Method of administration: intravenous infusion

[0101] Storage condition: 2-8℃, avoid light.

[0102] Drug source: provided by Shijiazhuang Yiling Pharmaceutical Co., Ltd., prepared according to PCT / CN2024 / 093528.

[0103] 2) Osimertinib mesylate tablets

[0104] Active ingredient: osimertinib mesylate

[0105] Drug dosage form: tablets

[0106] Specification: 40 mg or 80 mg / tablet

[0107] Method of administration: oral

[0108] Storage condition: below 30℃

[0109] Drug source: commercially available

[0110] 2. Study design

[0111] This study is a randomized, open-label, multi-center phase Ib / III clinical trial. The study population is EGFR-mutated locally advanced or metastatic NSCLC. The phase Ib study includes a dose escalation phase and a dose selection phase. The phase III study is the key clinical study.

[0112] Phase Ib study

[0113] Dose escalation phase

[0114] Dose escalation is performed in EGFR-mutated advanced NSCLC who failed to EGFR-TKIs treatment using accelerated titration and traditional 3+3 design.

[0115] Only dose escalation is performed for ADC-1, and osimertinib is used at a fixed dose. The dose of osimertinib is 40 mg or 80 mg, once a day, orally.

[0116] The starting dose of ADC-1 is 1.8 mg / kg, and is escalated to 3.6 mg / kg, 4.8 mg / kg, respectively, intravenous infusion, once every 3 weeks (Q3W), and 21 days is a treatment cycle.

[0117] Only accelerated titration is used in the 1.8 mg / kg dose group. First, only one participant is enrolled, and if no DLT or second 2 or more adverse events related to the test drug occur within the DLT observation period, the 3+3 design dose escalation study is started in the next higher dose group; otherwise, the dose level is expanded to enroll 3 participants, and the 3+3 design is used for dose escalation study.

[0118] Dose selection phase

[0119] Based on the safety, tolerability, and PK data of different dose groups in the dose escalation phase, two dose groups are selected for dose selection, and compared with osimertinib monotherapy to further evaluate the safety, PK characteristics, and preliminary efficacy of ADC-1 combined with osimertinib. 150-200 EGFR-mutated locally advanced or metastatic NSCLC participants are randomly assigned to the following three groups according to the ratio of 2:2:1:

[0120] ADC-1 + osimertinib group 1

[0121] ADC-1 + osimertinib group 2

[0122] Osimertinib monotherapy group

[0123] Based on the safety, tolerability, PK, and preliminary efficacy data, one dose of ADC-1 combined with osimertinib is selected as the RP3D.

[0124] Phase III study

[0125] Approximately 450 participants are enrolled and randomized 1:1 to trial arm: ADC-1 + osimertinib, control arm: osimertinib. Randomization stratification factors include: ECOG performance status (0, 1 score), brain metastasis (yes, no), EGFR mutation type (ex19del, L858R, if co-mutation exists, stratify by ex19del).

[0126] All participants are assessed for safety according to the protocol after the first dose of study drug and for PK and immunogenicity blood sampling after a single dose and during continuous dosing. In addition, participants are assessed for tumor imaging every 6 weeks (±7 days) for the first 24 weeks after start of study drug treatment according to RECIST vl. l criteria, every 12 weeks (±7 days) after 24 weeks, and at the end of treatment (if tumor imaging was not performed within the previous 4 weeks). All participants receive study drug treatment continuously until the protocol-specified treatment discontinuation criteria are met, after which they enter the follow-up period.

[0127] 3. Subject selection

[0128] Participants must meet all of the following inclusion criteria to be enrolled in the study: 18 to 75 years of age, inclusive, both genders. Pathologically confirmed locally advanced or metastatic NSCLC patients, including: Stage ⅢB or ⅢC patients based on AJCC 8th edition who are not suitable for surgical resection or radical radiotherapy and chemotherapy, or Stage IV advanced NSCLC patients. Dose escalation phase requires EGFR-mutant locally advanced or metastatic NSCLC patients who have failed previous standard treatment, dose selection phase and phase III study require EGFR-mutant locally advanced or metastatic NSCLC patients who have not received EGFR-TKIs or other systemic treatment, and patients who have received adjuvant / neoadjuvant chemotherapy and disease progression 6 months after treatment are allowed to be included; at least one EGFR sensitive mutation (ex19del or L858R, can be combined with other EGFR mutations). EGFR mutation: Ib phase: can be enrolled based on previous test results. Phase III: enroll based on central laboratory test results; at least one CT or MRI confirmed measurable lesion according to RECIST vl. l criteria.

[0129] 4. Safety evaluation

[0130] From the time of participant's signature of informed consent until 90 days after the last dose, all participants are observed and recorded for any AE, including clinical symptoms and abnormal vital signs, abnormalities in laboratory tests, and the relevance between the study drug is determined.

[0131] Participants will be required to undergo safety evaluations, including physical examination, ECOG performance status, laboratory tests, and electrocardiogram, at screening, baseline, and post-dose.

[0132] 5. Efficacy evaluation

[0133] Efficacy evaluation will be performed according to RECIST v1.1 criteria. CT / MRI imaging evaluation: Participants will undergo tumor imaging evaluation every 6 weeks within the first 24 weeks after the first dose, and every 12 weeks thereafter. The allowed window for imaging is ± 7 days.

[0134] 6. Efficacy analysis

[0135] The Phase Ib study will provide a descriptive summary of efficacy by dose group.

[0136] The Phase III study will analyze IRC-assessed progression-free survival (PFS). The median PFS time will be estimated using the Kaplan-Meier method, along with the 95% CI for the median PFS. The disease-free survival rates at 12, 24, and 36 months, and their 95% CIs, will also be calculated. The difference in PFS between the two groups will be tested by stratified Log-rank test. The HR and its 95% CI between treatment groups will be estimated by stratified Cox proportional hazards model. The stratification variable is the randomization stratification factor.

[0137] The secondary endpoints of the Phase III study include investigator-assessed PFS, OS, ORR, DCR, DoR, etc. Investigator-assessed PFS, OS, and DoR will be analyzed using similar statistical methods as the primary endpoint PFS. The 95% CIs for ORR and DCR will be calculated based on the Clopper-Pearson method, and the difference in ORR and DCR rates between the two groups and its 95% CI will be estimated.

[0138] The results of the study show that the combination of ADC-1 and osimertinib can effectively treat advanced malignant tumors, especially EGFR-positive advanced solid tumors, such as EGFR-positive non-small cell lung cancer. It can overcome EGFR-TKI resistance and bring clinical benefits to patients with advanced solid tumors, including non-small cell lung cancer, and the disease can be controlled or relieved.

[0139] Phase 1 results

[0140] 95 patients with EGFR-mutant NSCLC were enrolled in the Phase lb study and received ADC-1 treatment, covering 4 dose levels, 1.8 mg / kg (n=l), 3.6 mg / kg (n=3), 4.2 mg / kg (n=16), 4.5 mg / kg (n=6), once every 3 weeks (Q3W). 13 patients were previously treated patients, who had received 1-3 lines of treatment, including 11 patients who had received 3rdgeneration EGFR TKI treatment; 82 patients were newly treated patients. One case of dose-limiting toxicity (DLT) was pulmonary embolism; one patient in the 3.6 mg / kg dose group developed interstitial pneumonia (ILD) at 4 months of treatment, and permanently discontinued treatment.

[0141] Among 55 patients who were evaluable for efficacy, the objective response rate (ORR) and disease control rate (DCR) were 60% and 100%, respectively.

[0142] Summary: ADC-1 was well tolerated at doses ranging from 1.8 to 4.5 mg / kg once every 21 days, intravenous administration, and the maximum tolerated dose (MTD) has not been reached, with a manageable safety profile. In the absence of MTD, encouraging antitumor activity was observed in both dose escalation and dose expansion, in both previously treated and newly treated patients: the objective response rate (ORR) was 60% and the disease control rate (DCR) was 100% in all patients who were evaluable for efficacy, with long-term drug use, prolonging the PFS of patients.

[0143] Case 1:

[0144] A patient, 61 years old, male, with a diagnosis of lung adenocarcinoma, EGFR gene 19 exon in-frame deletion mutation, abundance 11.19%, clinical stage IV. The patient had received a third-generation EGFR TKI for more than a year, and after five cycles of immunotherapy combined with pemetrexed, carboplatin, and bevacizumab, the disease progressed. The patient participated in the ADC-1 combined EGFR TKI clinical study, and the left upper lobe of the lung, lymph nodes, pleural metastasis, and right frontal lobe metastasis were screened, with a large tumor burden (target lesion 48.7 mm at baseline). The patient received combined treatment (ADC-1: intravenous infusion 1.8 mg / kg Q3W, osimertinib: oral administration, 80 mg / tablet, QD), and the first efficacy evaluation at week 6 showed a 15.2% reduction (target lesion reduced to 41.3 mm), and the tumor continued to shrink at weeks 12, 18, 24, and 36. The 24-week efficacy evaluation showed a 32.9% reduction (target lesion reduced to 32.8 mm), and the 36-week efficacy evaluation maintained PR. The patient is still in treatment (PFS>9 months).

[0145] Case 2:

[0146] A patient, 56 years old, female, disease diagnosis is lung adenocarcinoma, EGFR gene 19 exon whole code deletion mutation, abundance 33.43%, clinical stage IV. The patient received the third generation EGFR TKI for one and a half years before the disease progressed. Participate in ADC-1 combined with EGFR TKI clinical research, screening period double lung nodules, mediastinal lymph nodes, multiple metastases of vertebral body, target lesion 34.72mm at baseline. Receive combined treatment (ADC-1: intravenous infusion 4.2mg / kg Q3W, osimertinib: oral administration, 80mg / tablet, QD), the first efficacy evaluation at the sixth week is SD reduced by 27% (target lesion reduced to 25.3mm), the efficacy evaluation at the 12th week is PR reduced by 38% (target lesion reduced to 21.32mm), maintain PR at the 18th week and the 24th week. The patient is still in treatment (PFS>7 months).

[0147] Typical case 3:

[0148] A patient, 71 years old, male, disease diagnosis is lung adenocarcinoma, EGFR exon21 L858R mutation, clinical stage IV. The patient received the third generation EGFR TKI for six months before the disease progressed. Participate in ADC-1 combined with EGFR TKI clinical research, screening period left lung upper lobe, brain, lymph nodes (mediastinum, neck) and multiple metastases, target lesion 62mm at baseline. Receive combined treatment (ADC-1: intravenous infusion 4.5mg / kg Q3W, osimertinib: oral administration, 80mg / tablet, QD), the first efficacy evaluation at the sixth week is PR reduced by 59.7% (target lesion reduced to 25mm), maintain PR at the 12th week and the 18th week. The patient is still in treatment (PFS>5 months).

[0149] Typical case 4:

[0150] A patient, 51 years old, female, disease diagnosis is lung squamous carcinoma, EGFR gene 19 exon whole code deletion mutation, clinical stage IV, initial treatment patient. Participate in ADC-1 combined with EGFR TKI clinical research, screening period left lung upper lobe, brain, lymph nodes (mediastinum, neck) and multiple metastases, target lesion 56mm at baseline. Receive combined treatment (ADC-1: intravenous infusion 4.5mg / kg Q3W, osimertinib: oral administration, 80mg / tablet, QD), the first efficacy evaluation at the sixth week is PR reduced by 57.6% (target lesion reduced to 23.75mm). The patient is still in treatment.

[0151] The sequences used in the above examples of the present application are shown in the following sequence table. It should be understood that the following sequences are only exemplary sequences of the embodiments of the present application, and are not any limitation on the embodiments of the present application.

[0152] Sequence table:

[0153] EGFR antibody SWY2110

[0154] SWY2110 HCDR1 : NYDVH SEQ ID NO: 1 (kabat)

[0155] SWY2110 HCDR2: VIWSGGNTDYNTPFTS SEQ ID NO: 2 (kabat)

[0156] SWY2110 HCDR3: ALDYYDYEFAY SEQ ID NO: 3 (kabat)

[0157] SWY2110 LCDR1 : RASQSIGTNIH SEQ ID NO: 4 (kabat)

[0158] SWY2110 LCDR2: YASESIS SEQ ID NO: 5 (kabat)

[0159] SWY2110 LCDR3: QQNNEWPTS SEQ ID NO: 6 (kabat)

[0160] SWY2110 VH: SEQ ID NO: 7

[0161] SWY2110 VL: SEQ ID NO: 8

[0162] SWY2110 heavy chain (SEQ ID NO: 9):

[0163] SWY2110 light chain (SEQ ID NO: 10):

Claims

1. A medicine for treating tumor of a combination drug, comprising an antibody conjugate drug shown in formula (I) and osimertinib, wherein Ab is an antibody or antigen-binding fragment thereof targeting EGFR, and n is selected from an integer from 1 to 8 or a decimal number from 1 to 8, preferably an integer from 4 to 8 or a decimal number from 4 to 8, further preferably 1, 2, 3, 4, 5, 6, 7, 8, and more preferably 8.

2. A method of treating a tumor, the method comprising administering to a patient or subject in need of treatment a therapeutically effective amount of an antibody drug conjugate represented by Formula (I) and osimertinib, wherein Ab is an antibody or antigen-binding fragment thereof targeting EGFR, and n is selected from an integer from 1 to 8 or a decimal number from 1 to 8, preferably an integer from 4 to 8 or a decimal number from 4 to 8, further preferably 1, 2, 3, 4, 5, 6, 7, 8, and more preferably 8.

3. Use of an antibody drug conjugate represented by Formula (I) in the manufacture of a medicament for treating a tumor in combination with osimertinib, wherein Ab is an antibody or antigen-binding fragment thereof targeting EGFR, and n is selected from an integer from 1 to 8 or a decimal number from 1 to 8, preferably an integer from 4 to 8 or a decimal number from 4 to 8, further preferably 1, 2, 3, 4, 5, 6, 7, 8, and more preferably 8.

4. The medicament of claim 1, or the method of claim 2, or the use of claim 3, wherein the antibody or antigen-binding fragment thereof targeting EGFR comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein, The heavy chain variable region comprises a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2), and a heavy chain complementarity determining region 3 (HCDR3), and the light chain variable region comprises a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2), and a light chain complementarity determining region 3 (LCDR3), wherein the amino acid sequence of HCDR1 is shown as SEQ ID NO: 1, the amino acid sequence of HCDR2 is shown as SEQ ID NO: 2, the amino acid sequence of HCDR3 is shown as SEQ ID NO: 3, and / or the amino acid sequence of LCDR1 is shown as SEQ ID NO: 4, the amino acid sequence of LCDR2 is shown as SEQ ID NO: 5, and the amino acid sequence of LCDR3 is shown as SEQ ID NO: 6; Preferably, the antibody or antigen-binding fragment thereof targeting EGFR comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the amino acid sequence of the heavy chain variable region is shown as SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is shown as SEQ ID NO: 8; More preferably, the antibody or antigen-binding fragment thereof targeting EGFR comprises a heavy chain (HC) and a light chain (LC), wherein the amino acid sequence of the heavy chain is shown as SEQ ID NO: 9, and the amino acid sequence of the light chain is shown as SEQ ID NO:

10.

5. The medicament of claim 1, or the method of claim 2, or the use of claim 3, wherein, The antibody drug conjugate of formula (I) is: SWY2110 is an antibody having two heavy chains with the amino acid sequence shown as SEQ ID NO: 9 and two light chains with the amino acid sequence shown as SEQ ID NO:

10.

6. The medicament of any one of claims 1 and 4-5, or the method of any one of claims 2 and 4-5, or the use of any one of claims 3-5, wherein, The antibody conjugate drug represented by formula (I) and osimertinib are simultaneously contained in one clinically acceptable pharmaceutical preparation (single preparation, or prepared into clinically acceptable dosage forms respectively, packaged in combination as the drug; preferably the antibody conjugate drug represented by formula (I) and osimertinib are respectively contained in different preparation units, presented in the form of combination packaging; further preferably the antibody conjugate drug represented by formula (I) is a lyophilized powder or injection, and the osimertinib is a solid oral preparation (such as tablets or capsules) or an injection.

7. The medicament of any one of claims 1 and 4-6, or the method of any one of claims 2 and 4-6, or the use of any one of claims 3-6, wherein, The antibody drug conjugate of formula (I) and osimertinib are administered simultaneously, or separately; preferably the antibody drug conjugate of formula (I) and osimertinib are contained in different formulation units, administered simultaneously or in parallel, or administered sequentially at different times within one day with clinically acceptable time intervals, or administered separately with clinically acceptable time intervals, according to the dosing frequency and cycle of the antibody drug conjugate of formula (I) and osimertinib, respectively; more preferably, osimertinib is administered orally first, and the antibody drug conjugate of formula (I) is administered by injection later.

8. The medicament of any one of claims 1 and 4-7, wherein, The mass ratio of the antibody drug conjugate of formula (I) and osimertinib is selected from (1-100):(1-100), such as (1-50):(1-50), (1-10):(1-10), (5-15):(1-5), 1:(5-15), 1:15, 1:10, 1:8, 1:4, 1:2 and 3:

10.

9. The method of any one of claims 2 and 4-7, or the use of any one of claims 3-7, wherein the ratio of the amount of the antibody drug conjugate of formula (I) and osimertinib is selected from (1-100):(1-100), such as (1-50):(1-50), (1-10):(1-10), (5-15):(1-5), 1:(5-15), 1:15, 1:10, 1:8, 1:4, 1:2 and 3:

10.

10. The medicament of any one of claims 1 and 4-8, or the method of any one of claims 2, 4-7, and 9, or the use of any one of claims 3-7, and 9, wherein, The therapeutically effective amount of the antibody drug conjugate of formula (I) is 1 mg / kg-15 mg / kg, such as about 1.5 mg / kg, about 1.8 mg / kg, about 2.0 mg / kg, about 2.2 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.8 mg / kg, about 3 mg / kg, about 3.2 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.8 mg / kg, about 4.0 mg / kg, about 4.2 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.8 mg / kg, about 5.0 mg / kg, about 5.2 mg / kg, about 5.4 mg / kg, about 5.5 mg / kg, about 5.6 mg / kg, about 5.8 mg / kg, about 6.0 mg / kg, about 6.2 mg / kg, about 6.4 mg / kg, about 6.6 mg / kg, about 6.8 mg / kg, about 7.0 mg / kg, about 7.2 mg / kg, about 7.5 mg / kg, about 7.8 mg / kg, about 8.0 mg / kg, about 8.2 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.8 mg / kg, about 9.0 mg / kg, about 9.5 mg / kg, about 10.0 mg / kg, about 10.5 mg / kg, about 11 mg / kg, about 11.5 mg / kg, about 12.0 mg / kg, about 13 mg / kg, about 14 mg / kg, wherein mg is the amount of the antibody drug conjugate of formula I, and kg is the weight of the patient.

11. The medicament of any one of claims 1, 4-8 and 10, or the method of any one of claims 2, 4-7 and 9-10, or the use of any one of claims 3-7 and 9-10, wherein, The therapeutically effective amount of the osimertinib is 20 mg-200 mg per day, such as about 30 mg per day, about 40 mg per day, about 50 mg per day, about 60 mg per day, about 70 mg per day, about 80 mg per day, about 90 mg per day, about 100 mg per day, about 110 mg per day, about 120 mg per day, about 130 mg per day, about 140 mg per day, about 150 mg per day, about 160 mg per day, about 170 mg per day, about 180 mg per day, about 190 mg per day.

12. The medicament of any one of claims 1, 4-8 and 10-11, or the method of any one of claims 2, 4-7 and 9-11, or the use of any one of claims 3-7 and 9-11, wherein, The antibody drug conjugate of Formula (I) and / or the osimertinib is administered once a day (QD), or the therapeutically effective amount thereof is administered as a total daily dose in divided doses over a day, for example, in two divided doses (BID) or in three divided doses (TID) per day; or once a week (QW), or the therapeutically effective amount thereof is administered as a total weekly dose in divided doses over a plurality of days in a week, for example, in two divided doses (BIW) or in three divided doses (TIW) per week; or once in two weeks (Q2W), or the therapeutically effective amount thereof is administered as a total weekly dose in divided doses over a plurality of days in two weeks, for example, in two divided doses (BI2W) or in three divided doses (TI2W) per two weeks; or once in three weeks (Q3W), or the therapeutically effective amount thereof is administered as a total dose in divided doses over a plurality of days in three weeks, for example, in two divided doses (BI3W, such as D1, D8 administration, one cycle every three weeks) or in three divided doses (TI3W) per three weeks; or once in a month (QM), or the therapeutically effective amount thereof is administered as a total dose in divided doses over a plurality of days in a month, for example, in two divided doses (BI2M) or in three divided doses (TIM) per month; or interval administration, such as once in 2-7 days, or once in 3 days, or once in 4 days, or once in 5 days, or once in 6 days, or once in 2-4 weeks, such as once in 2 weeks (once in 3 weeks, one cycle every 3 weeks), once in 1 week (once in 2 weeks, one cycle every 2 weeks or one cycle every 4 weeks) or once in 3 weeks (once in 4 weeks, one cycle every 4 weeks), or once in 1-3 months, such as once in 1 month (once in 2 months); or continuous administration for 3 weeks, 1 week off, one cycle every 4 weeks, or continuous administration for 2 weeks, 1 week off, one cycle every 3 weeks, or continuous administration for 2 weeks, 2 weeks off, one cycle every 4 weeks, or once in 1 week (once in 2 weeks), one cycle every 4 weeks; preferably, the antibody drug conjugate of Formula (I) is administered once a week (QW), or once in two weeks (Q2W), or once in three weeks (Q3W); the osimertinib is administered once a day (QD), or the therapeutically effective amount thereof is administered as a total daily dose in divided doses over a day, for example, in two divided doses (BID) or in three divided doses (TID) per day, more preferably, the antibody drug conjugate of Formula (I) is administered once in three weeks (Q3W); the osimertinib is administered once a day (QD).

13. The medicament of any one of claims 1, 4-8 and 10-12 for use in the treatment of a tumor.

14. The method of any one of claims 2, 4-7 and 9-12, or the use of any one of claims 3-7 and 9-13, wherein the tumor is lung cancer, preferably non-small cell lung cancer (NSCLC); more preferably EGFR-mutant non-small cell lung cancer, further preferably EGFR-mutant locally advanced or metastatic non-small cell lung cancer, more further preferably non-small cell lung cancer of stage III B or III C and not suitable for surgical resection or to receive radical radiochemotherapy, or advanced stage IV non-small cell lung cancer, or EGFR-mutant locally advanced or metastatic non-small cell lung cancer that failed prior standard treatment, or EGFR-mutant locally advanced or metastatic non-small cell lung cancer that has not received prior EGFR-TKI or other systemic therapy, or non-small cell lung cancer that received prior adjuvant / neoadjuvant chemotherapy and progressed after treatment ended 6 months ago, or non-small cell lung cancer that harbors at least one EGFR sensitive mutation (ex19del or L858R, possibly in combination with other mutations of EGFR).

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