Application or pharmaceutical composition of gsoraxestole for treating lung cancer

Abstract

The invention belongs to the field of medicine, and provides an application of gsoraxestole for treating lung cancer or a pharmaceutical composition of the gsoraxestole, especially for KRAS G12C mutation positive non-small cell lung cancer, the gsoraxestole tablet and a first pharmaceutical active component are combined for administration for treating lung cancer, larger and more lasting response can be realized, tumor growth can be totally relieved, and the curative effect of the gsoraxestole tablet is improved. Earnings can be obtained from clinical patients.

Description

Technical Field

[0001] This application belongs to the field of medicine. Specifically, this application relates to the use of gosorex for the treatment of lung cancer or its pharmaceutical composition. Background Art

[0002] The Lungscape project, which evaluated the prognostic role of KRAS G12C mutations in NSCLC in the European population, showed that in a cohort of 2,055 NSCLC patients, the KRAS mutation rate was 23%, and the KRAS G12C mutation rate was 10.5%. Among adenocarcinoma patients, the KRAS mutation rate was 38.0%, and the KRAS G12C mutation rate was 17.0%.

[0003] There is still a lack of specific first-line treatment regimens for advanced NSCLC with KRAS G12C mutations. Currently, the treatment mainly refers to the treatment of advanced NSCLC without driver genes in the 2021 Chinese Society of Clinical Oncology (CSCO) NSCLC guidelines. The first-line treatment regimens include platinum-based doublet chemotherapy combined with anti-PD-1 / PD-L1 or platinum-based doublet chemotherapy combined with anti-angiogenesis or anti-PD-1 / PD-L1 monotherapy, but there is no large-scale randomized clinical trial to evaluate its effectiveness in patients with advanced NSCLC with KRAS G12C mutation positive.

[0004] After advanced NSCLC with KRAS G12C mutation positive receives first-line treatment, the second-line treatment options are very limited and the effectiveness is poor. The second-line treatment regimens actually used clinically are mainly docetaxel chemotherapy and pemetrexed monotherapy, and the ORRs are only 4.2 - 5.5% and 8.5% respectively. The ORR of docetaxel combined with ramucirumab for second-line treatment is up to 23% at most, but ramucirumab has not been approved for the treatment of advanced NSCLC in China.

[0005] Currently, in clinical practice, there is still a lack of treatment regimens for advanced NSCLC with KRAS G12C mutation positive. Summary of the Invention

[0006] On the one hand, this application provides a pharmaceutical composition, which consists of a first drug active ingredient and a second drug active ingredient, wherein the first drug active ingredient is compound I or its pharmaceutically acceptable salt, hydrate or its prodrug, and the second drug active ingredient is compound II or its pharmaceutically acceptable salt, hydrate or its prodrug. .

[0007] In some embodiments, the pharmaceutical composition is used for the treatment of lung cancer.

[0008] Second aspect, the present application provides the use of the pharmaceutical composition described in the present application in the preparation of a medicament for treating lung cancer.

[0009] Use of a first pharmaceutically active ingredient in the preparation of a medicament for a combination therapy for treating lung cancer, wherein the medicament will be administered in combination with a second pharmaceutically active ingredient to treat lung cancer.

[0010] Use of a second pharmaceutically active ingredient in the preparation of a medicament for a combination therapy for treating lung cancer, wherein the medicament will be administered in combination with a first pharmaceutically active ingredient to treat lung cancer.

[0011] Use of a second pharmaceutically active ingredient in the preparation of a medicament for use in combination with a first pharmaceutically active ingredient for treating lung cancer.

[0012] Use of a first pharmaceutically active ingredient in the preparation of a medicament for use in combination with a second pharmaceutically active ingredient for treating lung cancer.

[0013] Third aspect, the present application provides a method for treating lung cancer, which comprises administering the pharmaceutical composition described in the present application to a subject in need thereof.

[0014] In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient are non-fixed combinations.

[0015] In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient in the non-fixed combination are each in the form of a pharmaceutical composition.

[0016] In some embodiments, in the non-fixed combination, the pharmaceutical composition of the first pharmaceutically active ingredient comprises one or more pharmaceutically acceptable excipients, and the pharmaceutical composition of the second pharmaceutically active ingredient comprises one or more pharmaceutically acceptable excipients.

[0017] In some embodiments, the first pharmaceutically active ingredient is a pharmaceutically acceptable salt of Compound I. In some embodiments, the second pharmaceutically active ingredient is Compound II.

[0018] In some embodiments, the first pharmaceutically active ingredient is a pharmaceutically acceptable salt of Compound I, such as hydrochloride or maleate. In some embodiments, the second pharmaceutically active ingredient is the free base of Compound II.

[0019] The first pharmaceutically active ingredient or its pharmaceutical composition In the present application, the chemical name of Compound I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine, and it has the following structural formula: Compound I.

[0020] In the present application, the pharmaceutically acceptable salts of Compound I can be produced from different organic acids and inorganic acids by methods well-known in the art. "Pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, etc. In some embodiments, the pharmaceutically acceptable salt of Compound I is the hydrochloride salt of Compound I. In some embodiments, the pharmaceutically acceptable salt of Compound I is the monohydrochloride salt of Compound I. In some embodiments, the pharmaceutically acceptable salt of Compound I is the dihydrochloride salt of Compound I. In some embodiments, the hydrochloride salt of Compound I is in crystalline form. In some embodiments, the pharmaceutically acceptable salt of Compound I is the crystal of the dihydrochloride salt of Compound I. In some embodiments, the pharmaceutically acceptable salt of Compound I is the maleate salt of Compound I.

[0021] In the present application, in some embodiments, Compound I is in the form of a free base. In some embodiments, the free base of Compound I is in amorphous form.

[0022] In some embodiments, the first pharmaceutically active ingredient is in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is selected from solid pharmaceutical compositions, more preferably from tablets or capsules.

[0023] In some embodiments, the first pharmaceutically active ingredient is Anlotinib Hydrochloride.

[0024] In some embodiments, the single dose of the first pharmaceutically active ingredient is 6 mg to 20 mg. In some embodiments, the single dose of the first pharmaceutically active ingredient is 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 16 mg, 18 mg or any range formed by the above values. In some embodiments, the single dose of the first pharmaceutically active ingredient is 8 mg to 16 mg.

[0025] The second pharmaceutically active ingredient or its pharmaceutical composition In the present application, Compound II has the following structural formula: Compound II.

[0026] In the present application, in some embodiments, Compound II is in the form of a free base. In some embodiments, the free base of Compound II is in an amorphous form.

[0027] In some embodiments, the pharmaceutically acceptable salts of Compound II can be produced from different organic and inorganic acids by methods well-known in the art. "Pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, etc. In some embodiments, the pharmaceutically acceptable salts of Compound II are in crystalline form.

[0028] In some embodiments, the second pharmaceutically active ingredient is in the form of a pharmaceutical composition; preferably, the pharmaceutical composition is selected from solid pharmaceutical compositions, more preferably from tablets or capsules.

[0029] In some embodiments, the second pharmaceutically active ingredient is gesoresib.

[0030] In some embodiments, the single dose of the second pharmaceutically active ingredient is from 50 mg to 2000 mg. In some embodiments, the single dose of the second pharmaceutically active ingredient is 200 mg, 300 mg, 400 mg, 600 m, 800 mg, 900 mg, 1000 mg, 1200 mg or a range formed by any of the above values. In some embodiments, the single dose of the second pharmaceutically active ingredient is from 400 mg to 1200 mg.

[0031] Pharmaceutical composition In some embodiments, the components in the pharmaceutical composition described in the present application can optionally be used in combination with one or more pharmaceutically acceptable carriers, where the components can each independently, or some or all of them together, contain pharmaceutically acceptable carriers and / or excipients.

[0032] The pharmaceutical compositions described in the present application can be formulated separately, or some or all of them can be formulated together. Preferably, the components of the pharmaceutical compositions are formulated separately, or each is formulated into a suitable pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present application can be formulated into pharmaceutical compositions suitable for single or multiple administrations. In some specific embodiments, the pharmaceutical composition containing Compound I or its pharmaceutically acceptable salt, hydrate or prodrug can be selected from solid pharmaceutical compositions, which include but are not limited to tablets or capsules. In some specific embodiments, the pharmaceutical composition containing Compound II or its pharmaceutically acceptable salt, hydrate or prodrug can be selected from solid pharmaceutical compositions, which include but are not limited to tablets or capsules.

[0033] In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient of the pharmaceutical composition are each in the form of a pharmaceutical composition. In some embodiments, in the pharmaceutical composition, it includes: 1) the first pharmaceutically active ingredient described in the present application with a single dose of 6 mg to 20 mg and 2) the second pharmaceutically active ingredient with a single dose of 50 mg to 2000 mg.

[0034] In some embodiments, in the pharmaceutical composition, it includes 1) a pharmaceutical composition containing 6 mg, 8 mg, 10 mg or 12 mg of the first pharmaceutically active ingredient and 2) a pharmaceutical composition containing 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of the second pharmaceutically active ingredient.

[0035] In some embodiments, the ratio of the single dose of the first pharmaceutically active ingredient to the single dose of the second pharmaceutically active ingredient is selected from 0.1:100 to 100:100. In some embodiments, the ratio of the single dose of the first pharmaceutically active ingredient to the single dose of the second pharmaceutically active ingredient is selected from 0.1:100, 0.2:100, 0.3:100, 0.4:100, 0.5:100, 0.6:100, 0.7:100, 0.8:100, 0.9:100, 1:100, 2:100, 3:100, 4:100, 5:100, 6:100, 7:100, 8:100, 9:100, 10:100, 20:100, 30:100, 40:100, 50:100, 60:100, 70:100, 80:100, 90:100, 100:100 or the range formed by any of the above values. In some embodiments, the ratio of the single dose of the first pharmaceutically active ingredient to the single dose of the second pharmaceutically active ingredient is selected from 3:100, 4:100, 5:100 or 6:100.

[0036] In some embodiments, the dose ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is selected from 0.1:600 to 100:600. In some embodiments, the dose ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is selected from 0.1:600, 0.2:600, 0.3:600, 0.4:600, 0.5:600, 0.6:600, 0.7:600, 0.8:600, 0.9:600, 1:600, 2:600, 3:600, 4:600, 5:600, 6:600, 7:600, 8:600, 9:600, 10:600, 20:600, 30:600, 40:600, 50:600, 60:600, 70:600, 80:600, 90:600, 100:600 or the range formed by any of the above values. In some embodiments, the dose ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is selected from 3:600, 4:600, 5:600 or 6:600.

[0037] Administration / treatment or prevention regimen of the pharmaceutical composition In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient can be administered separately, without regard to order. In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient can be administered simultaneously.

[0038] In some embodiments, an effective amount of the first pharmaceutically active ingredient and the second pharmaceutically active ingredient can be administered to an individual in need thereof simultaneously, sequentially or at intervals.

[0039] In some embodiments, an effective amount of the first pharmaceutically active ingredient and the second pharmaceutically active ingredient can be administered to an individual in need thereof according to the same or different dosing regimens.

[0040] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0041] In some embodiments, the first pharmaceutically active ingredient is administered orally. In some embodiments, the first pharmaceutically active ingredient is administered at least once a day or once every two days. For example, the first pharmaceutically active ingredient is administered once a day, twice a day, or three times a day. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of about 6 mg to about 20 mg. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of 6 mg, 8 mg, 10 mg, or 12 mg. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of 6 mg, 8 mg, 10 mg, or 12 mg once a day. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of 6 mg, 8 mg, 10 mg, or 12 mg once a day, and the dose per administration is 6 mg, 8 mg, 10 mg, or 12 mg.

[0042] In some embodiments, the second pharmaceutically active ingredient is administered orally. In some embodiments, the second pharmaceutically active ingredient is administered at least once a day or once every two days. For example, the second pharmaceutically active ingredient is administered once a day, twice a day, or three times a day. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of about 1 mg to about 2000 mg. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 900 mg, 1000 mg, or 1200 mg. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of 100 mg, 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 900 mg, 1000 mg, or 1200 mg twice a day. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of 100 mg, 200 mg, 300 mg, 400 mg, or 600 mg twice a day, and the dose per administration is 400 mg, 600 mg, or 800 mg. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of 200 mg twice a day, and the dose per administration is 600 mg.

[0043] In some embodiments, the administration includes administering the first pharmaceutically active ingredient and the second pharmaceutically active ingredient separately or simultaneously.

[0044] In the present application, the components of the pharmaceutical composition can be administered to a patient simultaneously, alternately or sequentially as independent entities (such as a pharmaceutical composition), wherein the active ingredient administered to the patient reaches a therapeutically effective amount level. The individual active components can be packaged, sold or administered as completely independent pharmaceutical compositions. Examples that can be cited are combination therapies, such as administering 3 or more active components.

[0045] The amounts of the components in the pharmaceutical composition of the present application can be determined according to the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health status of the patient. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof is 6 mg to 20 mg; preferably 8 mg to 16 mg; more preferably 8 mg to 14 mg; most preferably 8 mg, 10 mg or 12 mg. In some embodiments, Compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof can be administered once or more times a day, preferably once a day; in some embodiments, Compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered once a day in an oral solid dosage form.

[0046] In some embodiments, the daily dose of Compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof is 1 mg to 4000 mg; preferably 400 mg to 2000 mg; more preferably 600 mg to 1800 mg; most preferably 800 mg, 1000 mg, 1200 mg, 1400 mg or 1600 mg. In some embodiments, Compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof can be administered once or more times a day, preferably twice a day; in some embodiments, Compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered twice a day in an oral solid dosage form.

[0047] In the present application, the dosing regimen can be comprehensively determined based on the activity and toxicity of the drug, the tolerance of the patient, etc. Generally, the components of the pharmaceutical composition of the present application can be administered according to the dosing regimens well-known in the art. In some embodiments, Compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered in an intermittent dosing manner; the intermittent dosing includes a dosing period and a drug withdrawal period, and can be administered once or multiple times a day during the dosing period. In some embodiments, the ratio of the number of days in the dosing period to the number of days in the drug withdrawal period is 2:0.5 - 5, preferably 2:0.5 - 3, more preferably 2:0.5 - 2, and even more preferably 2:0.5 - 1. As a further preferred intermittent dosing manner, it is one of the following: continuous administration for 2 weeks and then drug withdrawal for 2 weeks, continuous administration for 2 weeks and then drug withdrawal for 1 week, or continuous administration for 5 days and then drug withdrawal for 2 days. In certain specific embodiments, Compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof is orally administered at a dose of 8, 10 and / or 12 mg once a day for 2 consecutive weeks and then drug withdrawal for 1 week.

[0048] In some embodiments, every 21 days is a treatment cycle. In some embodiments, every 3 weeks is a treatment cycle. In some embodiments, the patient continuously takes Compound I dihydrochloride orally for 2 weeks and then discontinues for 1 week, once a day, 8 or 10 mg each time. In some embodiments, the patient takes Compound II orally every day, twice a day, 600 mg each time. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with a positive KRAS G12C mutation. In some embodiments, the non-small cell lung cancer is non-small cell lung adenocarcinoma with a positive KRAS G12C mutation. In some embodiments, the non-small cell lung cancer is non-small cell lung squamous cell carcinoma with a positive KRAS G12C mutation.

[0049] In some embodiments, for the non-small cell lung cancer, its histological types include but are not limited to adenocarcinoma, squamous cell carcinoma, large cell carcinoma or non-small cell lung cancer of undetermined type; its clinical stages include but are not limited to locally advanced, and / or advanced (such as stage IIIB / IV) and / or metastatic non-small cell lung cancer.

[0050] In some embodiments, the non-small cell lung cancer is locally advanced, and / or advanced and / or metastatic non-small cell lung cancer. In some embodiments, the metastatic non-small cell lung cancer includes, but is not limited to, single-site metastasis, disseminated metastasis, and diffuse metastasis; in some embodiments, the metastatic lesions of the metastatic non-small cell lung cancer include, but are not limited to, lymph nodes, pleura, bone, brain, pericardium, adrenal gland, and liver; in some embodiments, the non-small cell lung cancer is non-small cell lung cancer with brain metastasis. In some embodiments, the non-small cell lung cancer is recurrent non-small cell lung cancer, including, but not limited to, non-small cell lung cancer with endobronchial obstruction, resectable recurrent non-small cell lung cancer, non-small cell lung cancer with mediastinal lymph node recurrence, non-small cell lung cancer with superior vena cava (SVC) obstruction, and non-small cell lung cancer with severe hemoptysis.

[0051] In some preferred embodiments, the non-small cell lung cancer is non-small cell lung cancer that has not received prior systemic treatment. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has progressed or recurred after receiving at least one treatment regimen. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has failed after treatment with at least one regimen. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has failed after treatment with two regimens. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that cannot tolerate chemotherapy. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has failed after anti-PD-1 / PD-L1 treatment and / or platinum-containing chemotherapy.

[0052] In some embodiments, the patient with non-small cell lung cancer is a pathologically confirmed locally advanced, unresectable and / or metastatic, KRAS G12C-mutated non-small cell lung cancer patient who has had disease progression after prior anti-PD-1 / PD-L1 treatment and platinum-containing chemotherapy or is intolerant to the above treatments due to toxicity, and / or the patient has not used a KRAS G12C inhibitor or an anti-angiogenic drug and has no other driver gene mutations with standard treatment measures. Optionally, the driver gene mutations are selected from EGFR, ALK, BRAF (V600E), HER2, MET (exon14), ROS1, RET, or NTRK1 / 2 / 3, etc.

[0053] In a xenograft tumor animal model, a pharmaceutical combination product containing a first pharmaceutically active ingredient and a second pharmaceutically active ingredient can produce synergistic anti-tumor activity compared to a single pharmaceutically active ingredient. The experimental data show that for locally advanced or metastatic non-small cell lung cancer with KRASG12C mutation positive, the combination of the first pharmaceutically active ingredient and the second pharmaceutically active ingredient can achieve a greater and more durable response. Importantly, when used as a single pharmaceutically active ingredient, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient can only reduce the tumor growth rate, while at the same dose, the combination of the two pharmaceutically active ingredients can achieve a reduction in tumor volume, thus generally alleviating tumor growth.

[0054] Benefits are obtained in clinical patients, including but not limited to: prolonged progression-free survival (PFS), prolonged overall survival (OS), increased objective response rate (ORR), increased disease control rate (DCR), reduced number and / or degree of adverse reactions, decreased distant metastasis rate, and decreased local control rate, etc. Specifically, in some embodiments of the present application, especially in the specific examples of the present application, in the clinical trial, the progression-free survival (PFS) of human patients with non-small cell lung cancer is prolonged by about 1 - 3 months, preferably prolonged by about 4 - 6 months, further preferably prolonged by about 7 - 9 months, more preferably prolonged by about 10 - 12 months; the objective response rate of the patients reaches more than about 10%, preferably reaches more than about 15%, further preferably reaches more than about 20%, more preferably reaches more than about 30%, especially reaches more than 35%; the disease control rate of the patients reaches more than 50%, preferably reaches about 60% or more, further preferably reaches about 70% or more, more preferably reaches about 80% or more, especially reaches 90% or more.

[0055] In some embodiments, the pharmaceutical composition of the present application is optionally combined with surgical resection and / or radiotherapy, and its use in the preparation of a medicament for treating non-small cell lung cancer.

[0056] The dosing regimen can be determined comprehensively based on the activity and toxicity of the drug, the patient's tolerance, etc. Generally, each component of the pharmaceutical composition of the present application can be administered according to the dosing regimens well-known in the art. In some embodiments, Compound I or its pharmaceutically acceptable salt, hydrate or prodrug is administered in an intermittent dosing manner; the intermittent dosing includes a dosing period and a drug withdrawal period, and it can be administered once or multiple times a day during the dosing period. In some embodiments, the ratio of the number of days of the dosing period to the number of days of the drug withdrawal period is 2:0.5 - 5, preferably 2:0.5 - 3, more preferably 2:0.5 - 2, and even more preferably 2:0.5 - 1. As a further preferred intermittent dosing manner, it is one of the following ways: continuous administration for 2 weeks followed by drug withdrawal for 2 weeks, continuous administration for 2 weeks followed by drug withdrawal for 1 week, or continuous administration for 5 days followed by drug withdrawal for 2 days. In certain specific embodiments, Compound I or its pharmaceutically acceptable salt, hydrate or prodrug is orally administered at a dose of 8, 10 and / or 12 mg once a day for 2 consecutive weeks followed by a 1-week drug withdrawal.

[0057] In some embodiments, each 21 days is a treatment cycle; in some embodiments, each 3 weeks is a treatment cycle; in some embodiments, the patient continuously takes Compound I dihydrochloride orally for 2 weeks followed by a 1-week drug withdrawal, once a day, 8 or 10 mg each time. In some embodiments, the patient takes Compound II orally twice a day, 600 mg each time.

[0058] Definitions and Explanations In this article, unless otherwise specified, the doses and ranges provided here are based on the molecular weight of the free base of the active ingredient.

[0059] Unless otherwise specified, for the purposes of the present application, the following terms used in this specification and claims shall have the following meanings. A particular term should not be considered indefinite or unclear without a special definition, but should be understood according to the ordinary meaning in the art.

[0060] When a trade name appears in the present disclosure, it is intended to refer to the corresponding product or its active ingredient.

[0061] In the present application, unless otherwise specified, the terms "comprise, comprises and comprising" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps can also be covered.

[0062] Unless otherwise specifically stated, singular terms cover plural terms, and plural terms cover singular terms. Unless otherwise specifically stated, the word "a" or "an" means "at least one" or "at least one kind". Unless otherwise stated, the use of "or" means "and / or".

[0063] For purposes of description and disclosure, all patents, patent applications, and other identified publications are hereby expressly incorporated by reference into the present application. These publications are provided only because their disclosures are prior to the filing date of the present application. All statements as to the dates of these documents or the representation of the content of these documents are based on the information available to the applicant and do not constitute any admission as to the dates of these documents or the correctness of the content of these documents. Moreover, in any country, any reference to these publications in this application does not constitute an admission that such publication is part of the common general knowledge in the art.

[0064] As used in this application, unless otherwise indicated, the single dose or dosage of the first and second pharmaceutically active ingredients is calculated in the free base form of the compound.

[0065] "Patient" or "subject" means a mammal, preferably a human.

[0066] "Pharmaceutically acceptable" means that it is used in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes that it is acceptable for human pharmaceutical use.

[0067] "Therapeutically effective amount" means an amount of a compound which, when administered to a human for treating a disease, is sufficient to effect treatment of the disease.

[0068] "Treatment" means any administration of a therapeutically effective amount of a compound and includes: (1) inhibiting the disease in a human who is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and / or symptomatology), or (2) ameliorating the disease in a human who is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and / or symptomatology).

[0069] The term "prevention" generally means (a) preventing the occurrence of a disease or (b) delaying the onset of a disease or the onset of symptoms of a disease.

[0070] The term "effective amount" means an amount of a compound of the present application that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described in the present application. The amount of the active substance (such as an antibody or compound of the present application) that constitutes a "therapeutically effective amount" can vary depending on several factors, such as the disease state, age, sex, and weight of the individual, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. An effective amount can also routinely be determined by those skilled in the art based on their own knowledge and the present disclosure.

[0071] The term "administer" or "administration" means physically introducing a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0072] The term "pharmaceutically acceptable" or "medicinally acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0073] The term "pharmaceutically acceptable salt" includes salts formed from a compound containing a basic radical ion and a free acid or salts formed from a compound containing an acidic radical ion and a free base.

[0074] The term "pharmaceutical composition" refers to a substance formed by combining one or more active ingredients of the present application, and the active ingredients in the substance can form a mixture with pharmaceutically acceptable excipients either jointly or individually. The purpose of the pharmaceutical composition is to facilitate the administration of the compound or its pharmaceutical combination of the present application to a subject.

[0075] The term "pharmaceutically acceptable excipient" refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well-known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0076] The term "single-dose pharmaceutical composition" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single-dose pharmaceutical composition; or each vial of injection is a single-dose pharmaceutical composition. In the present application, the terms "single-dose pharmaceutical composition" and "unit-dose pharmaceutical composition" have the same meaning and can be used interchangeably.

[0077] The term "fixed combination" refers to the administration of active ingredients to an individual simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation. In some embodiments, for example, it is present in the same tablet, the same capsule, the same injection, or the same sachet.

[0078] The term "non-fixed combination" refers to the administration of two or more active ingredients to an individual simultaneously, in parallel or sequentially without a specific time limit as independent entities (such as pharmaceutical compositions, pharmaceutical formulations), where the active ingredients administered to the individual reach a therapeutically effective amount level. Examples of non-fixed combinations that can be cited are cocktail therapies, for example, the administration of 2, 3 or more active ingredients. In a non-fixed combination, each of the active ingredients can be packaged, sold or administered as a completely independent pharmaceutical composition. The "non-fixed combination" also includes the combined use between "fixed combinations", or between a "fixed combination" and any one or more independent entities of active ingredients.

[0079] "Treatment failure" means that the toxic side effects are intolerable, the disease progresses during treatment, or recurs after the end of treatment.

[0080] "Optional" means including, or not including.

[0081] "CR" refers to complete remission, that is, all target lesions disappear, and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10 mm.

[0082] "PR" refers to partial remission, and the sum of the diameters of the target lesions is reduced by at least 30% compared to the baseline level.

[0083] "ORR" refers to the objective response rate, which is the sum of the proportions of complete remission and partial remission. That is, ORR = CR + PR.

[0084] "PD" refers to disease progression. Taking the minimum value of the sum of the diameters of all measured target lesions during the entire study process as a reference, the sum of the diameters increases by at least 20% (if the baseline measurement value is the smallest, the baseline value is used as a reference); and it must meet the condition that the relative value of the sum of the diameters increases by at least 5 mm. The appearance of one or more new lesions is also regarded as disease progression.

[0085] "SD" refers to stable disease, where the degree of reduction of the target lesions does not reach the level of PR, and the degree of increase does not reach the level of PD, being between the two.

[0086] "DCR" refers to the disease control rate, which includes the percentage of cases with complete remission, partial remission and stable disease for more than 4 weeks among patients with evaluable efficacy.

[0087] "PFS" refers to progression-free survival, which is the time from randomization until objective tumor progression or patient death.

[0088] "OS" refers to overall survival, which is the time from the start of enrollment to death due to any cause. Measured in days, for subjects lost to follow-up, the last follow-up time is usually counted as death.

[0089] "DOR" refers to disease remission duration, starting from the time when the tumor is first evaluated as complete remission or partial remission until the time of first disease progression or death from any cause. If the tumor remission is not confirmed, it is not adopted. For patients who have not had disease progression or died from any cause before the data analysis cutoff date, they are treated as censored data, and the censoring date is determined using the PFS censoring time to determine the duration of remission.

[0090] Technical effects Surprisingly, it is found that the first drug active ingredient and the second drug active ingredient according to the present application can synergistically achieve overall tumor remission and increase the median survival percentage in preclinical models, and obtain benefits in clinical patients. At the same time, the pharmaceutical composition of the present application has good safety.

[0091] Furthermore, the pharmaceutical composition of the present application will contribute to the safety of medication, the progression-free survival (PFS), overall survival (OS), disease remission duration (DOR), disease control rate (DCR), objective remission rate (ORR) of patients, and its pharmacokinetics. Specific embodiments

[0092] The present application will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present application and not to limit the protection scope of the present application.

[0093] Example 1 Pharmacodynamic evaluation in the NCI-H358 human lung cancer CB-17 SCID mouse xenograft tumor model The first drug active ingredient is compound I dihydrochloride, which is prepared by the method of Example 24 in reference to WO2008112407 to obtain 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine, and then prepared according to the preparation method of "Examples of salt forms" in the specification of WO2008112407 to obtain compound I dihydrochloride. Among them, the required dose of the first drug active ingredient is calculated in the free base form of compound I.

[0094] The second drug active ingredient is compound II, which is prepared by the method disclosed in patent application WO2020233592.

[0095] Female CB-17 SCID mice at the SPF level (source: Shanghai Lingchang Biotechnology Co., Ltd.) were subcutaneously inoculated with NCI-H358 (KRAS G12C) human lung cancer cells in the right axillary region at a dose of 5×10 6 cells / mouse (inoculated with Matrigel at a 1:1 ratio). When the average tumor volume reached approximately 200 mm3, the animals were divided into 4 groups of 6 mice each. The specific grouping and dosing regimens are shown in Table 1: Table 1 Grouping and dosing regimens

[0096] The day of grouping was designated as Day 0, and dosing began on Day 0. Tumor volume was measured 2-3 times per week, and the body weight of the mice was also measured simultaneously. Data were recorded; the general condition of the mice was observed and recorded daily. After the experiment ended, the tumors were dissected, weighed, and photographed.

[0097] The detection indices and calculation formulas are as follows: Tumor volume, TV (mm 3 ) = 1 / 2 × (a × b 2 ); where a is the long diameter of the tumor and b is the short diameter of the tumor.

[0098] Relative tumor volume, RTV = TV t / TV0; where TV0 is the tumor volume on Day 0, and TV t is the tumor volume at each measurement.

[0099] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV × 100%; where T RTV is the RTV of the treatment group; C RTV is the RTV of the vehicle control group.

[0100] Tumor growth inhibition rate, TGI (%) = (1 - TW / TW0) × 100%; where TW is the tumor weight of the treatment group and TW0 is the tumor weight of the vehicle control group.

[0101] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0 × 100%; where Wt0 is the body weight of the mice on Day 0, and Wt t is the body weight of the mice at each measurement.

[0102] The results of each detection index on the 20th day are shown in Table 2 below. There was no obvious toxicity in each administration group. After the combination of the second drug active ingredient group and the first drug active ingredient group, they had obvious inhibitory activity against NCI-H358 human lung cancer subcutaneous transplanted tumors. Compared with the single active ingredient group, the tumor volume of mice decreased more significantly. Using the One-way ANOVA method to compare the combined group and the single active ingredient group, the P value was <0.01, indicating a significant difference.

[0103] Table 2 Effects of combination on each index in the subcutaneous transplantation tumor model of NCI-H358 human lung cancer mice

[0104] Note: Compared with the solvent control group, ***p<0.001. Compared with the first drug active ingredient group, ### p<0.001. Compared with the second drug active ingredient group, △△ p<0.01.

[0105] Example 2 Enrolled patients: Pathologically confirmed locally advanced, unresectable and / or metastatic non-small cell lung cancer patients with KRAS G12C mutation who had disease progression after previous anti-PD-1 / PD-L1 treatment and platinum-containing chemotherapy or were intolerant to the above treatments due to toxicity, and had not used KRAS G12C inhibitors or anti-angiogenic drugs, and had no other driver gene mutations with standard treatment measures (such as EGFR, ALK, BRAF(V600E), HER2, MET(exon14), ROS1, RET or NTRK1 / 2 / 3, etc.).

[0106] Drug administration plan: The second drug active ingredient 600 mg BID + the first drug active ingredient 8 mg QD or compound II 600mg BID + compound I dihydrochloride 10 mg QD. Among them, the first drug active ingredient is compound I dihydrochloride, and the required dose is calculated according to the free base form of compound I.

[0107] During the research process, according to the tolerance and adverse reactions of patients, the drug administration dose can be reduced. At most, the dose can be reduced 2 times. Compound I dihydrochloride is reduced in sequence according to 10 mg - 8 mg - 6 mg, and cross-dose adjustment is not allowed. Compound II can be reduced from 600 mg BID to 600 mg QD, 400mg QD.

[0108] Dosage and administration: Compound I dihydrochloride: Take on an empty stomach, once a day, 8 or 10 mg each time, take orally continuously for 2 weeks and stop for 1 week, that is, 3 weeks (21 days) is a treatment cycle.

[0109] Compound II: Oral administration, 600 mg BID, with each 21-day period as a treatment cycle. The subjects will orally take Compound II on an empty stomach every day (no food intake, except for water, 2 hours before and after drug administration).

[0110] In this study, efficacy evaluation and data analysis will be conducted every 2 cycles (C2, i.e., 6 weeks). The primary endpoints include observing the safety of the combined medication and the progression-free survival (PFS) of the patients; the secondary endpoints include overall survival (OS), duration of disease remission (DOR), disease control rate (DCR), objective response rate (ORR), and their pharmacokinetic parameters.

[0111] Experimental results: The combination of the first active pharmaceutical ingredient and the second active pharmaceutical ingredient has achieved benefits in clinical patients, with the progression-free survival of the patients extended and the disease control rate and objective response rate improved.

Claims

1. A pharmaceutical composition, characterized in that It is composed of a first active pharmaceutical ingredient and a second active pharmaceutical ingredient, wherein the first active pharmaceutical ingredient is compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and the second active pharmaceutical ingredient is compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof, 。 2. Use of a pharmaceutical composition in the preparation of a drug for treating lung cancer, characterized in that It is composed of a first active pharmaceutical ingredient and a second active pharmaceutical ingredient, wherein the first active pharmaceutical ingredient is compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and the second active pharmaceutical ingredient is compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof, 。 3. The pharmaceutical composition according to claim 1 or the use according to claim 2, wherein: The first pharmaceutically active ingredient is compound I in the form of a free base, or a salt formed by compound I and any of the following acids: an acid addition salt formed by hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or an organic acid such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid; Among them, the second active ingredient of the drug is compound II in the form of a free base, or a salt formed by compound II and any of the following acids: an acid addition salt formed by hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with an organic acid such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, and stearic acid.

4. The pharmaceutical composition according to claim 1 or the use according to claim 2, wherein The first pharmaceutically active ingredient is Compound I dihydrochloride.

5. The pharmaceutical composition according to claim 1 or the use according to claim 2, wherein The single dose of the first pharmaceutically active ingredient is 6 mg to 20 mg, and the single dose of the second pharmaceutically active ingredient is 50 mg to 2000 mg.

6. The pharmaceutical composition according to claim 1 or the use according to claim 2, wherein: The single dose of the first active ingredient of the drug is 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 16 mg, 18 mg or a range formed by any of the above values; the single dose of the second active ingredient of the drug is 200 mg, 300 mg, 400 mg, 600 mg, 800 mg, 900 mg, 1000 mg, 1200 mg or a range formed by any of the above values.

7. The pharmaceutical composition according to claim 1 or the use according to claim 2, wherein the first active pharmaceutical ingredient and the second active pharmaceutical ingredient are a non-fixed combination, wherein: The first pharmaceutically active ingredient and the second pharmaceutically active ingredient are each in the form of a pharmaceutical composition, wherein the pharmaceutical composition of the first pharmaceutically active ingredient comprises one or more pharmaceutically acceptable excipients, and the pharmaceutical composition of the second pharmaceutically active ingredient comprises one or more pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 1 or the use according to claim 2, wherein: The pharmaceutical composition of the first pharmaceutically active ingredient is selected from capsules, and the pharmaceutical composition of the second pharmaceutically active ingredient is selected from tablets.

9. The pharmaceutical composition according to claim 1 or the use according to claim 2, comprising: 1) a single dose of 6 mg to 20 mg of a first pharmaceutically active ingredient and 2) a single dose of 50 mg to 2000 mg of a second pharmaceutically active ingredient.

10. The pharmaceutical composition according to claim 1 or the use according to claim 2, comprising: 1) a single dose of 6 mg, 8 mg, 10 mg or 12 mg of a first pharmaceutically active ingredient and 2) a single dose of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of a second pharmaceutically active ingredient.

11. The pharmaceutical composition according to claim 1 or the use according to claim 2, wherein: The single dose ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is selected from 0.1:100 to 100:100; or, the dose ratio of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is selected from 0.1:600 ​​to 100:

600.

12. The pharmaceutical composition according to claim 1 or the use according to claim 2, wherein: The ratio of a single dose of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is selected from 0.1:100, 0.2:100, 0.3:100, 0.4:100, 0.5:100, 0.6:100, 0.7:100, 0.8:100, 0.9:100, 1:100, 2:100, 3:100, 4:100, 5:100, 6:100, 7:100, 8:100, 9:100, 10:100, 20:100, 30:100, 40:100, 50:100, 60:100, 70:100, 80:100, 90:100, 100:100 or a range formed by any of the above values; or or a range formed by any of the above values.

13. The use according to claim 2, wherein: The lung cancer is non-small cell lung cancer.

14. The use according to claim 13, wherein The non-small cell lung cancer is gene mutation-positive non-small cell lung cancer.

15. The use according to claim 14, wherein The non-small cell lung cancer is KRAS G12C mutation-positive non-small cell lung cancer.

16. The use according to claim 13, wherein The non-small cell lung cancer is locally advanced, and / or advanced and / or metastatic non-small cell lung cancer; the non-small cell lung cancer is non-small cell lung cancer that has not received systemic treatment before.

17. The use according to claim 13, wherein The non-small cell lung cancer is non-small cell lung cancer that has progressed or relapsed after receiving at least one treatment regimen; the non-small cell lung cancer is non-small cell lung cancer that has failed at least one treatment regimen; the non-small cell lung cancer is non-small cell lung cancer that has failed two treatment regimens; the non-small cell lung cancer is non-small cell lung cancer that cannot tolerate chemotherapy; the non-small cell lung cancer is non-small cell lung cancer that has failed anti-PD-1 / PD-L1 treatment and / or platinum-containing chemotherapy.

18. The use according to claim 2, wherein: The compound I or a pharmaceutically acceptable salt thereof is administered in a manner of alternating between a dosing period and a drug-free period, and the ratio of the dosing period to the drug-free period in days is 2:0.5-5.

19. The use according to claim 18, wherein The ratio of the drug administration period to the drug withdrawal period in terms of days is 2:0.5-1.

20. The use according to claim 2, wherein: The compound I or a pharmaceutically acceptable salt thereof is administered in a manner with an administration period and a withdrawal period separated by one of the following: continuous administration for 2 weeks and withdrawal for 2 weeks, continuous administration for 2 weeks and withdrawal for 1 week, or continuous administration for 5 days and withdrawal for 2 days; the compound II or a pharmaceutically acceptable salt, hydrate or a prodrug thereof can be administered once or more daily.

21. The use according to claim 20, wherein The compound I or a pharmaceutically acceptable salt thereof is continuously administered for 2 weeks and then stopped for 1 week, and the compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered twice a day.

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