Use of gossypol for treating lung cancer or pharmaceutical composition thereof

Abstract

The application belongs to the field of medicine, and provides a use of glesatumcel for treating lung cancer or a pharmaceutical composition thereof, especially for non-small cell lung cancer positive for KRAS G12C mutation, wherein glesatumcel tablets are administered in combination with a first pharmaceutical active ingredient for treating lung cancer, which can achieve greater and more durable response, overall remission of tumor growth, and obtain benefits in clinical patients.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, in particular, the present application relates to the use of glosorel for treating lung cancer or a pharmaceutical composition thereof. BACKGROUND

[0002] The Lungscape project evaluated the prognostic role of KRAS G12C mutation in NSCLC in a European population showed that in a cohort of 2055 NSCLC patients, the KRAS mutation rate was 23%, and the KRAS G12C mutation rate was 10.5%. In patients with adenocarcinoma, 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 for advanced NSCLC with KRAS G12C mutation, and its treatment currently refers to the 2021 Chinese Society of Clinical Oncology (CSCO) NSCLC guidelines for advanced NSCLC without driver genes. The first-line treatment regimen includes platinum doublet chemotherapy combined with anti-PD-1 / PD-L1 or platinum 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 KRAS G12C mutation-positive advanced NSCLC.

[0004] The treatment of advanced NSCLC with KRAS G12C mutation-positive after first-line treatment is very limited and has poor effectiveness. The second-line treatment regimen actually used in clinical practice is mainly docetaxel chemotherapy and pemetrexed monotherapy, and the ORR is only 4.2-5.5% and 8.5%, respectively. The ORR of docetaxel combined with ramucirumab (ramucirumab) in second-line treatment is as high as 23%, but ramucirumab has not been approved in China for the treatment of advanced NSCLC.

[0005] At present, there is still a lack of treatment regimen for advanced NSCLC with KRAS G12C mutation-positive in clinical practice. SUMMARY

[0006] In one aspect, the present application provides a pharmaceutical composition consisting of a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, wherein the first pharmaceutically active ingredient is Compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and the second pharmaceutically active ingredient is Compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof,

[0007] .

[0008] In some embodiments, the pharmaceutical composition is used for treating lung cancer.

[0009] In a second aspect, the present application provides use of a pharmaceutical composition described herein in the manufacture of a medicament for the treatment of lung cancer.

[0010] Use of a first pharmaceutically active ingredient in the manufacture of a medicament for a combination therapy for the treatment of lung cancer, wherein the medicament is to be administered in combination with a second pharmaceutically active ingredient, thereby treating lung cancer.

[0011] Use of a second pharmaceutically active ingredient in the manufacture of a medicament for a combination therapy for the treatment of lung cancer, wherein the medicament is to be administered in combination with a first pharmaceutically active ingredient, thereby treating lung cancer.

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

[0013] Use of a first pharmaceutically active ingredient in the manufacture of a medicament for use in combination with a second pharmaceutically active ingredient for the treatment of lung cancer.

[0014] In a third aspect, the present application provides a method of treating lung cancer, comprising administering to a subject in need thereof a pharmaceutical composition described herein.

[0015] In some embodiments, the first and second pharmaceutically active ingredients of the non-fixed combination are not pharmaceutically acceptable salts of each other.

[0016] In some embodiments, the first and second pharmaceutically active ingredients of the non-fixed combination are each in the form of a pharmaceutical composition.

[0017] In some embodiments, the pharmaceutical composition of the first pharmaceutically active ingredient of the non-fixed combination comprises one or more pharmaceutically acceptable excipients, and the pharmaceutical composition of the second pharmaceutically active ingredient comprises one or more pharmaceutically acceptable excipients.

[0018] 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.

[0019] In some embodiments, the first pharmaceutically active ingredient is a pharmaceutically acceptable salt of Compound I, such as a hydrochloride salt or a maleate salt. In some embodiments, the second pharmaceutically active ingredient is the free base of Compound II.

[0020] a first pharmaceutically active ingredient or a pharmaceutical composition thereof

[0021] 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, which has the following structural formula:

[0022] Compound I.

[0023] In this application, a pharmaceutically acceptable salt of Compound I can be produced from various organic and inorganic acids using methods known in the art. "Pharmaceutically acceptable salt" includes, but is 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, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, etc. In some embodiments, a pharmaceutically acceptable salt of Compound I is a hydrochloride salt of Compound I. In some embodiments, a pharmaceutically acceptable salt of compound I is a monohydrochloride salt of compound I. In some embodiments, a pharmaceutically acceptable salt of compound I is a dihydrochloride salt of compound I. In some embodiments, the hydrochloride salt of compound I is in crystalline form. In some embodiments, a pharmaceutically acceptable salt of compound I is a crystal of compound I dihydrochloride. In some embodiments, a pharmaceutically acceptable salt of compound I is a maleate salt of compound I.

[0024] In some embodiments of this application, compound I is in the form of a free base. In some embodiments, the free base of compound I is in an amorphous form.

[0025] In some embodiments, the first active pharmaceutical 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.

[0026] In some implementations, the first active pharmaceutical ingredient is anlotinib hydrochloride.

[0027] In some embodiments, a single dose of the first active pharmaceutical ingredient is 6 mg to 20 mg. In some embodiments, a single dose of the first active pharmaceutical ingredient is 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, 16 mg, 18 mg, or any range thereof. In some embodiments, a single dose of the first active pharmaceutical ingredient is 8 mg to 16 mg.

[0028] a second pharmaceutically active ingredient or a pharmaceutical composition thereof

[0029] In this application, compound II has the following structural formula:

[0030] Compound II.

[0031] In some embodiments of this application, compound II is in the form of a free base. In some embodiments, the free base of compound II is in an amorphous form.

[0032] In some embodiments, a pharmaceutically acceptable salt of compound II can be produced from various organic and inorganic acids using methods known in the art. "Pharmaceutically acceptable salt" includes, but is 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, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, etc. In some embodiments, the pharmaceutically acceptable salt of compound II is in crystalline form.

[0033] In some embodiments, the second active pharmaceutical 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.

[0034] In some implementations, the second active pharmaceutical ingredient is gelsorex.

[0035] In some embodiments, a single dose of the second active pharmaceutical ingredient is from 50 mg to 2000 mg. In some embodiments, a single dose of the second active pharmaceutical ingredient 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. In some embodiments, a single dose of the second active pharmaceutical ingredient is from 400 mg to 1200 mg.

[0036] pharmaceutical composition

[0037] In some embodiments, the components of the pharmaceutical composition described in this application may optionally be used in combination with one or more pharmaceutically acceptable carriers, wherein the components may be independent of each other, or may contain, in part or in whole, a pharmaceutically acceptable carrier and / or excipient.

[0038] The pharmaceutical compositions described in this application can be formulated separately, or some or all of them can be formulated together. Preferably, the components of the pharmaceutical composition are formulated separately, or each is formulated into a suitable pharmaceutical composition. In some embodiments, the pharmaceutical compositions of this application can be formulated into pharmaceutical compositions suitable for single or multiple administration. In some specific embodiments, a pharmaceutical composition containing compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof may be selected from a solid pharmaceutical composition, including but not limited to tablets or capsules. In some specific embodiments, a pharmaceutical composition containing compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof may be selected from a solid pharmaceutical composition, including but not limited to tablets or capsules.

[0039] In some embodiments, the first and second active pharmaceutical ingredients of the pharmaceutical composition are each in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises: 1) a single dose of 6 mg to 20 mg of the first active pharmaceutical ingredient as described in this application and 2) a single dose of 50 mg to 2000 mg of the second active pharmaceutical ingredient.

[0040] In some embodiments, the pharmaceutical composition comprises 1) a pharmaceutical composition containing 6 mg, 8 mg, 10 mg or 12 mg of a first active pharmaceutical ingredient and 2) a pharmaceutical composition containing 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of a second active pharmaceutical ingredient.

[0041] In some embodiments, the ratio of a single dose of the first active pharmaceutical ingredient to the second active pharmaceutical ingredient is selected from 0.1:100 to 100:100. In some embodiments, the ratio of a single dose of the first active pharmaceutical ingredient to the second active pharmaceutical 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 any range of the above values. In some embodiments, the ratio of a single dose of the first active pharmaceutical ingredient to the second active pharmaceutical ingredient is selected from 3:100, 4:100, 5:100, or 6:100.

[0042] In some embodiments, the ratio of the dose of the first active pharmaceutical ingredient to the dose of the second active pharmaceutical ingredient is selected from 0.1:600 ​​to 100:600. In some embodiments, the ratio of the first active pharmaceutical ingredient to the second active pharmaceutical 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 any range of the above values. In some embodiments, the ratio of the dose of the first active pharmaceutical ingredient to the dose of the second active pharmaceutical ingredient is selected from 3:600, 4:600, 5:600 or 6:600.

[0043] dosing / treatment or prevention regimen of the pharmaceutical composition

[0044] In some embodiments, the first active pharmaceutical ingredient and the second active pharmaceutical ingredient can be administered separately, without any order of administration. In some embodiments, the first active pharmaceutical ingredient and the second active pharmaceutical ingredient can be administered simultaneously.

[0045] In some implementations, effective amounts of the first and second active pharmaceutical ingredients may be administered to individuals in need simultaneously, sequentially, or at intervals.

[0046] In some implementations, effective amounts of the first and second active pharmaceutical ingredients may be administered to the individual in need according to the same or different dosing regimens.

[0047] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

[0048] In some embodiments, the first active pharmaceutical ingredient is administered orally. In some embodiments, the first active pharmaceutical ingredient is administered at least once daily or every two days, for example, once daily, twice daily, or three times daily. In some embodiments, the first active pharmaceutical ingredient is administered in a single dose of about 6 mg to about 20 mg. In some embodiments, the first active pharmaceutical ingredient is administered in a single dose of 6 mg, 8 mg, 10 mg, or 12 mg. In some embodiments, the first active pharmaceutical ingredient is administered in a single dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily. In some embodiments, the first active pharmaceutical ingredient is administered in a single dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily, with each administration dose being 6 mg, 8 mg, 10 mg, or 12 mg.

[0049] In some embodiments, the second active pharmaceutical ingredient is administered orally. In some embodiments, the second active pharmaceutical ingredient is administered at least once daily or every two days, for example, once daily, twice daily, or three times daily. In some embodiments, the second active pharmaceutical ingredient is administered in a single dose of about 1 mg to about 2000 mg. In some embodiments, the first active pharmaceutical 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 active pharmaceutical 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 daily. In some embodiments, the second active pharmaceutical ingredient is administered as a single dose of 100 mg, 200 mg, 300 mg, 400 mg, or 600 mg twice daily, with each dose being 400 mg, 600 mg, or 800 mg. In some embodiments, the second active pharmaceutical ingredient is administered as a single dose of 200 mg twice daily, with each dose being 600 mg.

[0050] In some embodiments, the administration includes administering the first active pharmaceutical ingredient and the second active pharmaceutical ingredient separately or simultaneously.

[0051] In this application, the components of the pharmaceutical composition can be administered to a patient simultaneously, alternately, or sequentially as independent entities (e.g., the pharmaceutical composition itself), wherein the active ingredient administered to the patient reaches a therapeutically effective level. Each active component can be packaged, marketed, or administered as a completely independent pharmaceutical composition. Examples include cocktail therapy, such as administering three or more active components.

[0052] The amount of each component in the pharmaceutical composition of this application administered may be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the patient's age, and health status. In some embodiments, the daily dose of compound I or its 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; and most preferably 8 mg, 10 mg, or 12 mg. In some embodiments, compound I or its pharmaceutically acceptable salt, hydrate, or prodrug thereof may be administered once or more daily, preferably once daily; in some embodiments, compound I or its pharmaceutically acceptable salt, hydrate, or prodrug thereof is administered once daily in an oral solid dosage form.

[0053] In some embodiments, the daily dose of compound II or its pharmaceutically acceptable salt, hydrate, or prodrug is from 1 mg to 4000 mg; preferably from 400 mg to 2000 mg; more preferably from 600 mg to 1800 mg; and most preferably 800 mg, 1000 mg, 1200 mg, 1400 mg, or 1600 mg. In some embodiments, compound II or its pharmaceutically acceptable salt, hydrate, or prodrug may be administered once or more daily, preferably twice daily; in some embodiments, compound II or its pharmaceutically acceptable salt, hydrate, or prodrug is administered twice daily in an oral solid dosage form.

[0054] In this application, the dosing regimen can be determined comprehensively based on the drug's activity, toxicity, and patient tolerability. Generally, the components of the pharmaceutical composition of this application can be administered according to dosing regimens known in the art. In some embodiments, compound I or its pharmaceutically acceptable salts, hydrates, or prodrugs are administered in an intermittent manner; the intermittent dosing includes a dosing period and a withdrawal period, during which it can be administered once or multiple times daily. In some embodiments, the ratio of the dosing period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, and more preferably 2:0.5 to 1. A further preferred intermittent dosing method is one of the following: continuous dosing for 2 weeks followed by a 2-week break, continuous dosing for 2 weeks followed by a 1-week break, or continuous dosing for 5 days followed by a 2-day break. In certain specific embodiments, compound I or its pharmaceutically acceptable salts, hydrates, or prodrugs are administered orally once daily at a dose of 8, 10, and / or 12 mg for 2 weeks followed by a 1-week break.

[0055] In some implementations, a treatment cycle is every 21 days. In some implementations, a treatment cycle is every 3 weeks. In some implementations, the patient takes compound I dihydrochloride orally for 2 weeks on, 1 week off, 8 or 10 mg once daily. In some implementations, the patient takes compound II orally twice daily, 600 mg each time. In some implementations, the non-small cell lung cancer is KRAS G12C mutation-positive non-small cell lung cancer. In some implementations, the non-small cell lung cancer is KRAS G12C mutation-positive non-small cell lung adenocarcinoma. In some implementations, the non-small cell lung cancer is KRAS G12C mutation-positive non-small cell lung squamous cell carcinoma.

[0056] In some implementations, the non-small cell lung cancer described herein includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or undetermined non-small cell lung cancer in histological classification; and in clinical stage including, but not limited to, locally advanced, and / or advanced (e.g., stage IIIB / IV) and / or metastatic non-small cell lung cancer.

[0057] 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 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 glands, and liver; in some embodiments, the non-small cell lung cancer is brain metastasis. In some embodiments, the non-small cell lung cancer is recurrent non-small cell lung cancer, including, but not limited to, bronchial obstruction non-small cell lung cancer, resectable recurrent non-small cell lung cancer, mediastinal lymph node recurrent non-small cell lung cancer, superior vena cava (SVC) obstruction non-small cell lung cancer, and severe hemoptysis non-small cell lung cancer.

[0058] In some preferred embodiments, the non-small cell lung cancer (NSCLC) is NSCLC that has not previously received systemic therapy. In some embodiments, the NSCLC is NSCLC that has progressed or relapsed after receiving at least one prior treatment regimen. In some embodiments, the NSCLC is NSCLC that has failed after at least one treatment regimen. In some embodiments, the NSCLC is NSCLC that has failed after two treatment regimens. In some embodiments, the NSCLC is NSCLC that is intolerant to chemotherapy. In some embodiments, the NSCLC is NSCLC that has failed anti-PD-1 / PD-L1 therapy and / or platinum-based chemotherapy.

[0059] In some embodiments, the non-small cell lung cancer patient is a pathologically confirmed locally advanced, unresectable, and / or metastatic non-small cell lung cancer patient with a KRAS G12C mutation who has progressed after prior anti-PD-1 / PD-L1 therapy and platinum-based chemotherapy or is intolerant to the above treatments due to toxicity, and / or the patient has not used KRAS G12C inhibitors, anti-angiogenic drugs, and has no other driver gene mutations with standard treatment measures. Optionally, the driver gene mutation is selected from EGFR, ALK, BRAF (V600E), HER2, MET (exon14), ROS1, RET, or NTRK1 / 2 / 3, etc.

[0060] In xenograft tumor animal models, drug combinations containing a primary active ingredient and a secondary active ingredient exhibit synergistic antitumor activity compared to single active ingredients. Trial data show that in KRASG12C mutation-positive locally advanced or metastatic non-small cell lung cancer, the combination of the primary and secondary active ingredients achieves a greater and more durable response. Importantly, while the primary and secondary active ingredients, when used as single active ingredients, only reduce tumor growth rate, the same dose in combination of the two active ingredients results in tumor volume reduction, thereby achieving an overall reduction in tumor growth.

[0061] Benefits obtained in clinical patients include, but are not limited to: prolonged progression-free survival (PFS), prolonged overall survival (OS), improved objective response rate (ORR), improved disease control rate (DCR), reduced number and / or severity of adverse reactions, and decreased distant metastasis rate and local control rate. Specifically, in some embodiments of this application, and particularly in specific embodiments thereof, in clinical trials, the progression-free survival (PFS) of human patients with non-small cell lung cancer is prolonged by approximately 1-3 months, preferably by approximately 4-6 months, further preferably by approximately 7-9 months, and more preferably by approximately 10-12 months; the objective response rate reaches approximately 10% or more, preferably approximately 15% or more, further preferably approximately 20% or more, more preferably approximately 30% or more, and especially approximately 35% or more; and the disease control rate reaches 50% or more, preferably approximately 60% or more, further preferably approximately 70% or more, more preferably approximately 80% or more, and especially approximately 90% or more.

[0062] In some embodiments, the pharmaceutical composition of this application is optionally combined with surgical resection and / or radiation therapy, and used in the preparation of a medicament for treating non-small cell lung cancer.

[0063] The dosing regimen can be determined comprehensively based on the drug's activity, toxicity, and patient tolerability. Generally, the components of the pharmaceutical composition of this application can be administered according to dosing regimens known in the art. In some embodiments, compound I or its pharmaceutically acceptable salts, hydrates, or prodrugs are administered in an intermittent manner; the intermittent dosing includes a dosing period and a withdrawal period, during which it can be administered once or multiple times daily. In some embodiments, the ratio of the dosing period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, and more preferably 2:0.5 to 1. A further preferred intermittent dosing method is one of the following: continuous dosing for 2 weeks followed by a 2-week break, continuous dosing for 2 weeks followed by a 1-week break, or continuous dosing for 5 days followed by a 2-day break. In certain specific embodiments, compound I or its pharmaceutically acceptable salts, hydrates, or prodrugs are administered orally once daily at a dose of 8, 10, and / or 12 mg for 2 weeks followed by a 1-week break.

[0064] In some implementations, a treatment cycle is every 21 days; in some implementations, a treatment cycle is every 3 weeks; in some implementations, the patient takes compound I dihydrochloride orally for 2 weeks, then stops for 1 week, once daily at a dose of 8 or 10 mg. In some implementations, the patient takes compound II orally twice daily at a dose of 600 mg.

[0065] Definitions and Explanations

[0066] Unless otherwise stated, the dosages and ranges provided herein are based on the molecular weight of the free base of the active ingredient.

[0067] Unless otherwise stated, for the purposes of this application, the following terms as used in this specification and claims shall have the following meanings. A particular term, without a specific definition, should not be considered uncertain or unclear, but should be understood in accordance with its ordinary meaning in the art.

[0068] When a trade name appears in this disclosure, it is intended to refer to the corresponding product or its active ingredient.

[0069] In this application, unless otherwise stated, the terms “comprise,” “comprises,” and “comprising” or their equivalents are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0070] Unless otherwise specified, singular terms encompass plural terms, and plural terms encompass singular terms. Unless otherwise specified, the words "a" or "an" mean "at least one" or "at least one". Unless otherwise specified, the use of "or" means "and / or".

[0071] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0072] As used in this application, unless otherwise indicated, the single dose or dose of the first and second active pharmaceutical ingredients is calculated in the form of the free base of the compound.

[0073] "Patient" or "subject" refers to a mammal, preferably a human.

[0074] "Pharmaceutical acceptable" means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes that it is acceptable for human pharmaceutical use.

[0075] "Therapeutic effective amount" means the amount of a compound that, when given to a person to treat a disease, is sufficient to achieve the therapeutic effect on that disease.

[0076] "Treatment" means any application of a therapeutically effective amount of a compound, and includes:

[0077] (1) Inhibit the disease in a human body that is experiencing or exhibiting the pathology or symptomology of the disease (i.e., block the further development of the pathology and / or symptomology), or

[0078] (2) Improve the pathology or symptomology of the disease in a human body that is experiencing or exhibiting the pathology or symptomology of the disease (i.e., reverse the pathology and / or symptomology).

[0079] The term “prevention” generally refers to (a) preventing the occurrence of disease or (b) delaying the onset of disease or the onset of disease symptoms.

[0080] The term "therapeutic effective amount" means the amount of the compound of this application used to (i) treat a specific disease, condition, or disorder; (ii) alleviate, improve, or eliminate one or more symptoms of a specific disease, condition, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a specific disease, condition, or disorder described in this application. The amount of active substance constituting a "therapeutic effective amount" (e.g., the antibody or compound of this application) may vary depending on factors such as an individual's disease state, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response in the individual. The effective amount may also be routinely determined by a person skilled in the art based on their own knowledge and the contents of this disclosure.

[0081] The terms “application” or “administration” mean introducing a composition containing a therapeutic agent into a host body using any of a variety of methods and delivery systems known to those skilled in the art.

[0082] The terms “pharmaceutical acceptable” or “medicinal” refer to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0083] The term "pharmaceutically acceptable salt" includes salts formed by a base-containing compound and a free acid, or salts formed by a acid-containing compound and a free base.

[0084] The term "pharmaceutical composition" refers to a substance formed by combining one or more active ingredients of this application, wherein the active ingredients may, together or individually, form a mixture with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound of this application or a combination thereof to a subject.

[0085] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to 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.

[0086] The term "single-dose pharmaceutical composition" refers to the smallest packaging unit containing a certain amount of pharmaceutical product. For example, if a box of medicine contains seven capsules, then each capsule is a single-dose pharmaceutical composition; or each vial of injection is a single-dose pharmaceutical composition. In this application, the terms "single-dose pharmaceutical composition" and "unit-dose pharmaceutical composition" have the same meaning and can be used interchangeably.

[0087] The term "fixed combination" refers to the simultaneous administration of the active ingredients to an individual at a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition, or formulation. In some embodiments, this may be, for example, present in the same tablet, capsule, injection, or pouch.

[0088] The term "non-fixed combination" refers to the simultaneous, concurrent, or sequential administration of two or more active ingredients as independent entities (e.g., pharmaceutical compositions, pharmaceutical formulations) to an individual without a specific time limit, wherein the active ingredient administered to the individual reaches a therapeutically effective level. Examples of non-fixed combinations include cocktail therapy, such as administering two, three, or more active ingredients. In a non-fixed combination, the individual active ingredients can be packaged, marketed, or administered as completely independent pharmaceutical compositions. The term "non-fixed combination" also includes the combined use of "fixed combinations" between each other, or of a "fixed combination" with any one or more independent entities of active ingredients.

[0089] "Treatment failure" refers to intolerable side effects, disease progression during treatment, or relapse after treatment.

[0090] "Optional / location" means whether it contains or does not contain.

[0091] "CR" means complete remission, which means that all target lesions disappear and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10mm.

[0092] "PR" refers to partial remission, where the sum of the diameters of the target lesions is reduced by at least 30% compared to the baseline level.

[0093] "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.

[0094] "PD" refers to disease progression, which is defined as the minimum sum of the diameters of all target lesions measured throughout the study, with a relative increase of at least 20% (or the baseline value if the baseline measurement is the minimum). The relative increase of the sum of the diameters must be at least 5 mm. The appearance of one or more new lesions is also considered disease progression.

[0095] "SD" means that the disease is stable, and the reduction in target lesions does not reach the PR level, nor does the increase reach the PD level, falling between the two.

[0096] "DCR" refers to the disease control rate, which is the percentage of patients with complete remission, partial remission, and stable disease for more than 4 weeks among those with evaluable efficacy.

[0097] "PFS" refers to progression-free survival, the time from randomization to objective progression of the tumor or death of the patient.

[0098] "OS" refers to overall survival, which is the time from enrollment to death from any cause. It is measured in days. For subjects lost to follow-up, the last follow-up date is usually counted as death.

[0099] "DOR" refers to the duration of disease response, calculated from the initial assessment of complete or partial response to the first disease progression or death from any cause. If a response is not confirmed, it is not included. Patients who did not experience disease progression or death from any cause before the data analysis cutoff date are treated as censored data, and the censoring date is determined using the PFS censoring time to determine the duration of response.

[0100] Technical effect

[0101] Surprisingly, the first and second active pharmaceutical ingredients of this application can synergistically achieve overall tumor remission and increase the median survival percentage in preclinical models, resulting in benefits in clinical patients. Furthermore, the pharmaceutical composition of this application exhibits good safety profile.

[0102] Furthermore, the pharmaceutical composition of this application will contribute to the safety of medication, progression-free survival (PFS), overall survival (OS), time to disease response (DOR), disease control rate (DCR), objective response rate (ORR), and its pharmacokinetics. Detailed Implementation

[0103] The present application will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present application.

[0104] Example 1: Pharmacodynamic evaluation in the NCI-H358 human lung cancer CB-17 SCID mouse xenograft tumor model

[0105] The first active pharmaceutical ingredient is compound I dihydrochloride, which was prepared according to the method described in Example 24 of WO2008112407 to obtain 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinoline-7-yl]oxy]methyl]cyclopropylamine, and then prepared according to the preparation method in the "Examples of Salt Form" of the specification of WO2008112407. The required dosage of the first active pharmaceutical ingredient is calculated based on the free base form of compound I.

[0106] The second active pharmaceutical ingredient is compound II, which is prepared according to the method disclosed in patent application WO2020233592.

[0107] SPF-grade female CB-17 SCID mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) were subcutaneously inoculated with NCI-H358 (KRAS G12C) human lung cancer cells in the right axilla, 5 × 10⁶ cells per cell line. 6 One dose per animal (1:1 Matrigel mixture inoculated). When the average tumor volume reached approximately 200 mm³, the animals were divided into 4 groups of 6 animals each. The specific grouping and dosage are shown in Table 1.

[0108] Table 1 Grouping and Dosage

[0109]

[0110] Day 0 was designated as the day of grouping, and medication was administered starting on day 0. Tumor volume was measured 2-3 times per week, and mouse weight was recorded. General behavior of the mice was observed and recorded daily. At the end of the experiment, the tumors were removed, weighed, and photographed.

[0111] The detection indicators and calculation formulas are as follows:

[0112] 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.

[0113] Relative to tumor volume, RTV = TV t / TV0; where TV0 is the tumor volume on day 0, TV t This represents the tumor volume at each measurement.

[0114] Relative tumor proliferation rate, T / C (%) = T RTV / C RTV × 100%; where T RTV For the treatment group, RTV; C RTV The solvent control group is RTV.

[0115] Tumor growth inhibition rate, TGI(%) = (1 - TW / TW0) × 100%; where TW is the tumor weight in the treatment group and TW0 is the tumor weight in the solvent control group.

[0116] Weight change rate, WCR (%) = (Wt) t -Wt0) / Wt0× 100%; where Wt0 is the mouse's body weight on day 0, Wt t The mouse's weight at each measurement.

[0117] The results of each test indicator on day 20 are shown in Table 2 below. No significant toxicity was observed in any of the treatment groups. The combined use of the second active ingredient group and the first active ingredient group showed significant inhibitory activity against subcutaneous xenografts of NCI-H358 human lung cancer mice, with a more significant reduction in tumor volume compared to the single active ingredient group. A one-way ANOVA comparison between the combined group and the single active ingredient group showed a p-value <0.01, indicating a significant difference.

[0118] Table 2. Effects of combined treatments on various indicators in the NCI-H358 human lung cancer mouse subcutaneous metaplastic tumor model.

[0119]

[0120] Note: Compared with the solvent control group, ***p<0.001. Compared with the first active ingredient group, ### p<0.001. Compared with the second active ingredient group, △△ p<0.01.

[0121] Example 2

[0122] Patients included:

[0123] Patients with locally advanced, unresectable, and / or metastatic non-small cell lung cancer with KRAS G12C mutations who have progressed after prior anti-PD-1 / PD-L1 therapy and platinum-based chemotherapy or are intolerant to the above treatments due to toxicity, and who have been pathologically confirmed to have KRAS G12C inhibitors, anti-angiogenic drugs, or other driver gene mutations that are not covered by standard treatment (such as EGFR, ALK, BRAF (V600E), HER2, MET (exon14), ROS1, RET, or NTRK1 / 2 / 3, etc.).

[0124] Dosage regimen:

[0125] The second active pharmaceutical ingredient is 600 mg BID + the first active pharmaceutical ingredient is 8 mg QD, or compound II is 600 mg BID + compound I dihydrochloride is 10 mg QD. The first active pharmaceutical ingredient is compound I dihydrochloride, and the required dose is calculated based on the free base form of compound I.

[0126] During the study, the dosage may be reduced based on patient tolerance and adverse reactions, up to a maximum of two dose reductions. Compound I dihydrochloride may be reduced sequentially by 10 mg, then 8 mg, then 6 mg; cross-dose adjustments are not permitted. Compound II may be reduced from a 600 mg BID to a 600 mg QD, then a 400 mg QD.

[0127] Usage and dosage:

[0128] Compound I dihydrochloride: Take 8 or 10 mg once daily on an empty stomach for 2 weeks, then stop for 1 week, for a total of 3 weeks (21 days) as one treatment cycle.

[0129] Compound II: Oral administration, 600 mg BID, every 21 days as one treatment cycle. Subjects will take Compound II orally on an empty stomach (no food or water for 2 hours before and after administration).

[0130] In this study, efficacy was evaluated and data analyzed every two cycles (C2, i.e., 6 weeks). The primary endpoints included the safety of the combination therapy and progression-free survival (PFS); secondary endpoints included overall survival (OS), time to disease response (DOR), disease control rate (DCR), objective response rate (ORR), and their pharmacokinetic parameters.

[0131] Experimental results: The combined use of the first and second active pharmaceutical ingredients yielded benefits in clinical patients, with prolonged progression-free survival and improved disease control and objective response rates.

Claims

1. The use of a pharmaceutical composition in the preparation of a medicament for treating KRAS G12C mutation-positive non-small cell lung cancer, characterized in that... It comprises 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 thereof, and the second active pharmaceutical ingredient is compound II or a pharmaceutically acceptable salt thereof.

2. The use according to claim 1, wherein, The first active pharmaceutical ingredient is compound I in the form of a free base, or a salt formed by compound I with any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic 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 sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid; The second active pharmaceutical ingredient is compound II in the form of a free base, or a salt formed by compound II and any of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic 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 sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, and stearic acid.

3. The use according to claim 1, wherein, The first active pharmaceutical ingredient is compound I dihydrochloride.

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

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

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

7. The use according to claim 1, wherein, The pharmaceutical composition of the first active pharmaceutical ingredient is selected from capsules, and the pharmaceutical composition of the second active pharmaceutical ingredient is selected from tablets.

8. The use according to claim 1, comprising: 1) A first active pharmaceutical ingredient in a single dose of 6 mg to 20 mg and 2) a second active pharmaceutical ingredient in a single dose of 50 mg to 2000 mg.

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

10. The use according to claim 1, wherein, The ratio of a single dose of the first active pharmaceutical ingredient to the second active pharmaceutical ingredient is selected from 0.3:100 to 40:

100.

11. The use according to claim 1, wherein, The ratio of the dose of the first active pharmaceutical ingredient to the dose of the second active pharmaceutical ingredient is selected from 3:600 to 6:

600.

12. The use according to claim 1, wherein, The KRAS G12C mutation-positive non-small cell lung cancer refers to locally advanced, and / or advanced and / or metastatic non-small cell lung cancer; the KRAS G12C mutation-positive non-small cell lung cancer refers to non-small cell lung cancer that has not previously received systemic treatment.

13. The use according to claim 1, wherein, The KRAS G12C mutation-positive non-small cell lung cancer refers to non-small cell lung cancer that has progressed or relapsed after receiving at least one prior treatment regimen; the KRAS G12C mutation-positive non-small cell lung cancer refers to non-small cell lung cancer that has failed after receiving at least one treatment regimen; the KRAS G12C mutation-positive non-small cell lung cancer refers to non-small cell lung cancer that has failed after receiving two treatment regimens; the KRAS G12C mutation-positive non-small cell lung cancer refers to non-small cell lung cancer that cannot tolerate chemotherapy; the KRAS G12C mutation-positive non-small cell lung cancer refers to non-small cell lung cancer that has failed after receiving anti-PD-1 / PD-L1 therapy and / or platinum-based chemotherapy.

14. The use according to claim 1, wherein, The compound I or a pharmaceutically acceptable salt thereof is administered via a dosing and discontinuation interval, wherein the ratio of the dosing to the discontinuation interval in days is 2:0.5 to 5.

15. The use according to claim 1, wherein, The ratio of the dosing period to the withdrawal period, in days, is 2:0.5 to 1.

16. The use according to claim 1, wherein, The compound I or a pharmaceutically acceptable salt thereof may be administered in one of the following ways with dosing and discontinuation intervals: continuous administration for 2 weeks followed by a 2-week break, continuous administration for 2 weeks followed by a 1-week break, or continuous administration for 5 days followed by a 2-day break; the compound II or a pharmaceutically acceptable salt thereof may be administered once or more daily.

17. The use according to claim 16, wherein, Compound I or a pharmaceutically acceptable salt thereof was administered continuously for 2 weeks and then on for 1 week. Compound II or a pharmaceutically acceptable salt thereof was administered twice daily.

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