CN120154618B - Use of Caesalpinia cristata Lei Sai for the treatment of lung cancer or pharmaceutical compositions thereof - Google Patents

Abstract

This application belongs to the pharmaceutical field and provides the use of gaserexate for the treatment of lung cancer or a pharmaceutical composition thereof, particularly for KRAS G12C mutation-positive non-small cell lung cancer, wherein gaserexate tablets are administered in combination with a first active pharmaceutical ingredient for the treatment of lung cancer, which can achieve a greater and more durable response, overall reduction of tumor growth, and benefit clinical patients.

Description

Use of Caesalpinia cristata Lei Sai for the treatment of lung cancer or pharmaceutical compositions thereof

Technical Field

The application belongs to the field of medicines, and particularly relates to an application of a guo Lei Sai in treating lung cancer or a pharmaceutical composition thereof.

Background

A study in which item Lungscape evaluates the prognostic role of KRAS G12C mutations in NSCLC in european populations showed that KRAS mutation rate was 23% and KRAS G12C mutation rate was 10.5% in the cohort of 2055 NSCLC patients. In patients with adenocarcinoma, the KRAS mutation rate was 38.0% and the KRAS G12C mutation rate was 17.0%.

The advanced NSCLC of KRAS G12C mutation has not yet lacked a specific first-line treatment regimen, which is currently mostly referred to advanced NSCLC without driver gene by NSCLC guide of the national institute of clinical oncology (CSCO) in 2021. First-line treatment regimens include platinum-containing dual-drug chemotherapy in combination with anti-PD-1/PD-L1 or platinum-containing dual-drug chemotherapy in combination with anti-angiogenic or anti-PD-1/PD-L1 single agents, but no large randomized clinical trial has yet evaluated their effectiveness in KRAS G12C mutation-positive advanced NSCLC patients.

After receiving first-line treatment, KRAS G12C mutation-positive advanced NSCLC, second-line treatment approaches were very limited and less effective. The two-line treatment scheme used in clinic mainly comprises docetaxel chemotherapy and pemetrexed single-drug chemotherapy, and ORR is only 4.2-5.5% and 8.5% respectively. Docetaxel combined with ramucirumab (ramucirumab) two-line therapy has ORR up to 23%, but ramucirumab was not approved domestically for advanced NSCLC treatment.

In current clinical practice, there is still a lack of treatment regimens for advanced NSCLC positive for KRAS G12C mutations.

Disclosure of Invention

In one aspect, the application provides a pharmaceutical composition comprising a first pharmaceutically active ingredient which is compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and a second pharmaceutically active ingredient which is compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof,

。

In some embodiments, the pharmaceutical composition is for treating lung cancer.

In a second aspect, the application provides the use of a pharmaceutical composition according to the application for the manufacture of a medicament for the treatment of lung cancer.

Use of a first pharmaceutically active ingredient in the manufacture of a medicament for use in 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.

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

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

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

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 of the present application.

In some embodiments, the first pharmaceutically active ingredient is in a non-fixed combination with the first second pharmaceutically active ingredient.

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.

In some embodiments, 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 in the non-fixed combination.

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.

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

First pharmaceutically active ingredient or pharmaceutical composition thereof

In the application, the chemical name of the compound I is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, which has the following structural formula:

a compound I.

In the present application, pharmaceutically acceptable salts of compound I can be produced from different organic and inorganic acids according to methods well known in the art. "pharmaceutically acceptable salts" include, but are not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, caproic 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, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and the like. 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 a monohydrochloride salt of compound I. In some embodiments, the 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, the pharmaceutically acceptable salt of compound I is a crystal of compound I dihydrochloride. In some embodiments, the pharmaceutically acceptable salt of compound I is the maleate salt of compound I.

In some embodiments of the application, compound I is in the form of the free base. In some embodiments, the free base of compound I is in an amorphous form.

In some embodiments, the first pharmaceutically active ingredient is in the form of a pharmaceutical composition, preferably the pharmaceutical composition is selected from a solid pharmaceutical composition, more preferably from a tablet or capsule.

In some embodiments, the first pharmaceutically active ingredient is An Luoti nii hydrochloride.

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

Second pharmaceutically active ingredient or pharmaceutical composition thereof

In the present application, compound II has the following structural formula:

Compound II.

In some embodiments of the application, compound II is in the form of the free base. In some embodiments, the free base of compound II is in an amorphous form.

In some embodiments, pharmaceutically acceptable salts of compound II can be produced from different organic and inorganic acids according to methods well known in the art. "pharmaceutically acceptable salts" include, but are not limited to, acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, caproic 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, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and the like. In some embodiments, the pharmaceutically acceptable salt of compound II is in crystalline form.

In some embodiments, the second pharmaceutically active ingredient is in the form of a pharmaceutical composition, preferably the pharmaceutical composition is selected from a solid pharmaceutical composition, more preferably from a tablet or capsule.

In some embodiments, the second pharmaceutically active ingredient is a pessary Lei Sai.

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

Pharmaceutical composition

In some embodiments, each component of the pharmaceutical compositions described herein may optionally be combined with one or more pharmaceutically acceptable carriers, wherein the components may each independently, or some or all of them together contain pharmaceutically acceptable carriers and/or excipients.

The pharmaceutical compositions of the present application may be formulated separately from each other, or some or all of them may be formulated together. Preferably, the components of the pharmaceutical composition are formulated separately or each as a suitable pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present application may be formulated into pharmaceutical compositions suitable for single or multiple administration. In some particular embodiments, the pharmaceutical composition containing compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof may be selected from solid pharmaceutical compositions including, but not limited to, tablets or capsules. In some particular embodiments, the pharmaceutical composition containing compound II or a pharmaceutically acceptable salt, hydrate, or prodrug thereof may be selected from solid pharmaceutical compositions including, but not limited to, tablets or capsules.

In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient of the pharmaceutical composition are each in a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 1) a single dose of 6mg to 20mg of the first pharmaceutically active ingredient of the present application and 2) a single dose of 50mg to 2000mg of the second pharmaceutically active ingredient.

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

In some embodiments, the ratio of the single doses of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is selected from 0.1:100 to 100:100. In some embodiments, the ratio of the single doses 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 any of the ranges formed above. In some embodiments, the ratio of the single doses of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is selected from 3:100, 4:100, 5:100, or 6:100.

In some embodiments, the ratio of the dosages 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 ratio of the doses 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 any of the ranges formed above. In some embodiments, the ratio of the dosage of the first pharmaceutically active ingredient to the second pharmaceutically active ingredient is selected from 3:600, 4:600, 5:600, or 6:600.

Dosing/treatment or prevention regimen for pharmaceutical compositions

In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient may be administered separately, regardless of the order of administration. In some embodiments, the first pharmaceutically active ingredient and the second pharmaceutically active ingredient may be administered simultaneously.

In some embodiments, an effective amount of the first and second pharmaceutically active ingredients may be administered simultaneously, sequentially or at intervals to an individual in need thereof.

In some embodiments, an effective amount of the first and second pharmaceutically active ingredients may be administered to an individual in need thereof according to the same or different dosing regimen.

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

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, e.g., 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 6mg to about 20 mg. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of 6mg, 8mg, 10mg, 12mg. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of 6mg, 8mg, 10mg, 12mg, once daily. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of 6mg, 8mg, 10mg, 12mg, once daily, each dose being 6mg, 8mg, 10mg or 12mg.

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, e.g., 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 1mg to about 2000 mg. In some embodiments, the first pharmaceutically active ingredient is administered in a single dose of 100mg, 200mg, 300mg, 400mg, 600mg, 800mg, 900mg, 1000mg, 1200 mg. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of 100mg, 200mg, 300mg, 400mg, 600mg, 800mg, 900mg, 1000mg, 1200mg, twice daily. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of 100mg, 200mg, 300mg, 400mg, 600mg, twice daily, each dose being 400mg, 600mg or 800mg. In some embodiments, the second pharmaceutically active ingredient is administered in a single dose of 200mg twice daily, each dose being 600mg.

In some embodiments, the administering comprises administering the first pharmaceutically active ingredient separately or simultaneously with the second pharmaceutically active ingredient.

In the present application, the components of the pharmaceutical composition may be administered to a patient as separate entities (e.g., pharmaceutical compositions) simultaneously, alternately or sequentially, wherein the active ingredient administered to the patient is at a therapeutically effective level. The individual active components may be packaged, sold or administered as a completely separate pharmaceutical composition. An example is cocktail therapy, for example, administration of 3 or more active ingredients.

The amount of each component administered in the pharmaceutical composition of the present application may be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered at a daily dose of 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, the compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof may be administered one or more times daily, preferably once daily, and in some embodiments, the compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered once daily in an oral solid formulation.

In some embodiments, compound II, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, is administered at a daily dose of 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, the compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof may be administered one or more times daily, preferably twice daily, and in some embodiments, the compound II or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered twice daily in an oral solid formulation.

In the present application, the administration schedule can be comprehensively determined according to the activity, toxicity, tolerance of the patient, and the like of the drug. In general, the components of the pharmaceutical compositions of the present application may be administered according to dosing regimens known in the art. In some embodiments, compound I or a pharmaceutically acceptable salt, hydrate, or prodrug thereof is administered in a divided dosing regimen, including a dosing period and a dosing period, which may be administered one or more times per day during the dosing period. 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, more preferably 2:0.5 to 1. As a still more preferable mode of the interval administration, one of the following modes is that the administration is stopped for 2 weeks continuously, for 1 week continuously, for 2 weeks continuously, or for 2 days continuously, for 5 days continuously. In certain particular embodiments, compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered orally at a dose of 8, 10 and/or 12mg once daily for 2 weeks, and for 1 week in a continuous dosing regimen.

In some embodiments, one treatment cycle is every 21 days. In some embodiments, one treatment cycle is every 3 weeks. In some embodiments, the patient orally administers compound I dihydrochloride 1 time a day, 8 or 10 mg a day, for 2 weeks continuously for 1 week. In some embodiments, the patient orally administers compound II 2 times daily, 600 mg times daily. In some embodiments, the non-small cell lung cancer is KRAS G12C mutation-positive non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is KRAS G12C mutation positive non-small cell lung adenocarcinoma. In some embodiments, the non-small cell lung cancer is KRAS G12C mutation positive non-small cell lung squamous carcinoma.

In some embodiments, the non-small cell lung cancer is histologically typed including, but not limited to, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or undefined non-small cell lung cancer, and is clinically staged including, but not limited to, locally advanced, and/or advanced (e.g., stage IIIB/IV) and/or metastatic non-small cell lung cancer.

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, focal single metastasis, disseminated metastasis, 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, liver, in some embodiments, the non-small cell lung cancer is brain-metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is recurrent non-small cell lung cancer, including but not limited to intrabronchial obstructive non-small cell lung cancer, resectable recurrent non-small cell lung cancer, recurrent non-small cell lung cancer of the mediastinum lymph node, superior Vena Cava (SVC) obstructive non-small cell lung cancer, severe hemoptysis non-small cell lung cancer.

In some preferred embodiments, the non-small cell lung cancer is non-small cell lung cancer that has not previously been treated systematically. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that develops or recurs after having been previously subjected to at least one treatment regimen. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has failed treatment with at least one regimen. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has failed treatment by two regimens. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that is intolerant to chemotherapy. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has failed anti-PD-1/PD-L1 therapy and/or platinum-containing chemotherapy.

In some embodiments, the patient of non-small cell lung cancer is a patient of pathologically confirmed, locally advanced, unresectable and/or metastatic, KRAS G12C mutated non-small cell lung cancer who had undergone anti-PD-1/PD-L1 treatment and platinum-containing chemotherapy or who was intolerant of such treatment due to toxicity, and/or who has not used KRAS G12C inhibitors, anti-angiogenic drugs, has no other driver gene mutation with standard therapeutic measures, optionally selected from EGFR, ALK, BRAF (V600E), HER2, MET (exon 14), ROS1, RET, or NTRK1/2/3, and the like.

In animal models of xenograft tumors, a pharmaceutical combination comprising a first pharmaceutical active ingredient and a second pharmaceutical active ingredient may result in a synergistic anti-tumor activity compared to a single pharmaceutical active ingredient. Experimental data indicate that a combination of the first and second pharmaceutical active ingredients can achieve a greater and longer lasting response for locally advanced or metastatic non-small cell lung cancer positive for KRAS G12C mutations. Importantly, the first and second pharmaceutically active ingredients, when used as a single pharmaceutical active ingredient, only reduce the tumor growth rate, whereas the same dosage can achieve a reduction in tumor volume when the two pharmaceutically active ingredients are combined, thereby generally alleviating tumor growth.

Benefits are obtained in clinical patients, including, but not limited to, extended Progression Free Survival (PFS), extended Overall Survival (OS), improved Objective Remission Rate (ORR), improved Disease Control Rate (DCR), reduced number and/or extent of adverse reactions, reduced distant metastasis rates, and reduced local control rates, among others. In particular, in some embodiments of the application, and in particular embodiments of the application, progression Free Survival (PFS) in clinical trials in human patients with non-small cell lung cancer is extended for about 1-3 months, preferably about 4-6 months, more preferably about 7-9 months, more preferably about 10-12 months, objective remission rate of the patient is up to about 10% or more, preferably up to about 15% or more, more preferably up to about 20% or more, more preferably up to about 30% or more, especially up to 35% or more, disease control rate of the patient is up to 50% or more, preferably up to about 60% or more, more preferably up to about 70% or more, more preferably up to about 80% or more, especially up to 90% or more.

In some embodiments, the pharmaceutical composition of the application is optionally combined with surgical excision and/or radiation therapy, and is used in the manufacture of a medicament for the treatment of non-small cell lung cancer.

The dosage regimen may be determined in general terms of the activity, toxicity, tolerance of the drug, etc. In general, the components of the pharmaceutical compositions of the present application may be administered according to dosing regimens known in the art. In some embodiments, compound I or a pharmaceutically acceptable salt, hydrate, or prodrug thereof is administered in a divided dosing regimen, including a dosing period and a dosing period, which may be administered one or more times per day during the dosing period. 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, more preferably 2:0.5 to 1. As a still more preferable mode of the interval administration, one of the following modes is that the administration is stopped for 2 weeks continuously, for 1 week continuously, for 2 weeks continuously, or for 2 days continuously, for 5 days continuously. In certain particular embodiments, compound I or a pharmaceutically acceptable salt, hydrate or prodrug thereof is administered orally at a dose of 8, 10 and/or 12mg once daily for 2 weeks, and for 1 week in a continuous dosing regimen.

In some embodiments, one treatment cycle every 21 days, in some embodiments, one treatment cycle every 3 weeks, and in some embodiments, the patient orally administers compound I dihydrochloride 1 time a day, 8 or 10 mg a each time for 2 weeks continuously for 1 week. In some embodiments, the patient orally administers compound II 2 times daily, 600 mg times daily.

Definition and description

Herein, unless otherwise indicated, the dosages and ranges provided herein are based on the molecular weight of the free base of the active ingredient.

For the purposes of the present application, the following terms, as used in the specification and claims, shall have the following meanings, unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art.

When trade names are presented in this disclosure, it is intended to refer to their corresponding commercial products or active ingredients thereof.

In the present application, unless otherwise indicated, the terms "comprises," "comprising," and "includes," or equivalents thereof, are open ended and mean that other, unspecified elements, components, and steps are contemplated in addition to the listed elements, components, and steps.

Unless specifically stated otherwise, singular terms encompass a plurality of terms and plural terms encompass singular terms. The terms "a" or "an" mean "at least one" or "at least one" unless specifically indicated otherwise. The use of "or" means "and/or" unless stated otherwise.

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 for their disclosure prior to the filing date of the present application. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents. Moreover, any reference to such publications in this document does not constitute an admission that the publications are part of the common general knowledge in the art, in any country.

As used herein, unless otherwise indicated, the single dose or dosage of the first and second pharmaceutically active ingredients is calculated as the free base form of the compound.

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

By "pharmaceutically acceptable" is meant 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.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a human being for treating a disease, is sufficient to effect treatment of the disease.

"Treatment" means any administration of a therapeutically effective amount of a compound and includes:

(1) Inhibiting the disease in a human experiencing or exhibiting the pathology or symptomology of the disease (i.e., arresting further development of the pathology and/or symptomology), or

(2) Improving the disease in a human experiencing or exhibiting the pathology or symptomology of the disease (i.e., reversing the pathology and/or symptomology).

The term "preventing" generally refers to (a) preventing the onset of a disease or (b) delaying the onset of a disease or the onset of symptoms of a disease.

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

The term "administering" or "administering" means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art.

The term "pharmaceutically acceptable" or "pharmaceutically acceptable" is employed with respect to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" includes salts of the compound containing a base ion with a free acid or salts of the compound containing a base ion with a free base.

The term "pharmaceutical composition" refers to a substance formed by the combination of one or more active ingredients of the present application, which may be combined or individually combined with pharmaceutically acceptable excipients to form a mixture. The purpose of the pharmaceutical composition is to facilitate administration of the compound of the application or a pharmaceutical combination thereof to a subject.

The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The term "single dose pharmaceutical composition" refers to the smallest unit of packaging containing a quantity of a drug, e.g., a kit of seven capsules, each capsule being a single dose pharmaceutical composition, or a single dose pharmaceutical composition per vial of injectate. In the present application, the terms "single dose pharmaceutical composition" and "unit dose pharmaceutical composition" have the same meaning and are used interchangeably.

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

The term "non-fixed combination" refers to the simultaneous, concurrent or sequential administration of two or more active ingredients as separate entities (e.g., pharmaceutical compositions, pharmaceutical preparations) to an individual, wherein the administration of the active ingredients to the individual achieves a therapeutically effective amount level, without specific time limitations. An example of a non-fixed combination is a cocktail therapy, e.g., administration of 2, 3 or more active ingredients. In a non-fixed combination, the individual active ingredients may be packaged, marketed or administered as a fully independent pharmaceutical composition. The term "non-immobilized combination" also includes the use of "immobilized combinations" between, or in combination with, separate entities of any one or more of the active ingredients.

"Treatment failure" refers to intolerance of toxic or side effects, disease progression during treatment, or recurrence after treatment has ended.

"Optional/optionally" means that it is either inclusive or exclusive.

By "CR" is meant complete remission, i.e., all target lesions disappear, and all pathological lymph nodes (including target nodes and non-target nodes) short diameters must be reduced to <10mm.

By "PR" is meant partial remission, the sum of target lesion diameters is reduced by at least 30% from baseline levels.

"ORR" refers to the objective rate of remission, which is the sum of the ratio of complete remission and partial remission. That is, orr=cr+pr.

"PD" refers to disease progression, with reference to the minimum of the sum of diameters of all measured target lesions throughout the study, a diameter sum of at least 20% (reference to baseline if the baseline measurement is minimal), and a relative increase of at least 5mm must be met if one or more new lesions appear.

"SD" means that the disease is stable, the target lesions are reduced to a degree that does not reach PR levels, nor are increased to a degree that does not reach PD levels, between the two.

"DCR" refers to disease control rate and includes the percentage of patients who are fully relieved, partially and stable for disease and who have sustained more than 4 weeks of disease in which efficacy can be assessed.

"PFS" refers to progression-free survival from random grouping until the time of objective progression of the tumor or death of the patient.

"OS" refers to the total lifetime and refers to the time from the start of the group to death due to any source. Subjects who were not visited, in days, were generally counted as dead from the last follow-up time.

"DOR" refers to the time of disease remission, starting from the first assessment of tumor as complete remission or partial remission, to the time of first disease progression or death of various causes, and is not employed if tumor remission is not confirmed. If the patient does not develop disease progression or die of various causes before the date of data analysis expires, the date of deletion is treated with the deletion data and the PFS deletion time is used to determine the duration of remission.

Technical effects

Surprisingly, it was found that the first and second pharmaceutical active ingredients according to the application synergistically achieve overall tumor remission and increase the median percent survival in preclinical models, yielding benefits in clinical patients. Meanwhile, the pharmaceutical composition provided by the application has good safety.

Further, the pharmaceutical composition of the present application will contribute to safety of administration, patient Progression Free Survival (PFS), total survival (OS), time to disease remission (DOR), rate of Disease Control (DCR), rate of objective remission (ORR), and pharmacokinetics thereof.

Detailed Description

The application will be further illustrated with reference to specific examples. It is understood that these examples are provided only for illustrating the present application and are not intended to limit the scope of the present application.

EXAMPLE 1 pharmacodynamic evaluation in NCI-H358 human lung cancer CB-17 SCID mouse xenograft tumor model

The first pharmaceutically active ingredient is compound I dihydrochloride, which is prepared according to the method described in example 24 of WO2008112407 to give 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, followed by the preparation method described in the specification of WO2008112407 as "examples in salt form". Wherein the required dose of the first pharmaceutically active ingredient is calculated as the free base form of compound I.

The second pharmaceutically active ingredient is compound II, which is prepared according to the method disclosed in patent application WO 2020233592.

NCI-H358 (KRAS G12C) human lung cancer cells were inoculated subcutaneously in the right armpit of SPF-grade female CB-17 SCID mice (source: shanghai Ling Biotechnology Co., ltd.) at 5X 10 ⁶/1:1 mixed Matrigel inoculation. When the average tumor volume reached around 200mm3, animals were divided into 4 groups of 6 animals each, and the specific groupings and doses are shown in table 1:

TABLE 1 grouping and dosing agent

The day of the grouping was day 0 and dosing was started on day 0. Tumor volumes were measured 2-3 times a week, mice were weighed and data recorded, and mice were observed and recorded daily for general performance. After the experiment is finished, the tumors are peeled, weighed and photographed.

The detection index and the calculation formula are as follows:

Tumor volume, TV (mm ³)= 1/2 × (a × b²), where a is tumor major diameter and b is tumor minor diameter.

Rtv=tv _t/TV₀, where TV ₀ is the tumor volume on day 0 and TV _t is the tumor volume at each measurement.

Relative to tumor proliferation rate, T/C (%) =t _RTV/C_RTV ×100%, where T _RTV is RTV in the treatment group and C _RTV is RTV in the vehicle control group.

Tumor growth inhibition, TGI (%) = (1-TW/TW ₀) ×100%, wherein TW is the tumor weight of the treatment group and TW ₀ is the tumor weight of the vehicle control group.

Weight change rate, WCR (%) = (Wt _t-Wt₀)/ Wt₀ ×100%; where Wt ₀ is the mouse weight on day 0 and Wt _t is the mouse weight at each measurement.

The results of the detection indexes on day 20 are shown in the following table 2, and each administration group has no obvious toxicity, and the second drug active ingredient group and the first drug active ingredient group have obvious inhibition activity on NCI-H358 human lung cancer subcutaneous transplantation tumor after being combined, so that the tumor volume of mice with single active ingredient group is reduced more remarkably. The P value obtained by comparing the combination group with the single active ingredient group by using the One-way ANOVA method is less than 0.01, and the difference is obvious.

TABLE 2 influence of combination on various indices in NCI-H358 human lung cancer mouse subcutaneous engram model

Note that p <0.001 compared to vehicle control. ^### p <0.001 compared to the first pharmaceutically active ingredient group. ^△△ p <0.01 compared to the second pharmaceutical active ingredient group.

Example 2

Enrolling patients:

No KRAS G12C inhibitor, anti-angiogenic drug, and no other driver mutations with standard therapeutic measures (e.g., EGFR, ALK, BRAF (V600E), HER2, MET (exon 14), ROS1, RET, or NTRK1/2/3, etc.) have been used in pathologically established, locally advanced, unresectable and/or metastatic, KRAS G12C mutated, non-small cell lung cancer patients who had undergone anti-PD-1/PD-L1 treatment and platinum-containing chemotherapy or who had failed to tolerate such treatment due to toxicity.

Dosing regimen:

The second pharmaceutically active ingredient mg BID + the first pharmaceutically active ingredient 8mg QD or compound II mg BID + compound I dihydrochloride 10mg QD. Wherein the first pharmaceutically active ingredient is compound I dihydrochloride, and the required dosage is calculated according to the free base form of compound I.

The dose administered can be adjusted down, up to 2 doses, depending on patient tolerance and adverse reactions during the course of the study. Compound I dihydrochloride was down-regulated in sequence according to 10 mg-8 mg-6 mg, disallowing cross-dose adjustment. Compound II can be reduced from 600 mg BID to 600 mg QD, 400mg QD.

The usage amount is as follows:

compound I dihydrochloride is administered on an empty stomach 1 time a day, 8 or 10 mg a times a day, for 2 weeks continuously for 1 week, i.e. 3 weeks (21 days) as a treatment cycle.

Compound II was orally administered, 600 mg BID, every 21 days for a treatment period, and subjects would take compound II orally on an empty stomach (2 hours before and after dosing, except for drinking water) each day.

In this study, efficacy was evaluated every 2 cycles (C2, i.e., 6 weeks) and data analysis was performed. The primary indicators include safety of observed combination, patient Progression Free Survival (PFS), and the secondary indicators include total survival (OS), time to disease remission (DOR), rate of Disease Control (DCR), rate of objective remission (ORR), and pharmacokinetic parameters thereof.

The experimental result shows that the combination of the first medicine active ingredient and the second medicine active ingredient can obtain benefits in clinical patients, the progression-free survival time of the patients is prolonged, and the disease control rate and the objective remission rate are improved.

Claims (17)

1. The application of a pharmaceutical composition in preparing a medicament for treating KRAS G12C mutation positive non-small cell lung cancer is characterized by comprising a first pharmaceutical active ingredient and a second pharmaceutical active ingredient, wherein the first pharmaceutical active ingredient is a compound I or pharmaceutically acceptable salt thereof, the second pharmaceutical active ingredient is a compound II or pharmaceutically acceptable salt thereof,

2. The use according to claim 1, wherein the first pharmaceutically active ingredient is compound I in the form of the free base or a salt of compound I with any of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, caproic 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, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid;

the second active pharmaceutical ingredient is compound II in the form of free base or the salt formed by compound II and any acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, propionic acid, caproic 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, t-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid and stearic acid.

3. Use according to claim 1, wherein the first pharmaceutically active ingredient is compound I dihydrochloride.

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

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

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

7. Use according to claim 1, 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.

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

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

10. The use according to claim 1, wherein the ratio of the single doses of the first and second pharmaceutically active ingredients is selected from 0.3:100 to 40:100.

11. The use according to claim 1, wherein the ratio of the doses of the first and second pharmaceutically active ingredients 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 is locally advanced, and/or advanced and/or metastatic non-small cell lung cancer, and wherein the KRAS G12C mutation positive non-small cell lung cancer is non-small cell lung cancer that has not previously been treated systematically.

13. The use of claim 1, wherein the KRAS G12C mutation-positive non-small cell lung cancer is non-small cell lung cancer that progressed or relapsed after having been previously subjected to at least one treatment regimen, wherein the KRAS G12C mutation-positive non-small cell lung cancer is non-small cell lung cancer that failed treatment by at least one regimen, wherein the KRAS G12C mutation-positive non-small cell lung cancer is non-small cell lung cancer that failed treatment by both regimens, wherein the KRAS G12C mutation-positive non-small cell lung cancer is non-small cell lung cancer that is not resistant to chemotherapy, and wherein the KRAS G12C mutation-positive non-small cell lung cancer is non-small cell lung cancer that failed treatment by anti-PD-1/PD-L1 and/or platinum-containing chemotherapy.

14. The use according to claim 1, wherein the compound I or a pharmaceutically acceptable salt thereof is administered in a ratio of 2:0.5 to 5 in days between administration period and withdrawal period.

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

16. The use according to claim 1, wherein the compound I or a pharmaceutically acceptable salt thereof is administered at intervals between administration periods and withdrawal periods in one of 2 weeks of continuous administration, 1 week of continuous administration or 5 days of continuous administration for 2 days of withdrawal, and the compound II or a pharmaceutically acceptable salt thereof may be administered one or more times daily.

17. The use of claim 16, wherein the compound I or pharmaceutically acceptable salt thereof is administered 2 weeks off for 1 week and the compound II or pharmaceutically acceptable salt thereof is administered twice daily.