CN120093749A

CN120093749A - Treatment of Breast Cancer

Info

Publication number: CN120093749A
Application number: CN202411761654.6A
Authority: CN
Inventors: 张和胜; 霍爱红; 刘秀萍; 李幸稳; 吕晶晶
Original assignee: Ganzhou Hemay Pharmaceutical Co Ltd
Current assignee: Ganzhou Hemay Pharmaceutical Co Ltd
Priority date: 2023-12-04
Filing date: 2024-12-03
Publication date: 2025-06-06

Abstract

Disclosed is the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in preparing a drug for treating breast cancer in an individual in combination with endocrine therapy. wherein the individual is hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+).

Description

Treatment of breast cancer

FIELD

The present disclosure relates generally to the field of biological medicine, and more particularly, to the treatment of breast cancer.

Background

Breast cancer is the most common cancer worldwide. Human epidermal growth factor receptor 2 (Human Epidermal Growth Factor Receptor, HER 2) is overexpressed in 20% to 25% of all breast cancers. HER2 positive (her2+) breast cancers exhibit aggressive clinical behavior, respond poorly to chemotherapy, and have higher metastasis and recurrence rates. HER 2-targeted therapies including trastuzumab, pertuzumab, pyrroltinib, lapatinib, and enmeltrastuzumab have significantly improved results in patients with her2+ breast cancer over the last two decades, regardless of the expression of Hormone Receptors (HR). The main guidelines recommend that HER2 targeted therapy be combined with chemotherapy as the basis for the treatment of hr+/her2+ breast cancer, independent of HR status. However, resistance to anti-HER 2 therapy remains challenging, highlighting the clinical need for new therapeutic approaches.

Co-expression of the Hormone Receptor (HR) affects about 50% of HER2+ breast cancers, thus HR+HER2+ breast cancers account for 10% to 15% of the total breast cancer population. Preclinical studies have shown that complex molecular signaling crosstalk between HER2 and ER signaling pathways may contribute to treatment resistance and will promote tumor progression. Indeed, the reduced responsiveness of hr+/her2+ disease to neoadjuvant anti-HER 2 targeting therapy in combination with chemotherapy results in a reduced likelihood of achieving complete remission of the pathology (pCR) compared to HR-/her2+ breast cancer.

SUMMARY

In one aspect, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of breast cancer in a subject in combination with endocrine therapy,

Wherein the individual is a hormone receptor positive (hr+) and/or human epidermal growth factor receptor 2 positive (her2+) individual.

In another aspect, the present disclosure relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating breast cancer in a subject in combination with endocrine therapy,

Brief description of the drawings

Figure 1 shows test information in which a Full Analysis Set (FAS) contains patients who received at least one dose of study drug, a safety data set (SS) contains patients who received at least one study drug and have a safety profile record, and an Effective Analysis Set (EAS) contains patients who received at least one study drug and evaluated at least once for efficacy after initial administration.

Detailed description of the preferred embodiments

In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, etc.

Throughout the specification and claims which follow, unless the context requires otherwise, the words "comprise" and "comprising" are to be construed in an open-ended, inclusive sense, i.e. "including but not limited to.

Reference throughout this specification to "one embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" means that a particular reference element, structure, or feature described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "one embodiment" or "an embodiment" or "another embodiment" appearing in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

It should be understood that, as used in the specification of this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically acceptable excipient includes a compound of formula (I) together with a pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

In this disclosure, the term "and/or" will be seen as a specific disclosure of each of two particular features or components, with or without the other. Thus, the term "and/or" as used in phrases such as "a and/or B" in this disclosure is intended to include "a and B", "a or B", "a" (alone) and "B" (alone). Also, the term "and/or" as used in phrases such as "A, B and/or C" is intended to encompass the various aspects A, B and C, A, B or C, A or B, B or C, A and B, B and C, A (alone), B (alone), and C (alone).

Definition of the definition

Accordingly, the following terms, as used in the specification and the appended claims, have the following meanings, unless otherwise indicated to the contrary:

in the present disclosure, the term "breast cancer" refers to a disease in which cells in the breast undergo uncontrolled proliferation. Breast cancer is generally classified into invasive ductal carcinoma and invasive lobular carcinoma.

In the present disclosure, the term "invasive ductal carcinoma" refers to the growth of cancer cells from the duct and then out of the duct to other sites of breast tissue.

In the present disclosure, the term "invasive lobular carcinoma" refers to the spread of cancer cells from the lobules, then from the lobules to the adjacent breast tissue.

In the present disclosure, the term "endocrine treatment" refers to any treatment capable of removing estrogen, blocking estrogen production, reducing estrogen levels, blocking estrogen effects, reducing estrogen effects, and/or causing instability, degradation, and/or downregulation of estrogen receptors in the menopausal state.

In the present disclosure, the term "agent for endocrine treatment" refers to any chemical compound or biological agent capable of removing estrogen, blocking estrogen production, and/or reducing estrogen levels.

In the present disclosure, the term "human epidermal growth factor receptor (Human Epidermal Growth Factor Receptor, HER 2)" refers to a protein encoded by the ERBB2 gene. HER2 is a member of the epidermal growth factor receptor (EGFR/ErbB) family. HER2 is a receptor tyrosine kinase that binds to the surface of cell membranes and is involved in signal transduction pathways leading to cell growth and differentiation, encoded by the proto-oncogene HER 2/neu.

In the present disclosure, the terms "ErbB2" and "HER2" are used interchangeably and refer to, for example, the human HER2 protein described in Semba et al, PNAS (USA) 82:6497-6501 (1985) and Yamamoto et al Nature319:230-234 (1986) (Genebank accession number X03363). The term "erbB2" refers to a gene encoding human erbB2, and "neu" refers to a gene encoding rat p185 neu.

In the present disclosure, a cell is said to be "HER2 positive" when HER2 is amplified or overexpressed in or on the cell. The level of HER2 amplification or overexpression in HER2 positive cells is typically expressed as a score of 0 to 3 (i.e., HER 20, HER 21 +, her22+ or HER 23 +), with higher scores corresponding to higher degrees of expression.

In the present disclosure, the term "Hormone Receptor" refers to a protein that is located on the surface of or within a cell, binds to a specific Hormone, and initiates a physiological biochemical reaction in the cell.

In the present disclosure, the term "estrogen receptor (Estrogen Receptor, ER)" refers to a protein that is located in a cell and that, as a receptor, can bind to and act on an estrogen molecule such as estradiol.

In the present disclosure, the term "hormone receptor positive (hr+)" refers to estrogen receptor positive (er+) or estrogen receptor positive (er+) and/or progesterone receptor positive (pr+).

In the present disclosure, the term "estrogen receptor positive (er+)" refers to positive expression tests of ER. According to recommendations provided by the american society of pathologists (CAP) and the American Society of Clinical Oncology (ASCO), if at least 1% of tumor cells are tested (e.g., by immunohistochemistry) for ER positive, the tumor is er+.

In the present disclosure, "er+ breast cancer" refers to breast cancer whose tumor cells express the Estrogen Receptor (ER). This sensitizes the tumor to estrogen, meaning that estrogen causes cancerous breast tumors to grow. In contrast, "ER-breast cancer" refers to breast cancer whose tumor cells do not express the Estrogen Receptor (ER). Wherein ER+ breast cancer includes Luminal A and subtypes B.

In the present disclosure, the term "postmenopausal" refers to any one of four conditions that have been previously followed by bilateral ovariectomy, age no less than 60 years, natural withdrawal no less than 12 months, and in the case of no chemotherapy, tamoxifen, toremifene or ovarian castration in the last 1 year, follicular Stimulating Hormone (FSH) and estradiol levels are in the postmenopausal range (using the reference range of the local laboratory). Patients of age <60 years who are taking tamoxifen or toremifene have FSH and estradiol levels in the postmenopausal range (using the reference range of the local laboratory).

In the present disclosure, ECOG scoring criteria is an indicator of a patient's physical strength as to his general health status and ability to tolerate treatment. The score of the ECOG physical condition scoring standard is 0 to 1 to 2, 3 to 4 to 5.

In the present disclosure, adverse events occurring in clinical trials are classified, with reference to adverse event term evaluation criteria (common terminology criteria for ADVERSE EVENTS, CTCAE) into a class 1 to a class 5. Grade 1, mild, no clinical symptoms or mild clinical symptoms, only seen clinically or diagnostically, no need for treatment. Grade 2, moderate, requiring minor, local or non-invasive treatment, limited tool activities of daily living (ACTIVITIES OF DAILY LIVING, ADL) comparable to the age, which are cooking, purchasing clothing, using telephone, financial, etc. The tool-type daily life activities refer to cooking, purchasing clothes, using a telephone, financial management and the like, and the self-care daily life activities refer to bathing, putting on and taking off clothes, eating, washing, taking medicine and the like, and are not bedridden. Grade 3, severe or medical significance but not immediately life threatening, hospitalization or prolonged hospitalization time, disability, limitation of self-care daily life. The self-rational daily life refers to bathing, dressing and taking off, eating, washing, taking medicine, etc., and is not bedridden. Grade 4, life threatening, requiring urgent treatment. Grade 5, death associated with adverse events.

In the present disclosure, the term "compound of the present disclosure or a pharmaceutically acceptable salt thereof" refers to a compound represented by formula (I) of the present disclosure and a pharmaceutically acceptable salt thereof.

In the present disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cattle, sheep, horses, and humans. In certain embodiments, the mammal comprises a human.

In the present disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cows, pigs, and sheep). In certain embodiments, the patient is a mammal comprising a male and a female. In certain embodiments, the patient is a human.

In the present disclosure, the term "pharmaceutically acceptable" refers to carriers, vehicles, diluents, excipients and/or salts that must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

In this disclosure, the term "arbitrary" or "arbitrarily" means that the subsequently described event or condition may or may not occur, and that the description includes instances where the event or condition occurs as well as instances where it does not.

In the present disclosure, the term "pharmaceutically acceptable adjuvant" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier, and the like that have been approved by the U.S. food and drug administration for use in humans or animals.

In the present disclosure, the term "vector" is defined as a compound that facilitates the introduction of the compound into a cell or tissue. Dimethyl sulfoxide (DMSO), for example, is commonly used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

In the present disclosure, the term "pharmaceutically acceptable salt" refers in particular to (S, E) -N- (4- (3-chloro-4- (pyridin-2-yl-methoxy) phenylamino) -3-cyano-7- (tetrahydrofuran-3-yloxy) quinolin-6-yl) -4- (dimethylamino) -but-2-enamide sesamimate.

In the present disclosure, the term "pharmaceutical composition" refers to a formulation of a compound described in the present disclosure with a medium that delivers a biologically active compound to a mammal, such as a human, as is commonly accepted in the art. Such vehicles include all pharmaceutically acceptable carriers, diluents or excipients.

In the present disclosure, the term "effective amount" refers to an amount of a drug effective to treat a tumor in a patient. An effective amount of the agent may reduce the number of cancer cells, reduce the size of the tumor, inhibit (i.e., slow to a certain degree and preferably prevent) infiltration of cancer cells into surrounding organs, inhibit (i.e., slow to a certain degree and preferably prevent) metastasis of the tumor, inhibit tumor growth to some extent, and/or alleviate one or more symptoms associated with the cancer to some extent. To the extent that the drug can prevent growth and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic. An effective amount may extend progression free survival (e.g., as measured by changes in the solid tumor efficacy assessment criteria RECIST or CA-125), result in objective relief (including partial relief or complete relief), increase overall survival, and/or improve one or more symptoms of the tumor (e.g., as assessed by FOSI).

In the present disclosure, the term "treatment" refers to any type of therapy that aims at terminating, preventing, ameliorating or reducing the susceptibility to clinical outcome described in the present disclosure. In certain embodiments, the term "treatment" relates to prophylactic treatment of a disorder or disease state defined in the present disclosure (i.e., a therapy that reduces susceptibility to a clinical condition). Thus, "treating," "treating" and their equivalents refer to any treatment of a pathological condition or disorder in a mammal (including a human) that achieves a desired pharmacological or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disorder or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure of the disorder and/or adverse effects attributable to the disorder. That is, "treating" includes (1) preventing the occurrence or recurrence of a disorder in an individual, (2) inhibiting the disorder, e.g., arresting its development, (3) stopping or terminating the disorder or at least symptoms associated therewith, so that the host is no longer afflicted with the disorder or symptoms thereof, e.g., by restoring or repairing lost, or defective function, or stimulating an ineffective process to cause regression of the disorder or symptoms thereof, or (4) alleviating, or ameliorating the disorder or symptoms associated therewith, wherein improvement is used broadly to refer to a reduction in the magnitude of at least a parameter, e.g., inflammation, pain, or immunodeficiency.

As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably or may be different in that a particular disease or disease state may not have known causative agents (and therefore cannot be interpreted by etiology) and therefore is not recognized as a disease, but rather is considered an undesired disease state or condition in which a clinician has identified more or less of a particular set of symptoms.

In the present disclosure, the term "concurrently administered" means that the first and second treatments in the combination treatment are administered for a time interval of no more than about 15 minutes, such as no more than any of about 10, 5, or 1 minute. When the first and second treatments are administered simultaneously, the first and second treatments may be contained in the same composition (e.g., the composition includes both the first and second treatments) or in separate compositions (e.g., the first treatment is contained in one composition and the second treatment is contained in another composition).

In the present disclosure, the term "sequentially administered" means that the first and second treatments in the combination treatment are administered for a time interval of greater than about 15 minutes, such as any of greater than about 20, 30, 40, 50, 60, or more minutes. Either the first treatment or the second treatment may be administered first. The first and second treatments are contained in separate compositions, which may be contained in the same or different packages or kits.

In the present disclosure, the term "simultaneous administration" means that administration of a first treatment and administration of a second treatment overlap each other in combination treatment.

In the present disclosure, the term "adverse event" (ADVERSE EVENT, AE) refers to any unexpected medical event in a patient receiving a market pharmaceutical product or in a patient participating in a clinical trial, being receiving a study or non-study medication. Adverse events are not necessarily causally related to patient treatment. Thus, the adverse event may be any adverse and unexpected sign, symptom, or disease associated with the application of the medical product at the time (temporally), whether or not considered related to the medical product. Many adverse events may be associated with the progression of a patient's underlying malignancy. Adverse events include, but are not limited to, pre-existing exacerbations of the disease, pre-existing occasional events or increases in frequency or intensity of the condition, detection or diagnosis of the condition after study drug administration, even though it may already exist prior to study initiation, and continued progression of the disease or symptom that exists at baseline and worsens after study initiation. Adverse events typically do not include medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, or blood transfusion), however, the condition that caused the procedure is an adverse event, pre-existing diseases, conditions, or laboratory abnormalities that exist or are detected at the beginning of the study, admission or procedures for selective purposes that are unrelated to unexpected medical events (e.g., admission to a hospital or social/convenient admission for cosmetic or selective surgery), the disease being studied or signs/symptoms associated with the disease unless the patient's condition is more severe than expected, and study drug overdose without any clinical signs or symptoms.

In the present disclosure, the term "serious adverse event (SEVERE ADVERSE EVENT, SAE)" refers to any unexpected medical event at any dose, including, but not limited to, a) fatal, b) life threatening (defined as the risk of immediate death upon occurrence of the event), c) resulting in sustained or significant disability or disability, d) requiring patient admission or prolonged existing admission (with the exception that admission with the aim of selectively treating a pre-existing condition that does not deteriorate during the study is not considered an adverse event. Complications that occur during admission are adverse events and are severe if the complications prolong admission), e) congenital anomalies/birth defects in the offspring of the patient receiving the drug, or f) conditions that are not encompassed by the definition above and that may jeopardize the patient or may require intervention to prevent one of the above listed consequences, unless clearly related to the underlying disease of the patient. "ineffective" (progressive disease) is not considered an adverse event. Signs and symptoms or clinical sequelae caused by the inefficiency should be reported if they meet the adverse event or severe adverse event definition.

In the present disclosure, the following definitions may be used to evaluate efficacy based on target lesions, "complete remission (complete response, CR)" means that all target lesions disappear, "Partial Remission (PR)" means that the sum of the longest diameters of target lesions (sum of the longest diameters, SLD) is reduced by at least 30% with reference to a baseline SLD, "disease stabilization (stabledisease, SD)" means that with reference to the minimum SLD, the target lesions begin to shrink neither sufficiently to meet partial remission nor sufficiently to meet disease progression, "disease progression (progressive disease, PD)" means that with reference to the reported minimum SLD, the SLD of the target lesions increases by at least 20% or one or more new lesions exist, "no evaluation (unable to evaluate, UE)" means that target lesions exist at baseline, the status of a specific tumor at a point in time at which a discussion cannot be determined is measured or cannot be evaluated (if SLD at a point in time at which disease progression is not specified is not applicable), the target lesions are not fully reduced to meet partial remission nor sufficiently to meet disease progression, the "disease progression (progressive disease, PD)" means that no evaluation is performed by a patient is not being able to evaluate the baseline), and "no evaluation" means that no evaluation of efficacy is performed by the patient is performed at the point (35 NA).

In the present disclosure, the definition of efficacy assessment may be used to assess non-target lesions where "complete remission (complete response, CR)" refers to the disappearance of all non-target lesions, "Stable Disease (SD)" refers to the persistence of one or more non-target lesions that do not meet complete remission or disease progression, "disease progression (progressive disease, PD)" refers to the "clear progression" of an existing non-target lesion, or the appearance of one or more new lesions is considered to be disease progression (if disease progression of a subject is assessed based on the progression of only non-target lesions, then other criteria need to be met.) in this case, lesions undergoing assessment of disease progression must be assessed retrospectively from baseline (or the lowest value), and compared to the point of time at which a study is made, disease progression of non-target lesions in this case may be assessed when SLD of lesions has increased by 20% or more and the Longest Dimension (LD) measurement of lesions at 10mm or more, if the non-target lesions do not meet the quantitative criteria, then it will not be assessed as such that do not meet the quantitative criteria (if fluid, fluid is assessed as described below) and fluid is assessed at any point of no more than 35, fluid is assessed at the point of time of no further than 35, fluid is assessed as being able to be stable as assessed at the point of no more than the baseline (or more than 35). ND) "means that no scan was performed at this time point to evaluate non-target lesions.

In this disclosure, the term "based on" includes assessing, determining or measuring patient characteristics described herein (and preferably selecting a patient suitable for receiving treatment). When an individual characteristic is "used as a basis" to administer or select a method of treatment described herein, the individual characteristic is evaluated prior to and/or during the treatment and the conclusions drawn are used by the clinician to evaluate any of (a) the likelihood that the individual initially received the treatment(s), (b) the likelihood that the individual initially received the treatment(s), (c) the treatment is alleviated, (d) the likelihood that the individual continues to receive the treatment(s), (e) the likelihood that the individual continues to receive the treatment(s), (f) the dose is adjusted, or (g) the likelihood of predicting clinical benefit.

In the present disclosure, the term "likely remission" or "remission" refers to any type of clinical or non-clinical improvement or positive response, including, but not limited to, a measurable decrease in tumor size or sign of disease or disease progression, complete remission, partial remission, disease stabilization, increased or prolonged progression-free survival, or increased or prolonged overall survival.

In the present disclosure, the term "progression free survival (progression free survival, PFS)" refers to the length of time during and after treatment that the tumor does not grow. Progression free survival includes the time that the patient experiences complete or partial remission, as well as the time that the patient experiences disease stabilization.

In the present disclosure, "complete remission (complete response, CR)" of a treatment is defined as a patient suffering from an estimated but not measurable disease whose tumor and all signs of disease have disappeared.

In this disclosure, a "Partial Response (PR)" definition of a treatment is that any patient less than complete relief is simply categorized as exhibiting partial relief.

In the present disclosure, the term "disease stable (stabledisease, SD)" means that the patient is stable.

In the present disclosure, the term "survival" refers to a patient that is still alive and includes Disease Free Survival (DFS), progression Free Survival (PFS), and total survival (OS). The survival can be assessed by the Kaplan-Meier method and any differences in survival calculated using a hierarchical log rank test (STRATIFIED LOG-rank test).

In the present disclosure, the term "disease-free survival (DFS)" refers to a defined period of time, e.g., about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc., for which the patient remains alive from the beginning of treatment or from an initial diagnosis, without recurrent cancer.

In this disclosure, the term "Overall Survival (OS)" refers to a defined period of time that a patient remains alive from the beginning of treatment or from an initial diagnosis, e.g., about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc. In the disclosure, the event for lifetime analysis is death due to any cause.

In the present disclosure, the term "neoadjuvant therapy" or "preoperative therapy" refers to therapy provided prior to surgery. The goal of neoadjuvant therapy is to provide immediate systemic treatment, possibly eradicating micrometastases (which would otherwise proliferate if following the standard order of surgery followed by systemic therapy). Neoadjuvant therapy may also help reduce tumor size thereby allowing complete resection of an initially unresectable tumor or preserving part of the organ and its function. In addition, neoadjuvant therapy allows for in vivo assessment of drug efficacy, which may guide subsequent treatment options.

In the present disclosure, the term "adjuvant therapy" refers to a therapy provided when no sign of residual disease can be detected after surgery to reduce the risk of disease recurrence. The goal of adjuvant therapy is to prevent recurrence of the tumor and thus reduce the chance of tumor-related death.

In the present disclosure, the term "metastasis" refers to the spread of a tumor from its primary site to elsewhere in the body. Cancer cells can detach from the primary tumor, infiltrate into lymphatic and blood vessels, circulate through the blood stream and grow (metastasize) in distant lesions in normal tissue elsewhere in the body. The transfer may be in situ or remote. Metastasis is a sequential process, depending on the situation where tumor cells are detached from the primary tumor, migrate through the blood stream, and reside at a remote site. At the new site, the cells establish a blood supply and can grow to form life threatening masses.

In the present disclosure, the term "recurrence" includes the reoccurrence of tumor cells at the same site and organ from which the disease originated, metastasis that may occur even after years of initial diagnosis and treatment of the cancer, or local events such as infiltration of tumor cells into regional lymph nodes. "distant recurrence" refers to the situation where cancer cells have spread (metastasized) to distant sites other than regional lymph nodes of the body (i.e., another organ).

Detailed Description

In yet another aspect, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating breast cancer in a subject in combination with endocrine therapy,

In certain embodiments, illustrative examples of individuals that can be used in the present disclosure include, but are not limited to, individuals that are estrogen receptor positive (er+), individuals that are human epidermal growth factor receptor 2 positive (her2+), and individuals that are both positive for estrogen receptor and human epidermal growth factor receptor 2 (er+her2+).

In certain embodiments, illustrative examples of individuals that can be used in the present disclosure include, but are not limited to, postmenopausal individuals that are positive for estrogen receptor (er+), postmenopausal individuals that are positive for human epidermal growth factor receptor 2 (her2+), and postmenopausal individuals that are both positive for estrogen receptor and human epidermal growth factor receptor 2 (er+her2+).

In certain embodiments, illustrative examples of breast cancers that can be used in the present disclosure include, but are not limited to, metastatic breast cancer and recurrent breast cancer.

In certain embodiments, illustrative examples of drugs that can be used in endocrine treatment of the present disclosure include, but are not limited to, estrogen receptor modulators, estrogen receptor inhibitors, and aromatase inhibitors.

In certain embodiments, illustrative examples of estrogen receptor modulators that can be used in the present disclosure include, but are not limited to, selective estrogen receptor down-regulators.

In certain embodiments, illustrative examples of selective estrogen receptor down-modulators that can be used in the present disclosure include, but are not limited to, fulvestrant.

In certain embodiments, illustrative examples of estrogen receptor inhibitors that can be used in the present disclosure include, but are not limited to, selective estrogen receptor inhibitors.

In certain embodiments, illustrative examples of selective estrogen receptor inhibitors that can be used in the methods of the present disclosure include, but are not limited to, tamoxifen, raloxifene, and toremifene.

In certain embodiments, illustrative examples of aromatase inhibitors that can be used in the present disclosure include, but are not limited to, letrozole, anastrozole, and exemestane.

In certain embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, and a therapeutically effective amount of exemestane is administered.

In certain embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, and a therapeutically effective amount of letrozole is administered.

In certain embodiments, 300mg to 600mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered daily to an individual.

In certain embodiments, 200mg, 300gm, 400mg, 500mg, or 600mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered daily to an individual.

In certain embodiments, 300mg to 600mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to an individual once daily.

In certain embodiments, 200mg, 300mg, 400mg, 500mg or 600mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered to an individual once daily.

In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a subject.

In certain embodiments, 200mg, 300gm, 400mg, 500mg, or 600mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is orally administered to a subject.

In certain embodiments, 200mg, 300gm, 400mg, 500mg, or 600mg of a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered orally to an individual once daily.

In certain embodiments, illustrative examples of pharmaceutically acceptable salts of compounds of formula (I) that can be used in the present disclosure include, but are not limited to, acid addition salts.

In certain embodiments, illustrative examples of pharmaceutically acceptable acid addition salts that can be used with the compounds of formula (I) of the present disclosure include, but are not limited to, inorganic acid addition salts and organic acid addition salts.

In certain embodiments, illustrative examples of pharmaceutically acceptable inorganic acid addition salts that can be used with the compounds of formula (I) of the present disclosure include, but are not limited to, addition salts of hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids.

In some embodiments of the present invention, in some embodiments, illustrative examples of pharmaceutically acceptable organic acid addition salts of the compounds of formula (I) that can be used in the present disclosure include, but are not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzene carboxylic acid, 4-acetaminophenylacetic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanyl sulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethane sulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, maleic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid and the addition salts of undecylenic acid.

In certain embodiments, the pharmaceutically acceptable salt of a compound of formula (I) that can be used in the present disclosure is the dimaleate salt.

In certain embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject and concurrently endocrine therapy is administered to the subject.

In certain embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject and the endocrine treatment is administered to the subject sequentially.

In certain embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to an individual and an endocrine treatment is administered simultaneously to the individual.

In certain embodiments, the present disclosure excludes chemotherapy.

Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand the aspects of the present application and the advantages thereof. However, it should be understood that the following examples are non-limiting and are merely illustrative of certain embodiments of the present disclosure.

Examples

Preparation example

Example 1

Preparation of (S, E) -N- (4- (3-chloro-4- (pyridin-2-yl-methoxy) phenylamino) -3-cyano-7- (tetrahydrofuran-3-yloxy) quinolin-6-yl) -4- (dimethylamino) -but-2-enamide

The title compound was prepared according to the procedure for the preparation of example 138 in CN 102933578B.

Example 2

Preparation of (S, E) -N- (4- (3-chloro-4- (pyridin-2-yl-methoxy) phenylamino) -3-cyano-7- (tetrahydrofuran-3-yloxy) quinolin-6-yl) -4- (dimethylamino) -but-2-enamide dimesylate

2.5G of the compound of example 1, 1.45g of maleic acid, 22.7ml of ethanol, 2.3ml of distilled water are stirred at 70 ℃. After the solution was completely dissolved, the solution was stirred again for about 5 minutes, suction filtration was performed, the filter cake was washed with 11ml of ethanol and discarded, and the washing solution and the filtrate were combined and stirred at room temperature overnight. After suction filtration and washing of the filter cake with 5.7ml ethanol, the title compound was obtained by drying in vacuo at 40 ℃.

Clinical trial

Patient and method

Patient population

1) The result of tumor histopathology is diagnosed as breast cancer patient;

2) Objective evidence shows that patients with advanced stages of metastasis or recurrence who fail to achieve cure by standard treatment;

3) ER positive (. Gtoreq.1%) and HER2 positive (immunohistochemical detection 3+ and/or in situ hybridization detection positive), suitable for exemestane as postmenopausal female patient for endocrine therapy;

4) Remark: expansion phase for which 6 subjects who included letrozole in combination and 6 subjects who included fulvestrant in combination were scheduled to be added, respectively, in the 400mg dose group, the expansion phase was for postmenopausal female patients who included "fit letrozole or fulvestrant as endocrine therapy" for this part of subjects;

5) Postmenopausal is defined as meeting any one of four conditions:

prior to double sided ovariectomy;

age no less than 60 years old;

age <60 years, natural withdrawal > 12 months, follicular Stimulating Hormone (FSH) and estradiol levels in postmenopausal ranges (reference range using local laboratories) without chemotherapy, tamoxifen, toremifene or ovarian castration in the last 1 year.

● Patients of age <60 years who are taking tamoxifen or toremifene, FSH and estradiol levels in the postmenopausal range (reference range using local laboratories);

Remark perimenopausal or perimenopausal women who do not meet the above menopausal criteria may also be enrolled in the study, but are concurrently undergoing norrader ovarian suppression therapy which has been initiated at least 14 days prior to initiation of the regimen and must continue for the duration of the regimen;

6) For subjects who are difficult to determine post-menopausal status, the determination of whether to enter the group is determined after the study is conducted in conjunction with the sponsor medical staff.

7) At least one evaluable tumor lesion (according to RECIST 1.1) or only bone metastases;

8) ECOG activity status score 0-1;

9) The expected survival time is more than 3 months;

10 The functions of the marrow are more than or equal to 1.5X109/L of ANC (neutrophil), more than or equal to 90g/L of HB (hemoglobin) (blood transfusion is allowed), and more than or equal to 80X 109/L of PLT (platelet). Liver function is satisfied with ALT (glutamic pyruvic transaminase) not more than 2.5 XULN (upper limit of normal), AST (aspartic aminotransferase) not more than 2.5 XULN, TBIL (total bilirubin) not more than 1.5 XULN (liver metastasis patient ALT not more than 5 XULN, AST not more than 5 XULN), kidney function is satisfied with blood creatinine not more than 1.5 XULN;

The main exclusion criteria is that the exemestane treatment was excluded from the queue of exemestane combinations (note: exemestane can be included if it was used for adjuvant therapy and was taken off for 12 months or more before this group). For the combination letrozole cohort, the past treatment with letrozole was excluded (note: letrozole could be included if it was used in the adjuvant phase and stopped for 12 months or more before this group was included). For the cohort of the combination fulvestrant, patients who had been treated with fulvestrant were excluded.

Study design

The study was divided into two parts. In the first section, a multi-center, open, combination, escalating dose trial design was used. The compounds shown in example 2 were dosed in four dose groups of 200mg, 300mg, 400mg and 500mg daily, in step-wise fashion, according to the conventional 3+3 principle. The second part adopts a multi-center, open, combined drug administration and dose expansion test design. Three dose groups (300 mg, 400mg and 500 mg) were selected for expansion.

Evaluation of efficacy

The solid tumor RECIST 1.1 (2009) standard was used as an estimated efficacy evaluation standard.

Efficacy assessment method the size of lesions in subjects is assessed by imaging. The subjects had the same imaging pattern at all follow-up points. Efficacy assessments were performed every 8 weeks during treatment.

The evaluation includes Objective Remission Rate (ORR), clinical Benefit Rate (CBR), defined as the ratio of Complete Remission (CR) +partial remission (PR) +disease Stabilization (SD) (. Gtoreq.24 weeks), disease Control Rate (DCR), defined as the ratio of cr+pr+sd, progression Free Survival (PFS).

Safety evaluation

Vital signs, physical examination, blood routine, urine routine + microscopy, blood biochemistry (liver and kidney function, electrolytes, blood glucose, blood lipids), blood clotting function, electrocardiogram (ECG), left ventricular ejection fraction, etc. were examined to observe and record Adverse Events (AEs) to assess safety. Adverse events were collected 30 days after the first dose to the last dose of the subject.

Conclusion(s)

Dose finding and expanding

In the up-dosing phase, 3 subjects were enrolled in each of four groups of 200mg, 300mg, 400mg and 500mg daily of the compound of example 2 in combination with 25mg daily exemestane. No dose limiting toxicity was observed in any of the cohorts during the first 4 weeks of treatment). For the dose extension phase, 3 dose groups (300 mg, 400mg and 500 mg) were selected. During the study period, the 300mg dose group was stopped based on the preliminary efficacy data. Queues 400mg and 500mg are still continuing to complete. In a 400mg cohort, 6 patients were combined with letrozole (25 mg per day), 6 patients were combined with fulvestrant (500 mg intramuscular once per day on days 1, 15, 29, and thereafter 500mg intramuscular once every 28[ ±3] days) to further investigate the safety of compound combinations of formula (I) to letrozole or fulvestrant.

Safety of

Among 55 subjects, treatment-induced adverse events (TEAE) were mostly within the 1-2 scale. The most common grade 3 TEAE is diarrhea (9.1%). No drug-related adverse reactions of grade 4 or more were observed in the test.

Efficacy of

Table 1. Efficacy data summary (EAS)

Note that NA: not available (unable to calculate)

In this disclosure, relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions.

From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without deviating from the spirit and scope of the disclosure. Such variations or modifications are intended to fall within the scope of the claims appended hereto.

Claims

1. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of breast cancer in a subject in combination with endocrine therapy,

Wherein the individual is a hormone receptor positive (hr+) and human epidermal growth factor receptor 2 positive (her2+).

2. The use of claim 1, wherein the individual is an individual that is estrogen receptor positive (er+) and human epidermal growth factor receptor 2 positive (her2+), preferably an individual that is postmenopausal estrogen receptor positive (er+) and human epidermal growth factor receptor 2 positive (her2+), wherein the breast cancer is metastatic breast cancer or recurrent breast cancer.

3. The use according to any one of claims 1 to 2, wherein the endocrine treatment comprises administering to the individual a therapeutically effective amount of an estrogen receptor modulator, an estrogen receptor inhibitor and/or an aromatase inhibitor, wherein the estrogen receptor modulator is a selective estrogen receptor down-regulator, preferably fulvestrant, wherein the estrogen receptor inhibitor is a selective estrogen receptor inhibitor, preferably tamoxifen, raloxifene and toremifene, wherein the aromatase inhibitor is selected from the group consisting of letrozole, anastrozole and exemestane.

4. Use according to any one of claims 1 to 3, wherein 200mg to 600mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual daily, preferably 200mg to 600mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual daily.

5. The use according to any one of claims 1 to 4, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

6. The use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of breast cancer in a subject in combination with endocrine therapy,

7. The method according to claim 6, wherein the individual is an individual positive for estrogen receptor (ER+) and positive for human EGF receptor 2 (HER2+), preferably an individual positive for estrogen receptor (ER+) and positive for human EGF receptor 2 (HER2+) after menopause, wherein the breast cancer is metastatic breast cancer or recurrent breast cancer.

8. The use according to any one of claims 6 to 7, wherein the endocrine treatment comprises administering to the individual a therapeutically effective amount of an estrogen receptor modulator, an estrogen receptor inhibitor and/or an aromatase inhibitor, wherein the estrogen receptor modulator is a selective estrogen receptor down-regulator, preferably fulvestrant, wherein the estrogen receptor inhibitor is a selective estrogen receptor inhibitor, preferably tamoxifen, raloxifene and toremifene, wherein the aromatase inhibitor is selected from letrozole, anastrozole and exemestane.

9. The use according to any one of claims 6 to 8, wherein 200mg to 600mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual daily, preferably 200mg to 600mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual daily.

10. The use according to any one of claims 6 to 9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.