Treatment of breast cancer

Abstract

Disclosed is the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer in an individual in combination with endocrine therapy # imgabs0 # wherein the individual is a hormone receptor positive (HR +) and human epidermal growth factor receptor 2 positive (HER2 +) individual.

Description

[0001] field

[0002] The present disclosure relates generally to the field of biomedicine, and more particularly to the treatment of breast cancer. background

[0003] Breast cancer is the most common cancer worldwide. Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in 20% to 25% of all breast cancers. HER2-positive (HER2+) breast cancer exhibits aggressive clinical behavior, responds poorly to chemotherapy, and has high rates of metastasis and recurrence. HER2-targeted therapies, including trastuzumab, pertuzumab, pyrotinib, lapatinib, and emtansine, have significantly improved outcomes in patients with HER2+ breast cancer over the past two decades, regardless of hormone receptor (HR) expression. Major guidelines recommend HER2-targeted therapy in combination with chemotherapy as the basis for the treatment of HR+ / HER2+ breast cancer, regardless of HR status. However, resistance to anti-HER2 therapy remains challenging, highlighting the clinical need for new treatments.

[0004] Co-expression of hormone receptors (HR) affects approximately 50% of HER2+ breast cancers, so 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. In fact, HR+ / HER2+ disease is less responsive to neoadjuvant anti-HER2 targeted therapy combined with chemotherapy compared to HR- / HER2+ breast cancer, resulting in a reduced likelihood of achieving pathological complete remission (pCR).

[0005] Overview

[0006] In one aspect, the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer in an individual in combination with endocrine therapy.

[0007]

[0008] The individual is a hormone receptor positive (HR+) and / or human epidermal growth factor receptor 2 positive (HER2+) individual.

[0009] In another aspect, the present disclosure relates to the use of a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer in an individual in combination with endocrine therapy.

[0010]

[0011] The individual is a hormone receptor positive (HR+) and / or human epidermal growth factor receptor 2 positive (HER2+) individual. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 The trial information is shown, including the full analysis set (FAS), which includes patients who have received at least one dose of study drug; the safety data set (SS), which includes patients who have received at least one study drug and have safety profile records; and the effective analysis set (EAS), which includes patients who have received at least one study drug and whose efficacy has been evaluated at least once after the initial dose.

[0013] Details

[0014] In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0015] Unless otherwise required by the present disclosure, throughout the specification and claims that follow, the words "including" and "comprising" should be interpreted in an open, inclusive sense, ie, "including, but not limited to."

[0016] References throughout this specification to "one embodiment" or "another embodiment" or "an embodiment" or "certain embodiments" mean that the specific referenced elements, structures, or features described in connection with the embodiment are included in at least one embodiment. Thus, the phrases "one embodiment" or "an embodiment" or "another embodiment" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any appropriate manner in one or more embodiments.

[0017] It should be understood that the singular article "a" (corresponding to the English "a", "an" and "the") used in the specification and the appended claims of the present disclosure includes plural objects, unless otherwise expressly provided in the text. Therefore, for example, the pharmaceutical composition comprising "a compound shown in formula (I) and a pharmaceutically acceptable excipient" mentioned includes a compound shown in formula (I) and a pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0018] In the present disclosure, the term "and / or" will be considered as a specific disclosure of each of two specific features or components with or without the other. Therefore, the term "and / or" used in phrases such as "A and / or B" in the present disclosure is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to cover the following aspects: A, B, and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0019] definition

[0020] Accordingly, unless otherwise indicated to the contrary, the following terms used in the specification and appended claims shall have the following meanings:

[0021] In this disclosure, the term "breast cancer" refers to a disease in which cells in the breast proliferate uncontrollably. Breast cancer is generally divided into invasive ductal carcinoma and invasive lobular carcinoma.

[0022] In this disclosure, the term "invasive ductal carcinoma" refers to cancer cells that begin in the ducts and then grow outside the ducts to other parts of the breast tissue.

[0023] In this disclosure, the term "invasive lobular carcinoma" means that the cancer cells start in the lobules and then spread from the lobules to nearby breast tissue.

[0024] In this disclosure, the term "endocrine therapy" refers to any treatment that can remove estrogen, block estrogen production, reduce estrogen levels, block the effect of estrogen, reduce the effect of estrogen and / or can cause instability, degradation and / or downregulation of estrogen receptors in the menopausal state.

[0025] In the present disclosure, the term "agent for endocrine therapy" refers to any chemical compound or biological agent that is capable of removing estrogen, blocking the production of estrogen and / or reducing the level of estrogen.

[0026] In the present disclosure, the term "human epidermal growth factor receptor 2 (HER2)" 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 cell membrane surface, participates in the signal transduction pathway that leads to cell growth and differentiation, and is encoded by the proto-oncogene HER2 / neu.

[0027] In the present disclosure, the terms "ErbB2" and "HER2" are used interchangeably and refer to the human HER2 protein (Genebank Accession No. X03363) described in, for example, Semba et al., PNAS (USA) 82: 6497-6501 (1985) and Yamamoto et al. Nature 319: 230-234 (1986). The term "erbB2" refers to the gene encoding human ErbB2, and "neu" refers to the gene encoding rat p185neu.

[0028] In the present disclosure, when HER2 is amplified or overexpressed in or on a cell, the cell is referred to as "HER2 positive." The level of HER2 amplification or overexpression in a HER2 positive cell is typically expressed as a score from 0 to 3 (i.e., HER2 0, HER2 1+, HER22+, or HER2 3+), with higher scores corresponding to higher levels of expression.

[0029] In the present disclosure, the term "hormone receptor" refers to a protein located on the cell surface or inside the cell that binds to a specific hormone and triggers a physiological and biochemical response in the cell.

[0030] In the present disclosure, the term "estrogen receptor (ER)" refers to a protein located in cells, which acts as a receptor and can bind to estrogen molecules (such as estradiol) and exert its effects.

[0031] 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+).

[0032] In the present disclosure, the term "estrogen receptor positive (ER+)" refers to a tumor that tests positive for the expression of ER. According to the recommendations provided by the College of American Pathologists (CAP) and the American Society of Clinical Oncology (ASCO), a tumor is ER+ if at least 1% of the tumor cells test positive for ER (e.g., by immunohistochemistry).

[0033] In the present disclosure, "ER+ breast cancer" refers to breast cancer whose tumor cells express estrogen receptors (ER). This makes the tumor sensitive to estrogen, which means that estrogen makes the cancerous breast tumor grow. Conversely, "ER- breast cancer" refers to breast cancer whose tumor cells do not express estrogen receptors (ER). ER+ breast cancer includes Luminal A and B subtypes.

[0034] In this disclosure, the term "postmenopausal" refers to any of the following four conditions: previous bilateral oophorectomy; age ≥ 60 years old; age < 60 years old, natural menopause ≥ 12 months, follicle stimulating hormone (FSH) and estradiol levels within the postmenopausal range (using the reference range of the local laboratory) without chemotherapy, tamoxifen, toremifene or ovarian castration in the past year. For patients aged < 60 years who are taking tamoxifen or toremifene, FSH and estradiol levels are within the postmenopausal range (using the reference range of the local laboratory).

[0035] In the present disclosure, the ECOG scoring standard is an indicator of the patient's general health status and tolerance to treatment based on his / her physical strength. The ECOG physical condition scoring standard is scored as 0, 1, 2, 3, 4, and 5 points.

[0036]

[0037] In the present disclosure, adverse events occurring in clinical trials are classified and graded from 1 to 5 with reference to the common terminology criteria for adverse events (CTCAE). Grade 1, mild, no clinical symptoms or mild clinical symptoms; only clinical or diagnostic findings; no treatment required. Grade 2, moderate, requiring minor, local or non-invasive treatment; limited instrumental activities of daily living (ADL) corresponding to age, instrumental activities of daily living refer to cooking, buying clothes, using the phone, managing finances, etc. Instrumental activities of daily living refer to cooking, buying clothes, using the phone, managing finances, etc.; self-care activities of daily living refer to bathing, dressing and undressing, eating, washing, taking medicine, etc., and are not bedridden. Grade 3, severe or of important medical significance but not immediately life-threatening; leading to hospitalization or prolonged hospitalization; disability; limited self-care daily life. Self-care daily life refers to: bathing, dressing and undressing, eating, washing, taking medicine, etc., and are not bedridden. Grade 4, life-threatening, requiring emergency treatment. Grade 5, death related to adverse events.

[0038] In the present disclosure, the term "compound of the present disclosure or a pharmaceutically acceptable salt thereof" refers to the compound represented by formula (I) of the present disclosure and a pharmaceutically acceptable salt thereof.

[0039] In the present disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans, etc. In certain embodiments, the mammal includes humans.

[0040] 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., cattle, pigs, and sheep). In certain embodiments, the patient is a mammal, including males and females. In certain embodiments, the patient is a human.

[0041] In the present disclosure, the term "pharmaceutically acceptable" refers to the carrier, vehicle, diluent, excipient and / or salt which must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0042] In the present disclosure, the terms “optional” or “arbitrarily” mean that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0043] In the present disclosure, the term "pharmaceutically acceptable excipients" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration for use in humans or animals, and various forms of carriers that have no side effects on the composition of the pharmaceutical composition.

[0044] In this disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is often used as a carrier because it facilitates the introduction of certain organic compounds into cells or tissues of an organism.

[0045] In the present disclosure, the term "pharmaceutically acceptable salt" refers specifically 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 disesquimaleate.

[0046] In the present disclosure, the term "pharmaceutical composition" refers to a preparation of the compounds described in the present disclosure and a medium generally accepted in the art for delivering the bioactive compound to mammals such as humans. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients.

[0047] In the present disclosure, the term "effective amount" refers to the amount of a drug that is effective in treating a tumor in a patient. An effective amount of a drug can reduce the number of cancer cells; reduce the size of a tumor; inhibit (i.e., slow down to a certain extent and preferably prevent) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down to a certain extent and preferably prevent) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent. To the extent that a drug can prevent growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. An effective amount can prolong progression-free survival (e.g., as measured by RECIST or CA-125 changes in solid tumor efficacy evaluation criteria), lead to objective remission (including partial remission or complete remission), increase overall survival, and / or improve one or more symptoms of a tumor (e.g., as assessed by FOSI).

[0048] In the present disclosure, the term "treatment" refers to any type of therapy, the purpose of which is to terminate, prevent, improve or reduce susceptibility to the clinical outcomes described in the present disclosure. In certain embodiments, the term "treatment" relates to the preventive treatment of the disorder or disease state defined in the present disclosure (i.e., a therapy that reduces susceptibility to the clinical condition). Therefore, "treatment", "treatment" and their equivalent terms refer to any treatment of a pathological state or disorder in a mammal (including a human) to obtain a desired pharmacological or physiological effect. The effect can be preventive in terms of completely or partially preventing a disorder or its symptoms, and / or can be therapeutic in terms of partial or complete cure of a disorder and / or a deleterious effect attributable to the disorder. That is, "treating" includes (1) preventing the occurrence or recurrence of a disorder in a subject, (2) inhibiting a disorder, such as arresting its development, (3) stopping or terminating the disorder or at least the symptoms associated therewith so that the host no longer suffers from the disorder or its symptoms, such as by restoring or repairing lost, lost or defective functions, or stimulating ineffective processes to cause regression of the disorder or its symptoms, or (4) alleviating, alleviating or ameliorating a disorder or symptoms associated therewith, where improvement is used in a broad sense to refer to at least a reduction in the magnitude of a parameter such as inflammation, pain or immune deficiency.

[0049] As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably, or may be distinct in that a particular disease or disease state may have no known causative agent (and therefore cannot be explained etiologically) and therefore is not recognized as a disease, but rather is considered an undesirable disease state or condition in which clinicians have identified a more or less specific set of symptoms.

[0050] In the present disclosure, the term "simultaneous administration" means that the first treatment and the second treatment in the combination therapy are administered no more than about 15 minutes apart, such as no more than about 10, 5, or 1 minute apart. When the first and second treatments are administered simultaneously, the first and second treatments can 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 in one composition and the second treatment is contained in another composition).

[0051] In the present disclosure, the term "sequential administration" means that the first treatment and the second treatment in the combination therapy are administered at a time interval of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first treatment or the second treatment can be administered first. The first and second treatments are contained in separate compositions, which can be contained in the same or different packages or kits.

[0052] In the present disclosure, the term "simultaneous administration" means that the administration of a first treatment and the administration of a second treatment in a combination therapy overlap with each other.

[0053] In this disclosure, the term "adverse event" (AE) refers to any unexpected medical occurrence in a patient receiving a marketed drug product or a patient participating in a clinical trial, receiving an investigational or non-investigational agent. An adverse event is not necessarily causally related to the patient's treatment. Therefore, an adverse event can be any unfavorable and unexpected sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered to be related to the medicinal product. Many adverse events may be related to the progression of a patient's underlying malignancy. Adverse events include, but are not limited to: worsening of a pre-existing disease; an increase in the frequency or intensity of a pre-existing incident or condition; the detection or diagnosis of a condition after the administration of the study drug, even if it may have existed before the start of the study; and the continuation of a disease or symptom that was present at baseline and worsened after the start of the study. Adverse events generally do not include: a medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, or blood transfusion); however, the condition leading to the procedure is an adverse event; a pre-existing disease, condition, or laboratory abnormality that was present or detected at the start of the study and did not worsen; an admission or procedure for an elective purpose not related to an unexpected medical event (e.g., admission for cosmetic or elective surgery or social / convenience admissions); the disease being studied or signs / symptoms related to that disease, unless the patient's condition is more severe than expected; and an overdose of study drug without any clinical signs or symptoms.

[0054] In this disclosure, the term "serious adverse event (SAE)" refers to any unexpected medical occurrence at any dose, including but not limited to the following: a) fatal; b) life-threatening (defined as an immediate risk of death when the event occurs); c) resulting in persistent or significant disability or incapacity; d) requiring hospitalization of the patient or prolonging an existing hospitalization (Exception: Hospitalization for the purpose of elective treatment of a pre-existing condition that does not worsen during the study is not considered an adverse event. Complications that occur during hospitalization are adverse events, and if the complication prolongs the hospitalization, the event is severe); e) congenital anomalies / birth defects in the offspring of the patient who received the drug; or f) a condition not included in the above definitions that may endanger the patient or may require intervention to prevent one of the consequences listed above, unless clearly related to the patient's underlying disease. "Ineffectiveness" (progressive disease) is not considered an adverse event. Signs and symptoms or clinical sequelae resulting from ineffectiveness should be reported if they meet the definition of an adverse event or serious adverse event.

[0055] In the present disclosure, the following definitions may be used to evaluate efficacy based on target lesions: "complete response (CR)" means that all target lesions disappear; "partial response (PR)" means that the sum of the longest diameters (SLD) of target lesions is reduced by at least 30% with the baseline SLD as a reference; "stable disease (SD)" means that the target lesions are neither reduced enough to meet the requirement of partial response nor increased enough to meet the requirement of disease progression since the start of treatment with the lowest SLD as a reference; "progressive disease (PD)" means that the SLD of target lesions increases by at least 20% or one or more new lesions since the start of treatment with the lowest reported SLD as a reference; "unable to assess" means that the target lesions are not significantly improved since the start of treatment, and the target lesions are not significantly improved. "evaluate (UE)" means that such target lesions are present at baseline, cannot be measured or cannot be evaluated, resulting in the inability to determine the specific tumor status at the time point being discussed (if the SLD at a time point cannot be determined and the disease progression provision is not applicable, the efficacy of complete response, partial response or stable disease cannot be attributed to that time point, and the efficacy at that time point will be unevaluable); "not applicable (NA)" means that no target lesions were identified at baseline (patients with no target lesions identified at baseline cannot be evaluated for efficacy. These patients will only be evaluated for progression); and "not done (ND)" means that no scan was performed to evaluate the target lesions at this time point.

[0056] In the present disclosure, the following definitions of efficacy evaluation can be used to evaluate non-target lesions: "complete response (CR)" means that all non-target lesions disappear; "stable disease (SD)" means that one or more non-target lesions that do not meet the criteria of complete response or disease progression persist; "progressive disease (SD)" means that "PD)" refers to "clear progression" of existing non-target lesions, or the appearance of one or more new lesions is considered to be disease progression (if the subject's disease progression at a time point is assessed based solely on the progression of non-target lesions, additional criteria need to be met. In this case, the lesions assessed for disease progression must be assessed retrospectively from baseline (or nadir) and compared to the time point in question. Disease progression of non-target lesions in this example can be assessed when the SLD of the lesion has increased by 20% or more and the longest dimension (LD) of the lesion at the time of progression is greater than or equal to 10 mm. If a non-target lesion does not meet the quantitative criteria, it will not be assessed as having progressed. Regarding pleural fluid, ascites, pericardial effusion, and other effusions, progression will be assessed when the fluid increase is estimated to be greater than 500cc in an otherwise stable or remitted individual and cannot be attributed to benign lesions identified by radiography); "unable to assess" "evaluate (UE)" refers to any non-target lesion that was present at baseline, not measurable, or not evaluable, resulting in uncertainty about the status of the specific tumor at the time point being investigated; "not applicable (NA)" means no non-target lesion was identified at baseline; and "not done (ND)" means no scan was performed to evaluate for non-target lesions at this time point.

[0057] In the present disclosure, the term "based on" includes assessing, determining or measuring the patient characteristics described herein (and preferably selecting patients suitable for treatment). When individual characteristics are "used as a basis" to administer the treatment methods described in the present disclosure or to select the treatment methods described in the present disclosure, the individual characteristics are assessed before and / or during treatment, and the conclusions obtained are used by the clinician to assess any of the following: (a) the possible suitability of the individual to initially receive (one or more) treatments; (b) the possible unsuitability of the individual to initially receive (one or more) treatments; (c) treatment remission; (d) the possible suitability of the individual to continue to receive (one or more) treatments; (e) the possible unsuitability of the individual to continue to receive (one or more) treatments; (f) to adjust the dosage; or (g) the ability to predict clinical benefit.

[0058] In this disclosure, the term "likely to respond" or "response" 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 signs of disease or disease progression, complete remission, partial remission, stable disease, increased or prolonged progression-free survival, or increased or prolonged overall survival.

[0059] In this disclosure, the term "progression free survival (PFS)" refers to the length of time during and after treatment that a tumor does not grow. Progression free survival includes the time a patient experiences a complete remission or partial remission, as well as the time a patient experiences stable disease.

[0060] In this disclosure, a "complete response" (CR) to treatment is defined as a patient with evaluable but non-measurable disease whose tumor and all signs of disease have disappeared.

[0061] In this disclosure, a "partial response (PR)" to treatment is defined as any patient with less than a complete response is simply classified as showing a partial response.

[0062] In the present disclosure, the term "stable disease (SD)" means that the patient is stable.

[0063] In the present disclosure, the term "survival" refers to the patient still alive, and includes disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS). Survival can be assessed by the Kaplan-Meier method, and any differences in survival are calculated using a stratified log-rank test.

[0064] In the present disclosure, the term "disease free survival (DFS)" refers to a defined period of time, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc., that a patient remains alive without recurrence of cancer from the start of treatment or from the initial diagnosis.

[0065] In the present disclosure, the term "overall survival (OS)" refers to a defined period of time that a patient remains alive from the start of treatment or from initial diagnosis, such as about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 10 years, etc. In the disclosure, the event used for survival analysis is death due to any cause.

[0066] In this 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, potentially eradicating micrometastases (which would otherwise proliferate if the standard sequence of surgery followed by systemic therapy was followed). Neoadjuvant therapy can also help reduce tumor size, thereby allowing complete resection of an initially unresectable tumor, or preservation of some organs and their function. In addition, neoadjuvant therapy allows for in vivo evaluation of drug efficacy, which can guide subsequent treatment selection.

[0067] In this disclosure, the term "adjuvant therapy" refers to therapy provided after surgery when no evidence of residual disease can be detected, in order to reduce the risk of disease recurrence. The goal of adjuvant therapy is to prevent the recurrence of tumors and thereby reduce the chance of tumor-related death.

[0068] In this disclosure, the term "metastasis" refers to the spread of a tumor from its primary site to other places in the body. Cancer cells can break away from the primary tumor, infiltrate lymphatic and blood vessels, circulate through the bloodstream and grow (metastasize) in distant lesions in normal tissues elsewhere in the body. Metastasis can be primary or distant. Metastasis is a sequential process, depending on the tumor cells breaking away from the primary tumor, traveling through the bloodstream and settling at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass.

[0069] In this disclosure, the term "recurrence" includes the reoccurrence of tumor cells at the same site and organ where the disease originated, metastasis, which may occur even many years after the initial diagnosis and treatment of the cancer, or local events such as the infiltration of tumor cells into local lymph nodes. "Distant recurrence" refers to a situation in which cancer cells have spread (metastasized) to a distant site (i.e., another organ) beyond the local lymph nodes in the body. DETAILED DESCRIPTION

[0070] In another aspect, the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer in an individual in combination with endocrine therapy.

[0071]

[0072] The individual is a hormone receptor positive (HR+) and / or human epidermal growth factor receptor 2 positive (HER2+) individual.

[0073] In certain embodiments, illustrative examples of individuals that can be used in the present disclosure include, but are not limited to, individuals who are estrogen receptor positive (ER+), individuals who are human epidermal growth factor receptor 2 positive (HER2+), and individuals who are both estrogen receptor and human epidermal growth factor receptor 2 positive (ER+HER2+).

[0074] In certain embodiments, illustrative examples of individuals that can be used in the present disclosure include, but are not limited to, postmenopausal estrogen receptor-positive (ER+) individuals, postmenopausal human epidermal growth factor receptor 2-positive (HER2+) individuals, and postmenopausal estrogen receptor and human epidermal growth factor receptor 2-positive (ER+HER2+) individuals.

[0075] In certain embodiments, illustrative examples of breast cancer that can be used in the present disclosure include, but are not limited to, metastatic breast cancer and recurrent breast cancer.

[0076] In certain embodiments, illustrative examples of drugs that can be used in the endocrine therapy of the present disclosure include, but are not limited to, estrogen receptor modulators, estrogen receptor inhibitors, and aromatase inhibitors.

[0077] 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.

[0078] In certain embodiments, illustrative examples of selective estrogen receptor down-regulators that can be used in the present disclosure include, but are not limited to, fulvestrant.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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 to the subject.

[0083] 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 to the subject.

[0084] In certain embodiments, 300 mg to 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject daily.

[0085] In certain embodiments, 200 mg, 300 gm, 400 mg, 500 mg or 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject daily.

[0086] In certain embodiments, 300 mg to 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject once daily.

[0087] In certain embodiments, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject once daily.

[0088] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a subject.

[0089] In certain embodiments, 200 mg, 300 gm, 400 mg, 500 mg or 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a subject.

[0090] In certain embodiments, 200 mg, 300 gm, 400 mg, 500 mg or 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a subject once daily.

[0091] In certain embodiments, illustrative examples of pharmaceutically acceptable salts of the compounds of formula (I) that can be used in the present disclosure include, but are not limited to, acid addition salts.

[0092] In certain embodiments, illustrative examples of pharmaceutically acceptable acid addition salts that can be used in the compounds of formula (I) of the present disclosure include, but are not limited to, inorganic acid addition salts and organic acid addition salts.

[0093] In certain embodiments, illustrative examples of pharmaceutically acceptable inorganic acid addition salts that can be used in the compounds of formula (I) of the present disclosure include, but are not limited to, addition salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0094] In certain 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, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, maleic acid, fumaric acid, mucic acid, gentisic acid, glucoheptose The invention also includes the following: an addition salt of 1,2-dihydro-2-naphthoic acid, ...

[0095] In certain embodiments, the pharmaceutically acceptable salt of the compound of formula (I) that can be used in the present disclosure is disesquimaleate.

[0096] 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 endocrine therapy is concurrently administered to the subject.

[0097] 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 endocrine therapy is subsequently administered to the subject.

[0098] 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 endocrine therapy is concurrently administered to the subject.

[0099] In certain embodiments, the present disclosure excludes chemotherapy.

[0100] In another aspect, the present disclosure relates to the use of a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer in an individual in combination with endocrine therapy.

[0101]

[0102] The individual is a hormone receptor positive (HR+) and / or human epidermal growth factor receptor 2 positive (HER2+) individual.

[0103] In certain embodiments, illustrative examples of individuals that can be used in the present disclosure include, but are not limited to, individuals who are estrogen receptor positive (ER+), individuals who are human epidermal growth factor receptor 2 positive (HER2+), and individuals who are both estrogen receptor and human epidermal growth factor receptor 2 positive (ER+HER2+).

[0104] In certain embodiments, illustrative examples of individuals that can be used in the present disclosure include, but are not limited to, postmenopausal estrogen receptor-positive (ER+) individuals, postmenopausal human epidermal growth factor receptor 2-positive (HER2+) individuals, and postmenopausal estrogen receptor and human epidermal growth factor receptor 2-positive (ER+HER2+) individuals.

[0105] In certain embodiments, illustrative examples of breast cancer that can be used in the present disclosure include, but are not limited to, metastatic breast cancer and recurrent breast cancer.

[0106] In certain embodiments, illustrative examples of drugs that can be used in the endocrine therapy of the present disclosure include, but are not limited to, estrogen receptor modulators, estrogen receptor inhibitors, and aromatase inhibitors.

[0107] 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.

[0108] In certain embodiments, illustrative examples of selective estrogen receptor down-regulators that can be used in the present disclosure include, but are not limited to, fulvestrant.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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 to the subject.

[0113] 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 to the subject.

[0114] In certain embodiments, 300 mg to 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject daily.

[0115] In certain embodiments, 200 mg, 300 gm, 400 mg, 500 mg or 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject daily.

[0116] In certain embodiments, 300 mg to 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject once daily.

[0117] In certain embodiments, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject once daily.

[0118] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a subject.

[0119] In certain embodiments, 200 mg, 300 gm, 400 mg, 500 mg or 600 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered to a subject once daily.

[0120] In certain embodiments, illustrative examples of pharmaceutically acceptable salts of the compounds of formula (I) that can be used in the present disclosure include, but are not limited to, acid addition salts.

[0121] In certain embodiments, illustrative examples of pharmaceutically acceptable acid addition salts that can be used in the compounds of formula (I) of the present disclosure include, but are not limited to, inorganic acid addition salts and organic acid addition salts.

[0122] In certain embodiments, illustrative examples of pharmaceutically acceptable inorganic acid addition salts that can be used in the compounds of formula (I) of the present disclosure include, but are not limited to, addition salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0123] In certain 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, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, maleic acid, fumaric acid, mucic acid, gentisic acid, glucoheptose The invention also includes the following: an addition salt of 1,2-dihydro-2-naphthoic acid, ...

[0124] In certain embodiments, the pharmaceutically acceptable salt of the compound of formula (I) that can be used in the present disclosure is disesquimaleate.

[0125] 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 endocrine therapy is concurrently administered to the subject.

[0126] 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 endocrine therapy is subsequently administered to the subject.

[0127] 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 endocrine therapy is concurrently administered to the subject.

[0128] In certain embodiments, the present disclosure excludes chemotherapy.

[0129] Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand the various aspects and advantages of the present application. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present disclosure.

[0130] Example

[0131] Preparation Example

[0132] Example 1

[0133] 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

[0134]

[0135] The title compound was prepared according to the preparation method of Example 138 in CN102933578 B.

[0136] Example 2

[0137] 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 di-sesquimaleate

[0138] 2.5 g of the compound of Example 1, 1.45 g of maleic acid, 22.7 ml of ethanol and 2.3 ml of distilled water were stirred at 70°C. After the solution was completely dissolved, it was stirred again for about 5 minutes, filtered with suction, the filter cake was washed with 11 ml of ethanol and discarded, the washing liquid and the filtrate were combined, stirred at room temperature overnight, filtered with suction, the filter cake was washed with 5.7 ml of ethanol, and vacuum dried at 40°C to obtain the title compound.

[0139] Clinical trials

[0140] Patients and methods

[0141] Patient population

[0142] 1) Patients diagnosed with breast cancer by tumor histopathology;

[0143] 2) Patients with advanced metastatic or recurrent disease who cannot be cured by standard treatment according to objective evidence;

[0144] 3) Postmenopausal women who are ER-positive (≥1%) and HER2-positive (immunohistochemistry 3+ and / or in situ hybridization positive), and are suitable for exemestane as endocrine therapy;

[0145] 4) Note: The extension period is planned to include 6 additional subjects in the 400 mg dose group who are combined with letrozole and 6 additional subjects who are combined with fulvestrant. Therefore, for these subjects, the extension period is to include "postmenopausal female patients who are suitable for letrozole or fulvestrant as endocrine therapy";

[0146] 5) Postmenopause is defined as meeting any of the following four conditions:

[0147] Previous bilateral oophorectomy;

[0148] Aged ≥ 60 years;

[0149] Aged < 60 years, menopausal for ≥ 12 months, with follicle-stimulating hormone (FSH) and estradiol levels within the postmenopausal range (using local laboratory reference ranges) without chemotherapy, tamoxifen, toremifene, or ovarian castration in the past year.

[0150] ● Patients younger than 60 years who are taking tamoxifen or toremifene and whose FSH and estradiol levels are within the postmenopausal range (using local laboratory reference ranges);

[0151] Note: Premenopausal or perimenopausal women who do not meet the above menopausal criteria can also be included in this study, but they must also receive ovarian suppression therapy with Noradrena. Ovarian suppression therapy must have been started at least 14 days before the start of treatment with this regimen and must continue during the treatment period of the regimen;

[0152] 6) For subjects whose postmenopausal status is difficult to determine, the decision on whether to include them in the study will be made after discussion between the researcher and the medical staff of the sponsor.

[0153] 7) At least one evaluable tumor lesion (according to RECIST1.1) or only bone metastasis;

[0154] 8) ECOG activity status score 0-1;

[0155] 9) The expected survival time is more than 3 months;

[0156] 10) Bone marrow function meets the following requirements: ANC (neutrophils) ≥ 1.5 × 109 / L, HB (hemoglobin) ≥ 90 g / L (blood transfusion is allowed), PLT (platelets) ≥ 80 × 109 / L. Liver function meets the following requirements: ALT (alanine aminotransferase) ≤ 2.5 × ULN (upper limit of normal), AST (aspartate aminotransferase) ≤ 2.5 × ULN, TBIL (total bilirubin) ≤ 1.5 × ULN (ALT ≤ 5 × ULN, AST ≤ 5 × ULN for patients with liver metastasis); renal function meets the following requirements: serum creatinine ≤ 1.5 × ULN;

[0157] Main exclusion criteria: For the cohort combined with exemestane, patients who had previously received exemestane treatment were excluded (Note: if exemestane was previously used for adjuvant treatment and had been discontinued for ≥12 months before this enrollment, they could be included in the group). For the cohort combined with letrozole, patients who had previously received letrozole treatment were excluded (Note: if letrozole was used in the adjuvant stage and had been discontinued for ≥12 months before this enrollment, they could be included in the group). For the cohort combined with fulvestrant, patients who had previously received fulvestrant treatment were excluded.

[0158] Study Design

[0159] This study is divided into two parts. In the first part, a multi-center, open, combined drug, and gradually increasing dosage experimental design was adopted. According to the traditional 3+3 principle, the compound shown in Example 2 was gradually increased in dosage in four dosage groups of 200 mg, 300 mg, 400 mg, and 500 mg per day. The second part adopted a multi-center, open, combined drug, and dose expansion experimental design. Three dosage groups (300 mg, 400 mg, and 500 mg) were selected in the expansion.

[0160] Efficacy evaluation

[0161] The RECIST 1.1 (2009) criteria for solid tumors were used as the evaluation criteria for efficacy.

[0162] Efficacy evaluation method: The lesion size of the subjects was evaluated by imaging. The subjects had the same imaging method at all follow-up points. Efficacy evaluation was performed every 8 weeks during treatment.

[0163] Evaluations included objective response rate (ORR), clinical benefit rate (CBR) - defined as the proportion of complete remission (CR) + partial remission (PR) + stable disease (SD) (≥24 weeks), disease control rate (DCR) - defined as the proportion of CR+PR+SD, and progression-free survival (PFS).

[0164] Safety evaluation

[0165] During the study, vital signs, physical examination, blood routine, urine routine + microscopy, blood biochemistry (liver and kidney function, electrolytes, blood sugar, blood lipids), coagulation function, electrocardiogram (ECG), left ventricular ejection fraction, etc. were checked to observe and record adverse events (AEs) to evaluate safety. Adverse events were collected from the first dose of the subject to 30 days after the last dose.

[0166] in conclusion

[0167] Dose finding and expansion

[0168] In the dose escalation phase, 3 subjects were included in each of the four groups of 200 mg, 300 mg, 400 mg and 500 mg of the compound of Example 2 combined with 25 mg of exemestane per day. No dose-limiting toxicity was observed in any cohort during the first 4 weeks of treatment). For the dose expansion phase, 3 dose groups (300 mg, 400 mg and 500 mg) were selected. During the study, the 300 mg dose group was stopped based on preliminary efficacy data. The 400 mg and 500 mg cohorts are still continuing to complete. In the 400 mg cohort, 6 patients were combined with letrozole (25 mg per day) and 6 patients were combined with fulvestrant (500 mg intramuscular injection once a day on the 1st, 15th and 29th days, and 500 mg intramuscular injection once every 28 [± 3] days thereafter) to further explore the safety of the compound shown in formula (I) combined with letrozole or fulvestrant.

[0169] Security

[0170] Among the 55 subjects, treatment-emergent adverse events (TEAEs) were mostly within grade 1-2. The most common grade 3 TEAE was diarrhea (9.1%). No drug-related grade 4 or higher adverse reactions occurred in the trial.

[0171] effect

[0172] Table 1. Efficacy Data Summary (EAS)

[0173]

[0174] Note: NA: not available (cannot be calculated)

[0175] In the present disclosure, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any such actual relationship or order between these entities or operations.

[0176] It can be understood from the foregoing that although the specific embodiments of the present disclosure are described for the purpose of illustrative illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. These modifications or improvements should all fall within the scope of the claims appended to the present disclosure.

Claims

1. Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of 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+).

2. The use according to claim 1, wherein the individual is an estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-positive (HER2+) individual, preferably a postmenopausal estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-positive (HER2+) individual, 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 therapy 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.

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

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

6. Use of a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament 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+).

7. The use according to claim 6, wherein the individual is an estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-positive (HER2+) individual, preferably a postmenopausal estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-positive (HER2+) individual; 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 therapy 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 200 mg to 600 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual daily, preferably 200 mg to 600 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual once daily.

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

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