Treatment of breast cancer using combination therapy including GDC-9545 and abemaciclib or ribociclib

Abstract

Provided herein are combination therapies comprising GDC-9545 and abemaciclib or ribociclib for the treatment of locally advanced or metastatic breast cancer.

Description

Technical Field

[0001] Related Applications

[0001] This non-provisional patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 149,941, filed on February 16, 2021, which is hereby incorporated by reference in its entirety for all purposes.

[0002] Field of the Invention

[0002] Disclosed herein is a combination therapy for treating breast cancer, comprising GDC-9545 or a pharmaceutically acceptable salt thereof, and abemaciclib or a pharmaceutically acceptable salt thereof or ribociclib or a pharmaceutically acceptable salt thereof.

Background Art

[0003]

[0003] Despite the effectiveness of endocrine therapy for ER-positive (ER+) breast cancer, many patients ultimately relapse or develop resistance. One such resistance mechanism is mutations in ESR1 that promote ER-dependent transcription and proliferation in the absence of estrogen.

[0004]

[0004] ER+ breast cancer accounts for over 70% of breast cancer subtypes, and the current treatment regimen for metastatic disease only prolongs the survival of these patients. Recently, until the emergence of selective CDK4 / 6 inhibitors, endocrine therapy (ET) remained the standard treatment for metastatic disease through multiple treatment lines, and then chemotherapy was performed in the end-stage of ET resistance. However, despite recent improvements with next-generation CDK4 / 6 inhibitors, the emergence of acquired resistance to such agents highlights the unmet need to identify new treatment regimens.

[0005]

[0005] Therefore, there is an urgent need for clinically active agents for the treatment of recurrent or resistant ER-positive breast cancer.

Summary of the Invention

[0006]

[0006] Solutions to the above-mentioned problems and other problems in the art are provided herein.

[0007]

[0007] This embodiment can be better understood by referring to embodiments and examples of the invention intended to illustrate non-limiting aspects. [Modes for carrying out the invention]

[0008]

[0008] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, apparatus and materials similar to or equivalent to those described herein may be used in carrying out the present invention.

[0009]

[0009] The following definitions are provided to facilitate the understanding of certain terms that are frequently used herein and are not intended to limit the scope of this disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0010]

[0010] As used herein, unless otherwise specified, the terms “about” and “approximately” mean, when referring to a dose, volume, or weight percentage of an ingredient in a composition or dosage form, a dose, volume, or weight percentage that is recognized by those skilled in the art as providing an equivalent pharmacological effect to that obtained from a specified dose, volume, or weight percentage. An equivalent dose, volume, or weight percentage may be 30%, 20%, 15%, 10%, 5%, 1%, or less than the specified dose, volume, or weight percentage.

[0011]

[0011] The "GDC-9545" has the following structure: This refers to a compound having TIFF0007846700000001.tif48170 and the chemical name 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidine-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol. As used herein, "GDC-9545" refers to the free base and pharmaceutically acceptable salts of GDC-9545 (including its tartrate). In one embodiment, GDC-9545 is a tartrate. GDC-9545 is also known as ziledestrant.

[0012]

[0012] "Abemaciclib" has the following structure: This refers to a compound having TIFF0007846700000002.tif41170 and the chemical name (2-pyrimidinamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyrimidinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]). As used herein, "abemacilib" refers to the free base and pharmaceutically acceptable salts of abemaciclib. "Abemaciclib" is marketed under the trade name VERZENIO®.

[0013]

[0013] "Ribociclib" has the following structure: This refers to a compound having TIFF0007846700000003.tif32170 and the chemical name (butanedioate 7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridine-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(1 / 1)). As used herein, "ribociclib" refers to the free base and pharmaceutically acceptable salts of ribociclib (including its succinate). Ribociclib is marketed under the trade name KISQALI®.

[0014]

[0014] "Overall survival" or "OS" refers to the time from registration to death for any cause.

[0015]

[0015] "Objective response" refers to a complete response or partial response determined by the principal investigator in accordance with RECIST v1.1.

[0016]

[0016] "Objective response rate" or "ORR" refers to the percentage of patients who have a confirmed complete response or partial response in two consecutive opportunities separated by ≥ 4 weeks, as determined by the principal investigator in accordance with RECIST v1.1.

[0017]

[0017] "Time to progression" or "TTP" refers to the time from randomization to objective tumor progression.

[0018]

[0018] "Duration of response" or "DOR" refers to the time from the first occurrence of a recorded objective response to the progression of the disease as determined by the principal investigator in accordance with RECIST v1.1, or death from any cause, whichever comes first.

[0019]

[0019] “Progression-free survival” or “PFS” refers to the time from enrollment to the earlier of the date of the first recorded disease progression or death for any cause, as determined by the principal investigator using RECIST v1.1.

[0020]

[0020] The "disease control rate" or "DCR" refers to the percentage of patients with CR or PR determined by the principal investigator of the clinical trial using stable disease or RECIST v1.1 over at least 12 weeks.

[0021]

[0021] The "clinical benefit rate" or "CBR" refers to the percentage of patients with confirmed complete or partial response determined by the principal investigator of the clinical trial according to stable disease or RECIST v1.1 over at least 24 weeks.

[0022]

[0022] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels.

[0023]

[0023] "Partial response" or "non-CR / non-PD" refers to the persistence of one or more non-target lesions and / or (if applicable) maintenance of tumor marker levels above the normal limit. PR may also refer to a reduction of ≥ 30% in the sum of the diameters of target lesions, new lesions, and clear progression in non-target lesions in the absence of CR.

[0024]

[0024] "Progressive disease" or "PD" refers to an increase of ≥ 20% in the sum of the diameters of target lesions, clear progression in non-target lesions, and / or the appearance of new lesions.

[0025]

[0025] "Stable disease" or "SD" refers to the absence of both a reduction sufficient to qualify for CR or PR and an increase in tumor growth sufficient to qualify for PD.

[0026]

[0026] The term "locally advanced breast cancer" refers to cancer that has spread from its origin in the breast to adjacent tissue or lymph nodes but has not spread to other parts of the body.

[0027]

[0027] The term "metastatic breast cancer" refers to cancer that has spread from the breast to other parts of the body, such as the bones, liver, lungs, or brain. Metastatic breast cancer may also be referred to as stage IV breast cancer.

[0028]

[0028] The term "treatment" refers to a clinical intervention designed to change the natural course of a patient or cell being treated during the course of clinical pathology. Desirable effects of treatment include reduction in the rate of disease progression, restoration or alleviation of the disease state, and remission or improvement of prognosis. For example, it includes, but is not limited to, reduction (or destruction) of cancer cell proliferation, reduction of symptoms caused by the disease, improvement in the quality of life of a person suffering from the disease, reduction in the dosage of other drugs required for treatment of the disease, and / or extension of the patient's survival period. The "treatment" of a patient is successful when one or more symptoms associated with the breast cancer described herein are reduced or eliminated.

[0029]

[0029] The term "delay the progression of" a disease refers to delaying, preventing, hindering, slowing, stabilizing, and / or postponing the onset of the breast cancer described herein. This delay can be of various lengths depending on the cancer history and / or the patient being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can, in essence, encompass prevention in terms of the patient not developing cancer.

[0030]

[0030] “Effective dose” means the minimum amount required to produce a measurable improvement or prevention of breast cancer as described herein. The effective dose as described herein may vary depending on factors such as the patient’s disease status, age, sex and weight, and the drug’s ability to induce a desired response in the patient. The effective dose is also the amount in which the therapeutically beneficial effect outweighs any toxic or adverse effects of the treatment. Beneficial or desired outcomes include the elimination or reduction of risk, reduction of severity, delay in the onset of the disease (including the biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes that appear during the onset of the disease), reduction of one or more symptoms resulting from the disease, improvement in the quality of life of the person with the disease, reduction in the dose of other drugs required to treat the disease, enhancement of the effect of another drug, such as by targeting, delay in disease progression, and / or extension of survival. In some embodiments, an effective dose of a drug may be effective in reducing the number of cancer cells; shrinking tumor size; inhibiting (i.e., delaying or stopping) cancer cell invasion into peripheral organs; inhibiting (i.e., delaying or stopping) tumor metastasis; inhibiting (i.e., delaying or stopping) tumor growth; and / or alleviating one or more symptoms associated with the disorder. An effective dose may be administered in one or more doses. An effective dose of a drug, compound, pharmaceutical composition or combination therapy described herein may be sufficient to achieve therapeutic treatment directly or indirectly. As clinically understood, an effective dose of a drug, compound or pharmaceutical composition may or may not be achieved in combination with another drug, compound or pharmaceutical composition or combination therapy. Thus, “effective dose” may be considered in relation to the administration of one or more therapeutic agents, and if a desired outcome can be achieved in combination with one or more other agents, or if it is achieved, then a single agent may be considered to be given in an effective dose.

[0031]

[0031] As used herein, the "E2 suppression score" refers to a numerical value that reflects the total expression level of a predetermined set of genes whose suppression reflects estrogen receptor (ER) pathway activity.

[0032]

[0032] As used herein, the "E2 induction score" refers to a numerical value that reflects the total expression level of a predetermined set of genes whose induction reflects estrogen receptor (ER) pathway activity.

[0033]

[0033] As used herein, "ER pathway activity score" refers to a numerical value that reflects the mathematical difference between the E2 induction score and the E2 suppression score.

[0034]

[0034] “Administration period” or “cycle” means a period including the administration of one or more of the drugs described herein (i.e., GDC-9545 or its pharmaceutically acceptable salts or abemaciclib or ribociclib), and any period not including the administration of one or more of the drugs described herein. For example, a cycle may be 28 days in total, including 21 days of administration of one or more drugs and 7 days of rest periods. “Rest period” means a period during which at least one of the drugs described herein (e.g., GDC-9545 or its pharmaceutically acceptable salts or abemaciclib or ribociclib) is not administered. In one embodiment, the rest period means a period during which none of the drugs described herein (e.g., GDC-9545 or its pharmaceutically acceptable salts or abemaciclib or ribociclib) is administered. The rest periods provided herein may, in some cases, include the administration of GDC-9545 or its pharmaceutically acceptable salts or another drug other than abemaciclib or ribociclib. In such cases, the administration of the other drug during the rest period should not interfere with or disadvantage the administration of the drugs described herein.

[0035]

[0035] “Medication regimen” means a period of administration of the drug described herein, comprising one or more cycles, each cycle of which may comprise administration of the drug described herein at different numbers or in different amounts.

[0036]

[0036] "QD" refers to administering the drug described herein once a day.

[0037]

[0037] "BID" refers to administering the drug described herein twice a day.

[0038]

[0038] "PO" refers to oral administration of the drug described herein.

[0039]

[0039] Graded adverse events refer to severity grading scales established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table. TIFF0007846700000004.tif50170

[0040] Combination therapy

[0040] A combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof (e.g., GDC-9545 tartrate) and a CDK4 / 6 inhibitor, including ribociclib or abemaciclib as described herein, is provided herein.

[0041]

[0041] In one embodiment, a combination therapy (CT1) is provided herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof administered as a QD on days 1 to 28 of the first 28-day cycle, and abemaciclib administered as a BID on days 1 to 28 of the first 28-day cycle.

[0042]

[0042] In one embodiment, a combination therapy (CT2) is provided herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof administered as a QD on days 1 to 28 of the first 28-day cycle, and ribociclib administered as a QD on days 1 to 21 of the first 28-day cycle.

[0043]

[0043] In one embodiment of the combination therapy described herein, GDC-9545 or a pharmaceutically acceptable salt thereof is administered as a fixed-dose QD (Quick Discharge) dose. In one embodiment, administration is oral (PO), and GDC-9545 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered as a QD dose in amounts of about 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 30 mg, 10 mg to 100 mg, 10 mg to 50 mg, or 10 mg to 30 mg. In another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of about 1, 5, 10, 15, 20, 25, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 10, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of 30 mg.

[0044]

[0044] In one embodiment of combination therapy CT1, abemaciclib is administered according to the package insert. In a preferred embodiment of combination therapy CT1, abemaciclib is administered in a dose of 150 mg.

[0045]

[0045] In one embodiment of combination therapy CT2, ribociclib is administered according to the package insert. In a preferred embodiment of combination therapy CT2, ribociclib is administered in a dose of 600 mg.

[0046]

[0046] The combination therapies described herein may be provided as kits comprising one or more agents for administration. In one embodiment, the kit comprises GDC-9545 or a pharmaceutically acceptable salt thereof for administration in combination with abemaciclib or ribociclib as described herein. In another embodiment, the kit comprises GDC-9545 or a pharmaceutically acceptable salt thereof packaged together with abemaciclib or ribociclib, and the kit comprises separately prescribed dosages of each agent. In yet another embodiment, the kit comprises GDC-9545 or a pharmaceutically acceptable salt thereof co-formulated with abemaciclib or ribociclib.

[0047]

[0047] In one embodiment, the combination therapy agents described herein are supplied in a kit in a ready-to-administer form, or, for example, as ready-to-take oral tablets / capsules. The kit described herein may include instructions, such as a package insert. In one embodiment, the instructions are a package insert, one for each agent in the kit.

[0048]

[0048] Further provided are kits for carrying out the methods detailed herein, including the combination therapies described herein and instructions for use in the treatment of breast cancer described herein.

[0049]

[0049] In one embodiment, the combination therapy described herein is useful for treating certain types of breast cancer described herein. For example, in one embodiment, the combination therapy described herein can be used for the treatment of estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In another embodiment, the combination therapy described herein can be used to treat ER+, HER2- locally advanced breast cancer (laBC), or ER+, HER2- metastatic breast cancer (mBC). In such one embodiment, the combination therapy described herein can be used for the treatment of ER+, HER2- laBC. In such one embodiment, the combination therapy described herein can be used for the treatment of ER+, HER2- mBC.

[0050] Treatment methods

[0050] Methods for treating ER+, HER2-laBC, or mBC in patients having such cancers are provided herein. In one embodiment, the method comprises treating ER+, HER2-laBC, or mBC in patients having such cancers by administering the combination therapy described herein to the patient over a 28-day cycle. In one embodiment, the cancer is inoperable locally advanced breast cancer (laBC) or metastatic ER+ breast cancer (mBC). In one such embodiment, a patient with inoperable locally advanced or metastatic ER+ breast cancer experienced disease progression during or after treatment with a CDK4 / 6 inhibitor in a 1L or 2L setting.

[0051]

[0051] A method (A1) for treating laBC or mBC in a patient having such cancer is provided herein, comprising administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib. In one embodiment of method (A1) provided herein, the method is used for the treatment of laBC. In another embodiment of method (A1) provided herein, the method is used for the treatment of mBC.

[0052]

[0052] A method (A2) for treating laBC or mBC in a patient having such cancer, comprising administering to the patient a combination therapy described herein, comprising a drug regimen comprising (i) a quarterly dose of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a bronchod dose of abemaciclib on days 1 to 28 of the first 28-day cycle. In one embodiment of method (A2) provided herein, the method is used for the treatment of laBC. In another embodiment of method (A2) provided herein, the method is used for the treatment of mBC.

[0053]

[0053] In one embodiment of the A1 or A2 method, GDC-9545 or a pharmaceutically acceptable salt thereof is administered as a fixed-dose QD dose. In one embodiment, administration is oral (PO), and GDC-9545 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered as a QD dose in amounts of about 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 30 mg, 10 mg to 100 mg, 10 mg to 50 mg, or 10 mg to 30 mg. In another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of about 1, 5, 10, 15, 20, 25, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 10, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 30 mg.

[0054]

[0054] In one embodiment of Method A1 or A2, abemaciclib is administered according to the package insert. In a preferred embodiment of Method A1 or A2, abemaciclib is administered in a dose of 150 mg.

[0055]

[0055] A method (A3) for treating laBC or mBC in a patient having such cancer is further provided herein, comprising administering to the patient a combination therapy described herein, which includes a drug regimen comprising (i) a QD administration of 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a BID administration of 150 mg of abemaciclib on days 1 to 28 of the first 28-day cycle. In one such embodiment, the drug regimen comprises two or more cycles described herein. In one embodiment of method (A3) provided herein, the method is used for the treatment of laBC. In another embodiment of method (A3) provided herein, the method is used for the treatment of mBC.

[0056]

[0056] In one embodiment, the patients described in Method A1, A2, or A3 do not have or have not developed interstitial lung disease or severe dyspnea.

[0057]

[0057] In one embodiment of Methods A1, A2, and A3, the combination of GDC-9545 or a pharmaceutically acceptable salt thereof with abemaciclib does not require co-administration (treatment) with a gonadotropin-releasing hormone (GnRH) agonist.

[0058]

[0058] In one embodiment of Methods A1, A2, and A3, the dose of abemaciclib may be reduced. In one such embodiment, the dose of abemaciclib may be reduced by 50 mg in a total of up to two reductions (i.e., a reduction to 100 mg BID or 50 mg BID). In one embodiment of Methods A1, A2, and A3, the administration of one of the drugs (GDC-9454 or its pharmaceutically acceptable salt or abemaciclib) during combination therapy may be interrupted for up to 28 days. In one embodiment of Methods A1, A2, and A3, the dose of GDC-9545 is not reduced.

[0059]

[0059] A method (R1) for treating laBC or mBC in a patient having such cancer is provided herein, comprising administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib. In one embodiment of method (R1) provided herein, the method is used for the treatment of laBC.

[0052] In another embodiment of (R1) provided herein, the method is used for the treatment of mBC. A method (R2) for treating laBC or mBC in a patient having such cancer is also provided herein, comprising administering to the patient a combination therapy described herein, comprising a drug regimen comprising (i) a QD administration of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a QD administration of ribociclib on days 1 to 21 of the first 28-day cycle. In one embodiment of method (R2) provided herein, the method is used for the treatment of laBC. In another embodiment of the method (R2) provided herein, the method is used for the treatment of mBC.

[0060]

[0060] In one embodiment of the method of R1 or R2, GDC-9545 or a pharmaceutically acceptable salt thereof is administered as a fixed-dose QD dose. In one embodiment, administration is oral (PO), and GDC-9545 or a pharmaceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered as a QD dose in amounts of about 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 30 mg, 10 mg to 100 mg, 10 mg to 50 mg, or 10 mg to 30 mg. In another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of about 1, 5, 10, 15, 20, 25, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 10, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of approximately 30 mg.

[0061]

[0061] In one embodiment of Method R1 or R2, ribociclib is administered according to the package insert. In a preferred embodiment of Method R1 or R2, ribociclib is administered in an amount of 600 mg.

[0062]

[0062] A method (R3) for treating laBC or mBC in a patient having such cancer is further provided herein, comprising administering to the patient a combination therapy described herein, which includes a drug regimen comprising (i) a QD administration of 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a QD administration of 600 mg of abemaciclib on days 1 to 21 of the first 28-day cycle. In one such embodiment, the drug regimen comprises two or more cycles described herein. In one embodiment of the method (R3) provided herein, the method is used for the treatment of laBC. In another embodiment of the method (R3) provided herein, the method is used for the treatment of mBC.

[0063]

[0063] In such R1, R2, or R3 methods, the combination of GDC-9545 or a pharmaceutically acceptable salt thereof with ribociclib does not increase the level of bradycardia or QT interval prolongation compared to monotherapy. In one such embodiment, administration of a compound to treat bradycardia or QT prolongation is not required. In further such embodiments, the dose of GDC-9545 or a pharmaceutically acceptable salt thereof is not changed. In such embodiments, if a patient described herein has one or more of the adverse events described herein, the dose of ribociclib is reduced by 200 mg increments.

[0064]

[0064] In one embodiment of Methods A1, A2, A3, R1, R2, and R3, the cancer is inoperable locally advanced breast cancer (laBC) or metastatic ER+ breast cancer (mBC).

[0065]

[0065] The methods for treating breast cancer provided herein (A1, A2, A3, R1, R2, and R3) may include the administration of the combination therapies described herein as part of a drug regimen. In one embodiment, the drug regimen comprises one or more cycles. In another embodiment, the drug regimen comprises at least two cycles. In yet another embodiment, drug regimens comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles are provided herein. In yet another embodiment, the drug regimen comprises approximately 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18, or 2-12 cycles. In one embodiment, the drug regimen comprises administering the combination therapy described herein for any number of cycles until the desired response (e.g., OR, PFS, OS, ORR, DOR, CBR) is reached (e.g., OR, PFS, OS, ORR, DOR, CBR are increased compared to the control described herein). In another embodiment, the drug regimen comprises administering the combination therapy described herein for any number of cycles until toxicity occurs or the patient experiences one or more adverse events (AEs) that prevent further administration. In yet another embodiment, the drug regimen comprises administering the combination therapy described herein for any number of cycles until disease progression.

[0066]

[0066] In one embodiment of the method described herein, the patient is a postmenopausal woman.

[0067]

[0067] In another embodiment of the method described herein, the patient is a premenopausal or perimenopausal (i.e., not postmenopausal) woman. In one such embodiment, the patient is treated with an LHRH agonist in combination with the combination therapy described herein. The LHRH agonist therapy may be initiated 28 days before day 1 of cycle 1. In one embodiment, the LHRH agonist is administered on day 1 of each cycle.

[0068]

[0068] In another embodiment of the method described herein, the patient is male. In one such embodiment, the patient is treated with an LHRH agonist in combination with the combination therapy described herein.

[0069] In one embodiment of the method described herein, the patient described herein is tested for the presence of estrogen receptors, prostaglandin receptors, or Ki67. In one embodiment of the method described herein, the patient described herein has a recorded ER-positive tumor in accordance with the guidelines of the American Society of Clinical Oncology / College of American Pathologists. In one such embodiment, the patient described herein has a recorded HER2-negative tumor.

[0070] In one embodiment of the method described herein, the patient described herein is treatment-naïve. In another embodiment of the method described herein, the patient described herein has not received prior chemotherapy prior to administration of the combination therapy. In yet another embodiment of the method described herein, the patient described herein has not been previously treated with an aromatase inhibitor or a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib), or a combination thereof. In one such embodiment, the aromatase inhibitor is anastrozole, exemestane, or letrozole. In yet another embodiment of the method described herein, the patient described herein has not undergone surgery, chemotherapy, or radiotherapy at least 14 days prior to administration of the combination therapy described herein. In yet another embodiment of the method described herein, the patient described herein has not been previously treated with SERD (e.g., fulvestrant) or tamoxifen.

[0071]

[0071] In one embodiment of the method described herein, the patient has been treated with one or more cancer therapies prior to the administration of the combination therapy described herein. In one embodiment of the method described herein, the patient has breast cancer described herein that is resistant to one or more cancer therapies. In one embodiment of the method described herein, resistance to cancer therapy includes recurrence of cancer or refractory cancer. Recurrence may refer to the re-development of cancer at the original site or a new site after treatment. In one embodiment of the method described herein, resistance to cancer therapy includes progression of cancer during treatment with anti-cancer therapy. In some embodiments of the method described herein, resistance to cancer therapy includes cancer that does not respond to treatment. Cancer may be resistant at the start of treatment or may become resistant during treatment. In some aspects of the method described herein, cancer is in an early stage or in an early stage.

[0072]

[0072] In one embodiment of the method described herein, the patient described herein has previously received treatment with an aromatase inhibitor (e.g., anastrozole, exemestane, or letrozole) or a CDK4 / 6 inhibitor (e.g., palbociclib, ribociclib, or abemaciclib), or a combination thereof. In one such embodiment, the patient has not experienced a recurrence of the disease during or within 12 months of completing such treatment with an aromatase inhibitor or CDK4 / 6 inhibitor.

[0073]

[0073] In one embodiment of the method described herein, the patient described herein has received prior treatment with a CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib) prior to administration of the combination therapy described herein. In one embodiment of the method described herein, the patient described herein has been previously treated with fulvestrant. In one embodiment, prior treatment with fulvestrant should be completed at least 28 days before the first dose of the combination therapy described herein. In yet another embodiment of the method described herein, the patient described herein has not been previously treated with a combination therapy comprising palbociclib and letrozole.

[0074]

[0074] Systemic chemotherapy is considered one of the standard of care (SOC) for patients with mBC, but there is no standard regimen or sequence. In one embodiment of the method described herein, the patient described herein has been previously treated with one or more therapies selected from the group consisting of anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, megestrol acetate, fluoxymesterone, trastuzumab and pertuzumab, or combinations thereof, prior to administration of the combination therapy described herein.

[0075]

[0075] In one embodiment of the method described herein, the patient described herein may have laBC or mBC described herein that is resistant to one or more monotherapy selected from the group consisting of anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, trastuzumab and pertuzumab, or combinations thereof.

[0076]

[0076] In one embodiment of the method described herein, the patient described herein may have undergone surgical treatment, for example, breast-conserving surgery (i.e., mammary tumor removal focused on the removal of the primary tumor with margins) or more extensive surgery (i.e., mastectomy aimed at the complete removal of all breast tissue) before administration of the combination therapy described herein. In another embodiment of the method described herein, the patient described herein may have undergone surgical treatment after treatment with the combination therapy described herein.

[0077]

[0077] Radiotherapy is also applied postoperatively to the breast / chest wall and / or regional lymph nodes with the aim of killing any microscopic cancer cells remaining after surgery. In the case of breast-conserving surgery, radiation is directed to the remaining breast tissue and sometimes to the regional lymph nodes (including axillary lymph nodes). Even in the case of mastectomy, radiation may still be administered if there are factors that predict a higher risk of local recurrence. In some embodiments of the methods provided herein, the patients described herein may have received radiotherapy before administration of the combination therapy described herein. In other embodiments of the methods provided herein, the patients described herein may receive radiotherapy after administration of the combination therapy described herein.

[0078]

[0078] In some embodiments of the methods described herein, the patient described herein has no history of other malignancies within five years prior to administration of the combination therapy described herein. In some embodiments of the methods described herein, the patient described herein does not have active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery, including gastrectomy. In some embodiments of the methods described herein, the patient described herein does not have heart disease or cardiac dysfunction.

[0079]

[0079] In one embodiment of the method described herein, treatment with combination therapy by the method provided herein increases the patient's OS compared to a control (e.g., no treatment, standard of care (SOC), or treatment with GDC-9545 alone). In one embodiment of the method described herein, treatment with combination therapy by the method provided herein increases the patient's OS by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 months or more compared to a control (e.g., no treatment, standard of care (SOC), or treatment with GDC-9545 alone).

[0080]

[0080] In one embodiment of the method described herein, treatment with combination therapy by the method provided herein increases the patient's ORR. In one such embodiment, treatment with combination therapy by the method provided herein results in more patients having a complete response (CR) or partial response (PR) than the control. In another embodiment of the method described herein, TTP increases in patients after treatment with combination therapy by the method provided herein. In yet another embodiment of the method described herein, the duration of response to combination therapy is increased compared to the control (e.g., no treatment, standard treatment (SOC), or treatment with GDC-9545 alone). In one such embodiment, the duration of response is increased by at least 1 to 3 months, 2 to 6 months, 3 to 8 months, 4 to 10 months, 5 to 12 months, 6 to 15 months, 8 to 20 months, or 1 to 24 months. In yet another embodiment of the method described herein, the patient described herein has an increased clinical benefit rate compared to a control (e.g., no treatment, standard of care (SOC), or treatment with GDC-9545 alone). In yet another embodiment of the method described herein, the patient has an increased progression-free survival compared to a control (e.g., no treatment, standard of care (SOC), or treatment with GDC-9545 alone).

[0081]

[0081] In one embodiment of the present invention provided herein, the patient is diagnosed with complete response (CR) after treatment with combination therapy according to the method provided herein. In one embodiment of the present invention provided herein, the patient is diagnosed with partial response (PR) after treatment with combination therapy according to the method provided herein. In one embodiment of the present invention provided herein, the patient is diagnosed with stable disease (SD) after treatment with combination therapy according to the method provided herein.

[0082]

[0082] Further use of the combination therapy described herein for the treatment of laBC or mBC as described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib or ribociclib, is provided herein. One embodiment is the use of the combination therapy described herein for the treatment of laBC or mBC as described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib, as described herein. One embodiment is the use of the combination therapy described herein for the treatment of laBC or mBC as described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib, as described herein.

[0083]

[0083] Further provided herein are the use of the combination therapy described herein (AU1) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib for the treatment of mBC as described herein. Further provided herein are the use of the combination therapy described herein (AU2) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib for the treatment of laBC as described herein.

[0084]

[0084] Further provided herein are combination therapy uses (AU3) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib for the treatment of laBC or mBC as described herein, comprising a drug regimen including (i) a quarterly dose of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a beamline dose of abemaciclib on days 1 to 28 of the first 28-day cycle. In one embodiment of use (AU3) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of use (AU3) provided herein, the combination therapy is for the treatment of mBC.

[0085]

[0085] Further provided herein are combination therapy uses (AU4) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib for the treatment of laBC or mBC as described herein, comprising a drug regimen comprising (i) a quarterly dose (QD) of 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a first dose (BID) of 150 mg of abemaciclib on days 1 to 28 of the first 28-day cycle. In one such embodiment, the drug regimen comprises two or more cycles as described herein. In one embodiment of use (AU4) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of use (AU4) provided herein, the combination therapy is for the treatment of mBC.

[0086]

[0086] Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib, for the treatment of mBC as described herein (RU1). Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib, for the treatment of laBC as described herein (RU2).

[0087]

[0087] Further provided herein are combination therapy uses (RU3) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib for the treatment of laBC or mBC as described herein, comprising a drug regimen including (i) a QD administration of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a QD administration of ribociclib on days 1 to 21 of the first 28-day cycle. In one embodiment of use (RU3) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of use (RU3) provided herein, the combination therapy is for the treatment of mBC.

[0088]

[0088] Further provided herein are combination therapy uses (RU4) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib for the treatment of laBC or mBC as described herein, comprising a drug regimen comprising (i) a QD administration of 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a QD administration of 600 mg of ribociclib on days 1 to 21 of the first 28-day cycle. In one such embodiment, the drug regimen comprises two or more cycles as described herein. In one embodiment of use (RU4) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of use (RU4) provided herein, the combination therapy is for the treatment of mBC.

[0089]

[0089] Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib, for the manufacture of a medicament for the treatment of laBC or mBC as described herein (AM1). Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib, for the manufacture of a medicament for the treatment of mBC as described herein (AM2). Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib, for the manufacture of a medicament for the treatment of laBC as described herein (AM3).

[0090]

[0090] Further provided herein are use(AM4) of combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib for the manufacture of a medicament for the treatment of laBC or mBC as described herein, comprising a drug regimen comprising (i) a quarterly dose of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a beamline dose of abemaciclib on days 1 to 28 of the first 28-day cycle. In one embodiment of use(AM4) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of use(AM4) provided herein, the combination therapy is for the treatment of mBC.

[0091]

[0091] Further provided herein are use(AM5) of combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib for the manufacture of a medicament for the treatment of laBC or mBC as described herein, comprising a dosing regimen comprising (i) a quarterly dose (QD) of 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a first dose (BID) of 150 mg of abemaciclib on days 1 to 28 of the first 28-day cycle. In one such embodiment, the dosing regimen comprises two or more cycles as described herein. In one embodiment of use(AM5) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of use(AM5) provided herein, the combination therapy is for the treatment of mBC.

[0092]

[0092] Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib, for the manufacture of a medicament for the treatment of laBC or mBC as described herein (RM1). Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib, for the manufacture of a medicament for the treatment of mBC as described herein (RM2). Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib, for the manufacture of a medicament for the treatment of laBC as described herein (RM3).

[0093]

[0093] Further provided herein are combination therapy uses (RM4) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib for the manufacture of a medicament for the treatment of laBC or mBC as described herein, comprising a drug regimen comprising (i) a quarterly dose of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a quarterly dose of ribociclib on days 1 to 21 of the first 28-day cycle. In one embodiment of use (RM4) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of use (RM4) provided herein, the combination therapy is for the treatment of mBC.

[0094]

[0094] Further provided herein are combination therapy uses (RM5) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ribociclib for the manufacture of a medicament for the treatment of laBC or mBC as described herein, comprising a dosing regimen comprising (i) a QD administration of 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a QD administration of 600 mg of ribociclib on days 1 to 21 of the first 28-day cycle. In one such embodiment, the dosing regimen comprises two or more cycles as described herein. In one embodiment of use (RM5) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of use (RM5) provided herein, the combination therapy is for the treatment of mBC.

[0095]

[0095] Methods for inhibiting tumor growth or causing tumor regression in patients described herein by administering combination therapies described herein are also provided herein. In one embodiment, a method for inhibiting tumor growth in patients having laBC described herein is provided by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib or ribociclib in one or more 28-day cycles described herein. In one embodiment, a method for inhibiting tumor growth in patients having mBC described herein is provided by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib or ribociclib in one or more 28-day cycles described herein. In some such embodiments, the combination comprises GDC-9545 and abemaciclib.

[0096]

[0096] In one embodiment, a method for producing or improving tumor regression in a patient having mBC as described herein is provided by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof with abemaciclib or ribociclib in one or more 28-day cycles as described herein. In one embodiment, a method for producing or improving tumor regression in a patient having laBC as described herein is provided by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof with abemaciclib or ribociclib in one or more 28-day cycles as described herein. In some such embodiments, the combination comprises GDC-9545 and abemaciclib.

[0097]

[0097] The development of combination therapies presents challenges, including, for example, the selection of agents for combination therapies that can lead to improved efficacy while maintaining acceptable toxicity. One particular challenge is the need to identify the escalating toxicity of combinations. In one embodiment of the method described herein, the combination therapy described herein (e.g., GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib or ribociclib) is administered in a dosing regimen that includes a time-staggered dosing schedule. In one such embodiment, the patient has a reduced number or grade of adverse events (AEs) compared to a control (e.g., SOC therapy, or GDC-9545 alone, abemaciclib alone, or ribociclib alone).

[0098]

[0098] In one embodiment of the method described herein, the drug regimen reduces the number or frequency of Grade 2, Grade 3, or higher adverse events compared to administration of either drug alone. In one such embodiment, the drug regimen eliminates the number or frequency of Grade 3 or higher AEs. In one embodiment, the drug regimen reduces the grade of bradycardia or QT prolongation compared to administration of either drug alone.

[0099]

[0099] In the event of an adverse event, it is generally understood that there are four options: (1) continue treatment as is with optional supplemental therapy; (2) adjust the dose of one or more drugs in the drug regimen; (3) temporarily discontinue the administration of one or more drugs in the drug regimen; or (4) discontinue the administration of one or more drugs in the drug regimen. In one embodiment, GDC-9545 is not adjusted.

[0100]

[0100] In one embodiment of the method described herein, the patient described herein experiences one or more adverse events, including fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, or itching. In one such embodiment, the patient described herein has the same or reduced level / severity as one or more such AEs. In another embodiment, the patient described herein has a reduced severity of one or more such AEs. In one embodiment, the patient described herein has a reduced severity of neutropenia, diarrhea, or bradycardia compared to a control. In one such embodiment, the control is (i) either the drug alone or SOC therapy.

[0101]

[0101] In one embodiment, the patient described herein has the same or reduced level of neutropenia after administration of the combination therapy compared to a control. In yet another embodiment, the patient described herein has the same or reduced level of bradycardia after administration of the combination therapy compared to a control, as described herein.

[0102]

[0102] In one embodiment of methods A1, A2, and A3 described herein, patients treated as described herein have a reduced incidence of interstitial lung disease compared to abemaciclib monotherapy.

[0103]

[0103] In one embodiment, the (one or more) adverse events experienced by the patient described herein receiving treatment with the combination therapy described herein are relatively reduced as described herein.

[0104]

[0104] In one embodiment of the method described herein, the patient described herein experiences an adverse event, including diarrhea. In one embodiment of the method described herein, less than 75%, less than 60%, less than 50%, less than 40%, less than 33%, less than 25%, less than 20%, less than 12%, or less than 5% of all treated patients experience one or more of neutropenia, diarrhea, or bradycardia resulting from treatment with the combination therapy described herein. In one embodiment of the method described herein, less than 85%, less than 75%, less than 60%, less than 50%, less than 40%, less than 33%, less than 25%, less than 20%, less than 17%, less than 10%, or less than 5% of all treated patients experience diarrhea as described herein resulting from treatment with the combination therapy described herein. In one embodiment of the method described herein, less than 60%, less than 50%, less than 45%, less than 33%, less than 25%, less than 10%, or less than 5% of all treated patients experience neutropenia resulting from treatment with the combination therapy described herein. In one embodiment of the method described herein, less than 75%, less than 60%, less than 50%, less than 40%, less than 33%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 8% of all treated patients experience bradycardia resulting from treatment with the combination therapy described herein. In some embodiments in which patients experience one or more AEs selected from the group consisting of neutropenia, diarrhea, and bradycardia resulting from treatment with the combination therapy described herein, the severity is grade 2 or less. In one embodiment, the patients described herein do not experience one or more AEs selected from the group consisting of neutropenia, diarrhea, and bradycardia resulting from treatment with the combination therapy described herein, and the severity of the AEs is higher than grade 2.

[0105] biomarkers

[0105] Breast cancer is a heterogeneous disease with many different subtypes defined by molecular signatures and diverse mutation profiles. Patients described herein may be tested for ER+ HER2-laBC or mBC using diagnostic methods or kits for informing the therapeutic or predictive response of patients to combination therapies described herein. In one embodiment, a patient may be tested by determining an ER pathway activity score, such as that described in U.S. Patent Application Publication No. 2020 / 0082944. In some embodiments, a patient sample is taken and tested to determine the ER pathway activity score. The score can be calculated using the signatures of 41 genes by subtracting the E2 suppression score (determined from the mean z-scored expression of genes including BAMBI, BCAS1, CCNG2, DDIT4, EGLN3, FAM171B, GRM4, IL1R1, LIPH, NBEA, PNPLA7, PSCA, SEMA3E, SSPO, STON1, TGFB3, TP53INP1, and TP53INP2) from the E2 induction score (determined from the mean z-scored expression of genes listed in AGR3, AMZ1, AREG, C5AR2, CELSR2, CT62, FKBP4, FMN1, GREB1, IGFBP4, NOS1AP, NXPH3, OLFM1, PGR, PPM1J, RAPGEFL1, RBM24, RERG, RET, SGK3, SLC9A3R1, TFF1, and ZNF703).

[0106]

[0106] In one embodiment, the patient-derived sample used to determine the ER pathway activity score is a tumor tissue sample (e.g., a formalin-fixed paraffin-embedded (FFPE), fresh-frozen (FF), preserved, fresh, or frozen tumor tissue sample).

[0107]

[0107] In some cases, patients described herein are administered the combination therapy described herein if their measured ER pathway activity score is between approximately -1.0 and approximately -0.2 (e.g., between approximately -0.9 and approximately -0.2, between approximately -0.8 and approximately -0.2, between approximately -0.7 and approximately -0.2, between approximately -0.6 and approximately -0.2, between approximately -0.5 and approximately -0.2, between approximately -0.4 and approximately -0.2, or between approximately -0.3 and approximately -0.2). In some cases, the ER activity score of the sample may be less than -1.0.

[0108]

[0108] In some embodiments, patient samples described herein may be evaluated for additional biomarkers in order to identify factors that may correlate with the safety and efficacy of the investigational treatment.

[0109]

[0109] In one embodiment of the methods described herein, NGS, whole-genome sequencing (WGS), other methods, or combinations thereof may be used on blood samples and DNA obtained from tumor tissues derived from patients described herein. Analysis of such samples may identify germline (e.g., BRCA1 / 2) and somatic cell changes that may predict response to the investigational drug, are related to progression to a more severe disease state, are related to acquired resistance to the investigational drug, or enhance knowledge and understanding of disease biology.

[0110] Pattern:

[0110] The following are exemplary embodiments of the present invention.

[0111]

[0111] Embodiment 1. A combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof administered as a QD on days 1 to 28 of the first 28-day cycle, and abemaciclib administered as a BID on days 1 to 28 of the first 28-day cycle.

[0112]

[0112] Embodiment 2. The combination therapy according to Embodiment 1, wherein abemaciclib is administered at a dose of 150 mg.

[0113]

[0113] Embodiment 3. A combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof administered as a QD on days 1 to 28 of the first 28-day cycle, and ribociclib administered as a QD on days 1 to 21 of the first 28-day cycle.

[0114]

[0114] Embodiment 4. The combination therapy according to Embodiment 3, wherein ribociclib is administered at a dose of 600 mg.

[0115]

[0115] Embodiment 5. The combination therapy according to any one of Embodiments 1 to 4, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 mg to about 100 mg.

[0116]

[0116] Embodiment 6. The combination therapy according to any one of Embodiments 1 to 5, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10, 30, 50, or 100 mg.

[0117]

[0117] Embodiment 7. The combination therapy according to any one of embodiments 1 to 6, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 30 mg.

[0118]

[0118] Embodiment 8. The combination therapy according to any one of Embodiments 1 to 7, wherein the drug regimen comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles.

[0119]

[0119] Embodiment 9. The combination therapy according to any one of embodiments 1 to 7, wherein the drug regimen comprises approximately 2 to 72, 2 to 66, 2 to 60, 2 to 54, 2 to 48, 2 to 42, 2 to 36, 2 to 30, 2 to 24, 2 to 18, or 2 to 12 cycles.

[0120]

[0120] Embodiment 10. A method for treating locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) having estrogen receptor-positive and HER2-negative laBC or mBC in a patient having receptor-positive and HER2-negative laBC or mBC, comprising administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib, wherein the combination therapy is administered over one or more 28-day cycles.

[0121]

[0121] Embodiment 11. A method for treating locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) that is estrogen receptor-positive and HER2-negative in a patient having receptor-positive and HER2-negative laBC or mBC, (i) QD administration of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, (ii) administer abemaciclib as a BID on days 1-28 of the first 28-day cycle. A method comprising administering a combination therapy to a patient, which includes a drug regimen containing [a specific substance].

[0122]

[0122] Embodiment 12. The method according to Embodiment 11, wherein abemaciclib is administered by BID at a dose of 150 mg.

[0123]

[0123] Embodiment 13. A method for treating locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) that is estrogen receptor-positive and HER2-negative in a patient having receptor-positive and HER2-negative laBC or mBC, (i) QD administration of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, (ii) administer ribociclib as a QD on days 1-21 of the first 28-day cycle. A method comprising administering a combination therapy to a patient, which includes a drug regimen containing [a specific substance].

[0124]

[0124] Embodiment 14. The method according to Embodiment 13, wherein ribociclib is administered in a dose of 600 mg.

[0125]

[0125] Embodiment 15. The method according to any one of Embodiments 10 to 14, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 mg to about 100 mg.

[0126]

[0126] Embodiment 16. The method according to Embodiment 15, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10, 30, 50, or 100 mg.

[0127]

[0127] Embodiment 17. The method according to Embodiment 15, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 30 mg.

[0128]

[0128] Embodiment 18. The method according to any one of Embodiments 11 to 17, wherein the medication regimen includes 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles.

[0129]

[0129] Embodiment 19. The method according to any one of embodiments 11 to 17, wherein the drug regimen comprises approximately 2 to 72, 2 to 66, 2 to 60, 2 to 54, 2 to 48, 2 to 42, 2 to 36, 2 to 30, 2 to 24, 2 to 18, or 2 to 12 cycles.

[0130]

[0130] Embodiment 20. The method according to any one of Embodiments 10 to 19, wherein the patient is premenopausal.

[0131]

[0131] Embodiment 21. The method according to any one of Embodiments 10 to 20, wherein the patient is tested for the presence of mutations in one or more of the estrogen receptor, prostaglandin receptor, or Ki67.

[0132]

[0132] Embodiment 22. The method according to any one of Embodiments 10 to 21, wherein the patient has reduced adverse events (AEs) compared to a control.

[0133]

[0133] Embodiment 23. The method according to Embodiment 22, wherein the patient has a reduced severity of one or more AEs selected from the group consisting of fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, or pruritus, compared to a control.

[0134]

[0134] Embodiment 24. The method according to Embodiment 22, wherein the patient has the same or reduced level of neutropenia after administration of the combination therapy compared to a control.

[0135]

[0135] Embodiment 25. The method according to Embodiment 22, wherein the patient has the same or reduced level of bradycardia after administration of the combination therapy compared to a control.

[0136]

[0136] Embodiment 26. The method according to any one of Embodiments 10 to 25, wherein the patient has increased overall survival (OS) compared to the control.

[0137]

[0137] Embodiment 27. The method according to Embodiment 26, wherein the patient has an increase of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 months, or longer, compared to the control.

[0138]

[0138] Embodiment 28. The method according to any one of Embodiments 10 to 27, wherein the duration of response to combination therapy is increased compared to the control.

[0139]

[0139] Embodiment 29. The method according to Embodiment 28, wherein the duration of response is increased by at least 1 to 3 months, 2 to 6 months, 3 to 8 months, 4 to 10 months, 5 to 12 months, 6 to 15 months, 8 to 20 months, or 1 to 24 months.

[0140]

[0140] Embodiment 30. The method according to any one of Embodiments 10 to 29, wherein the patient has an increased clinical benefit rate compared to the control.

[0141]

[0141] Embodiment 31. The method according to any one of Embodiments 10 to 30, wherein the patient has an increased progression-free survival compared to the control.

[0142]

[0142] Embodiment 32. The method according to Embodiment 31, wherein the increase is at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 36, 42, 48, 50, 54, 60, 66, or 72 months.

[0143]

[0143] Embodiment 33. The method according to any one of Embodiments 22 to 32, wherein the control is administered GDC-9545 alone.

[0144]

[0144] Embodiment 34. The method according to any one of Embodiments 10 to 33, wherein the patient has not received prior chemotherapy before administration of the combination therapy.

[0145]

[0145] Embodiment 35. The method according to any one of Embodiments 10 to 34, wherein the patient has been previously treated with tamoxifen.

[0146]

[0146] Embodiment 36. The method according to any one of Embodiments 10 to 33, wherein the patient has been previously treated with an aromatase inhibitor or a CDK4 / 6 inhibitor, or a combination thereof.

[0147]

[0147] Embodiment 37. The method according to any one of Embodiments 10 to 35, wherein the patient has been previously treated with fulvestrant.

[0148]

[0148] Embodiment 38. Use of combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof with abemaciclib or ribociclib for the treatment of laBC or mBC.

[0149]

[0149] Embodiment 39. Use of a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib or ribociclib for the manufacture of a pharmaceutical for the treatment of laBC or mBC.

[0150]

[0150] Embodiment 40. The use according to Embodiment 38 or 39, wherein the combination therapy includes abemaciclib.

[0151]

[0151] Embodiment 41. The use according to Embodiment 40, wherein the combination therapy comprises a drug regimen including (i) a QD administration of 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a BID administration of 150 mg of abemaciclib on days 1 to 28 of the first 28-day cycle.

[0152]

[0152] Embodiment 42. The use according to Embodiment 38 or 39, wherein the combination therapy comprises ribociclib.

[0153]

[0153] Embodiment 43. The use according to Embodiment 42, wherein the combination therapy comprises a drug regimen including (i) a QD administration of 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, and (ii) a QD administration of 600 mg of ribociclib on days 1 to 21 of the first 28-day cycle.

[0154]

[0154] Embodiment 44. Use according to any one of Embodiments 38 to 43, wherein the combination therapy is for the treatment of laBC.

[0155]

[0155] Embodiment 45. The use according to any one of Embodiments 38 to 43, wherein the combination therapy is for the treatment of mBC.

[0156]

[0156] Embodiment 46. A method for inhibiting tumor growth in a patient having laBC or mBC, comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib or ribociclib in one or more 28-day cycles.

[0157]

[0157] Embodiment 47. A method for inducing or improving tumor regression in a patient having laBC or mBC, comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and abemaciclib or ribociclib in one or more 28-day cycles.

[0158]

[0158] The following embodiments are presented as examples only, and are not limiting. [Examples]

[0159]

[0159] The role of estrogen in the pathogenesis and progression of breast cancer is well established (Colditz et al. N Engl J Med 1995;332:1589-93). Modulation of estrogen activity and / or synthesis is one therapeutic approach in ER+ breast cancer patients. Despite the effectiveness of available treatments for ER+ patients with locally advanced or metastatic disease, including endocrine therapy (ET) and combinations of endocrine therapy and targeted therapy, many patients eventually relapse or develop resistance to these factors and therefore require further treatment for optimal disease control. However, it is thought that the growth and survival of most tumors remain dependent on ER signaling, even after becoming resistant to AI or tamoxifen. Patients with ER+ breast cancer may still respond to second / tertiary hormone therapy even after progression of prior treatment (Di Leo et al. J Clin Oncol. 2010;28:4594-600; Baselga et al. N Engl J Med. 2012;366:520-9). While not bound by any particular theory, there is evidence that ER can be signaled ligand-independently in endocrine-resistant states (Miller et al. J Clin Invest 2010;120:2406-13; Van Tine et al. Cancer Discov 2011;1:287-8). Drugs (or combinations of drugs) that can target both ligand-dependent and ligand-independent ER signaling have the potential to improve treatment outcomes in patients with ER+ breast cancer.

[0160]

[0160] ESR1 mutations appear to be a major mechanism of acquired resistance to AI and are associated with worse outcomes (Schiavon et al. Sci Transl Med 2015;7:313ra182; Chandarlapaty et al. JAMA Oncol 2016;2:1310-15; Fribbens et al. J Clin Oncol 2016;34:2961-8). The prevalence of ESR1 mutations ranges from approximately 25% to 40% after AI exposure, but appears to be only 2% to 3% in ET-naive patients (Chandarlapaty et al. 2016). This suggests that ESR1 is a significant oncogenic factor under AI selective pressure. Research has identified mutations in ESR1, which encodes ER-α (mainly Y537S and D538G), that affect the ligand-binding domain "LBD" of ER-α (Segal and Dowsett Clin Cancer Res 2014;20:1724-6).Studies using clinical samples and nonclinical models have shown that ER antagonists appear to be effective against ligand-independent, constitutively active ER mutant receptors and may have therapeutic effects in patients resistant to AI (Li et al. Cell Rep. 2013;4:1116-30; Merenbakh-Lamin et al. Cancer Res 2013;73:6856-64; Robinson et al. Nat Genet 2013;45:1466-51; Toy et al. Nat Genet 2013;45:1439-45; Alluri et al. Breast Cancer Res 2014;16:494; Segal and Dowsett Clin Cancer Res 2014;20:1724-6; Jeselsohn et al. Nat Rev Clin Oncol 2015; 12:573-83; Niu et al. Onco Targets). Ther. 2015;8:3323-8; Schiavon et al. Sci Transl Med 2015;7:313ra182; Chu et al. Clin Cancer Res 2016; 22:993-9).

[0161]

[0161] Selective estrogen receptor degraders (SERDs) are recognized as being able to block endocrine-dependent and endocrine-independent ER signaling and provide a therapeutic approach for ER+ metastatic breast cancer. Fulvestrant, a first-generation SERD, binds to, blocks, and degrades the ER, resulting in inhibition of ER-mediated estrogen signaling. Fulvestrant has also shown to be more beneficial than anastrozole in first-line patients, as demonstrated in one study (NCT01602380). However, the bioavailability and delivery of fulvestrant hinder its efficacy management.

[0162]

[0162] Non-clinical studies comparing drug exposure and in vitro efficacy of GDC-9545 and fulvestrant demonstrated that the total steady-state drug exposure in humans with 30 mg once daily (QD) of GDC-9545 was approximately 10 times higher than the steady-state exposure of 500 mg intramuscular (IM) fulvestrant monthly. Furthermore, lower binding of GDC-9545 to plasma proteins results in higher free concentrations of GDC-9545 than fulvestrant. In in vitro cell and biochemical assays, GDC-9545 showed up to 10 times higher efficacy than fulvestrant in both wild-type and ESR1 mutant conditions. When administered according to clinically appropriate dosing schemes, fulvestrant was less effective than GDC-9545 in the evaluated xenograft models.

[0163]

[0163] The development and approval of CDK4 / 6-targeted drugs for HR+ and HER2-negative metastatic breast cancer has expanded the treatment options for breast cancer. Studies of approved CDK4 / 6i therapies (palbociclib, ribociclib, and abemaciclib) have established the ET+ targeted therapy strategy as a first-line treatment for patients with HR+ and HER2-negative metastatic breast cancer.

[0164]

[0164] Palbociclib, ribociclib, and abemaciclib have similar mechanisms of action, but there are important differences between them in terms of pharmacokinetics and toxicity, with abemaciclib being more selective to CDK4 than to CDK6. Unlike other CDK4 / 6i therapies, abemaciclib showed monotherapy activity even in endocrine-resistant tumors.

[0165]

[0165] The patient will receive one of the following: 1) Until unacceptable toxicity or disease progression is determined by the investigator in accordance with RECIST v1.1, combination therapy consisting of (a) GDC-9545 administered at a dose of 30 mg per 28-day cycle with a QD and (b) abemaciclib administered at a dose of 150 mg per 28-day cycle with a BID, or 2) Combination therapy consisting of (a) GDC-9545 administered via QD at a dose of 30 mg during each 28-day cycle, and (b) ribociclib administered via QD at a dose of 600 mg on days 1 to 21 of each 28-day cycle, until unacceptable toxicity or disease progression is determined by the principal investigator in accordance with RECIST v1.1.

[0166]

[0166] For both therapies 1) and 2) above, GDC-9545 should be taken daily at approximately the same time each day, starting on day 1 of cycle 1 and continuing on day 1 of each subsequent 28-day cycle. If the dose is not taken within 6 hours of the scheduled dose, it is considered not taken. If the dose is not taken or is vomited up, the patient should resume medication with the next scheduled dose, and the dose that was not taken or vomited up will not be compensated.

[0167]

[0167] In therapy 1 above, abemaciclib should be administered at intervals of approximately 12 hours, with a minimum interval of 6 hours. Abemaciclib should be taken at approximately the same time each day, regardless of whether a meal has been taken. If a dose is missed, the patient can take it as soon as they remember. The patient should wait at least 6 hours before taking the next scheduled dose.

[0168]

[0168] For both of therapies 1) and 2) above, patients are permitted to use the following combination therapies: a. Symptomatic treatment with antiemetics, antidiarrheal therapy, and palliative and supportive therapies for other disease-related symptoms. b. Analgesics administered in accordance with standard clinical practice. c. Bone-preserving agents (e.g., bisphosphonates, denosumab) for the treatment of osteoporosis / osteopenia or for the mitigation of bone metastases.

[0169]

[0169] Regarding the above therapy 1), patients who have been administered GDC-9545 and abemaciclib are not permitted to use the following combination therapies: a. The investigative treatment (other than the study treatment specified in the clinical trial protocol) was administered within 28 days prior to the first dose of GDC9545 and abemaciclib. b. Any combination therapy for the treatment of cancer, including but not limited to chemotherapy, immunotherapy, biological therapy, radiation therapy, or herbal therapy, is prohibited. c. Hormone replacement therapy, topical estrogens (including any vaginal preparations), megestrol acetate, and selective ER modulators (e.g., raloxifene). d. Primary prophylactic use of hematopoietic growth factors (e.g., erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor). e. Radiotherapy for clearly progressive disease, excluding new brain metastases in the following systemic response situations: Patients who have demonstrated control of systemic disease (defined as having received clinical benefit [i.e., PR, CR, or SD over ≥24 weeks]) but have developed isolated brain metastases treatable with radiation. ET (i.e., GDC-9545) can be administered concurrently with radiotherapy. f. Megestrol acetate is administered as an appetite stimulant after the start of the experimental treatment.

[0170]

[0170] Regarding therapy 2) above, take the medication at approximately the same time each day, preferably in the morning, for 21 consecutive days as a prescription dose, followed by a 7-day rest period to form a 28-day cycle. Ribociclib can be taken with or without food. If a dose is not taken or is vomited up, the patient should resume medication with the next scheduled dose.

[0171]

[0171] Regarding the above therapy 2), patients who have been administered GDC-9545 and ribociclib are not permitted to use the following combination therapies: a. The investigative treatment (other than the study treatment specified in the clinical trial protocol) was administered within 28 days prior to the first dose of GDC9545 and ribociclib. b. Any combination therapy for the treatment of cancer, including but not limited to chemotherapy, immunotherapy, biological therapy, radiation therapy, or herbal therapy, is prohibited. c. Antiarrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol), and other drugs known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide, and ondansetron), and other drugs known to potentially prolong the QT interval. Furthermore, ribociclib increases QT prolongation, and therefore, its use in combination with tamoxifen is not indicated. d. Co-administration with potent CYP3A inhibitors and inducers. e. Hormone replacement therapy, topical estrogens (including any vaginal preparations), megestrol acetate, and selective ER modulators (e.g., raloxifene). f. Primary prophylactic use of hematopoietic growth factors (e.g., erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor). g. Radiotherapy for clearly progressive disease, excluding new brain metastases in the following systemic response situations: Patients who have demonstrated control of systemic disease (defined as having received clinical benefit [i.e., PR, CR, or SD over ≥24 weeks]) but have developed isolated brain metastases treatable with radiation. ET (i.e., GDC-9545) can be administered concurrently with radiotherapy. h. Megestrol acetate is administered as an appetite stimulant after the start of the experimental treatment.

[0172]

[0172] GDC-9545 may be temporarily discontinued in patients experiencing toxicity thought to be related to the investigational treatment. Abemaciclib treatment may be temporarily discontinued in patients experiencing toxicity thought to be related to the investigational treatment. If either drug is discontinued, the other drug may be continued if the patient is likely to receive clinical benefit.

[0173]

[0173] Throughout this specification and the claims, the words “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense unless otherwise required by context. Embodiments described herein are understood to include embodiments that “consist of” and / or “essentially consist of.”

[0174]

[0174] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, each intermediate value up to one-tenth of the lower limit between the upper and lower limits of the range and any other stated or intermediate values ​​within that stated range should be understood to be included herein. The upper and lower limits of these smaller ranges, which can be independently included in smaller ranges, are also included herein, subject to the limits that are specifically excluded in the stated range. If a stated range includes one or both of the limits, the range excluding one or both of those included limits is also included herein.

[0175]

[0175] A person skilled in the art, having received the teachings presented in the foregoing description and the related drawings, will likely come to mind many modifications and other embodiments of the invention described herein. Therefore, it should be understood that the invention is not to be limited to any particular aspect disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Certain terms are used herein, but these are used in a general and descriptive sense only and are not intended to be limiting.

Claims

1. (i) GDC-9545 or a pharmaceutically acceptable salt thereof; (ii) Abemaciclib; or, (iii) The above (i) and the above (ii) including, A pharmaceutical product for treating locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) that is estrogen receptor-positive and HER2-negative in patients with laBC or mBC, i) QD administration of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, ii) Administer abemaciclib as a BID during days 1-28 of the first 28-day cycle. A pharmaceutical product in which a combination therapy regimen, including the drug containing [specific ingredient], is administered to a patient.

2. The pharmacopoeia according to claim 1, wherein abemaciclib is administered by BID at a dose of 150 mg.

3. (i) GDC-9545 or a pharmaceutically acceptable salt thereof; (ii) Ribociclib; or, (iii) The above (i) and the above (ii) including, A pharmaceutical product for treating locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) that is estrogen receptor-positive and HER2-negative in patients with laBC or mBC, i) QD administration of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle, ii) administer ribociclib as a QD dose on days 1-21 of the first 28-day cycle. A pharmaceutical product in which a combination therapy regimen, including the drug containing [specific ingredient], is administered to a patient.

4. The pharmacopoeia according to claim 3, wherein ribociclib is administered in a dose of 600 mg.

5. A pharmaceutical product according to any one of claims 1 to 4, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 10 mg to 100 mg.

6. The pharmaceutical product according to claim 5, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 10, 30, 50, or 100 mg.

7. The pharmaceutical product according to claim 5, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 30 mg.

8. A pharmaceutical product according to any one of claims 1 to 7, wherein the drug regimen comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles.

9. The pharmaceutical product according to any one of claims 1 to 8, wherein the patient is premenopausal.

10. A pharmaceutical product according to any one of claims 1 to 9, wherein the patient is tested for the presence of one or more mutations in estrogen receptors, prostaglandin receptors, or Ki67.

11. Patients experienced a reduction in adverse events (AEs) compared to the control group. The pharmacopoeia according to any one of claims 1 to 10, wherein the control is selected from the group consisting of standard-of-care (SOC) therapy, GDC-9545 alone, abemaciclib alone, or ribociclib alone.

12. The pharmacopoeia according to claim 11, wherein the patient has a reduced severity of one or more AEs selected from the group consisting of fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, or pruritus, compared to the control.

13. The pharmaceutical agent according to claim 11, wherein the patient has the same or reduced level of neutropenia after receiving combination therapy, compared to the control.

14. The pharmaceutical product according to claim 11, wherein the patient has the same or reduced level of bradycardia after receiving combination therapy compared to the control.

15. The pharmaceutical product according to any one of claims 1 to 14, wherein the patient has not received prior chemotherapy before receiving combination therapy.

16. The pharmaceutical product according to any one of claims 1 to 14, wherein the patient has previously been treated with tamoxifen.

17. The pharmaceutical product according to any one of claims 1 to 14, wherein the patient has previously been treated with an aromatase inhibitor or a CDK4 / 6 inhibitor, or a combination thereof.

18. A pharmaceutical product according to any one of claims 1 to 14, wherein the patient has previously been treated with fulvestrant.

19. (i) GDC-9545 or a pharmaceutically acceptable salt thereof; (ii) Abemaciclib and / or ribociclib, (iii) The above (i) and the above (ii) A pharmaceutical agent for inhibiting tumor growth in patients having laBC or mBC, including, A combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof with abemaciclib or ribociclib is administered in one or more 28-day cycles.

20. (i) GDC-9545 or a pharmaceutically acceptable salt thereof; (ii) Abemaciclib and / or ribociclib, (iii) The above (i) and the above (ii) A pharmaceutical product for causing or improving tumor regression in patients having laBC or mBC, including A pharmaceutical product comprising one or more 28-day cycles of combination therapy containing GDC-9545 or a pharmaceutically acceptable salt thereof with abemaciclib or ribociclib.

21. The combination therapy comprises abemaciclib, as described in claim 20.

22. The pharmacopoeia according to claim 21, wherein the combination therapy comprises a drug regimen of i) administering 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof as a QD on days 1 to 28 of the first 28-day cycle, and ii) administering 150 mg of abemaciclib as a BID on days 1 to 28 of the first 28-day cycle.

23. The pharmaceutical product according to claim 20, wherein the combination therapy comprises ribociclib.

24. The pharmacopoeia according to claim 23, wherein the combination therapy comprises a drug regimen of i) administering 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1 to 28 of the first 28-day cycle on a QD basis, and ii) administering 600 mg of ribociclib on days 1 to 21 of the first 28-day cycle on a QD basis.

25. The pharmaceutical product according to any one of claims 20 to 24, wherein the combination therapy is for the treatment of labic BC.

26. The pharmaceutical product according to any one of claims 20 to 24, wherein the combination therapy is for the treatment of mBC.

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