Treatment of breast cancer using combination therapy including GDC-9545 and GDC-0077

Abstract

Provided herein is a combination therapy comprising GDC-9545 and GDC-0077 for treating 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 / 149,944, filed on February 16, 2021, which is hereby incorporated by reference in its entirety for all purposes.

[0002] Field of the Invention

[0002] The present specification provides a combination therapy for treating breast cancer, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 or a pharmaceutically acceptable salt thereof.

Background Art

[0003]

[0003] Breast cancer is the most frequently occurring cancer diagnosed in women, and an estimated 2.1 million new incidences were reported worldwide in 2018 (Bray et al. CA Canver J Clin 2018;68:394-424). Breast cancer accounts for approximately 12% (about 627,000 cases) of all cancer deaths. The mortality rate of breast cancer varies by region, and better survival rates are observed in the advanced regions of the world (ibid.).

[0004]

[0004] The initial treatment of breast cancer is often guided by the presence of molecular markers found in breast cancer cells. These markers are used to identify subtypes of breast cancer and to assist in the development of treatments based on the presence of tumor hormone receptors (estrogen receptor [ER] / progesterone receptor [PR]). Hormone receptor-positive (HR+) breast cancer that expresses estrogen receptor-α (ER-α) accounts for 70% of all invasive breast cancers. PR expression in tumors is another marker of ER-α signaling. Endocrine agents are the standard treatment used to downregulate ER signaling in HR+ breast cancer.

[0005]

[0005] Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor tyrosine kinase that is amplified or overexpressed in 20% of breast cancers. Treatment regimens for HER2-positive breast cancer include HER2-targeted therapies (anti-HER2 antibodies and tyrosine kinase inhibitors).

[0006]

[0006] Not all HR+ breast cancers respond optimally to ET. Mechanisms that may lead to primary and / or secondary hormone resistance in HR+ breast cancer include reduced or absent hormone receptor expression, or upregulation of growth factor signaling pathways such as epidermal growth factor receptor, HER2, MAPK, or the PI3K / Akt / mTOR pathway (Johnston et al. 2009; Musgrove and Sutherland 2009). Recently, mutations in the gene encoding the estrogen receptor (ESR1) have been identified in metastatic ER-positive (ER+) tumors and associated with resistance to anti-estrogen therapy (Robinson et al. 2013; Toy et al. 2013; Jeselsohn et al. 2014).

[0007]

[0007] Therefore, there is an urgent need for clinically active agents for the treatment of recurrent or resistant ER-positive breast cancer. [Overview of the project]

[0008]

[0008] Solutions to the above-mentioned problems and other problems in the art are provided herein.

[0009]

[0009] This embodiment can be better understood by referring to embodiments and examples of the invention intended to illustrate non-limiting aspects. [Brief explanation of the drawing]

[0010] [Figure 1]

[0010] This shows the antiproliferative effect of endocrine suppression by E2 depletion or treatment with GDC-9545, either alone or in combination with PI3K or CDK4 / 6 inhibition, in MCF-7 cells containing wild-type ESR1. Cells were treated for 6 to 8 days as shown in the figure, and relative viability was evaluated. * p<0.0001, parametric t-test. [Figure 2]

[0011] This study demonstrates the antiproliferative effects of endocrine suppression in MCF-7 cells containing the mutant (Y537S)ESR1, induced by E2 depletion or treatment with GDC-9545, either alone or in combination with PI3K or CDK4 / 6 inhibition. Cells were treated for 6 to 8 days as shown in the figure, and relative viability was evaluated. * p<0.0001, parametric t-test. [Figure 3]

[0012] This study demonstrates the antiproliferative effects of endocrine suppression induced by E2 depletion or GDC-9545 treatment, either alone or in combination with PI3K or CDK4 / 6 inhibition, in T-47D cells containing wild-type ESR1. Cells were treated for 6 to 8 days as shown in the figure, and relative viability was assessed. * p<0.0001, parametric t-test. [Figure 4]

[0013] This study demonstrates the antiproliferative effects of endocrine suppression in T-47D cells containing the mutant (D538G)ESR1, induced by E2 depletion or treatment with GDC-9545, either alone or in combination with PI3K or CDK4 / 6 inhibition. Cells were treated for 6 to 8 days as shown in the figure, and relative viability was evaluated. * p<0.0001, parametric t-test. [Modes for carrying out the invention]

[0011]

[0014] 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.

[0012]

[0015] The following definitions are provided to facilitate understanding of certain terms frequently used herein and are not intended to limit the scope of this disclosure. All references mentioned herein are incorporated herein by reference in their entirety.

[0013]

[0016] As used herein, unless otherwise specified, the terms “about” and “approximately” refer to a dose, volume, or weight percentage of an ingredient in a composition or dosage form, meaning 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.

[0014]

[0017] The "GDC-9545" has the following structure: TIFF0007904849000001.tif49170 The chemical name refers to a compound having 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, including its pharmaceutically acceptable salts. In one embodiment, GDC-9545 is a tartrate. As used herein, "GDC-9545" refers to the free base and pharmaceutically acceptable salts of GDC-9545 (including its tartrate). GDC-9545 is also known as ziledestrant.

[0015]

[0018] The "GDC-0077" has the following structure: This refers to a compound having TIFF0007904849000002.tif38170 and the chemical name (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-3-oxazolidinyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-9-yl]amino]propanamide (including its pharmaceutically acceptable salts). In one embodiment, GDC-0077 is administered as a free base. As used herein, "GDC-0077" refers to the free base and pharmaceutically acceptable salts of GDC-0077. GDC-0077 is also known as inavolicib.

[0016]

[0019] The term “package insert” is used to refer to the instruction manual that is typically included in the product packaging of a therapeutic product and contains information about the efficacy, usage, dosage, administration, contraindications, and / or precautions for use of such therapeutic product.

[0017]

[0020] "Overall survival" or "OS" refers to the time from registration to death from any cause.

[0018]

[0021] "Objective response" refers to a complete or partial response as determined by the principal investigator in accordance with RECIST v1.1.

[0019]

[0022] "Objective response rate" or "ORR" refers to the proportion of patients with confirmed complete or partial response in two consecutive opportunities at least 4 weeks apart, determined by the investigator in charge of the clinical trial according to RECIST v1.1.

[0020]

[0023] "Time to progression" or "TTP" refers to the time from randomization to objective tumor progression.

[0021]

[0024] "Duration of response" or "DOR" refers to the time from the first occurrence of a recorded objective response to the earlier of disease progression determined by the investigator in charge of the clinical trial according to RECIST v1.1 or death from any cause.

[0022]

[0025] "Progression-free survival" or "PFS" refers to the time from registration to the earlier of the occurrence of the first recorded disease progression determined by the investigator in charge of the clinical trial using RECIST v1.1 or the date of death from any cause.

[0023]

[0026] "Disease control rate" or "DCR" refers to the proportion of patients with stable disease for at least 12 weeks or having CR or PR determined by the investigator in charge of the clinical trial using RECIST v1.1.

[0024]

[0027] "Clinical benefit rate" or "CBR" refers to the proportion of patients with stable disease for at least 24 weeks or having confirmed complete or partial response determined by the investigator in charge of the clinical trial according to RECIST v1.1.

[0025]

[0028] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels.

[0026]

[0029] "Partial response" or "non-CR / non-PD" refers to the persistence of one or more non-target lesions and / or (where applicable) the maintenance of tumor marker levels above the normal limit. PR may also refer to a reduction of ≥30% in the total diameter of target lesions in the absence of CR, new lesions, and clear progression in non-target lesions.

[0027]

[0030] "Progressive disease" or "PD" refers to a ≥20% increase in the total diameter of target lesions, clear progression in non-target lesions, and / or the appearance of new lesions.

[0028]

[0031] "Stable disease progression" or "SD" refers to a state where there is neither sufficient reduction in tumor size to qualify as complete response (CR) or partial response (PR), nor sufficient increase in tumor growth to qualify as progressive disease (PD).

[0029]

[0032] The term "locally advanced breast cancer" refers to cancer that has spread from its origin in the breast to nearby tissues or lymph nodes, but has not spread to other parts of the body.

[0030]

[0033] 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 called stage IV breast cancer.

[0031]

[0034] The term “treatment” refers to a clinical intervention designed to alter the natural course of the patient or cells being treated during the course of clinicopathology. Desired effects of treatment include a reduction in the rate of disease progression, recovery or mitigation of the disease state, and remission or improved prognosis. A patient’s “treatment” is considered successful if one or more of the breast cancer-related symptoms described herein are reduced or eliminated, including, but not limited to, a decrease (or destruction) of cancer cell proliferation, a reduction in disease-related symptoms, an improvement in the quality of life of the person with the disease, a reduction in the dosage of other drugs required to treat the disease, and / or an extension of the patient’s survival.

[0032]

[0035] The term “delaying the progression” of a disease means delaying, preventing, slowing, stabilizing, and / or postponing the onset of breast cancer as described herein. This delay may be of varying lengths depending on the patient’s cancer history and / or the patient being treated. As will be apparent to those skilled in the art, a sufficient or significant delay may substantially encompass prevention in that the patient does not develop cancer.

[0033]

[0036] "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 the 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 caused by 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.

[0034]

[0037] As used herein, the "E2 suppression score" refers to a numerical value that reflects the total expression level of a given set of genes whose suppression reflects estrogen receptor (ER) pathway activity.

[0035]

[0038] As used herein, the "E2 induction score" refers to a numerical value that reflects the total expression level of a given set of genes whose induction reflects estrogen receptor (ER) pathway activity.

[0036]

[0039] 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.

[0037]

[0040] "Administration period" or "cycle" means a period including the administration of one or more of the drugs described herein (i.e., GDC-9545 or a pharmaceutically acceptable salt thereof, or GDC-0077 or a pharmaceutically acceptable salt thereof), 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 of the 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 a pharmaceutically acceptable salt thereof, or GDC-0077 or a pharmaceutically acceptable salt thereof) 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 a pharmaceutically acceptable salt thereof, or GDC-0077 or a pharmaceutically acceptable salt thereof) is administered. The rest periods provided herein may, in some cases, include the administration of another drug other than GDC-9545 or a pharmaceutically acceptable salt thereof, or GDC-0077 or a pharmaceutically acceptable salt thereof. 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.

[0038]

[0041] "Medication regimen" means a period of administration of the drugs described herein, comprising one or more cycles, each cycle of which may consist of administration of the drugs described herein at different frequencies or in different amounts.

[0039]

[0042] "QD" refers to administering the compound once a day.

[0040]

[0043] "PO" refers to oral administration of the drugs described herein.

[0041]

[0044] A graded adverse event refers to a severity grading scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table. TIFF0007904849000003.tif50170

[0042] Combination therapy

[0045] A combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof (e.g., GDC-9545 tartrate) and GDC-0077 or a pharmaceutically acceptable salt thereof is provided herein. In one embodiment, the combination therapy described herein is useful for the treatment of a particular type of breast cancer described herein. In one embodiment, 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 GDC-0077 or a pharmaceutically acceptable salt thereof administered as a QD on days 1 to 28 of the first 28-day cycle is provided herein.

[0043]

[0046] 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 approximately 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 approximately 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 a dose of 30 mg.

[0044]

[0047] In one embodiment of the combination therapy described herein, GDC-0077 is administered in a dose of 9 mg. Such administration may be a single dose (i.e., one or more tablets). In one embodiment, if the patient described herein experiences an adverse event, the dose of GDC-0077 is reduced to 6 mg or 3 mg. GDC-0077 may be administered as a PO QD as described herein. In some embodiments, GDC-0077 is administered in one or more oral tablets as described herein. In one preferred embodiment, GDC-0077 is administered in an oral tablet in a dose of 9 mg.

[0045]

[0048] The combination therapies described herein may be provided as kits containing one or more agents for administration. In one embodiment, the kit contains GDC-9545 or a pharmaceutically acceptable salt thereof for administration in combination with GDC-0077 as described herein. In another embodiment, the kit contains GDC-9545 or a pharmaceutically acceptable salt thereof packaged together with GDC-0077, and the kit contains separately prescribed dosages of each agent. In yet another embodiment, the kit contains GDC-9545 or a pharmaceutically acceptable salt thereof co-formulated with GDC-0077.

[0046]

[0049] 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.

[0047]

[0050] Further kits are provided 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.

[0048]

[0051] In one embodiment, the combination therapy described herein can be used to treat 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 an embodiment, the combination therapy described herein can be used to treat ER+, HER2- laBC. In such an embodiment, the combination therapy described herein can be used to treat ER+, HER2- mBC.

[0049] Treatment methods

[0052] Methods for treating ER+, HER2-laBC, or mBC in patients having such cancers are provided herein. In one embodiment, a method (G1) for treating the laBC or mBC described herein in patients having such cancer is provided herein, comprising administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077. In one embodiment of method (G1) provided herein, the method is used for the treatment of laBC. In another embodiment of method (G1) provided herein, the method is used for the treatment of mBC.

[0050]

[0053] A method (G2) for treating laBC or mBC described herein in a patient having such cancer is further provided herein, comprising administering to the patient a combination therapy 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 GDC-0077 on days 1 to 28 of the first 28-day cycle. In one embodiment of method (G2) provided herein, the method is used for the treatment of laBC. In another embodiment of method (G2) provided herein, the method is used for the treatment of mBC.

[0051]

[0054] In one embodiment of the G1 or G2 method, 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 approximately 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 approximately 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.

[0052]

[0055] In one embodiment of method G1 or G2 described herein, GDC-0077 is administered in an amount of 9 mg. Such administration may be a single dose (i.e., one or more tablets). In one embodiment, if the patient described herein experiences an adverse event, the dose of GDC-0077 is reduced to 6 mg or 3 mg. GDC-0077 may be administered as a PO QD as described herein. In some embodiments, GDC-0077 is administered in one or more oral tablets as described herein. In one preferred embodiment, GDC-0077 is administered in an oral tablet in an amount of 9 mg.

[0053]

[0056] A method (G3) 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 9 mg of GDC-0077 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 (G3) provided herein, the method is used for the treatment of laBC. In another embodiment of method (G3) provided herein, the method is used for the treatment of mBC.

[0054]

[0057] In one embodiment of methods G1, G2, and G3, the cancer is inoperable locally advanced breast cancer (laBC) or metastatic ER+ breast cancer (mBC).

[0055]

[0058] In one embodiment of Methods G1, G2, and G3, the combination of GDC-9545 or a pharmaceutically acceptable salt thereof with GDC-0077 does not require co-administration (treatment) with a gonadotropin-releasing hormone (GnRH) agonist.

[0056]

[0059] In one embodiment of Methods G1, G2, and G3, the dose of GDC-0077 may be reduced. In one such embodiment, the dose of GDC-0077 may be reduced by 3 mg in a total of up to two reductions (i.e., reduced to 6 mg QD or 3 mg QD). In one embodiment of Methods G1, G2, and G3, the administration of one drug (GDC-9454 or a pharmaceutically acceptable salt thereof or GDC-0077) during combination therapy may be interrupted for up to 28 days. In one embodiment of Methods G1, G2, and G3, the dose of GDC-9545 is not reduced.

[0057]

[0060] Methods for treating breast cancer provided herein (G1, G2, and G3) may include the administration of 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 in any number of cycles until a desired response (e.g., OR, PFS, OS, ORR, DOR, CBR) is reached (e.g., increased OR, PFS, OS, ORR, DOR, CBR compared to the control described herein). In another embodiment, the drug regimen comprises administering the combination therapy described herein in 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 in any number of cycles until disease progression.

[0058]

[0061] In one embodiment of the method described herein, the patient is a postmenopausal woman. In such one embodiment, the patient is (i) 60 years of age or older; (ii) under 60 years of age and, in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone agonist or antagonist, has, as determined by local clinical laboratory evaluation, amenorrhea of ​​12 months or more, in addition to follicle-stimulating hormone (FSH) and plasma estradiol levels within the postmenopausal range; or (iii) has a record of having undergone bilateral oophorectomy.

[0059]

[0062] 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.

[0060]

[0063] 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.

[0061]

[0064] 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.

[0062]

[0065] In one embodiment of the method described herein, the patient described herein is treatment-naïve. In one such embodiment, the patient described herein has not received chemotherapy prior to administration of the combination therapy described herein. In 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 one embodiment, the patient described herein has not been previously treated with letrozole, palbociclib, or a combination thereof. 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. In another embodiment of the method described herein, the patient may have previously received treatment with tamoxifen, provided that they did not experience a relapse of the disease within the first 24 months of treatment with tamoxifen.

[0063]

[0066] In one embodiment of the method described herein, the patient has been treated with one or more cancer therapies prior to administration of the combination therapy described herein. In one embodiment, the patient described herein has previously been treated with tamoxifen. In another embodiment, the patient described herein has previously been treated with a PIK inhibitor or an mTOR inhibitor prior to administration of the combination therapy. In yet another embodiment, the patient described herein has previously been treated with fulvestrant.

[0064]

[0067] 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.

[0065]

[0068] Systemic chemotherapy is considered one of the standard of care (SOCs) for patients with membranous cell carcinoma (mBC), but there is no standard regimen or sequence. In one embodiment of the method described herein, the patient described herein has previously been treated with one or more therapies selected from the group consisting of anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxemesterone, ethinylestradiol, doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, albumin-conjugated paclitaxel, methotrexate, 5-fluorouracil (5-FU), methotrexate and 5-fluorouracil (5-FU), carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, eribulin, ixabepyrone, trastuzumab and pertuzumab, or combinations thereof, prior to administration of the combination therapy described herein.

[0066]

[0069] In one embodiment of the method described herein, the patient described herein may have laBC or mBC as described herein, resistant to one or more monotherapies selected from the group consisting of anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxemesterone, ethinylestradiol, doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, albumin-conjugated paclitaxel, methotrexate, 5-fluorouracil (5-FU), methotrexate and 5-fluorouracil (5-FU), carboplatin, cisplatin, capecitabine, gemcitabine, vinorelbine, eribulin, ixabepyrone, trastuzumab and pertuzumab, or combinations thereof.

[0067]

[0070] In one embodiment of the method described herein, the patient described herein may have undergone surgical treatment, for example, breast-conserving surgery (i.e., a mammary gland tumor removal focused on the removal of the primary tumor with margins) or more extensive surgery (i.e., a 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.

[0068]

[0071] Radiation therapy 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, additional radiation may be administered if there are factors that suggest a high risk of local recurrence. In some embodiments of the methods provided herein, the patients described herein may have received radiation therapy before receiving the combination therapy described herein. In other embodiments of the methods provided herein, the patients described herein may receive radiation therapy after receiving the combination therapy described herein.

[0069]

[0072] In some embodiments of the methods described herein, the patients described herein have 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 patients described herein do 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 patients described herein do not have heart disease or cardiac dysfunction.

[0070]

[0073] In one embodiment of the method described herein, treatment with combination therapy provided herein increases the patient's overall survival (OS) compared to a control (e.g., no treatment, standard of care (SOC), or treatment with one of the agents described herein (e.g., GDC-9545 or GDC-0077) alone). In one embodiment of the method described herein, treatment with combination therapy 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 longer compared to a control (e.g., no treatment, SOC, or treatment with one of the agents described herein (e.g., GDC-9545 or GDC-0077) alone).

[0071]

[0074] 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 with 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 increases compared to the control (e.g., no treatment, SOC, or treatment with one of the drugs described herein alone (e.g., GDC-9545 or GDC-0077)). In one such embodiment, the duration of response increases 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, SOC, treatment with GDC-9545 alone, or treatment with GDC-0077 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, SOC, treatment with GDC-9545 alone, or treatment with GDC-0077 alone).

[0072]

[0075] In one embodiment of the present invention provided herein, a 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, a 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, a patient is diagnosed with stable disease (SD) after treatment with combination therapy according to the method provided herein.

[0073]

[0076] Further provided herein are the use of the combination therapy described herein (U1) for the treatment of laBC or mBC as described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 or a pharmaceutically acceptable salt thereof. One embodiment is the use of the combination therapy described herein (U2) for the treatment of laBC or mBC as described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 or a pharmaceutically acceptable salt thereof. One embodiment is the use of the combination therapy described herein (U3) for the treatment of laBC or mBC as described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 or a pharmaceutically acceptable salt thereof.

[0074]

[0077] Further provided herein are the use of the combination therapy described herein (GU1) for the treatment of mBC described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077. Further provided herein are the use of the combination therapy described herein (GU2) for the treatment of laBC described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077.

[0075]

[0078] Further provided herein are combination therapy uses (GU3) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 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 quarterly dose of GDC-0077 on days 1 to 28 of the first 28-day cycle. In one embodiment of the use (GU3) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of the use (GU3) provided herein, the combination therapy is for the treatment of mBC.

[0076]

[0079] Further provided herein are combination therapy uses (GU4) of GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 for the treatment of laBC or mBC as described herein, comprising a drug regimen comprising (i) a quarterly dose 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 quarterly dose of 9 mg of GDC-0077 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 the use (GU4) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of the use (GU4) provided herein, the combination therapy is for the treatment of mBC.

[0077]

[0080] Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077, for the manufacture of a medicament for the treatment of laBC or mBC as described herein (GM1). Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077, for the manufacture of a medicament for the treatment of mBC as described herein (GM2). Further provided herein are the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077, for the manufacture of a medicament for the treatment of laBC as described herein (GM3).

[0078]

[0081] Further provided herein are combination therapy uses (GM4) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 for the manufacture of a medicament 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 quarterly dose of GDC-0077 on days 1 to 28 of the first 28-day cycle. In one embodiment of the use (IM4) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of the use (IM4) provided herein, the combination therapy is for the treatment of mBC.

[0079]

[0082] Further provided herein are combination therapy uses (GM5) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 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 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 dose of 9 mg of GDC-0077 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 the use (GM5) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of the use (GM5) provided herein, the combination therapy is for the treatment of mBC.

[0080]

[0083] Also provided herein are methods for inhibiting tumor growth or inducing tumor regression in patients described herein by administering the combination therapy described herein. In one embodiment, a method is provided herein for inhibiting tumor growth in patients having laBC described herein by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 in one or more 28-day cycles described herein. In one embodiment, a method is provided herein for inhibiting tumor growth in patients having mBC described herein by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 in one or more 28-day cycles described herein.

[0081]

[0084] 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 and GDC-0077 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 and GDC-0077 in one or more 28-day cycles as described herein.

[0082]

[0085] 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 GDC-0077) 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, treatment with one of the agents described herein (e.g., GDC-954 or GDC-0077) alone).

[0083]

[0086] In one embodiment of the method described herein, the drug regimen reduces the number or frequency of Grade 2 or Grade 3 or higher adverse events compared to administration of either GDC-9545 or GDC-0077 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. In another embodiment, the drug regimen reduces the grade of hyperglycemia. In another embodiment, the drug regimen reduces or eliminates ophthalmic toxicity such as swelling of lens fibers, separation of lens fibers, and / or accumulation of subcapsular protein-like substances.

[0084]

[0087] In another embodiment of the method described herein, the drug administration reduces the number or frequency of Grade 2, Grade 3, or higher adverse events compared to the administration of either drug alone.

[0085]

[0088] In the event of an adverse event, it is generally understood that there are four options: (1) continue treatment as is with optional adjunct therapy; (2) adjust the dose of one or more drugs in the drug regimen; (3) temporarily discontinue administration of one or more drugs in the drug regimen; or (4) discontinue administration of one or more drugs in the drug regimen. In one embodiment, GDC-9545 is not adjusted.

[0086]

[0089] 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.

[0087]

[0090] In some embodiments, when a patient experiences one or more AEs selected from the group consisting of hyperglycemia, ocular toxicity (e.g., as described herein), and bradycardia, attributing to treatment with the combination therapy described herein, the severity is grade 2 or less. In one embodiment, the patient described herein does not experience one or more AEs selected from the group consisting of hyperglycemia, ocular toxicity (e.g., as described herein), and bradycardia, attributing to treatment with the combination therapy described herein, and the severity of the AE is higher than grade 2.

[0088] biomarkers

[0091] 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).

[0089]

[0092] 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).

[0090]

[0093] 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.

[0091]

[0094] In some embodiments, patient samples described herein may be evaluated for additional biomarkers to identify factors that may correlate with the safety and efficacy of the investigational treatment.

[0092]

[0095] In one embodiment of the methods described herein, NGS, whole-genome sequencing (WGS), other methods, or a combination thereof may be used on DNA obtained from patient-derived blood samples and tumor tissue as described herein. Analysis of such samples may identify germline and somatic changes that 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 can enhance knowledge and understanding of disease biology. In one embodiment, patient samples are evaluated for Ki67 expression levels using one or more of the techniques described above.

[0093]

[0096] In one embodiment, patient samples are evaluated or tested for one or more PIK3CA mutations corresponding to positions 88, 106, 111, 118, 345, 420, 453, 542, 545, 546, 1043, 1047, and 1049. In another embodiment, patient samples are evaluated or tested for one or more PIK3CA mutations corresponding to one or more of the following positions: H1047, E545, E542, Q546, N345, C420, M1043, G1049, E453, K111, G106, G118, and R88. In one embodiment, a patient sample is evaluated or tested for one or more PIK3CA mutations corresponding to one or more positions selected from the group consisting of H1047D / I / L / N / P / Q / R / T / Y, E545A / D / G / K / L / Q / R / V, E542A / D / G / K / Q / R / V, Q546E / H / K / L / P / R, N345D / H / I / K / S / T / Y, C420R, M1043I / T / V, G1049A / C / D / R / S, E453A / D / G / K / Q / V, K111N / R / E, G106A / D / R / S / V, G118D, and R88Q. In one embodiment, a patient sample is evaluated or tested for one or more PIK3CA mutations corresponding to one or more positions selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R. In one embodiment, a patient sample is evaluated or tested for one or more PIK3CA mutations corresponding to one mutation selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R, and a second mutation selected from the group consisting of E453Q / K, E726K, and M1043L / I. In one embodiment, a patient sample is evaluated or tested for one or more PIK3CA mutations corresponding to positions selected from the group consisting of E542K+E453Q / K, E542K+E726K, E542K+M1043L / I;E545K+E453Q / K, E545K+E726K, E545K+M1043L / I;H1047R+E453Q / K, and H1047R+E726K.

[0094]

[0097] In one embodiment, the patient has breast cancer expressing a PIK3CA variant that includes a mutation corresponding to a position selected from the group consisting of H1047D / I / L / N / P / Q / R / T / Y, E545A / D / G / K / L / Q / R / V, E542A / D / G / K / Q / R / V, Q546E / H / K / L / P / R, N345D / H / I / K / S / T / Y, C420R, M1043I / T / V, G1049A / C / D / R / S, E453A / D / G / K / Q / V, K111N / R / E, G106A / D / R / S / V, G118D, and R88Q. In one embodiment, the patient has breast cancer expressing a PIK3CA variant containing a mutation corresponding to a position selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R. In another embodiment, the patient has a PIK3CA variant containing a mutation corresponding to a position containing one mutation selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R, and a second mutation selected from the group consisting of E453Q / K, E726K, and M1043L / I. In one embodiment, the patient has breast cancer expressing a PIK3CA variant containing a mutation corresponding to a position selected from the group consisting of E542K+E453Q / K, E542K+E726K, E542K+M1043L / I;E545K+E453Q / K, E545K+E726K, E545K+M1043L / I;H1047R+E453Q / K, and H1047R+E726K. In one embodiment, the PIK3CA variant tumor status is assessed by either a central blood test or a local blood or tumor tissue test. In one embodiment, the central test for identifying eligible PIK3CA variants is the FoundationOne Liquid Clinical Trial Assay performed by Foundation Medicine. In one embodiment, the local blood or tumor tissue test is performed using a PCR or NGS-based assay at a CLIA-certified or equivalent laboratory.

[0095] Pattern:

[0098] The following are exemplary embodiments of the present invention.

[0096]

[0099] 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 GDC-0077 administered as a QD on days 1 to 28 of the first 28-day cycle.

[0097]

[0100] Embodiment 2. The combination therapy according to Embodiment 1, wherein GDC-0077 is administered at a dose of 9 mg.

[0098]

[0101] Embodiment 3. The combination therapy according to Embodiment 1 or 2, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 30 mg.

[0099]

[0102] Embodiment 4. The combination therapy according to any one of Embodiments 1 to 3, 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.

[0100]

[0103] Embodiment 5. The combination therapy according to any one of Embodiments 1 to 4, 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.

[0101]

[0104] Embodiment 6. A method for treating estrogen receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in a patient having estrogen 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 GDC-0077, wherein the combination therapy is administered over one or more 28-day cycles.

[0102]

[0105] Embodiment 7. A method for treating locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) that is estrogen receptor-positive and HER2-negative in patients having receptor-positive and HER2-negative laBC or mBC, i. QD administration of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1-28 of the first 28-day cycle, ii. Administer GDC-0077 as a QD during 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].

[0103]

[0106] Embodiment 8. The method according to Embodiment 6 or 7, wherein GDC-0077 is administered in a dose of 9 mg.

[0104]

[0107] Embodiment 9. The method according to any one of Embodiments 6 to 8, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of 30 mg.

[0105]

[0108] Embodiment 10. The method according to any one of Embodiments 7 to 9, 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.

[0106]

[0109] Embodiment 11. The method according to any one of Embodiments 7 to 9, wherein the medication 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.

[0107]

[0110] Embodiment 12. The method according to any one of Embodiments 6 to 11, wherein the patient is premenopausal.

[0108]

[0111] Embodiment 13. The method according to any one of Embodiments 6 to 12, wherein the patient is tested for the presence of mutations in one or more of the estrogen receptor, prostaglandin receptor, or Ki67.

[0109]

[0112] Embodiment 14. The method according to any one of Embodiments 6 to 13, wherein the patient has a tumor containing one or more mutations of PIK3CA at a location corresponding to R88Q;G106, K111, G118, N345, C420, E453, E542, E545, Q546, M1043, H1047, or G1049, or a combination thereof.

[0110]

[0113] Embodiment 15. A mutation in PIK3CA R88Q; G106A / D / R / S / V; K111N / R / E; G118D; N345D / H / I / K / S / T / Y; C420R; E453A / D / G / K / Q / V; E542A / D / G / K / Q / R / V; E545A / D / G / K / L / Q / R / V; Q546E / H / K / L / P / R; M1043I / T / V; H1047D / I / L / N / P / Q / R / T / Y; or G1049A / C / D / R / S; or a combination thereof The method according to embodiment 14, which corresponds to the present invention.

[0111]

[0114] Embodiment 16. The method according to Embodiment 14 or 15, wherein the PIK3CA mutation comprises one mutation selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R, and a second mutation selected from the group consisting of E453Q / K, E726K, and M1043L / I.

[0112]

[0115] Embodiment 17. The method according to Embodiment 16, wherein the PIK3CA mutation is selected from a double mutation selected from the group consisting of E542K+E453Q / K, E542K+E726K, E542K+M1043L / I;E545K+E453Q / K, E545K+E726K, E545K+M1043L / I;H1047R+E453Q / K, and H1047R+E726K.

[0113]

[0116] Embodiment 18. The method according to any one of Embodiments 6 to 17, wherein the patient has reduced adverse events (AEs) compared to a control.

[0114]

[0117] Embodiment 19. The method according to Embodiment 18, wherein the patient has a reduced severity of one or more AEs selected from the group consisting of hepatotoxicity, bradycardia, hyperglycemia, stomatitis / oral mucositis, rash, diarrhea / colitis, or pneumonia, or a combination thereof, compared to a control.

[0115]

[0118] Embodiment 20. The method according to Embodiment 18, wherein the patient has the same or reduced level of bradycardia or hyperglycemia after administration of the combination therapy compared to a control.

[0116]

[0119] Embodiment 21. The method according to any one of Embodiments 6 to 20, wherein the patient has an increased overall survival (OS) compared to the control.

[0117]

[0120] Embodiment 22. The method according to Embodiment 21, 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.

[0118]

[0121] Embodiment 23. The method according to any one of Embodiments 6 to 22, wherein the duration of response to combination therapy is increased compared to the control.

[0119]

[0122] Embodiment 24. The method according to Embodiment 23, 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.

[0120]

[0123] Embodiment 25. The method according to any one of Embodiments 6 to 24, wherein the patient has an increased clinical benefit rate compared to the control.

[0121]

[0124] Embodiment 26. The method according to any one of Embodiments 6 to 25, wherein the patient has an increased progression-free survival compared to the control.

[0122]

[0125] Embodiment 27. The method according to Embodiment 26, 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.

[0123]

[0126] Embodiment 28. The method according to any one of Embodiments 18 to 27, wherein the control is administered either GDC-9545 alone or palbociclib in combination with letrozole.

[0124]

[0127] Embodiment 29. The method according to any one of Embodiments 6 to 28, wherein the patient has not received prior chemotherapy prior to the administration of the combination therapy.

[0125]

[0128] Embodiment 30. The method according to any one of Embodiments 6 to 28, wherein the patient has not been previously treated with PI3K, AKT, or mTOR inhibitors.

[0126]

[0129] Embodiment 31. The method according to any one of Embodiments 6 to 28, wherein the patient has been previously treated with fulvestrant.

[0127]

[0130] Embodiment 32. Use of combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 for the treatment of laBC or mBC.

[0128]

[0131] Embodiment 33. Use of a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 for the manufacture of a pharmaceutical for the treatment of laBC or mBC.

[0129]

[0132] Embodiment 34. The use according to Embodiment 33, 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 mg of GDC-0077 on days 1 to 28 of the first 28-day cycle.

[0130]

[0133] Embodiment 35. The use according to any one of Embodiments 32-34, wherein the combination therapy is for the treatment of laBC.

[0131]

[0134] Embodiment 36. The use according to any one of Embodiments 32-34, wherein the combination therapy is for the treatment of mBC.

[0132]

[0135] Embodiment 37. 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 GDC-0077 in one or more 28-day cycles.

[0133]

[0136] Embodiment 38. 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 GDC-0077 in one or more 28-day cycles.

[0134]

[0137] The following examples are presented as illustrations, not as limitations. [Examples]

[0135]

[0138] Example 1

[0139] 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.

[0136]

[0140] Despite the effectiveness of available treatments for patients with ER+, 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 believed 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 hormonal therapy 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 in endocrine-resistant states, the ER can signal independently of ligands (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.

[0137]

[0141] 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).

[0138]

[0142] Selective estrogen receptor degraders (SERDs) are recognized as providing a therapeutic approach for ER+ metastatic breast cancer by blocking endocrine-dependent and endocrine-independent ER signaling. 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.

[0139]

[0143] 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 GDC-9545 at 30 mg once daily (QD) 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 resulted in higher free concentrations of GDC-9545 than fulvestrant. In in vitro cell and biochemical assays, GDC-9545 demonstrated up to 10 times higher efficacy than fulvestrant in both wild-type and ESR1 mutant settings. When administered according to clinically appropriate dosing schemes, fulvestrant was less effective than GDC-9545 in the evaluated xenograft models.

[0140]

[0144] PI3K, Akt, and mammalian rapamycin target (mTOR) are major nodes in the PI3K / Akt / mTOR intracellular signaling pathway, crucial for cell cycle regulation, cell proliferation, metabolism, motility, and survival (Cantrell, J Cell Sci 2001; 114:1439-45; Hanahan and Weinberg, Cell, 2011; 144:646-74; Vanhaesebroeck et al. Nat Rev Mol Cell Biol 2012; 13:195-203). The PI3K / Akt / mTOR pathway is generally activated after ligand-receptor tyrosine kinase interactions. Under physiological conditions, the primary role of PI3K is to facilitate the metabolism of inositol phospholipids for intracellular signaling.

[0141]

[0145] There are three classes of PI3K, with class I being considered the most responsive to external stimuli. Class I PI3K consists of two subunits: the p110 catalytic subunit and the p85 regulatory adapter subunit. The p110 catalytic subunit of PI3K has four isoforms: α, β, gamma, and δ. These four isoforms are the products of the genes PIK3CA, PIK3CB, PIK3CG, and PIK3CD, respectively. PIK3CA and PIK3CB are expressed in all cells, while PIK3CD is mainly expressed in leukocytes, and PIK3CG is expressed in multiple tissues, including the pancreas, skeletal muscle, liver, and heart.

[0142]

[0146] Dysregulation of the PI3K / Akt / mTOR signaling pathway has been described in several solid malignancies, including glioblastoma, colorectal cancer, gastric cancer, lung cancer, endometrial cancer, ovarian cancer, prostate cancer, and breast cancer (Gustin et al. Curr Cancer Drug Targets 2008;8:733-40). Activation of the pathway can occur through multiple mechanisms, including deletion of tumor suppressor phosphatases and tensin homologs (PTEN), amplification or somatic mutation of PIK3CA, mutation of AKT, mutation of regulatory subunit p85, mutation and / or amplification of upstream receptor tyrosine kinases, mutation of RAS, deletion of liver kinase B1 (LKB1), type II inositol polyphosphate-4-phosphatase (INPP4B), or tuberous sclerosis (Staal Proc Natl Acad Sci USA 1987;84:5034-7; Cheng et al. Proc Natl Acad Sci USA 1992;89:9267-71; Bellacosa et al. Int J Cancer 1995;64:280-5; Li et al. Science 1997;275:1943-7; Steck et al. Nat Genet). 1997;15:356-62; Aoki et al. Proc Natl Acad Sci USA 1998;95:14950-5). Activating mutations in the PIK3CA gene are the most common genomic alterations, mainly occurring in exons 9 and 20, which encode the helical and kinase domains of the PI3K-α protein (Bachman et al. Cancer Biol Ther 2004;3:772-5; Samuels et al. Science 2004;304:554).

[0143]

[0147] Up to 70% of breast cancers may have some molecular abnormality in the PI3K / Akt / mTOR pathway (Cancer Genome Atlas Network Nature 2012;490:61-70). Enhancement of the PI3K / Akt / mTOR signaling pathway has been shown to promote both de novo and acquired resistance to hormone therapy in ER+ breast cancer cell lines and xenograft models (Sabnis et al. Clin Cancer Res 2007;13:2751-7). Furthermore, simultaneous blockade of the PI3K / Akt / mTOR pathway with everolimus and the ER pathway with letrozole results in higher antitumor activity than either drug alone (Boulay et al. Clin Cancer Res 2005;11:5319-28). Furthermore, evidence of baseline PI3K activation was found to predict poor prognosis after adjuvant-induced withdrawal (Miller et al. J Clin Invest 2010;120:2406-13).

[0144]

[0148] These data support the hypothesis that blocking the signaling pathway of the PI3K / Akt / mTOR pathway may have a therapeutic effect in patients with ER-positive, HER2-negative breast cancer.

[0145]

[0149] GDC-0077 is a potent and selective inhibitor of the class Iα isoform (PI3K-α) of phosphatidylinositol 3-kinase containing the p100α catalytic subunit (encoded by the PI3KCA gene). GDC-0077 exhibits >300-fold lower biochemical inhibition compared to other class I PI3Ks, including the β, δ, and γ isoforms, and shows higher efficacy in tumor cells with mutant p110α than in cells with wild-type p110α. Without being bound by any particular theory, GDC-0077 appears to exert its activity by binding to the adenosine 5'-triphosphate binding site of p110α, thereby inhibiting the phosphorylation of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). This inhibition reduces downstream activation of pathway effectors, including Akt and S6RP, resulting in reduced cell proliferation, metabolism, and angiogenesis. Non-clinical studies have demonstrated that GDC-0077 specifically degrades mutant p110α, inhibiting proliferation and inducing apoptosis in PIK3CA mutant breast cancer cell lines, inhibits tumor growth in a human breast cancer xenograft model with PIK3CA mutations, and reduces downstream PI3K pathway markers, including pAkt, threonine 246-phosphorylated PRAS40 (pPRAS40), and serine 235 / 236-phosphorylated S6RP (pS6RP).

[0146]

[0150] In one trial using GDC-0077 monotherapy, 20 patients with measurable disease were treated with GDC-0077 monotherapy at a QD starting dose of 6 mg, 9 mg, or 12 mg. Five patients (25%) achieved a partial response (PR), and nine patients (45%) achieved clinical benefit (defined as the percentage of patients achieving CR, PR, and / or SD [non-complete response / non-progressive disease for patients with unmeasurable disease at baseline] for ≥24 weeks, as defined in the Response Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1]). Furthermore, 14 of the 20 patients were enrolled at a QD starting dose of 6 mg or 9 mg, and three had received prior treatment with CDK4 / 6i.

[0147]

[0151] GDC-9545 is a potent, orally bioavailable ER-α antagonist and ER-α degradation inducer that competes with estrogen for binding to the ER at low nanomolar forces. GDC-9545 is being developed for the treatment of patients with ER-+ advanced or metastatic breast cancer. GDC-9545 demonstrated reliable activity in non-clinical studies in breast cancer models of disease with ESR1 wild-type and ESR1 mutations. Furthermore, fulvestrant, an approved SERD molecule, was less effective than GDC-9545 in evaluated xenograft models when administered according to clinically appropriate dosing schemes.

[0148]

[0152] During each 28-day cycle, the patient will receive 30 mg of GDC-9545 as an immediate-release capsule via a quiescent dose (QD), and 9 mg of GDC-0077 as an immediate-release tablet via a QD on days 1 through 28 of each 28-day cycle.

[0149]

[0153] Patients receiving GDC-9545 should take it daily at approximately the same time on day 1 of cycle 1 and 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 taking the next scheduled dose, and the missed or vomited dose will not be compensated. GDC-0077 should be taken daily at approximately the same time and within 9 hours of the scheduled time.

[0150]

[0154] Patients treated with GDC-9545 and GDC-0077 are not 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.

[0151]

[0155] Patients treated with GDC-9545 and GDC-0077 are not permitted to use the following combination therapies: a. 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 GDC-0077. 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. Quinidine or other antiarrhythmic drugs

[0152]

[0156] GDC-9545 may be temporarily discontinued in patients experiencing toxicity thought to be related to the investigational treatment. GDC-0077 may be temporarily discontinued in patients experiencing toxicity thought to be related to the investigational procedure. If either GDC-9545 or GDC-0077 is discontinued, the other drug may be continued as determined by the principal investigator, provided that the patient is likely to gain clinical benefit.

[0153]

[0157] Example 2

[0158] The combination of GDC-9545 and GDC-007 was investigated and compared to the efficacy of each monotherapy with AI + palbociclib control. Wild-type ESR1 MCF-7 (PIK3CA.E545K) cells and T-47D (PIK3CA.H1047R) cells, as well as engineered ESR1 mutant cells [MCF-7.ER.Y537S, T-47D.ER.D538G], were grown under standard cell culture conditions in RPMI medium containing 10% fetal bovine serum. One day prior to drug addition, cells were seeded into 384-well plates in phenol red-free RPMI medium containing 10% activated charcoal-removed fetal bovine serum to remove hormones from the cells. Quadruple replicate studies were performed for monotherapy with 300 nM GDC-9545, 80 nM GDC-0077, 125 nM palbociclib, or combinations thereof, in the presence of 0.1 nmol / L estradiol (E2) during 6 or 8 day culture periods. E2-free culture (-E2) mimics treatment with aromatase inhibitors (AIs). Combination therapy with E2 depletion plus palbociclib was also included, reflecting current standard treatment for metastatic breast cancer. Drug concentrations for GDC-0077 and palbociclib were selected for clinical significance based on human exposure levels. 300 nM GDC-9545 represents a saturation concentration lower than the 30 mg human dose. Relative viable cell counts at days 6 / 8 were measured using CyQUANT (ThermoFisher, C7026).

[0154]

[0159] In MCF-7 cells expressing wild-type ESR1, E2 depletion resulted in a gradual decrease in cell proliferation over the culture period. This was significantly enhanced by the addition of palbociclib (Figure 1). The direct ER antagonism by GDC-9545 had a significant impact on cell viability compared to the absence of estrogen. The antiproliferative effect of GDC-9545 was further enhanced when GDC-0077, a PI3K (p110α selective) inhibitor, was combined with GDC-9545. Cells treated with the combination of GDC-9545 and GDC-0077 showed a significant decrease in viability compared to cells treated with estrogen depletion + CDK4 / 6 inhibition, and cells treated with each drug alone (Figure 1).

[0155]

[0160] In MCF-7 cells engineered to express the ESR1 mutation (ER.Y537S), E2 depletion alone failed to inhibit cell proliferation, consistent with previously established estrogen-independent ER activity for this ER variant (Figure 2). Similarly, combining palbociclib with E2 depletion had little antiproliferative effect. In contrast, direct ER antagonism by GDC-9545 reduced cell number compared to the control condition. When used in combination with GDC-0077, it showed significantly higher antiproliferative effects than either drug alone or E2 depletion + CDK / 4 / 6 inhibition (Figure 2).

[0156]

[0161] In T-47D cells, which are wild-type ESR1 cells, suppression of ER activity by either E2 depletion or GDC-9545 treatment resulted in reduced cell proliferation compared to control treatment cells (Figure 3). Adding CDK4 / 6 inhibition to E2 depletion had a greater impact on cell viability than E2 depletion alone, but did not produce the same antiproliferative activity as the combination of GDC-9545 and GDC-0077 (Figure 3). Similarly, the addition of GDC-0077 alone or GDC-9545 alone did not produce the same antiproliferative activity as the combination of both agents.

[0157]

[0162] T-47D cells engineered to express the ESR1 mutation (ER.D538G) were only slightly affected by E2 depletion. Co-treatment with palbociclib improved the antiproliferative effect (Figure 4). In this cell line, GDC-9545 monotherapy had a significantly greater effect than E2 depletion, and the antiproliferative effect of GDC-9545 + GDC-0077 was greater than that of palbociclib and E2 depletion (Figure 1D). Similarly, the combination of GDC-9545 and GDC-0077 showed a considerable antiproliferative effect comparable to each drug alone.

[0158]

[0163] In PIK3CA mutant cell lines possessing either mutant ESR1 or wild-type ESR1, the antiproliferative effect of the combination of GDC-9545 and GDC-0077 was greater than that of GDC-9545 alone or GDC-0077 alone, and also greater than that of palbociclib combined with E2 removal. These preclinical data demonstrate that the combination of GDC-9545 and GDC-0077 has a higher antiproliferative effect than all other tested agents.

[0159]

[0164] 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.”

[0160]

[0165] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, it should be understood that the upper and lower limits of the range and any other stated or intervening values ​​within that stated range, up to one-tenth of the lower limit unit, are 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 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 limits is also included herein.

[0161]

[0166] A person skilled in the art, having received the teachings presented in the foregoing description and the accompanying drawings, will likely conceive of numerous 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 they are used only in a general and descriptive sense and not for limitation.

Claims

1. A pharmaceutical agent for treating locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) that is estrogen receptor-positive and HER2-negative in patients having laBC or mBC, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077, The medicine includes a drug regimen comprising one or more 28-day cycles. Each medication cycle comprises (i) a 30 mg dose of GDC-9545 in a QD form, and (ii) a 9 mg dose of GDC-0077 in a QD form.

2. A pharmaceutical product for treating locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) that is estrogen receptor-positive and HER2-negative in combination with GDC-0077 in patients having laBC or mBC, comprising GDC-9545 or a pharmaceutically acceptable salt thereof. The medicine includes a drug regimen comprising one or more 28-day cycles. Each medication cycle comprises (i) a 30 mg dose of GDC-9545 in a QD form, and (ii) a 9 mg dose of GDC-0077 in a QD form.

3. A pharmaceutical product for treating locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) that is estrogen receptor-positive and HER2-negative in combination with GDC-9545 or a pharmaceutically acceptable salt thereof in patients having laBC or mBC, comprising GDC-0077, The medicine includes a drug regimen comprising one or more 28-day cycles. Each medication cycle comprises (i) a 30 mg dose of GDC-9545 in a QD form, and (ii) a 9 mg dose of GDC-0077 in a QD form.

4. The pharmaceutical product according to any one of claims 1 to 3, 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.

5. The pharmaceutical product according to any one of claims 1 to 4, wherein the patient is premenopausal.

6. The pharmaceutical product according to any one of claims 1 to 5, wherein the patient has a tumor comprising one or more mutations in estrogen receptors, prostaglandin receptors, or Ki67.

7. The pharmaceutical agent according to any one of claims 1 to 6, wherein the patient has a tumor comprising one or more mutations of PIK3CA at a position corresponding to R88Q;G106, K111, G118, N345, C420, E453, E542, E545, Q546, M1043, H1047, or G1049, or a combination thereof.

8. Mutations in PIK3CA R88Q; G106A / D / R / S / V; K111N / R / E; G118D; N345D / H / I / K / S / T / Y; C420R; E453A / D / G / K / Q / V; E542A / D / G / K / Q / R / V; E545A / D / G / K / L / Q / R / V; Q546E / H / K / L / P / R; M1043I / T / V; H1047D / I / L / N / P / Q / R / T / Y; or G1049A / C / D / R / S; or a combination thereof The pharmaceutical product according to claim 7, which corresponds to the pharmaceutical product described in claim 7.

9. The pharmaceutical product according to claim 7 or 8, wherein the PIK3CA mutation comprises one mutation selected from the group consisting of E542K, E545K, Q546R, H1047L, and H1047R, and a second mutation selected from the group consisting of E453Q / K, E726K, and M1043L / I.

10. The pharmaceutical product according to claim 7 or 8, wherein the PIK3CA mutation is selected from a double mutation selected from the group consisting of E542K+E453Q / K, E542K+E726K, E542K+M1043L / I; E545K+E453Q / K, E545K+E726K, E545K+M1043L / I; H1047R+E453Q / K, and H1047R+E726K.

11. A pharmaceutical product according to any one of claims 1 to 10, wherein the patient has reduced adverse events (AEs) compared to a control.

12. The pharmaceutical product according to any one of claims 1 to 11, wherein the patient has a reduced severity of one or more AEs selected from the group consisting of hepatotoxicity, bradycardia, hyperglycemia, stomatitis / oral mucositis, rash, diarrhea / colitis, or pneumonia, or a combination thereof, compared to a control.

13. The pharmaceutical product according to any one of claims 1 to 12, wherein the patient has the same or reduced level of bradycardia or hyperglycemia after administration of the combination therapy compared to a control.

14. The pharmacopoeia according to any one of claims 11 to 13, wherein the control is administered GDC-9545 alone or palbociclib in combination with letrozole.

15. The pharmaceutical product according to any one of claims 1 to 14, wherein the patient has not received prior chemotherapy prior to the administration of GDC-9545 or GDC-0077.

16. A pharmaceutical product according to any one of claims 1 to 14, wherein the patient has not been previously treated with a PI3K, AKT, or mTOR inhibitor.

Images