Treatment of Breast Cancer Using a Combination Therapy Containing 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 February 16, 2021, the entirety of which is incorporated by reference herein for all purposes.

[0002] FIELD OF THEINVENTION

[0002] Provided herein is a combination therapy comprising GDC-9545, or a pharma- ceutically acceptable salt thereof, and GDC-0077, or a pharma- ceutically acceptable salt thereof, for the treatment of breast cancer. [Background technology]

[0003]

[0003] Breast cancer is the most frequent cancer diagnosed in women, with an estimated 2.1 million new cases reported worldwide in 2018 (Bray et al. CA Canver J Clin 2018;68:394-424). Breast cancer accounts for approximately 12% of all cancer deaths (approximately 627,000 cases). Breast cancer mortality rates vary by region, with better survival rates observed in developed regions of the world (ibid.).

[0004]

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

[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-directed therapy (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 lost hormone receptor expression, or upregulation of growth factor signaling pathways such as epidermal growth factor receptor or HER2, MAPK, or PI3K / Akt / mTOR pathways (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 are associated with resistance to anti-estrogen therapy (Robinson et al. 2013; Toy et al. 2013; Jeselsohn et al. 2014).

[0007]

[0007] Thus, there is an urgent need for clinically active agents for the treatment of recurrent or refractory ER-positive breast cancer. Summary of the Invention

[0008]

[0008] Solutions to the above problems, as well as other problems in the art, are provided herein.

[0009]

[0009] The present embodiments can be more fully understood by reference to the detailed description and examples, which are intended to illustrate non-limiting aspects. [Brief description of the drawings]

[0010] [Figure 1]

[0010] Antiproliferative effects of endocrine suppression by E2 deprivation or treatment with GDC-9545, 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 indicated and relative viability was assessed. *p<0.0001, parametric t-test. [Diagram 2]

[0011] Figure 1 shows the antiproliferative effect of endocrine suppression by E2 deprivation or treatment with GDC-9545, alone or in combination with PI3K or CDK4 / 6 inhibition, in MCF-7 cells containing mutant (Y537S) ESR1. Cells were treated for 6 to 8 days as indicated and relative viability was assessed. *p<0.0001, parametric t-test. [Diagram 3]

[0012] Figure 1 shows the antiproliferative effect of endocrine suppression by E2 deprivation or treatment with GDC-9545, 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 indicated and relative viability was assessed. *p<0.0001, parametric t-test. [Figure 4]

[0013] Figure 1 shows the antiproliferative effect of endocrine suppression by E2 deprivation or treatment with GDC-9545, alone or in combination with PI3K or CDK4 / 6 inhibition, in T-47D cells containing mutated (D538G) ESR1. Cells were treated for 6 to 8 days as indicated and relative viability was assessed. *p<0.0001, parametric t-test. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011]

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as 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).In carrying out the present invention, any method, device and material similar or equivalent to those described herein can be used.

[0012]

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

[0013]

[0016] As used herein, unless otherwise specified, the terms "about" and "approximately," when referring to a dose, amount, or weight percent of a component of a composition or dosage form, means a dose, amount, or weight percent that is recognized by one of skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. The equivalent dose, amount, or weight percent can be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percent.

[0014]

[0017] "GDC-9545" has the following structure: TIFF2024506385000002.tif49170 refers to the compound having the chemical name 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-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 pharmaceutically acceptable salts thereof. In one embodiment, GDC-9545 is the tartrate salt. As used herein, "GDC-9545" refers to the free base and pharmaceutically acceptable salts of GDC-9545, including the tartrate salt thereof. GDC-9545 is also known as diledestrant.

[0015]

[0018] "GDC-0077" has the following structure: TIFF2024506385000003.tif38170 and refers to the compound having the chemical name (2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-3-oxazolidinyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide, including pharmaceutically acceptable salts thereof. In one embodiment, GDC-0077 is administered as the 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 inavolisib.

[0016]

[0019] The term "package insert" is used to refer to instructions customarily included in the commercial packaging of a therapeutic product that contain information about the indications, usage, dosage, administration, contraindications and / or precautions for use of such therapeutic product.

[0017]

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

[0018]

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

[0019]

[0022] "Objective Response Rate" or "ORR" refers to the proportion of patients with a confirmed complete or partial response on two consecutive occasions ≥ 4 weeks apart as determined by the investigator 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 documented objective response to disease progression as determined by the investigator per RECIST v1.1, or death from any cause, whichever occurs first.

[0022]

[0025] "Progression-free survival" or "PFS" refers to the time from enrollment to the occurrence of first documented disease progression as determined by the investigator using RECIST v1.1 or death from any cause, whichever occurs first.

[0023]

[0026] "Disease control rate" or "DCR" refers to the proportion of patients with stable disease for at least 12 weeks or CR or PR as determined by the investigator 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 a confirmed complete or partial response as determined by the investigator according to RECIST v1.1.

[0025]

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

[0026]

[0029] "Partial response" or "non-CR / non-PD" refers to the persistence of one or more non-target lesions and / or maintenance of tumor marker levels above normal limits (if applicable). PR can also refer to a ≥ 30% reduction in the sum of the diameters of target lesions in the absence of CR, new lesions, and definite progression in non-target lesions.

[0027]

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

[0028]

[0031] "Stable disease" or "SD" refers to neither sufficient shrinkage to qualify as CR or PR, nor sufficient increase in tumor growth to qualify as PD.

[0029]

[0032] The term "locally advanced breast cancer" refers to cancer that has spread from where it began 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 change the natural course of the patient or cells being treated during the course of clinical pathology. Desirable effects of treatment include reducing the rate of disease progression, ameliorating or alleviating the disease state, and remission or improving prognosis. For example, a patient is "treated" successfully if one or more symptoms associated with breast cancer as described herein are alleviated or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancer cells, reducing symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drugs required to treat the disease, and / or prolonging the patient's survival.

[0032]

[0035] The term "delaying progression" of a disease refers to postponing, preventing, delaying, retarding, stabilizing, and / or postponing the onset of breast cancer as described herein. This delay can be of varying lengths of time depending on the history of the cancer and / or the patient being treated. As will be appreciated by those skilled in the art, a sufficient or significant delay can essentially encompass prevention, in that the patient does not develop cancer.

[0033]

[0036] An "effective amount" is at least the minimum amount required to effect a measurable improvement or prevention of breast cancer as described herein. The effective amount herein may vary depending on factors such as the disease state, age, sex, and weight of the patient, and the ability of the agent to induce a desired response in the patient. An effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or adverse effects of the treatment. Beneficial or desired results include results such as eliminating or reducing the risk, reducing the severity, delaying the onset of the disease (including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the development of the disease), reducing one or more symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drugs required to treat the disease, enhancing the effect of another drug, such as by targeting, delaying the progression of the disease, and / or prolonging survival. In some embodiments, an effective amount of a drug may be effective in reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing or stopping) cancer cell invasion into peripheral organs; inhibiting (i.e., slowing or stopping) tumor metastasis; inhibiting (i.e., slowing or stopping) tumor growth; and / or alleviating one or more symptoms associated with a disorder. An effective amount may be administered in one or more administrations. An effective amount of a drug, compound, pharmaceutical composition or combination therapy described herein may be an amount sufficient to directly or indirectly achieve a therapeutic treatment. As clinically understood, an effective amount 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, an "effective amount" may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if a desired result can be or is achieved in conjunction with one or more other agents.

[0034]

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

[0035]

[0038] As used herein, "E2 induction score" refers to a numerical value reflecting 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 repression score.

[0037]

[0040] "Administration period" or "cycle" refers to a period that includes administration of one or more agents described herein (i.e., GDC-9545 or a pharma- ceutically acceptable salt thereof, or GDC-0077 or a pharma- ceutically acceptable salt thereof), as well as any period that does not include administration of one or more agents described herein. For example, a cycle can be 28 days in total, including 21 days of administration of one or more agents, and a 7-day rest period. A "rest period" refers to a period during which at least one agent described herein (e.g., GDC-9545 or a pharma- ceutically acceptable salt thereof, or GDC-0077 or a pharma- ceutically acceptable salt thereof) is not administered. In one embodiment, a rest period refers to a period during which none of the agents described herein (e.g., GDC-9545 or a pharma- ceutically acceptable salt thereof, or GDC-0077 or a pharma- ceutically acceptable salt thereof) is administered. The rest periods provided herein may optionally include administration of another agent other than GDC-9545 or a pharma- ceutically acceptable salt thereof or GDC-0077 or a pharma- ceutically acceptable salt thereof, in which case the administration of the other agent during the rest period should not interfere with or be detrimental to the administration of the agent described herein.

[0038]

[0041] "Dosing regimen" refers to a period of administration of an agent described herein, which may include one or more cycles, each cycle may include administration of an agent described herein at different times or in different amounts.

[0039]

[0042] "QD" refers to administration of the compound once daily.

[0040]

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

[0041]

[0044] Graded adverse events refer to the severity grading scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table: TIFF2024506385000004.tif50170

[0042] Combination therapy

[0045] Provided herein is a combination therapy comprising GDC-9545 or a pharma- ceutically acceptable salt thereof (e.g., GDC-9545 tartrate) and GDC-0077 or a pharma- ceutically acceptable salt thereof. In one embodiment, the combination therapy described herein is useful for treating certain types of breast cancer described herein. In one embodiment, provided herein is a combination therapy comprising GDC-9545 or a pharma- ceutically acceptable salt thereof administered QD on days 1-28 of a first 28-day cycle, and GDC-0077 or a pharma- ceutically acceptable salt thereof administered QD on days 1-28 of a first 28-day cycle.

[0043]

[0046] In one embodiment of the combination therapy described herein, GDC-9545 or a pharma- ceutically acceptable salt thereof is administered as a fixed dose QD administration. In one embodiment, administration is oral (PO) and GDC-9545 or a pharma- ceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, GDC-9545 or a pharma- ceutically acceptable salt thereof is administered QD in an amount 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 pharma- ceutically acceptable salt thereof is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10, 30, 50, or 100 mg. In yet another embodiment, GDC-9545, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 30 mg.

[0044]

[0047] In one embodiment of the combination therapy described herein, GDC-0077 is administered in an amount of 9 mg. Such administration may be in a single dose (i.e., one or more tablets). In one embodiment, when a 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 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.

[0045]

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

[0046]

[0049] In one embodiment, the agents of the combination therapy described herein are provided in a kit in a ready-to-administer form, for example, as a ready-to-take oral tablet / capsule. The kits described herein can 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 provided are kits for carrying out the methods detailed herein that include the combination therapies described herein and instructions for use in treating breast cancer as 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 one such embodiment, the combination therapy described herein can be used to treat ER+, HER2- laBC. In one such embodiment, the combination therapy described herein can be used to treat ER+, HER2- mBC.

[0049] Treatment methods

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

[0050]

[0053] Further provided herein is a method (G2) for treating laBC or mBC as described herein in a patient having such cancer, comprising administering to the patient a combination therapy as described herein comprising a dosing regimen comprising (i) administering GDC-9545 or a pharma- ceutically acceptable salt thereof QD on days 1-28 of a first 28-day cycle, and (ii) administering GDC-0077 QD on days 1-28 of a first 28-day cycle. In one embodiment of the method (G2) provided herein, the method is used to treat laBC. In another embodiment of the method (G2) provided herein, the method is used to treat mBC.

[0051]

[0054] In one embodiment of the method of G1 or G2, GDC-9545 or a pharma- ceutically acceptable salt thereof is administered as a fixed dose QD administration. In one embodiment, administration is oral (PO) and GDC-9545 or a pharma- ceutically acceptable salt thereof is formulated as a tablet or capsule. In one embodiment, GDC-9545 or a pharma- ceutically acceptable salt thereof is administered QD in an amount 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 pharma- ceutically acceptable salt thereof is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10, 30, 50, or 100 mg.In yet another embodiment, GDC-9545 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 30 mg.

[0052]

[0055] In one embodiment of the methods G1 or G2 described herein, GDC-0077 is administered in an amount of 9 mg. Such administration may be in a single dose (i.e., one or more tablets). In one embodiment, when a 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 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] Further provided herein is a method (G3) of treating laBC or mBC in a patient with such cancer, comprising administering to the patient a combination therapy as described herein comprising a dosing regimen comprising (i) administering 30 mg of GDC-9545 or a pharma- ceutically acceptable salt thereof QD on days 1-28 of a first 28-day cycle, and (ii) administering 9 mg of GDC-0077 QD on days 1-28 of a first 28-day cycle. In one such embodiment, the dosing regimen comprises two or more cycles as described herein. In one embodiment of the method (G3) provided herein, the method is used to treat laBC. In another embodiment of the method (G3) provided herein, the method is used to treat 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 pharma- ceutically acceptable salt thereof, and 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 dosage of GDC-0077 may be decreased. In one such embodiment, the dose of GDC-0077 may be decreased by 3 mg with a maximum of two total reductions (i.e., to 6 mg QD or to 3 mg QD). In one embodiment of methods G1, G2, and G3, administration of one agent in the combination therapy (GDC-9454 or a pharma- ceutically acceptable salt thereof or GDC-0077) may be suspended for up to 28 days. In one embodiment of methods G1, G2, and G3, the dose of GDC-9545 is not decreased.

[0057]

[0060] The methods of treating breast cancer provided herein (G1, G2, and G3) can include administration of a combination therapy described herein as part of a dosing regimen. In one embodiment, the dosing regimen includes one or more cycles. In another aspect, the dosing regimen includes at least two cycles. In another aspect, dosing regimens including 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 dosing regimen includes about 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 dosing regimen comprises administration of a combination therapy described herein for any number of cycles until a desired response (e.g., OR, PFS, OS, ORR, DOR, CBR) is achieved, as desired (e.g., increased OR, PFS, OS, ORR, DOR, CBR compared to a control described herein). In another aspect, the dosing regimen comprises administration of a combination therapy described herein for any number of cycles until toxicity occurs or the patient otherwise experiences one or more adverse events (AEs) that prevent further administration. In yet another aspect, the dosing regimen comprises administration of a combination therapy described herein for any number of cycles until disease progression.

[0058]

[0061] In one embodiment of the methods described herein, the patient is a postmenopausal female. In one such embodiment, the patient is (i) 60 years of age or older; (ii) younger than 60 years of age and has 12 months or more of amenorrhea in addition to follicle-stimulating hormone (FSH) and plasma estradiol levels within the postmenopausal range as assessed by local laboratory assessment in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone agonists or antagonists; or (iii) has undergone a documented bilateral oophorectomy.

[0059]

[0062] In another embodiment of the methods described herein, the patient is a pre-menopausal or menopausal (i.e., not post-menopausal) woman. In one such embodiment, the patient is treated with an LHRH agonist in combination with the combination therapy described herein. LHRH agonist therapy can be initiated 28 days prior to 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 methods described herein, the patient is male. In one such embodiment, the patient is treated with an LHRH agonist in combination with a combination therapy described herein.

[0061]

[0064] In one embodiment of the methods described herein, the patients described herein have been tested for the presence of estrogen receptors, prostaglandin receptors, or Ki67. In one embodiment of the methods described herein, the patients described herein have documented ER-positive tumors according to the American Society of Clinical Oncology / College of American Pathologists guidelines. In one such embodiment, the patients described herein have documented HER2-negative tumors.

[0062]

[0065] In one embodiment of the methods described herein, the patients described herein are treatment naive. In one such embodiment, the patients described herein have not received chemotherapy prior to administration of the combination therapy described herein. In another embodiment of the methods described herein, the patients described herein have 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 aspect, the aromatase inhibitor is anastrozole, exemestane, or letrozole. In one embodiment, the patients described herein have not been previously treated with letrozole, palbociclib, or a combination thereof. In yet another embodiment of the methods described herein, the patients described herein have not received surgery, chemotherapy, or radiation therapy at least 14 days prior to administration of the combination therapy described herein. In yet another aspect of the methods described herein, the patients described herein have not been previously treated with a SERD (e.g., fulvestrant) or tamoxifen. In another embodiment of the methods described herein, the patient may have previously been treated with tamoxifen, provided that the patient did not exhibit a recurrence of disease within the first 24 months of treatment with tamoxifen.

[0063]

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

[0064]

[0067] In one embodiment of the methods described herein, the patient has a breast cancer described herein that is resistant to one or more cancer therapies. In one embodiment of the methods described herein, resistance to cancer therapy includes recurrence of cancer or refractory cancer. Recurrence can refer to the reoccurrence of cancer at the original site or a new site after treatment. In one embodiment of the methods described herein, resistance to cancer therapy includes progression of cancer during treatment with anti-cancer therapy. In some aspects of the methods described herein, resistance to cancer therapy includes cancer that does not respond to treatment. Cancer can be resistant at the start of treatment or can become resistant during treatment.

[0065]

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

[0066]

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

[0067]

[0070] In one embodiment of the methods described herein, the patients described herein may have undergone surgical treatment prior to administration of the combination therapy described herein, such as, for example, breast-conserving surgery (i.e., lumpectomy focused on removing the primary tumor with margins) or more extensive surgery (i.e., mastectomy aimed at complete removal of all breast tissue). In another embodiment of the methods described herein, the patients described herein may have undergone surgical treatment following 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 to kill any remaining microscopic cancer cells after surgery. In breast-conserving surgery, radiation is administered to the remaining breast tissue and sometimes regional lymph nodes (including axillary lymph nodes). In mastectomy, radiation may also be administered if factors predict a high risk of local recurrence. In some aspects of the methods provided herein, the patients described herein may have received radiation therapy prior to administration of the combination therapy described herein. In other aspects of the methods provided herein, the patients described herein may receive radiation therapy after administration of the combination therapy described herein.

[0069]

[0072] In some embodiments of the methods described herein, the patients described herein do not have a history of other malignancies within 5 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 cardiac disease or cardiac dysfunction.

[0070]

[0073] In one embodiment of the methods described herein, treatment with the combination therapy according to the methods provided herein increases the OS of the patient as compared to a control (e.g., no treatment, standard of care (SOC), or treatment with one agent described herein (e.g., GDC-9545 or GDC-0077) alone). In one embodiment of the methods described herein, treatment with the combination therapy according to the methods provided herein increases the OS of the patient by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 or more months as compared to a control (e.g., no treatment, SOC, treatment with one agent described herein (e.g., GDC-9545 or GDC-0077) alone).

[0071]

[0074] In one embodiment of the methods described herein, treatment with the combination therapy according to the methods provided herein increases the amount of ORR in the patient. In one such embodiment, treatment with the combination therapy according to the methods provided herein results in more patients having a complete response (CR) or partial response (PR) than a control. In another aspect of the methods described herein, TTP is increased in the patient following treatment with the combination therapy according to the methods provided herein. In yet another embodiment of the methods described herein, the duration of response to the combination therapy is increased compared to a control (e.g., no treatment, SOC, or treatment with one agent described herein alone (e.g., GDC-9545 or GDC-0077)). In one such embodiment, the duration of response is increased by at least 1 month to 3 months, 2 months to 6 months, 3 months to 8 months, 4 months to 10 months, 5 months to 12 months, 6 months to 15 months, 8 months to 20 months, or 1 month to 24 months. In yet another embodiment of the methods described herein, the patients described herein have 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 methods described herein, the patients have 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 invention provided herein, the patient is diagnosed with CR after treatment with the combination therapy according to the methods provided herein. In one embodiment of the invention provided herein, the patient is diagnosed with PR after treatment with the combination therapy according to the methods provided herein. In one embodiment of the invention provided herein, the patient is diagnosed with SD after treatment with the combination therapy according to the methods provided herein.

[0073]

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

[0074]

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

[0075]

[0078] Further provided herein is a combination therapy (GU3) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 as described herein for the treatment of laBC or mBC as described herein, comprising a dosing regimen comprising (i) administering GDC-9545 or a pharmaceutically acceptable salt thereof QD on days 1-28 of a first 28-day cycle, and (ii) administering GDC-0077 QD on days 1-28 of a 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 is a combination therapy (GU4) comprising GDC-9545 or a pharmaceutically acceptable salt thereof and GDC-0077 as described herein for the treatment of laBC or mBC as described herein, comprising a dosing regimen comprising (i) 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof QD administration on days 1-28 of a first 28-day cycle, and (ii) 9 mg of GDC-0077 QD administration on days 1-28 of a 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 (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 is the use of a combination therapy as 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 is the use of a combination therapy as 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 is the use of a combination therapy as 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 is the use of a combination therapy 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 (GM4), comprising a dosing regimen comprising (i) administering GDC-9545 or a pharmaceutically acceptable salt thereof QD on days 1-28 of a first 28-day cycle, and (ii) administering GDC-0077 QD on days 1-28 of a 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 is a use of a combination therapy 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 (GM5), comprising a dosing regimen comprising (i) administering 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof QD on days 1-28 of a first 28-day cycle, and (ii) administering 9 mg of GDC-0077 on days 1-28 of a 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 of inhibiting tumor growth or causing tumor regression in patients as described herein by administering a combination therapy as described herein. In one embodiment, provided herein are methods of inhibiting tumor growth in patients with laBC as 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 as described herein. In one embodiment, provided herein are methods of inhibiting tumor growth in patients with mBC as 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 as described herein.

[0081]

[0084] In one embodiment, provided herein is a method of producing or improving tumor regression in a patient with mBC as 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 as described herein. In one embodiment, provided herein is a method of producing or improving tumor regression in a patient with laBC as 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 as described herein.

[0082]

[0085] The development of combination therapy has challenges, including, for example, the selection of agents for combination therapy that can lead to improved efficacy while maintaining acceptable toxicity. One particular challenge is the need to identify incremental toxicity of the combination. In one embodiment of the methods described herein, the combination therapy described herein (e.g., GDC-9545 or a pharma- ceutically acceptable salt thereof and GDC-0077) is administered in a dosing regimen that includes a 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 agent described herein (e.g., GDC-954 or GDC-0077) alone).

[0083]

[0086] In one embodiment of the methods described herein, the dosing regimen reduces the number or frequency of grade 2 or grade 3 or higher grade adverse events compared to administration of either GDC-9545 or GDC-0077 alone. In one such aspect, the dosing regimen eliminates the number or frequency of grade 3 or higher AEs. In one embodiment, the dosing regimen reduces the grade of bradycardia. In another embodiment, the dosing regimen reduces the grade of hyperglycemia. In another embodiment, the dosing regimen reduces or eliminates ocular toxicity such as lens fiber swelling, lens fiber separation, and / or accumulation of subcapsular proteinaceous material.

[0084]

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

[0085]

[0088] It is generally understood that if an adverse event occurs, there are four options: (1) continue treatment as is, optionally with concomitant therapy; (2) adjust the dose of one or more of the agents in the dosing regimen; (3) suspend administration of one or more of the agents in the dosing regimen; or (4) discontinue administration of one or more of the agents in the dosing regimen. In one embodiment, GDC-9545 is not adjusted.

[0086]

[0089] In one embodiment, the adverse event(s) experienced by a patient described herein undergoing treatment with a combination therapy described herein, as described herein, is relatively reduced.

[0087]

[0090] In some embodiments where a patient experiences one or more AEs selected from the group consisting of hyperglycemia, ocular toxicity (e.g., as described herein), and bradycardia from treatment with a combination therapy described herein, the severity is less than or equal to Grade 2. In one embodiment, a 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 from treatment with a combination therapy described herein, and the severity of the AE is greater than Grade 2.

[0088] Biomarkers

[0091] Breast cancer is a heterogeneous disease with many different subtypes defined by molecular signatures and many diverse mutation profiles. Patients described herein can be tested for ER+ HER2- laBC or mBC using diagnostic methods or kits to inform treatment or prediction of patient response to combination therapy described herein. In one embodiment, patients can be tested by determining an ER pathway activity score, such as that described in US Patent Application Publication No. 2020 / 0082944. In some aspects, patient samples are collected and tested to determine an ER pathway activity score. A score can be calculated using the 41-gene signature by subtracting the E2 repression score (determined from the average 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 average 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), archived, fresh, or frozen tumor tissue sample).

[0090]

[0093] In some examples, a patient described herein is administered a combination therapy described herein when the measured ER pathway activity score is between about -1.0 and about -0.2 (e.g., between about -0.9 and about -0.2, e.g., between about -0.8 and about -0.2, e.g., between about -0.7 and about -0.2, e.g., between about -0.6 and about -0.2, e.g., between about -0.5 and about -0.2, e.g., between about -0.4 and about -0.2, or e.g., between about -0.3 and about -0.2). In some examples, the ER activity score of the sample may be less than -1.0.

[0091]

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

[0092]

[0095] In one embodiment of the methods described herein, NGS, whole genome sequencing (WGS), other methods, or a combination thereof, can be used on DNA obtained from blood samples and tumor tissues from patients described herein. Such samples can be analyzed to identify germline and somatic alterations that may predict response to investigational drugs, be associated with progression to more severe disease states, be associated with acquired resistance to investigational drugs, or increase knowledge and understanding of disease biology. In one embodiment, patient samples are evaluated for expression levels of Ki67 using one or more techniques as described above.

[0093]

[0096] In one embodiment, patient samples are assessed 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 one embodiment, patient samples are assessed or tested for one or more PIK3CA mutations corresponding to one or more of positions H1047, E545, E542, Q546, N345, C420, M1043, G1049, E453, K111, G106, G118 and R88. In one embodiment, patient samples are assessed 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, the patient sample is assessed 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, the patient sample is assessed 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, patient samples are assessed 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 a breast cancer expressing a PIK3CA mutant comprising 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 mutant PIK3CA comprising a mutation corresponding to a position selected from the group consisting of E542K, E545K, Q546R, H1047L and H1047R. In one embodiment, the patient has a mutant PIK3CA comprising 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 mutant comprising 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 mutant tumor status is assessed by either central testing of blood or local testing of blood or tumor tissue. In one embodiment, the central testing to identify eligible PIK3CA mutations is the FoundationOne Liquid Clinical Trial Assay performed at Foundation Medicine. In one embodiment, local testing of blood or tumor tissue is performed using PCR or NGS-based assays in a CLIA-certified or equivalent laboratory.

[0095] Aspects:

[0098] Below, exemplary embodiments of the present invention are presented.

[0096]

[0099] Embodiment 1. Combination therapy comprising GDC-9545, or a pharma- ceutically acceptable salt thereof, administered QD on days 1-28 of an initial 28 day cycle, and GDC-0077, administered QD on days 1-28 of an initial 28 day cycle.

[0097]

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

[0098]

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

[0099]

[0102] Embodiment 4. The combination therapy of any one of embodiments 1-3, wherein the dosing 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 of any one of embodiments 1-4, wherein the dosing regimen comprises about 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18, or 2-12 cycles.

[0101]

[0104] Embodiment 6. A method of treating estrogen receptor positive and HER2 negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in a patient with 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 for one or more 28 day cycles.

[0102]

[0105] Embodiment 7. A method of treating estrogen receptor positive and HER2 negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in a patient with receptor positive and HER2 negative laBC or mBC, comprising: i. administering GDC-9545 or a pharma- ceutically acceptable salt thereof QD on days 1-28 of an initial 28-day cycle; ii. GDC-0077 will be administered QD on days 1-28 of the first 28-day cycle; administering to the patient a combination therapy comprising a dosing regimen comprising:

[0103]

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

[0104]

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

[0105]

[0108] Embodiment 10. The method of any one of embodiments 7 to 9, wherein the dosing 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.

[0106]

[0109] Embodiment 11. The method according to any one of embodiments 7 to 9, wherein the dosing regimen comprises about 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 one or more mutations in the estrogen receptor, the prostaglandin receptor, or Ki67.

[0109]

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

[0110]

[0113] Embodiment 15. The PIK3CA mutation is 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 15. The method of embodiment 14, corresponding to

[0111]

[0114] Embodiment 16. The method of 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 mutation in PIK3CA 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 the control.

[0114]

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

[0115]

[0118] Embodiment 20. The method of embodiment 18, wherein the patient has the same or reduced levels 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 a control.

[0117]

[0120] Embodiment 22. The method of 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 or more months compared to the control.

[0118]

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

[0119]

[0122] Embodiment 24. The method according to embodiment 23, wherein the duration of response is increased by at least 1 month to 3 months, 2 months to 6 months, 3 months to 8 months, 4 months to 10 months, 5 months to 12 months, 6 months to 15 months, 8 months to 20 months, or 1 month 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 a control.

[0122]

[0125] Embodiment 27. The method of 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 of any one of embodiments 18 to 27, wherein the control is administered GDC-9545 alone or palbociclib in combination with letrozole.

[0124]

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

[0125]

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

[0126]

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

[0127]

[0130] Embodiment 32. The use of a combination therapy comprising GDC-9545 or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof and GDC-0077 for the manufacture of a medicament for the treatment of laBC or mBC.

[0129]

[0132] Embodiment 34. The use of embodiment 33, wherein the combination therapy comprises a dosing regimen comprising: (i) 30 mg of GDC-9545 or a pharma- ceutically acceptable salt thereof administered QD on days 1 to 28 of a first 28-day cycle; and (ii) mg of GDC-0077 administered QD on days 1 to 28 of a first 28-day cycle.

[0130]

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

[0131]

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

[0132]

[0135] Embodiment 37. A method of inhibiting tumor growth in a patient with laBC or mBC, comprising administering a combination therapy comprising GDC-9545 or a pharmacologic acceptable salt thereof and GDC-0077 in one or more 28-day cycles.

[0133]

[0136] Embodiment 38. A method of causing or improving tumor regression in a patient with laBC or mBC, comprising administering a combination therapy comprising GDC-9545 or a pharmacologic acceptable salt thereof and GDC-0077 in one or more 28-day cycles.

[0134]

[0137] The following examples are offered by way of illustration and not by way of limitation. EXAMPLES

[0135]

[0138] Example 1

[0139] The role of estrogen in the pathogenesis and disease 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 patients with ER+ breast cancer.

[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 agents, and therefore require further treatment for optimal disease control. However, it is believed that the growth and survival of most tumors remains dependent on ER signaling, even after becoming resistant to AI or tamoxifen. Patients with ER+ breast cancer can still respond to second / third line hormonal therapy after progression of previous treatments (Di Leo et al. J Clin Oncol. 2010;28:4594-600; Baselga et al. N Engl J Med. 2012;366:520-9). Without being bound by any particular theory, there is evidence that in endocrine resistant states, ER can signal in a ligand-independent manner (Miller et al. J Clin Invest 2010;120:2406-13; Van Tine et al. Cancer Discov 2011;1:287-8). Agents (or combinations of agents) 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 AIs and are associated with poorer 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 indicates that ESR1 may be one important oncogenic factor under AI selection pressure. Studies have identified mutations (mainly Y537S and D538G) in ESR1, which encodes ER-α, that affect the ligand-binding domain, or "LBD," of ER-α (Segal and Dowsett Clin Cancer Res 2014;20:1724-6). Studies using clinical samples and preclinical models have described that ER antagonists appear to be effective against ligand-independent, constitutively active ER mutant receptors and may have therapeutic value in patients resistant to AIs (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 to be able to block endocrine-dependent and endocrine-independent ER signaling, providing a therapeutic approach for ER+ metastatic breast cancer. Fulvestrant, a first-generation SERD, binds, blocks, and degrades ER, resulting in inhibition of estrogen signaling through ER. Fulvestrant has also shown benefits over anastrozole in frontline patients, as demonstrated in one study (NCT01602380). However, the bioavailability and delivery of fulvestrant hinder its efficacy management.

[0139]

[0143] Nonclinical studies comparing drug exposure and in vitro efficacy of GDC-9545 and fulvestrant demonstrated that human steady-state total drug exposure of GDC-9545 at 30 mg once daily (QD) was approximately 10-fold higher than the steady-state exposure of fulvestrant 500 mg intramuscularly (IM) monthly. Furthermore, lower binding of GDC-9545 by plasma proteins results in higher free concentrations of GDC-9545 than fulvestrant. In in vitro cellular and biochemical assays, GDC-9545 demonstrated up to 10-fold higher potency than fulvestrant in both wild-type and ESR1 mutant contexts. Fulvestrant was less effective than GDC-9545 in the xenograft models evaluated when administered according to clinically relevant dosing schemes.

[0140]

[0144] PI3K, Akt, and mammalian target of rapamycin (mTOR) are key nodes of the PI3K / Akt / mTOR intracellular signaling pathway, which is important 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 interaction. Under physiological conditions, the main role of PI3K is to promote the metabolism of inositol phospholipids for intracellular signaling.

[0141]

[0145] There are three classes of PI3K, with class I thought to be the most responsive to external stimuli. Class I PI3Ks are composed of two subunits, the p110 catalytic subunit and the regulatory adaptor subunit p85. 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 expressed primarily 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 multiple solid malignancies, including, for example, 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). Pathway activation can occur through multiple mechanisms, including deletion of tumor suppressor phosphatase and tensin homolog (PTEN), amplification or somatic mutation of PIK3CA, mutation of AKT, mutation of the 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 alteration and occur primarily 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 hormonal 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 has greater antitumor activity than either agent 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 ET (Miller et al. J Clin Invest 2010;120:2406-13).

[0144]

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

[0145]

[0149] GDC-0077 is a potent and selective inhibitor of the class I α isoform of phosphatidylinositol 3-kinase (PI3K-α), which contains the p100α catalytic subunit (encoded by the PI3KCA gene). GDC-0077 exhibits >300-fold lower biochemical inhibitory activity against other class I PI3Ks, including the β, δ, and γ isoforms, and is more potent in tumor cells with mutant p110α than in cells with wild-type p110α. Without being bound to a 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. GDC-0077 has been demonstrated in preclinical studies to specifically degrade mutant p110α, inhibit proliferation, and induce apoptosis in PIK3CA mutant breast cancer cell lines, inhibit tumor growth in human breast cancer xenograft models harboring PIK3CA mutations, and reduce downstream PI3K pathway markers including pAkt, PRAS40 phosphorylated at threonine 246 (pPRAS40), and S6RP phosphorylated at serine 235 / 236 (pS6RP).

[0146]

[0150] In one study using single-agent GDC-0077, 20 patients with measurable disease were treated with GDC-0077 single agent at starting doses of 6 mg, 9 mg, or 12 mg QD; 5 (25%) achieved PR and 9 (45%) achieved clinical benefit (defined as the proportion of patients achieving CR, PR, and / or SD [noncomplete response / nonprogressive disease for patients with nonmeasurable disease at baseline] as defined by Response Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1] for ≥24 weeks). Additionally, 14 of the 20 patients enrolled at starting doses of 6 mg or 9 mg QD and 3 had received prior CDK4 / 6i therapy.

[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 with low nanomolar potency. GDC-9545 is being developed for the treatment of patients with ER+ advanced or metastatic breast cancer. GDC-9545 has demonstrated robust activity in preclinical studies in breast cancer models of ESR1 wild-type and ESR1 mutated disease. In addition, fulvestrant, an approved SERD molecule, was less effective than GDC-9545 in the xenograft models evaluated when administered according to clinically relevant dosing schemes.

[0148]

[0152] Patients will receive GDC-9545 as an immediate-release capsule at a dose of 30 mg QD PO during each 28-day cycle and GDC-0077 as an immediate-release tablet at a dose of 9 mg QD PO on days 1-28 of each 28-day cycle.

[0149]

[0153] Patients receiving GDC-9545 should take the dose PO at approximately the same time each day, starting on Day 1 of Cycle 1 and continuing on Day 1 of each 28-day cycle thereafter. If a dose is not taken within 6 hours of the scheduled dose, it is considered not taken. If a dose is missed or expelled, patients should resume dosing with the next scheduled dose; the missed or expelled dose will not be made up. GDC-0077 should be taken at approximately the same time each day, and no later than 9 hours after the scheduled time.

[0150]

[0154] Patients receiving GDC-9545 and GDC-0077 are not permitted to use the following concomitant therapies: Symptomatic antiemetic, antidiarrheal, and other palliative and supportive treatment for disease-related symptoms. b. Analgesics administered according to standard clinical practice. c. Bone-sparing agents (e.g., bisphosphonates, denosumab) for the treatment of osteoporosis / osteopenia or palliation of bone metastases.

[0151]

[0155] Patients receiving GDC-9545 and GDC-0077 are not permitted to use the following concomitant therapies: Investigational treatment (other than the protocol-defined investigational treatment) within 28 days prior to the first dose of GDC9545 and GDC-0077. b. Any combination therapy intended to treat 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 preparation), megestrol acetate and selective ER modulators (e.g., raloxifene). d. Primary preventative use of hematopoietic growth factors (e.g., erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor). e. Radiation therapy for well-defined progressive disease, with the exception of new brain metastases in the setting of a systemic response as follows: Patients who demonstrated systemic disease control (defined as receiving clinical benefit [i.e., PR, CR, or SD for ≥24 weeks]) but developed solitary brain metastases treatable with radiation. ET (i.e., GDC-9545) can be administered simultaneously with radiation therapy. f. Quinidine or other antiarrhythmic drugs.

[0152]

[0156] GDC-9545 may be temporarily interrupted in patients experiencing toxicity believed to be related to study treatment. GDC-0077 may be temporarily interrupted in patients experiencing toxicity believed to be related to study treatment. If either drug, GDC-9545 or GDC-0077, is discontinued, the other drug may be continued if the patient is likely to derive clinical benefit, as determined by the investigator.

[0153]

[0157] Example 2

[0158] The combination of GDC-9545 and GDC-007 was examined and compared to the efficacy of each monotherapy and to the AI+palbociclib control. ESR1 wild-type MCF-7 (PIK3CA.E545K) 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 before drug addition, cells were seeded in 384-well plates in phenol red-free RPMI containing 10% charcoal-stripped fetal bovine serum to remove hormones from the cells. Single agents 300 nM GDC-9545, 80 nM GDC-0077, 125 nM palbociclib, or combinations were tested in quadruplicate in the presence of 0.1 nmol / L estradiol (E2) for 6 or 8 days of culture. The absence of E2 in the medium (-E2) mimics aromatase inhibitor (AI) treatment. Combination treatment of E2 ablation + palbociclib was also included, reflecting the current standard of care for metastatic breast cancer. Drug concentrations of GDC-0077 and palbociclib were selected to be clinically relevant based on human exposure. 300 nM GDC-9545 is a saturating concentration below the human equivalent dose of 30 mg. Relative numbers of viable cells at 6 / 8 days were measured by CyQUANT (ThermoFisher, C7026).

[0154]

[0159] In MCF-7 cells expressing wild-type ESR1, E2 deprivation caused a gradual decrease in cell proliferation over the culture period, which was much enhanced by the addition of palbociclib (Figure 1). Direct ER antagonism by GDC-9545 had a greater effect 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 estrogen deprivation + CDK4 / 6 inhibition and cells treated with each drug alone (Figure 1).

[0155]

[0160] In MCF-7 cells engineered to express an ESR1 mutation (ER.Y537S), E2 deprivation alone failed to inhibit cell proliferation, consistent with the estrogen-independent ER activity previously established for this ER mutant (Figure 2). Combining palbociclib with E2 deprivation similarly had little antiproliferative effect. In contrast, direct ER antagonism with GDC-9545 reduced cell numbers compared to control conditions. In combination with GDC-0077, it showed a significantly greater antiproliferative effect than either agent alone and E2 deprivation plus CDK / 4 / 6 inhibition (Figure 2).

[0156]

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

[0157]

[0162] T-47D cells engineered to express an ESR1 mutation (ER.D538G) are only modestly affected by E2 deprivation. Co-treatment with palbociclib improved the antiproliferative effect (Figure 4). In this cell line, GDC-9545 alone was significantly more impactful than E2 deprivation, and the antiproliferative effect of GDC-9545+GDC-0077 was greater than the combination of palbociclib and E2 deprivation (Figure 1D). Similarly, the combination of GDC-9545 and GDC-0077 showed a significant antiproliferative effect comparable to each agent alone.

[0158]

[0163] The antiproliferative effect of the combination of GDC-9545 and GDC-0077 in PIK3CA mutant cell lines harboring either mutant or wild-type ESR1 is greater than that of GDC-9545 alone, GDC-0077 alone, and greater than that of palbociclib in combination with E2 depletion. These preclinical data demonstrate that the combination of GDC-9545 and GDC-0077 has a greater antiproliferative effect than all other agents tested.

[0159]

[0164] Throughout this specification and the claims, the words "comprise," "comprises," and "comprising" are used in their non-exclusive sense, unless the context requires otherwise. It is understood that the embodiments described herein include "consisting of" and / or "consisting essentially of" embodiments.

[0160]

[0165] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of the range and any other stated or intervening value in that stated range is included herein. The upper and lower limits of these smaller ranges that may be independently included in the smaller ranges are also included herein, subject to any specifically excluded limit in the stated range. Where one or both of the limits are included in the stated range, ranges excluding either or both of those included limits are also included herein.

[0161]

[0166] Numerous modifications and other embodiments of the invention described herein will occur to those skilled in the art having the benefit of the teachings presented in the foregoing description and the associated drawings. It is to be understood, therefore, that the invention is not to be limited to the specific aspects disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms have been employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. A pharmaceutical for treating estrogen receptor-positive, HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in patients with estrogen receptor-positive, HER2-negative laBC or mBC, the pharmaceutical comprising GDC-9545 or a pharma- ceutical acceptable salt thereof and GDC-0077.

2. A pharmaceutical for treating estrogen receptor-positive, HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in patients with estrogen receptor-positive, HER2-negative laBC or mBC in combination with GDC-0077, the pharmaceutical comprising GDC-9545 or a pharma- ceutical acceptable salt thereof.

3. A pharmaceutical for treating estrogen receptor-positive, HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in patients with estrogen receptor-positive, HER2-negative laBC or mBC in combination with GDC-9545 or a pharma- ceutical acceptable salt thereof, comprising GDC-0077.

4. i. administering GDC-9545 or a pharma- ceutically acceptable salt thereof QD on days 1 to 28 of an initial 28-day cycle; ii. GDC-0077 administered QD on days 1-28 of the first 28-day cycle; The pharmaceutical composition according to any one of claims 1 to 3, which is administered according to a dosing regimen comprising:

5. The pharmaceutical composition of claim 1, administered according to a dosing regimen 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.

6. The method of any one of claims 1 to 5, wherein GDC-0077 is in an amount of 9 mg.

7. The medicament according to any one of claims 1 to 6, wherein the GDC-9545 or a pharma- ceutically acceptable salt thereof is in an amount of 30 mg.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the patient is premenopausal.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the patient has a tumor containing one or more mutations of estrogen receptor, prostaglandin receptor, or Ki67.

10. The medicament of any one of claims 1 to 9, wherein the patient has a tumor comprising one or more mutations in PIK3CA at positions corresponding to R88Q; G106, K111, G118, N345, C420, E453, E542, E545, Q546, M1043, H1047, or G1049, or a combination thereof.

11. 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 composition according to claim 10, which corresponds to

12. The pharmaceutical according to claim 10 or 11, 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.

13. The pharmaceutical agent according to claim 10 or 11, 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.

14. The method of any one of claims 1 to 13, wherein the patient has reduced adverse events (AEs) compared to a control.

15. The medicament of any one of claims 1 to 14, wherein the patient has reduced severity of one or more AEs selected from the group consisting of hepatotoxicity, bradycardia, hyperglycemia, stomatitis / oral mucositis, rash, diarrhea / colitis, or pneumonitis, or a combination thereof, compared to a control.

16. The method of any one of claims 1 to 15, wherein the patient has the same or reduced levels of bradycardia or hyperglycemia after administration of the combination therapy compared to a control.

17. The method of claim 15 or 16, wherein the control is administered GDC-9545 alone or palbociclib in combination with letrozole.

18. The medicament of any one of claims 1 to 17, wherein the patient has not received prior chemotherapy prior to administration of GDC-9545 or GDC-0077.

19. The method of any one of claims 1 to 18, wherein the patient has not been previously treated with a PI3K, AKT, or mTOR inhibitor.

20. The method of any one of claims 1 to 19, wherein the patient has previously been treated with fulvestrant.

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