Treatment of breast cancer using combination therapies comprising GDC-9545 and CDK4 / 6 inhibitor

Abstract

To provide a method for treating locally advanced breast cancer or metastatic breast cancer.SOLUTION: This method includes administering a combination therapy comprising GDC-9545 and a CDK4 / 6 inhibitor to a patient.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 023501, filed May 12, 2020, which is incorporated by reference in its entirety for all purposes.

[0002] Provided herein is a combination therapy comprising GDC-9545, or a pharmaceutically acceptable salt thereof, and a CDK4 / 6 inhibitor (e.g., palbociclib) for the treatment of breast cancer. [Background technology]

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

[0004] Therefore, there is an urgent need for clinically active agents for the treatment of recurrent or resistant ER-positive breast cancer. Summary of the Invention

[0005] Solutions to the above problems and other problems in the art are provided herein.

[0006] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to illustrate non-limiting embodiments. [Brief explanation of the drawings]

[0007] [Figure 1] Time plot for the study of patients described herein treated with the combination of GDC-9545 and palbociclib. uPR = unconfirmed partial response; cPR = confirmed partial response. [Figure 2]Graph showing tumor responses across patients treated with GDC-9545 and GDC-9545 and palbociclib DETAILED DESCRIPTION OF THE INVENTION

[0008] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. 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 methods, devices, and materials similar or equivalent to those described herein can be used.

[0009] 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 cited herein are incorporated by reference in their entirety.

[0010] 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, mean a dose, amount, or weight percent that would be recognized by one of ordinary 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.

[0011] "GDC-9545" is a 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 and the structure: TIFF2023175688000002.tif52170. GDC-9545 is also known as diredestrant. In one embodiment, GDC-9545 is the tartrate salt.

[0012] "Palbociclib" refers to a compound having the chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one and the structure: Palbociclib refers to compounds having the TIFF2023175688000003.tif37170. Palbociclib is commercially available under the trade name IBRANCE®. Palbociclib is an exemplary "CDK4 / 6 inhibitor" - a class of drugs that target cyclin-dependent kinases 4 and 6 (CDK4 and CDK6, respectively).

[0013] Other exemplary CDK4 / 6 inhibitors include ribociclib (butanedioic acid-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (1 / 1); commercially available as KISQALI®); abemaciclib, (2-pyrimidinamine,N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[ 4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl], commercially available as VERZENIO®; and trilaclisib (2'-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-7',8'-dihydro-6'H-spiro(cyclohexane-1,9'-pyrazino(1',2':1,5)pyrrolo(2,3-d)pyrimidin)-6'-one).

[0014] "Time to worsening in pain level" refers to the time from the first recorded baseline measurement to an increase of at least 2 points (e.g., by using the Brief Pain Inventory-Short Form (BPI-SF) questionnaire).

[0015] "Time to worsening in pain presence and interference" refers to the time to the first recorded increase of at least 10 points from the baseline measurement (e.g., by using the linearly transformed pain scale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)).

[0016] "Time to deterioration in physical function" refers to the time from the first recorded baseline measurement to a decline of at least 10 points (e.g., by using the linearly transformed physical function scale score of the EORTC QLQ-C30).

[0017] "Time to deterioration in role functioning" refers to the time from the first recorded baseline measurement to a decline of at least 10 points (e.g., by using the linearly transformed role functioning scale score of the EORTC QLQ-C30).

[0018] "Time to deterioration in global health status and quality of life" or "GHS / QoL" refers to the time to the first recorded decline of at least 10 points from the baseline measurement (e.g., by using the linearly transformed GHS / QoL scale score of the EORTC QLQ-C30).

[0019] "Overall survival" or "OS" refers to the time from enrollment to death from any cause.

[0020] "Objective response rate" or "ORR" refers to the proportion of patients who achieve a confirmed complete or partial response on two consecutive occasions at least four weeks apart, as determined by the investigator according to RECIST v1.1.

[0021] "Time to progression" or "TTP" refers to the time from randomization to objective tumor progression.

[0022] "Duration of response" or "DOR" refers to the time from the first occurrence of a documented objective response to the date of investigator-determined disease progression per RECIST v1.1, or death from any cause, whichever occurs first.

[0023] "Progression-free survival" or "PFS" refers to the time from enrollment to the occurrence of first documented disease progression or death from any cause, whichever occurs first, as determined by the investigator using RECIST v1.1.

[0024] "Clinical benefit rate" or "CBR" refers to the proportion of patients who have 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] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions and, where applicable, normalization of tumor marker levels.

[0026] "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 may also refer to a 30% or greater decrease in the sum of the diameters of target lesions in the absence of CR, new lesions, and overt progression in non-target lesions.

[0027] "Progressive disease" or "PD" refers to a 20% or greater increase in the sum of the diameters of target lesions, overt progression in non-target lesions, and / or the appearance of new lesions.

[0028] "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] 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] The term "metastatic breast cancer" refers to cancer that has spread from the breast to other parts of the body, such as the bone, liver, lungs, or brain. Metastatic breast cancer is sometimes called stage IV breast cancer.

[0031] The term "treatment" refers to a clinical intervention designed to alter the natural history of the patient or cells being treated during clinical pathology. Desirable effects of treatment include reducing the rate of disease progression, reversing or alleviating the disease state, and ameliorating or improving prognosis. For example, a patient is successfully "treated" if one or more symptoms associated with breast cancer described herein are reduced or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancerous cells, alleviating symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other medications required to treat the disease, and / or extending the patient's survival.

[0032] The term "delaying progression" of disease refers to postponing, preventing, delaying, slowing, stabilizing, and / or postponing the onset of breast cancer as described herein. This delay can be of varying lengths of time, depending on the cancer being treated and / or the medical history of the patient. As will be apparent to one of skill in the art, a sufficient or significant delay can effectively encompass prevention, in that the patient does not develop cancer.

[0033] An "effective amount" is at least the minimum amount required to achieve measurable improvement or prevention of breast cancer as described herein. The effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, as well as the ability of the agent to elicit a desired response in the patient. An effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or detrimental effects of the treatment. Beneficial or desired results include 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 manifesting during the development of the disease), alleviating one or more symptoms resulting from the disease, improving the quality of life of those suffering from the disease, reducing the dose of other agents required to treat the disease, enhancing the effect of another agent by targeting, etc., slowing the progression of the disease, and / or prolonging survival, etc. In some embodiments, an effective amount of a drug may have the effect of 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 can 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 achieve therapeutic treatment either directly or indirectly. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, pharmaceutical composition, or combination therapy. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in combination with one or more other agents, a desired result can be or is achieved.

[0034] 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] 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] 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] A "dosing period" or "cycle" refers to a period that includes the administration of one or more agents described herein (i.e., GDC-9545 or a pharmaceutically acceptable salt thereof, or palbociclib), as well as any period that does not include the 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 of the agents described herein (e.g., GDC-9545 or a pharmaceutically acceptable salt thereof, or palbociclib) 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 pharmaceutically acceptable salt thereof, or palbociclib) is administered. The rest periods provided herein may, in some cases, include the administration of another agent other than GDC-9545 or a pharmaceutically acceptable salt thereof, or palbociclib. In such cases, administration of the other agent during the rest period should not interfere with or be detrimental to the administration of the agents described herein.

[0038] "Dosing regimen" refers to a period of administration of an agent described herein, including one or more cycles, each cycle can include administration of an agent described herein for a different time or in a different amount.

[0039] "QD" refers to administration of the compound once daily.

[0040] "PO" refers to oral administration of the agents described herein.

[0041] 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: TIFF2023175688000004.tif58170

[0042] Combination therapy Provided herein is a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof (e.g., GDC-9545 tartrate) and a CDK4 / 6 inhibitor. In one embodiment, the combination therapy is useful for treating certain types of breast cancer described herein. For example, 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.

[0043] In another aspect, provided herein is a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof (e.g., GDC-9545 tartrate) and palbociclib. As used herein, "palbociclib" refers to the free base and any pharmaceutically acceptable salts of palbociclib.

[0044] The combination therapies described herein can be provided as a kit 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 palbociclib as described herein. In another embodiment, the kit contains GDC-9545 or a pharmaceutically acceptable salt thereof packaged with palbociclib, the kit containing separately formulated dosages of each agent. In yet another embodiment, the kit contains GDC-9545 or a pharmaceutically acceptable salt thereof co-formulated with palbociclib.

[0045] Treatment method Provided herein are methods for treating ER+, HER2- laBC or mBC in patients with such cancers. In one embodiment, the method comprises treating ER+, HER2- laBC or mBC in patients with such cancers by administering to the patient a combination therapy described herein over a 28-day cycle.

[0046] Further provided herein is a method of treating ER+, HER2- laBC or mBC in a patient with such cancer, the method comprising administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib, wherein the combination therapy is administered for one or more 28-day cycles.

[0047] Further still provided herein is a method of treating ER+, HER2- laBC or mBC in patients with such cancer, wherein the method comprises administering to the patient a combination therapy 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 palbociclib QD on days 1-21 of a first 28-day cycle.

[0048] In one embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered as a fixed dose or QD administration. 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 in an amount of about 1 mg-100 mg, 1 mg-50 mg, 1 mg-30 mg, 10 mg-100 mg, 10 mg-50 mg, or 10 mg-30 mg QD. In another embodiment, GDC-9545 or a pharmaceutically 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 pharmaceutically acceptable salt thereof is administered in an amount of about 10, 30, 50, or 100 mg. In yet another embodiment, GDC-9545, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 30 mg.

[0049] In one embodiment, palbociclib is administered according to the package insert. In a preferred embodiment, palbociclib is administered in an amount of 125 mg.

[0050] Further still provided herein is a method of treating ER+, HER2- laBC or mBC in patients with such cancer, comprising administering to the patient a combination therapy described herein 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 125 mg of palbociclib QD on days 1-21 of a first 28-day cycle. In one such embodiment, the dosing regimen comprises two or more cycles described herein.

[0051] The methods of treating breast cancer provided herein can include administering a combination therapy described herein as part of a dosing regimen. In one embodiment, the dosing regimen includes one or more cycles. In another embodiment, 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 administering a combination therapy described herein for any number of cycles until a desired response (e.g., PFS, OS, ORR, DOR, CBR) results in a desired outcome (e.g., increased PFS, OS, ORR, DOR, CBR compared to a control described herein). In another embodiment, the dosing regimen comprises administering a combination therapy described herein for any number of cycles until toxicity occurs or the patient experiences one or more adverse events (AEs) that otherwise prevent further administration. In yet another embodiment, the dosing regimen comprises administering a combination therapy described herein for any number of cycles until disease progression occurs.

[0052] In one embodiment, the patient is a postmenopausal woman. In one such embodiment, the patient is (i) 60 years of age or older; (ii) under 60 years of age and has had amenorrhea for 12 months or more in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone agonists or antagonists, along with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range as assessed by a local laboratory; or (iii) has had a documented bilateral oophorectomy.

[0053] In another embodiment, the patient is a pre- or peri-menopausal (i.e., not post-menopausal) woman. In one such embodiment, the patient is treated with an LHRH agonist in combination with a combination therapy described herein. LHRH agonist therapy can begin 28 days prior to day 1 of cycle 1. In one embodiment, the LHRH agonist is administered on day 1 of each cycle.

[0054] In another embodiment, the patient is male. In one such embodiment, the patient is treated with an LHRH agonist in combination with a combination therapy described herein.

[0055] In one embodiment, the patient described herein has been tested for the presence of estrogen receptors, prostaglandin receptors, or Ki67. In one embodiment, the patient described herein has a documented ER-positive tumor according to the American Society of Clinical Oncology / College of American Pathologists guidelines. In one such embodiment, the patient described herein has a documented HER2-negative tumor. In one embodiment, the patient described herein has received prior treatment with an aromatase inhibitor (e.g., anastrozole, exemestane, or letrozole), or a CDK4 / 6 inhibitor (e.g., palbociclib), or a combination thereof. In one such embodiment, the patient has had no disease recurrence while completing such treatment with the aromatase inhibitor or CDK4 / 6 inhibitor or within 12 months of completion.

[0056] In one embodiment, the patient described herein has not been treated. In another embodiment, the patient described herein has not received prior chemotherapy prior to administration of the combination therapy. In another embodiment, the patient described herein has not been previously treated with an aromatase inhibitor, or a CDK4 / 6 inhibitor, or a combination thereof. In one such embodiment, the CDK4 / 6 inhibitor is palbociclib. In another such embodiment, the aromatase inhibitor is anastrozole, exemestane, or letrozole. In one embodiment, the patient described herein has not been previously treated with either letrozole or palbociclib. In yet another embodiment, the patient described herein has not undergone surgery, chemotherapy, or radiation therapy at least 14 days prior to administration of the combination therapy described herein. In yet another embodiment, the patient described herein has not been previously treated with a SERD (e.g., fulvestrant) or with tamoxifen. In another embodiment, the patient may have been previously treated with tamoxifen, provided that the patient did not experience a recurrence of disease within the first 24 months of treatment with tamoxifen.

[0057] In one embodiment of the methods 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 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 recurrent or refractory cancer. Recurrence can refer to the return 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 the progression of cancer during treatment with an anti-cancer therapy. In some embodiments of the methods described herein, resistance to cancer therapy includes cancer that does not respond to treatment. The cancer may be resistant at the start of treatment or may become resistant during treatment. In some embodiments of the methods described herein, the cancer is in an early stage or a late stage.

[0058] Systemic chemotherapy is considered one of the standards of care (SOC) for patients with mBC, but no standard regimen or sequence exists. In one embodiment of the methods described herein, a 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, 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 a combination thereof, prior to administration of a combination therapy described herein.

[0059] In one embodiment of the methods described herein, the patient described herein is treated with anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxemesterone, ethinyl estradiol, doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, tamoxifen, toremifene, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxemesterone, ethinyl estradiol, doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, docetaxel, pacli ... The patient may have laBC or mBC as described herein that is resistant to one or more single drug therapies selected from the group consisting of clitaxel, 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.

[0060] In one embodiment of the methods described herein, the patients described herein may have undergone surgical treatment, such as, for example, breast-conserving surgery (i.e., lumpectomy focused on removing the primary tumor along with the margins) or more extensive surgery (i.e., mastectomy aimed at complete removal of all breast tissue), prior to administration of the combination therapy described herein. In another embodiment, the patients described herein may undergo surgical treatment after treatment with the combination therapy described herein.

[0061] Radiation therapy is also administered postoperatively to the breast / chest wall and / or regional lymph nodes to kill any microscopic cancer cells remaining after surgery. In the case of breast-conserving surgery, radiation is administered to the remaining breast tissue and sometimes regional lymph nodes (including axillary lymph nodes). In the case of mastectomy, radiation may be administered further if factors predicting a higher risk of local recurrence are present. In some embodiments of the methods provided herein, the patients described herein may have received radiation therapy before the administration of the combination therapy described herein. In other embodiments of the methods provided herein, the patients described herein may have received radiation therapy after the combination therapy described herein.

[0062] In some embodiments, 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, the patients described herein do not have active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or have not undergone major upper gastrointestinal surgery, including gastrectomy. In some embodiments, the patients described herein do not have cardiac disease or cardiac dysfunction.

[0063] In one embodiment, treatment with a combination therapy according to the methods provided herein increases the OS of a patient compared to a control (e.g., no treatment, standard of care (SOC) treatment, or a combination of palbociclib and letrozole). In one embodiment, treatment with a combination therapy according to the methods provided herein increases the OS of a patient compared to a control (e.g., no treatment, standard of care (SOC) treatment, or a combination of palbociclib and letrozole) by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 months or longer compared to the control.

[0064] In one embodiment, treatment with the combination therapy according to the methods provided herein increases the amount of ORR in a 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 embodiment, TTP is increased in a patient after treatment with the combination therapy according to the methods provided herein. In yet another embodiment, the duration of response to the combination therapy is increased compared to a control (e.g., no treatment, standard of care (SOC) treatment, or the combination of palbociclib and letrozole). In one such embodiment, the duration of response is increased by at least 1-3, 2-6, 3-8, 4-10, 5-12, 6-15, 8-20, or 1-24 months. In yet another embodiment, a patient described herein has an increased clinical benefit rate compared to a control (e.g., no treatment, standard of care (SOC) treatment, or the combination of palbociclib and letrozole). In yet another embodiment, the patient has increased progression-free survival compared to a control (eg, no treatment, standard of care (SOC) treatment, or the combination of palbociclib and letrozole).

[0065] In one embodiment provided herein, the patient is diagnosed with CR after treatment with the combination therapy according to the methods provided herein. In one embodiment provided herein, the patient is diagnosed with PR after treatment with the combination therapy according to the methods provided herein. In one embodiment provided herein, the patient is diagnosed with SD after treatment with the combination therapy according to the methods provided herein.

[0066] Further provided herein is the use of a combination therapy described herein comprising GDC-9545, or a pharmaceutically acceptable salt thereof, as described herein, and palbociclib for the treatment of laBC or mBC as described herein.

[0067] Further provided herein is the use of a combination therapy described herein comprising GDC-9545, or a pharmaceutically acceptable salt thereof, as described herein, and palbociclib for the treatment of mBC as described herein.Further still provided herein is the use of a combination therapy described herein comprising GDC-9545, or a pharmaceutically acceptable salt thereof, as described herein, and palbociclib for the treatment of laBC as described herein.

[0068] Further provided herein is the use of a combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib as described herein for the manufacture of a medicament for treating laBC or mBC as described herein. Still further provided herein is the use of a combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib as described herein for the manufacture of a medicament for treating mBC as described herein. Further provided herein is the use of a combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib as described herein for the manufacture of a medicament for treating laBC as described herein.

[0069] Also provided herein are methods of inhibiting tumor growth or causing tumor regression in a patient described herein by administering a combination therapy described herein. In one embodiment, provided herein is a method of inhibiting tumor growth in a patient with laBC described herein by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles as described herein. In one embodiment, provided herein is a method of inhibiting tumor growth in a patient with mBC described herein by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles as described herein.

[0070] In one embodiment, provided herein is a method of causing or ameliorating tumor regression in a patient with mBC described herein by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles as described herein. In one embodiment, provided herein is a method of causing or ameliorating tumor regression in a patient with laBC described herein by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles as described herein.

[0071] The development of combination therapies has challenges, including, for example, selecting agents for combination therapy that can lead to improved efficacy while maintaining acceptable toxicity. One particular challenge is the need to identify the progressive toxicity of the combination. In one embodiment of the methods described herein, the combination therapy described herein (e.g., GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib) is administered in a dosing regimen that includes a staggered dosing schedule. In one such embodiment, patients have a reduced number or grade of adverse events (AEs) compared to a control (e.g., SOC therapy or palbociclib and letrozole).

[0072] In one embodiment of the methods described herein, the dosing regimen reduces the number or frequency of Grade 2 or Grade 3 or higher adverse events compared to administration of palbociclib and letrozole. In one such embodiment, the dosing regimen eliminates the number or frequency of Grade 3 or higher AEs.

[0073] 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.

[0074] It is generally understood that if an adverse event occurs, four options exist: (1) continue treatment as is with optional concomitant therapy; (2) adjust the dose of one or more drugs in the dosing regimen; (3) temporarily suspend one or more drugs in the dosing regimen; or (4) discontinue one or more drugs in the dosing regimen.

[0075] In one embodiment of the methods described herein, the patient described herein experiences one or more adverse events, including fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, or pruritus. In one such embodiment, the patient described herein has the same level or a reduced level / severity of one or more such AEs. In another embodiment, the patient described herein has a reduced severity of one or more such AEs. In one embodiment, the patient described herein has a reduced severity of neutropenia, diarrhea, or bradycardia compared to a control. In one such embodiment, the control is (i) either agent alone; (ii) palbociclib and letrozole; or (iii) SOC therapy.

[0076] In one embodiment, the patient described herein has the same or a reduced level of neutropenia after administration of the combination therapy compared to the control. In one such embodiment, the control is palbociclib alone; GDC-9545 or a pharmaceutically acceptable salt thereof alone; palbociclib and letrozole; or SOC therapy. In another embodiment, the control is palbociclib alone, or palbociclib and letrozole. In yet another embodiment, the patient described herein has the same or a reduced level of bradycardia after administration of the combination therapy compared to the control. In another embodiment, the control is GDC-9545 or a pharmaceutically acceptable salt thereof alone, or palbociclib and letrozole.

[0077] In one embodiment, a patient described herein undergoing treatment with a combination therapy described herein experiences a relatively reduced adverse event(s), as described herein.

[0078] In one embodiment of the methods described herein, the patients described herein experience adverse events including diarrhea. In one embodiment of the methods described herein, less than 75%, less than 60%, less than 50%, less than 40%, less than 33%, less than 25%, less than 20%, less than 12%, or less than 5% of all treated patients experience one or more of neutropenia, diarrhea, or bradycardia from treatment with a combination therapy described herein. In one embodiment of the methods described herein, less than 85%, less than 75%, less than 60%, less than 50%, less than 40%, less than 33%, less than 25%, less than 20%, less than 17%, less than 10%, or less than 5% of all treated patients experience diarrhea as described herein from treatment with a combination therapy described herein. In one embodiment of the methods described herein, less than 60%, less than 50%, less than 45%, less than 33%, less than 25%, less than 10%, or less than 5% of all treated patients experience neutropenia from treatment with a combination therapy described herein. In one embodiment of the methods described herein, less than 75%, less than 60%, less than 50%, less than 40%, less than 33%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 8% of all treated patients experience bradycardia as described herein from treatment with a combination therapy described herein. In some embodiments, where a patient experiences one or more AEs selected from the group consisting of neutropenia, diarrhea, and bradycardia from treatment with a combination therapy described herein, the severity is Grade 2 or less. In one embodiment, a patient described herein does not experience one or more AEs selected from the group consisting of neutropenia, diarrhea, and bradycardia from treatment with a combination therapy described herein (the AEs are greater than Grade 2 in severity).

[0079] Biomarkers Breast cancer is a heterogeneous disease with many different subtypes defined by molecular signatures and diverse mutational profiles. Patients described herein can be tested for ER+ HER2- laBC or mBC using the diagnostic methods or kits described herein to inform treatment or predict patient response to combination therapy. In one embodiment, patients can 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, 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 mean z-score 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-score expression of the listed genes: AGR3, AMZ1, AREG, C5AR2, CELSR2, CT62, FKBP4, FMN1, GREB1, IGFBP4, NOS1AP, NXPH3, OLFM1, PGR, PPM1J, RAPGEFL1, RBM24, RERG, RET, SGK3, SLC9A3R1, TFF1, and ZNF703).

[0080] 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).

[0081] In some cases, a patient described herein is administered a combination therapy described herein that results in a measured ER pathway activity score of 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 cases, the ER activity score from the sample may be less than -1.0.

[0082] 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 the investigational treatment.

[0083] 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 tissue from patients described herein. Such samples can be analyzed to identify germline (e.g., BRCA1 / 2) and somatic alterations that predict response to investigational drugs, are associated with progression to more severe disease states, are associated with acquired resistance to investigational drugs, or can increase knowledge and understanding of disease biology.

[0084] Implementation: Below, exemplary embodiments of the present invention are provided.

[0085] Embodiment 1. 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 administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and a CDK4 / 6 inhibitor, wherein the combination therapy is administered over a 28-day cycle.

[0086] Embodiment 2. 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 administering to the patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib, wherein the combination therapy is administered for one or more 28-day cycles.

[0087] Embodiment 3. A method of treating estrogen receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in patients with receptor-positive and HER2-negative laBC or mBC, comprising: (i) administering GDC-9545 or a pharmaceutically acceptable salt thereof QD on days 1-28 of an initial 28-day cycle; and (ii) Palbociclib QD on days 1-21 of the first 28-day cycle administering to the patient a combination therapy comprising a dosing regimen comprising:

[0088] Embodiment 4. The method of embodiment 1, wherein the CDK4 / 6 inhibitor is palbociclib.

[0089] Embodiment 5. The method of any one of embodiments 1 to 4, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 mg to about 100 mg.

[0090] Embodiment 6. The method of embodiment 5, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10, 30, 50, or 100 mg.

[0091] Embodiment 7. The method of embodiment 5, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 30 mg.

[0092] Embodiment 8. The method of any of embodiments 2 to 7, wherein palbociclib is administered in an amount of about 125 mg.

[0093] Embodiment 9. The method of any of embodiments 3 to 8, wherein the administration 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.

[0094] Embodiment 10. The method of any of embodiments 3 to 8, 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.

[0095] Embodiment 11. The method of any one of embodiments 1 to 8, wherein the patient is premenopausal.

[0096] Embodiment 12. The method of any one of embodiments 1 to 8, wherein the patient is male.

[0097] Embodiment 13. The method of embodiment 11 or 12, wherein the patient is further administered luteinizing hormone-releasing hormone (LHRH).

[0098] Embodiment 14. The method of embodiment 13, wherein the patient is administered LHRH on day 1 of each cycle.

[0099] Embodiment 15. The method of any preceding embodiment, wherein the patient is tested for the presence of one or more mutations in estrogen receptor, prostaglandin receptor, or Ki67.

[0100] Embodiment 16. The method of any one of embodiments 1 to 15, wherein the patient has a reduced adverse event (AE) compared to a control.

[0101] Embodiment 17. The method of embodiment 16, wherein the control is letrozole administered in combination with palbociclib.

[0102] Embodiment 18. The method of embodiment 16 or 17, wherein the number or frequency of Grade 3 or higher AEs is reduced.

[0103] Embodiment 19. The method of any of embodiments 16 to 18, wherein the patient experiences a decrease in severity of one or more AEs selected from the group consisting of fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, or pruritus compared to a control.

[0104] Embodiment 20. The method of any of embodiments 1 to 19, wherein the patient has the same or a reduced level of neutropenia after administration of the combination therapy compared to the control.

[0105] Embodiment 21. The method of any of embodiments 1 to 20, wherein the patient has the same or a reduced level of bradycardia after administration of the combination therapy compared to the control.

[0106] Embodiment 22. The method of any of embodiments 1 to 21, wherein the patient has increased overall survival (OS) compared to a control.

[0107] Embodiment 23. The method of embodiment 22, wherein the patient has an increase in serotonin levels for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 months or longer compared to the control.

[0108] Embodiment 24. The method of any of embodiments 1 to 23, wherein the objective response rate of patients to the combination therapy results in more patients having a complete response (CR) or a partial response (PR) compared to controls.

[0109] Embodiment 25. The method of any one of embodiments 1 to 24, wherein the duration of response to the combination therapy is increased compared to a control.

[0110] Embodiment 26. The method of embodiment 25, wherein the duration of response is increased by at least 1-3, 2-6, 3-8, 4-10, 5-12, 6-15, 8-20, or 1-24 months.

[0111] Embodiment 27. The method of any one of embodiments 1 to 26, wherein the patient has an increased clinical benefit rate compared to the control.

[0112] Embodiment 28. The method of any one of embodiments 1 to 27, wherein the patient has increased progression-free survival compared to a control.

[0113] Embodiment 29. The method of embodiment 28, 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.

[0114] Embodiment 30. The method of any of embodiments 1 to 29, wherein the patient has a shortened time to deterioration in (i) pain level; (ii) the presence or absence of pain and its interference; (iii) physical function; (iv) role function; (v) overall health and quality of life; or (vi) a combination thereof.

[0115] Embodiment 31. The method of any of embodiments 22 to 30, wherein the control is palbociclib alone or palbociclib administered in combination with letrozole.

[0116] Embodiment 32. The method of any one of embodiments 1 to 31, wherein the patient is postmenopausal.

[0117] Embodiment 33. The method of embodiment 32, wherein the patient has undergone bilateral oophorectomy.

[0118] Embodiment 34. The method of any one of embodiments 1 to 33, wherein the patient has not received prior chemotherapy prior to administration of the combination therapy.

[0119] Embodiment 35. The method of any one of embodiments 1 to 33, wherein the patient has previously been treated with tamoxifen.

[0120] Embodiment 36. The method of any one of embodiments 1 to 33, wherein the patient has previously been treated with an aromatase inhibitor, or a CDK4 / 6 inhibitor, or a combination thereof.

[0121] Embodiment 37. The method of any one of embodiments 1 to 33, wherein the patient has not been previously treated with an aromatase inhibitor, or a CDK4 / 6 inhibitor, or a combination thereof.

[0122] Embodiment 38. The method of any of embodiments 1 to 33, wherein the patient has not undergone surgery, chemotherapy, or radiation therapy at least 14 days prior to administration of the combination therapy.

[0123] Embodiment 39. The method of any one of embodiments 1 to 33, wherein the patient does not have cardiac disease or cardiac dysfunction.

[0124] Embodiment 40. Use of a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib for the treatment of laBC or mBC as described herein.

[0125] Embodiment 41. The use of a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib for the manufacture of a medicament for the treatment of laBC or mBC.

[0126] Embodiment 42. A method for inhibiting tumor growth in a patient with laBC or mBC, comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles.

[0127] Embodiment 43. A method for causing or improving tumor regression in patients with laBC or mBC, comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib in one or more 28-day cycles.

[0128] The following examples are offered by way of illustration and not by way of limitation. [Example]

[0129] Patients: Eligible patients had ER+ (HER2-) metastatic breast cancer and had been treated with adjuvant endocrine therapy for ≥24 months and / or endocrine therapy in the refractory, locally advanced, or metastatic setting, with ≤2 prior therapies in the advanced or metastatic setting that relapsed or progressed while receiving clinical benefit from therapy (i.e., at least 6 months of tumor response or stable disease). Prior treatment with CDK4 / 6i was not permitted for patients receiving palbociclib. TIFF2023175688000005.tif124170

[0130] Safety. Treatment-emergent AEs (TEAEs) were reported in 78% and 96% of patients treated in Cohorts A and B, respectively. In Cohort A, 58% of patients had AEs related to GDC-9545; these were generally grade 1-2, with the exception of three grade 3 events: fatigue, increased transaminases, and diarrhea. No patients discontinued study treatment due to an AE. In Cohort B, 58% of patients had AEs related to GDC-9545; AEs were grade 1 or 2 in severity, with the exception of one SAE of grade 3 QT prolongation with T-wave inversion reported in a 69-year-old woman. This patient had a baseline QTcF of 441 ms, and at the Cycle 6 Day 1 visit, while asymptomatic, her QTcF was 506 ms. This case was confounded by the patient's history of preexisting coronary artery disease (30-50% stenosis of the coronary arteries), right bundle branch block, and possible concurrent use of pregabalin. In response to the QT prolongation, treatment with palbociclib and GDC-9545 was discontinued, which resulted in resolution of the QT prolongation approximately 16 days after onset.

[0131] Bradycardia AEs were reported in three patients (8%) in Cohort A and 15 (31%) in Cohort B; all were grade 1 and asymptomatic, except for grade 2 bradycardia in one patient (Cohort B) who also experienced grade 2 dizziness. ECG data showed similar heart rate changes in Cohorts A and B, and there was no further change in heart rate with the addition of palbociclib. Heart rate (HR) changes returned to baseline upon completion of treatment. The mean maximum HR change in both cohorts was 19 and 20 beats per minute (bpm) for baseline HRs ≥ 60 bpm and 13 bpm for Cohorts A and B, respectively, for baseline HRs < 60 bpm. TIFF2023175688000006.tif98170

[0132] Pharmacokinetics. The exposure of GDC-9545 in combination with palbociclib was generally similar to that observed with single-agent GDC-9545. Palbociclib PK was unchanged when given with GDC-9545 and was consistent with reported values.

[0133] Pharmacological efficacy: Decreases in ER (10 / 12, 83%), PR (7 / 8, 88%), and Ki67 (9 / 12, 75%) protein levels, as well as the ER pathway signature score (8 / 12, 67%) (Guan et al., Cell, 2019), were observed in evaluable paired pre- and on-treatment biopsies (n=12).

[0134] A decrease from baseline in ctDNA ESR1 mutant allele frequency was observed in all patients in both cohorts (n=26).

[0135] Clinical Activity: In Cohort A, 22 / 40 patients (55%) achieved clinical benefit, defined as a CR, PR, or the first occurrence of progressive disease observed at or after 24 weeks. Partial responses were observed in 4 / 31 (13%) of patients with measurable disease at baseline. In Cohort B, 35 / 48 (81%) patients achieved clinical benefit, with 14 / 45 (33%) achieving PR. In both cohorts, clinical benefit was observed in patients previously treated with fulvestrant (2 / 7 (29%) and 2 / 3 (67%) in Cohorts A and B, respectively) and in patients with detectable ESR1 mutations at enrollment (8 / 13 (62%) and 11 / 11 (100%)). TIFF2023175688000007.tif79170

[0136] Throughout this specification and claims, the words "comprise," "comprises," and "comprising" are used in their non-exclusive sense, unless the context otherwise requires. It is understood that the embodiments described herein include embodiments "consisting of" and / or "consisting essentially of."

[0137] 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 that range and any other stated or intervening value in that stated range is included herein. The upper and lower limits of these smaller ranges, which may be independently included in smaller ranges, are also included herein, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included herein.

[0138] Many modifications and other embodiments of the inventions described herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. 1. A medicament for treating estrogen receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in patients with receptor-positive and HER2-negative laBC or mBC, comprising: (i) GDC-9545 or a pharmaceutically acceptable salt thereof, administered in an amount of about 30 mg QD on days 1-28 of an initial 28-day cycle; and (ii) palbociclib administered in an amount of 125 mg QD on days 1-21 of an initial 28-day cycle. Including, GDC-9545 has 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 and the following structure: A pharmaceutical composition comprising the compound

2. The method of claim 1, wherein the patient is premenopausal.

3. The method of claim 1, wherein the patient is male.

4. 4. The method of claim 2 or 3, wherein the patient is further administered luteinizing hormone-releasing hormone (LHRH) on day 1 of each cycle.

5. 5. The method of claim 1, wherein the patient is tested for the presence of a mutation in one or more of the estrogen receptor, prostaglandin receptor, or Ki67.

6. The method of any one of claims 1 to 5, wherein the patient is postmenopausal.

7. The method of claim 1, wherein the patient has undergone bilateral oophorectomy.

8. The method of any one of claims 1 to 7, wherein the patient has not received prior chemotherapy prior to administration of the combination therapy.

9. The method of any one of claims 1 to 7, wherein the patient has previously been treated with tamoxifen.

10. 8. The method of claim 1, wherein the patient has previously been treated with an aromatase inhibitor or a CDK4 / 6 inhibitor, or a combination thereof.

11. 8. The method of claim 1, wherein the patient has not been previously treated with an aromatase inhibitor or a CDK4 / 6 inhibitor, or a combination thereof.

12. 8. The method of claim 1, wherein the patient has not undergone surgery, chemotherapy, or radiation therapy at least 14 days prior to administration of the combination therapy.

13. A pharmaceutical composition for inhibiting tumor growth in a patient with laBC or mBC, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib, GDC-9545 has 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 and the following structure: is a compound having the formula Medicine.

14. A pharmaceutical agent for causing or improving tumor regression in a patient with laBC or mBC, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib, GDC-9545 has 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 and the following structure: is a compound having the formula Medicine.

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