Treatment of Breast Cancer Using a Combination Therapy Comprising GDC-9545 and Ipatasertib

Abstract

Provided herein is a combination therapy comprising GDC-9545 and ipatasertib for treating locally advanced or metastatic breast cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This non-provisional patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 149,947, filed February 16, 2021, which is incorporated by reference herein in its entirety for all purposes.

[0002] FIELD OF THEINVENTION Provided herein is a combination therapy comprising GDC-9545, or a pharmaceutically acceptable salt thereof, and ipatasertib, or a pharmaceutically acceptable salt thereof, for treating breast cancer. [Background technology]

[0003] background Breast cancer is the most common cancer diagnosed in women, with an estimated global incidence of 2.1 million new cases reported 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 geographic region, with more favorable survival rates observed in more developed parts of the world (ibid.).

[0004] Early treatment of breast cancer is often guided by the presence of molecular markers found on breast cancer cells. These markers are used to identify breast cancer subtypes and aid in the development of treatments based on the presence of tumor hormone receptor content (estrogen receptor [ER] / progesterone receptor [PR]). Hormone receptor positive (HR+) breast cancers with estrogen receptor-alpha (ER-α) expression constitute 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 for HR+ breast cancers.

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

[0006] Not all HR+ breast cancers respond optimally to ET. Mechanisms that may result in primary and / or secondary hormone resistance in HR+ breast cancer include a reduction or loss of hormone receptor expression, or upregulation of growth factor signaling pathways, such as epidermal growth factor receptor or HER2, MAPK or PI3K / Akt / mTOR pathways. 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.

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

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

[0010] [Figure 1] Figure 1 summarizes the benefit of the combination of GDC-9545 and ipatasertib across a range of HR+ cell lines. Systematic increased efficacy is shown across four of the nine lines tested.

[0011] [Diagram 2]Figure 2 summarizes the synergistic response of GDC-9545 and ipatasertib across various HR+ cell lines, as excess over the Bliss index. Systematic increased efficacy is shown across four of the nine lines tested.

[0012] [Diagram 3] Figure 3 shows single dose responses of GDC-9545 and GDC-0068 with HAS excess less than -0.1. Combination benefit is shown in 5 of 9 strains tested. GDC-0068 = Ipatasertib. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description 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.

[0014] 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.

[0015] As used herein, unless otherwise specified, the terms "about" and "approximately," when referring to a dose, amount, or weight percentage of a component of a composition or dosage form, means a dose, amount, or weight percentage that would be recognized by one of skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percentage. The equivalent dose, amount, or weight percentage may be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percentage.

[0016] "GDC-9545" has the following structure: TIFF2024506347000001.tif49170, "GDC-9545" 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 diredestrant.

[0017] Ipatasertib has the structure: TIFF2024506347000002.tif56170, It refers to the compound having the chemical name (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one, including pharmaceutically acceptable salts thereof. In one embodiment, ipatasertib is an amorphous mono-HCl salt. As used herein, "ipatasertib" refers to pharmaceutically acceptable salts of ipatasertib, including the free base and the mono-HCl salt thereof.

[0018] "Overall survival" or "OS" refers to the time from enrollment to death from any cause.

[0019] "Objective response" refers to a complete or partial response as determined by the investigator according to RECIST v1.1.

[0020] "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.

[0021] "Time to tumor 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 documented objective response to disease progression as determined by the investigator 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 as determined by the investigator using RECIST v1.1 or death from any cause, whichever occurs first.

[0024] "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.

[0025] "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.

[0026] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions and normalization of tumor marker levels (if applicable).

[0027] "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.

[0028] "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.

[0029] "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.

[0030] 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.

[0031] 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 may also be called stage IV breast cancer.

[0032] 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. The desired effects of treatment include reducing the rate of disease progression, ameliorating or alleviating the disease state, and improving remission or prognosis. For example, a patient is "treated" successfully if one or more symptoms associated with breast cancer as described herein are reduced 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 agents required to treat the disease, and / or prolonging the patient's survival.

[0033] The term "delaying progression" of disease refers to delaying, preventing, retarding, delaying, stabilizing and / or postponing the development of breast cancer as described herein. This delay can be of various lengths of time depending on the history of 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.

[0034] 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 risk, reducing severity, delaying the onset of the disease (including the biochemical, histological and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the 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 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 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 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] "Administration period" or "cycle" refers to a period including administration of one or more agents described herein (i.e., GDC-9545 or a pharmaceutically acceptable salt thereof, or ipatasertib or a pharmaceutically acceptable salt thereof), as well as any period not including 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. "Rest period" refers to a period during which at least one agent described herein (e.g., GDC-9545 or a pharmaceutically acceptable salt thereof, or ipatasertib or a pharmaceutically 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 pharmaceutically acceptable salt thereof, or ipatasertib or a pharmaceutically acceptable salt thereof) is administered. The resting periods provided herein may, in some cases, include administration of another agent other than GDC-9545 or a pharma- ceutically acceptable salt thereof or ipatasertib or a pharma- ceutically acceptable salt thereof, In such cases, administration of the other agent during the resting period should not interfere with or be detrimental to administration of the agents described herein.

[0039] A "dosing regimen" refers to a period of administration of an agent described herein, which period may include one or more cycles, each of which may include administration of an agent described herein at different times or in different amounts.

[0040] "QD" refers to administration of the compound once daily.

[0041] "PO" refers to oral administration of the agents described herein.

[0042] 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: TIFF2024506347000003.tif43170

[0043] Combination therapy Provided herein is a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof (e.g., GDC-9545 tartrate) and ipatasertib or a pharmaceutically acceptable salt thereof (e.g., ipatasertib mono HCl). In one embodiment, the combination therapy described herein is useful for treating certain types of breast cancer described herein. In one aspect, provided herein is a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof administered QD on days 1-28 of a first 28-day cycle, and ipatasertib or a pharmaceutically acceptable salt thereof administered QD on days 1-21 of said first 28-day cycle.

[0044] 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.

[0045] In one embodiment of the combination therapy described herein, ipatasertib is administered in an amount of 400mg. Such administration can be a single dose (i.e., single or multiple pills). In one embodiment, if a patient described herein experiences an adverse event, the dose of ipatasertib is reduced to 300mg or 200mg. Ipatasertib can be administered PO QD as described herein.

[0046] The combination therapy described herein can be provided as a kit containing one or more active substances for administration.In one embodiment, the kit contains GDC-9545 or a pharmaceutically acceptable salt thereof for administration in combination with ipatasertib as described herein.In another embodiment, the kit contains GDC-9545 or a pharmaceutically acceptable salt thereof packaged together with ipatasertib, and the kit contains separate formulated dosages of each active substance.In yet another embodiment, the kit contains GDC-9545 or a pharmaceutically acceptable salt thereof co-formulated with ipatasertib.

[0047] In one embodiment, the active substances of the combination therapy described herein are provided in a kit in a ready-to-administer form or, for example, as a ready-to-take oral tablet / capsule.The kit described herein can include instructions, such as a package insert.In one embodiment, the instructions are a package insert, one for each active substance in the kit.

[0048] Further provided are kits for practicing the methods detailed herein that include the combination therapies described herein and instructions for use in treating breast cancer as described herein.

[0049] 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.

[0050] Treatment Method Provided herein is a method for treating ER+, HER2- laBC or mBC in patients with such cancer. In one aspect, provided herein is a method (I1) for treating laBC or mBC as described herein in patients with such cancer, comprising administering to said patient a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib. In one embodiment of the method (I1) provided herein, the method is used to treat laBC. In another embodiment of the method (I1) provided herein, the method is used to treat mBC.

[0051] Further provided herein is a method (I2) of treating laBC or mBC as described herein in a patient with such cancer, comprising administering to said patient a combination therapy 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 ipatasertib QD on days 1-21 of said first 28-day cycle. In one embodiment of the method (I2) provided herein, the method is used to treat laBC. In another embodiment of the method (I2) provided herein, the method is used to treat mBC.

[0052] In one embodiment of the method of I1 or I2, 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.

[0053] In one embodiment of the method I1 or I2 described herein, ipatasertib is administered in an amount of 400mg. Such administration can be a single dose (i.e., single or multiple pills). In one embodiment, if a patient described herein experiences adverse events associated with treatment with ipatasertib, or if, for example, the dose of ipatasertib is otherwise not tolerated by the patient during treatment, the dose of ipatasertib is reduced to 300mg or 200mg. Ipatasertib can be administered PO QD as described herein.

[0054] Further provided herein is a method (I3) of treating laBC or mBC in a patient with such cancer, comprising administering to said 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 400 mg of ipatasertib QD on days 1-21 of said 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 (I3) provided herein, the method is used to treat laBC. In another embodiment of the method (I3) provided herein, the method is used to treat mBC.

[0055] In one embodiment of Methods I1, I2 and I3, the cancer is inoperable locally advanced (laBC) or metastatic ER+ breast cancer (mBC).

[0056] In one embodiment of Methods I1, I2, and I3, the combination of GDC-9545, or a pharma- ceutically acceptable salt thereof, and ipatasertib does not require co-administration (treatment) with a gonadotropin-releasing hormone (GnRH) agonist.

[0057] In one embodiment of methods I1, I2 and I3, the dosage of ipatasertib can be reduced. In one such embodiment, the dose of ipatasertib is reduced by 100 mg with a maximum of two total reductions (i.e., to 300 mg QD or 200 mg QD). In one embodiment of methods I1, I2 and I3, the administration of one agent (GDC-9454 or its pharma- ceutically acceptable salt or ipatasertib) in the combination therapy can be suspended for up to 28 days. In one embodiment of methods I1, I2 and I3, the dose of GDC-9545 is not reduced.

[0058] The methods I1, I2 and I3 of treating breast cancer provided herein can include administering the 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 includes 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 as described herein). In another embodiment, the dosing regimen includes 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 embodiment, the dosing regimen includes administration of a combination therapy described herein for any number of cycles until disease progression.

[0059] In one aspect of the methods described herein, the patient is a postmenopausal woman.

[0060] In another embodiment of the method 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 before day 1 of cycle 1.In one embodiment, the LHRH agonist is administered on day 1 of each cycle.

[0061] 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.

[0062] In one embodiment of the method described herein, the patient described herein is tested for the presence of estrogen receptor, prostaglandin receptor or Ki67.In one embodiment of the method described herein, 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.

[0063] In one embodiment of the method described herein, the patient described herein is treatment naive. In one such embodiment, the patient described herein has not received prior chemotherapy prior to administration of the combination therapy described herein. In another embodiment of the method described herein, the patient described herein has not been previously treated with an aromatase inhibitor or CDK4 / 6 inhibitor (e.g., palbociclib, abemaciclib, or ribociclib) or a combination thereof. In one such embodiment, the aromatase inhibitor is anastrozole, exemestane, or letrozole. In one embodiment, the patient described herein has not been previously treated with either letrozole or palbociclib, or a combination thereof. In yet another embodiment of the method described herein, the patient described herein has not been previously treated with a SERD (e.g., fulvestrant) or tamoxifen. In another embodiment of the method described herein, the patient has not been previously treated with an AKT inhibitor.

[0064] In one embodiment of the method described herein, the patient has been treated with one or more cancer therapies before administering the combination therapy described herein.In another embodiment, the patient described herein has been previously treated with a PI3K inhibitor or an mTOR inhibitor before administering the combination therapy.In another embodiment, the patient described herein has been previously treated with fulvestrant.

[0065] 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, the 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, the resistance to cancer therapy includes the progression of cancer during treatment with anti-cancer therapy. In some embodiments of the methods described herein, the resistance to cancer therapy includes cancer that does not respond to treatment. The cancer can be resistant at the start of treatment or can become resistant during treatment. In some embodiments of the methods described herein, the cancer is in an early stage or in a late stage.

[0066] Systemic chemotherapy is considered one of the standard of care (SOC) for patients with mBC, but there is no standard regimen or sequence. In one embodiment of the methods described herein, the patient described herein has been previously treated with one or more therapies selected from the group consisting of anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, trastuzumab and pertuzumab, or combinations thereof, prior to administration of the combination therapy described herein.

[0067] In one embodiment of the methods described herein, the patient described herein can have laBC or mBC as described herein that is refractory to one or more monotherapies selected from the group consisting of anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, trastuzumab and pertuzumab, or combinations thereof.

[0068] In one aspect of the methods described herein, the patients described herein may have undergone a surgical procedure prior to administration of the combination therapy described herein, such as, for example, a breast-conserving surgery (i.e., a lumpectomy focused on removing the primary tumor with margins) or a more extensive surgery (i.e., a mastectomy aimed at the complete removal of all breast tissue). In another aspect of the methods described herein, the patients described herein may undergo a surgical procedure following treatment with the combination therapy described herein.

[0069] Radiation therapy is also applied postoperatively to the breast / chest wall and / or regional lymph nodes to kill microscopic cancer cells remaining 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 still be administered if factors predict a higher 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.

[0070] In some embodiments of the methods described herein, the patient described herein does 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 patient described herein does not have active inflammatory bowel disease, chronic diarrhea, short bowel syndrome or major upper gastrointestinal surgery, including gastrectomy.In some embodiments of the methods described herein, the patient described herein does not have cardiac disease or cardiac dysfunction.

[0071] 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 compared to a control (e.g., no treatment, standard of care (SOC) treatment, or treatment with one agent described herein (e.g., GDC-9545 or ipatasertib) 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 compared to a control (e.g., no treatment, standard of care (SOC) treatment, treatment with one agent described herein (e.g., GDC-9545 or ipatasertib) alone) by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 or more months compared to the control.

[0072] 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 embodiment of the methods described herein, TTP is increased in the patient after 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, standard of care (SOC) treatment, treatment with one agent described herein (e.g., GDC-9545 or ipatasertib) alone). 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., untreated, treated with standard of care (SOC), treated with GDC-9545 alone, or treated with ipatasertib alone). In yet another embodiment of the methods described herein, the patients have an increased progression-free survival compared to a control (e.g., untreated, treated with standard of care (SOC), treated with GDC-9545 alone, or treated with ipatasertib alone).

[0073] In one aspect of the invention provided herein, the patient is diagnosed with CR after treatment with combination therapy according to the method provided herein.In one aspect of the invention provided herein, the patient is diagnosed with PR after treatment with combination therapy according to the method provided herein.In one aspect of the invention provided herein, the patient is diagnosed with SD after treatment with combination therapy according to the method provided herein.

[0074] Further provided herein is the use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib or a pharmaceutically acceptable salt thereof (U1) for the treatment of laBC or mBC as described herein. In one embodiment, the use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib or a pharmaceutically acceptable salt thereof (U2) for the treatment of laBC or mBC as described herein. In one embodiment, the use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib or a pharmaceutically acceptable salt thereof (U3) for the treatment of laBC or mBC as described herein.

[0075] Further provided herein is the use of a combination therapy as described herein comprising GDC-9545, or a pharmaceutically acceptable salt thereof, and ipatasertib (IU1) for the treatment of mBC as described herein. Further provided herein is the use of a combination therapy as described herein comprising GDC-9545, or a pharmaceutically acceptable salt thereof, and ipatasertib (IU2) for the treatment of laBC as described herein.

[0076] Further provided herein is a use (IU3) of the combination therapy described herein comprising GDC-9545 or a pharma- ceutically acceptable salt thereof and ipatasertib for the treatment of laBC or mBC described herein, comprising a dosing regimen comprising: (i) QD administration of GDC-9545 or a pharma- ceutically acceptable salt thereof on days 1-28 of a first 28-day cycle; and (ii) QD administration of ipatasertib on days 1-21 of said first 28-day cycle. In one embodiment of the use (IU3) provided herein, the combination therapy is for the treatment of laBC. In another embodiment of the use (IU3) provided herein, the combination therapy is for the treatment of mBC.

[0077] Further provided herein is a use of the combination therapy described herein comprising GDC-9545 or a pharma- ceutically acceptable salt thereof and ipatasertib for the treatment of laBC or mBC 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 400 mg of ipatasertib QD on days 1-21 of said first 28-day cycle (IU4). In one such embodiment, the dosing regimen comprises two or more cycles described herein. In one embodiment of the use provided herein (IU4), the combination therapy is for the treatment of laBC. In another embodiment of the use provided herein (IU4), the combination therapy is for the treatment of mBC.

[0078] Further provided herein is the use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib (IM1) for the manufacture of a medicament for the treatment of laBC or mBC as described herein. Further provided herein is the use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib (IM2) for the manufacture of a medicament for the treatment of mBC as described herein. Further provided herein is the use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib (IM3) for the manufacture of a medicament for the treatment of laBC as described herein.

[0079] Further provided herein is a use of the combination therapy described herein comprising GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib for the manufacture of a medicament for the treatment of laBC or mBC described herein, comprising a dosing regimen comprising: (i) QD administration of GDC-9545 or a pharmaceutically acceptable salt thereof on days 1-28 of a first 28-day cycle; and (ii) QD administration of ipatasertib on days 1-21 of said first 28-day cycle (IM4). In one embodiment of the use provided herein (IM4), the combination therapy is for the treatment of laBC. In another embodiment of the use provided herein (IM4), the combination therapy is for the treatment of mBC.

[0080] Further provided herein is a use of the combination therapy described herein comprising GDC-9545 or a pharma- ceutically acceptable salt thereof and ipatasertib for the manufacture of a medicament for the treatment of laBC or mBC 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 400 mg of ipatasertib on days 1-21 of said first 28-day cycle (IM5). In one such embodiment, the dosing regimen comprises two or more cycles described herein. In one embodiment of the use provided herein (IM5), the combination therapy is for the treatment of laBC. In another embodiment of the use provided herein (IM5), the combination therapy is for the treatment of mBC.

[0081] Also provided herein is a method of inhibiting tumor growth or causing tumor regression in a patient as described herein by administering a combination therapy as described herein.In one aspect, provided herein is a method of inhibiting tumor growth in a patient with laBC as described herein by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib in one or more 28-day cycles as described herein.In one aspect, provided herein is a method of inhibiting tumor growth in a patient with mBC as described herein by administering a combination therapy comprising administering GDC-9545 or a pharmaceutically acceptable salt thereof and ipatasertib in one or more 28-day cycles as described herein.

[0082] In one aspect, 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 ipatasertib in one or more 28-day cycles as described herein. In one aspect, 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 ipatasertib in one or more 28-day cycles as described herein.

[0083] The development of combination treatments 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 the incremental toxicity of the combination. In one embodiment of the methods described herein, the combination therapy described herein (e.g., GDC-9545 or its pharma- ceutically acceptable salt and ipatasertib) is administered in a dosing regimen that includes a staggered dosing schedule. In one such embodiment, the patient has a reduction in the number or grade of adverse events (AEs) compared to a control (e.g., SOC therapy, treatment with one agent described herein (e.g., GDC-9545 or ipatasertib) alone).

[0084] 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 comparable to administration of either GDC-9545 or ipatasertib alone. In one such embodiment, 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 or QT prolongation.

[0085] In another embodiment of the methods described herein, the dosing reduces the number or frequency of grade 2 or grade 3 or higher adverse events comparable to administration of either agent alone.

[0086] 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 agents in the dosing regimen; (3) suspend administration of one or more agents in the dosing regimen; or (4) discontinue administration of one or more agents in the dosing regimen. In one embodiment, GDC-9545 is not adjusted.

[0087] In one embodiment of the method described herein, the patient described herein experiences one or more adverse events, including rash, bradycardia, hyperglycemia, diarrhea, nausea 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 hyperglycemia, diarrhea or bradycardia compared to the control. In one such embodiment, the control is either (i) the agent alone or (ii) SOC therapy.

[0088] In one embodiment, the patient described herein has the same or reduced level of hyperglycemia after administration of combination therapy compared to control.In one such embodiment, the control is ipatasertib alone.In yet another embodiment, the patient described herein has the same or reduced level of bradycardia after administration of combination therapy compared to GDC-9545 alone.

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

[0090] In one embodiment of the method described herein, the patient described herein experiences an adverse event comprising diarrhea. In one embodiment of the method described herein, the patient described herein experiences an adverse event comprising hyperglycemia. In one embodiment of the method described herein, the patient described herein experiences an adverse event comprising bradycardia. In some embodiments, the patient experiences one or more AEs selected from the group consisting of hyperglycemia, diarrhea and bradycardia from treatment with the combination therapy described herein, the severity is Grade 2 or less. In one embodiment, the patient described herein does not experience one or more AEs selected from the group consisting of hyperglycemia, diarrhea and bradycardia from treatment with the combination therapy described herein, and the severity of the AE is greater than Grade 2.

[0091] Biomarkers 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 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 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 the table).

[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).

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

[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 the test treatment.

[0095] In one embodiment of the method described herein, NGS, whole genome sequencing (WGS), other methods, or a combination thereof are used on the DNA obtained from blood samples and tumor tissues from patients described herein.Such samples can be analyzed to identify germline 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.

[0096] In one embodiment, the patient may be tested for PIK3CA / AKT1 / PTEN-altered status. In one embodiment, the patient described herein may be tested for one or more of phosphatase and tensin homolog (PTEN) mutations, PTEN loss (or loss of PTEN function), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, protein kinase B alpha (AKT1) mutations, or combinations thereof. In one such embodiment, a patient described herein has a breast cancer comprising a PIK3CA mutation 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 a breast cancer that expresses a PIK3CA mutant that includes 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 mutated PIK3CA that includes a mutation corresponding to a position that includes 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 a 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 / I545K+E453Q / K, E545K+E726K, E545K+M1043L / I;H1047R+E453Q / K and H1047R+E726K. In one embodiment, the PIK3CA mutation tumor status is assessed by either central testing of blood or local testing of blood or tumor tissue.

[0097] In another such embodiment, the patient samples described herein can be evaluated for additional biomarkers to identify factors that may be correlated with the safety and efficacy of test treatment.In one embodiment, the patient described herein has a tumor that comprises the loss of PTEN, for example, as characterized by IHC or NGS test.In another embodiment, the patient described herein has a tumor that comprises one or more amino acid mutations of PTEN.In yet another embodiment, the patient described herein has a tumor that comprises one or more amino acid mutations of AKT corresponding to position E17, L52 or Q79.

[0098] Circulating tumor DNA (ctDNA) can be detected in the blood of cancer patients with epithelial cancer and can have diagnostic and therapeutic significance.For example, the mutation status of tumor cells can be obtained by isolating ctDNA (Maheswaran S, et al. N Engl J Med 2008;359:366-77), and ctDNA has been used to monitor the effectiveness of treatment in melanoma (Shinozaki M, et al. Clin Cancer Res 2007;13:2068-74).Blood samples from patients described herein can be collected at screening, at first tumor evaluation, and / or at study completion / early termination visit.

[0099] In one embodiment, the patient has the structure: TIFF2024506347000004.tif49170 and is tested for the presence, level or amount of a compound having the chemical name (S)-3-amino-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one, which is a metabolite of ipatasertib.

[0100] Aspects: Below, exemplary embodiments of the present invention are provided.

[0101] Embodiment 1. 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 ipatasertib, or a pharma- ceutically acceptable salt thereof, administered QD on days 1-21 of said first 28 day cycle.

[0102] Embodiment 2. The combination therapy of embodiment 1, wherein ipatasertib, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 400 mg.

[0103] Aspect 3. The combination therapy of Aspect 1 or Aspect 2, wherein GDC-9545, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 10 mg to about 100 mg.

[0104] Embodiment 4. The combination therapy of any one of embodiments 1-3, wherein GDC-9545, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 10, 30, 50, or 100 mg.

[0105] Embodiment 5. The combination therapy of any one of embodiments 1-4, wherein GDC-9545, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 30 mg.

[0106] Aspect 6. The combination therapy of any one of aspects 1-5, 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.

[0107] Embodiment 7. The combination therapy of any one of embodiments 1-5, 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.

[0108] Embodiment 8. A method of treating estrogen receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in a patient having estrogen receptor-positive and HER2-negative laBC or mBC, comprising administering to said patient a combination therapy comprising GDC-9545, or a pharmaceutical acceptable salt thereof, and ipatasertib, or a pharmaceutical acceptable salt thereof, wherein said combination therapy is administered for a 28 day cycle.

[0109] Aspect 9. The combination therapy comprises: (i) administering GDC-9545, or a pharma- ceutical acceptable salt thereof, QD on days 1 to 28 of an initial 28-day cycle; (ii) administering ipatasertib, or a pharma- ceutically acceptable salt thereof, QD on days 1 to 21 of said first 28-day cycle; The method of embodiment 8, further comprising a dosing regimen comprising:

[0110] Embodiment 10. The method of embodiment 8 or embodiment 9, wherein ipatasertib, or a pharma- ceutically acceptable salt thereof, is administered at a dose of 400 mg.

[0111] Aspect 11. The method of any one of aspects 8 to 10, wherein GDC-9545 or a pharma- ceutically acceptable salt thereof is administered in an amount of about 10 mg to about 100 mg.

[0112] Embodiment 12. The method of any one of embodiments 8 to 11, wherein GDC-9545, or a pharma- ceutically acceptable salt thereof, is administered in an amount of about 10, 30, 50, or 100 mg.

[0113] Embodiment 13. The method of any one of embodiments 8 to 11, wherein GDC-9545, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 30 mg.

[0114] Aspect 14. The method of any one of aspects 8-13, wherein said 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.

[0115] Aspect 15. The method of any one of aspects 8-13, 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.

[0116] Embodiment 16 The method according to any one of embodiments 8 to 15, wherein the patient is premenopausal.

[0117] Aspect 17. The method of any one of aspects 8 to 16, wherein the patient is male.

[0118] Embodiment 18. The method according to any one of embodiments 8 to 17, wherein said patient is tested for the presence of a mutation in one or more of the estrogen receptor, the prostaglandin receptor or Ki67.

[0119] Aspect 19. The method of any one of aspects 8 to 18, wherein the patient has a tumor comprising loss of phosphatase and tensin homolog (PTEN).

[0120] Aspect 20. The method of any one of aspects 8 to 18, wherein the patient has a tumor comprising a phosphatase and tensin homolog (PTEN) mutation.

[0121] Embodiment 21. The method according to any one of embodiments 8 to 19, wherein said patient has a tumor comprising a mutation in AKT1 corresponding to position E17, L52 or Q79.

[0122] Aspect 22. The method of any one of aspects 8 to 21, wherein the patient has reduced adverse events (AEs) compared to a control.

[0123] Aspect 23. The method of aspect 22, wherein said patient has reduced severity of one or more AEs selected from the group consisting of hyperglycemia, bradycardia, diarrhea, nausea or pruritus compared to said control.

[0124] Aspect 24. The method of aspect 22, wherein said patient has the same or a reduced level of bradycardia after administration of said combination therapy compared to said control.

[0125] Embodiment 25. The method according to any one of embodiments 8 to 24, wherein said patient has an increased overall survival (OS) compared to a control.

[0126] A method according to embodiment 25, wherein said patient has an increased overall survival (OS) of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 or more months comparable to a control.

[0127] Aspect 27. The method of any one of aspects 8 to 26, wherein the duration of response to the combination therapy is increased as compared to a control.

[0128] Aspect 28. The method of aspect 27, wherein the duration of response is increased by at least 1 to 3, 2 to 6, 3 to 8, 4 to 10, 5 to 12, 6 to 15, 8 to 20, or 1 to 24 months.

[0129] Embodiment 29. The method according to any one of embodiments 8 to 28, wherein the patient has an increased progression-free survival compared to a control.

[0130] Aspect 30. The method of aspect 29, wherein said 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.

[0131] Aspect 31. The method of any one of aspects 22 to 30, wherein said control is GDC-9545 administered alone, or a pharma- ceutically acceptable salt thereof. Aspect 32. The method of any one of aspects 22 to 30, wherein said control is GDC-9545 administered alone, or a pharma- ceutically acceptable salt thereof.

[0132] Aspect 32. The method of any one of aspects 8 to 31, wherein said patient has not undergone prior chemotherapy prior to administration of said combination therapy.

[0133] Embodiment 33 The method according to any one of embodiments 8 to 31, wherein said patient has previously been treated with tamoxifen.

[0134] Embodiment 34. The method of any one of embodiments 8 to 31, wherein said patient has been previously treated with a PI3K inhibitor or an mTOR inhibitor prior to administration of said combination therapy.

[0135] Embodiment 35. The method according to any one of embodiments 8 to 31, wherein said patient has not been previously treated with an aromatase inhibitor or a CDK4 / 6 inhibitor, or a combination thereof.

[0136] Embodiment 36. A kit comprising the combination therapy of embodiment 1 and instructions for use.

[0137] Embodiment 37. The kit according to embodiment 36, wherein GDC-9545, or a pharma- ceutically acceptable salt thereof, and ipatasertib, or a pharma- ceutically acceptable salt thereof, are co-formulated.

[0138] Aspect 38. The use of a combination therapy comprising GDC-9545, or a pharma- ceutically acceptable salt thereof, and ipatasertib, or a pharma- ceutically acceptable salt thereof, for the treatment of laBC or mBC.

[0139] Aspect 39. Use of a combination therapy comprising GDC-9545, or a pharma- ceutically acceptable salt thereof, and ipatasertib, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of laBC or mBC.

[0140] Aspect 40. The use of aspect 38 or 39, wherein said combination therapy comprises a dosing regimen comprising: (i) administering 30 mg of GDC-9545, or a pharma- ceutically acceptable salt thereof, QD on days 1 to 28 of a first 28 day cycle; and (ii) administering ipatasertib, or a pharma- ceutically acceptable salt thereof, on days 1 to 21 of said first 28 day cycle.

[0141] Embodiment 41. The use according to any one of embodiments 38 to 40, wherein the combination therapy is for the treatment of laBC.

[0142] Embodiment 42. The use according to any one of embodiments 38 to 40, wherein the combination therapy is for the treatment of mBC.

[0143] Aspect 43. A method of 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 ipatasertib, or a pharmaceutically acceptable salt thereof, in one or more 28-day cycles.

[0144] Aspect 44. 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 pharmaceutically acceptable salt thereof, and ipatasertib, or a pharmaceutically acceptable salt thereof, in one or more 28-day cycles.

[0145] The following examples are offered by way of illustration and not by way of limitation. EXAMPLES

[0146] 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.

[0147] 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 secondary or tertiary ET after progression on 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.

[0148] 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 documented that ER antagonists appear to be effective against ligand-independent constitutively active ER mutant receptors and may have therapeutic benefit for patients who were 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).

[0149] 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.

[0150] Nonclinical studies comparing drug exposure and in vitro potency 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.

[0151] Akt is the central point of the PI3K / Akt / mammalian target of rapamycin (mTOR) signaling axis and represents the main downstream effector of receptor tyrosine kinases. Without being bound to any particular theory, the activation of the PI3K / Akt pathway leads to essential cellular functions, including cell survival, growth and proliferation, which are the underlying characteristics of human cancer. The PI3K / Akt pathway can be activated, for example, through the loss of the tumor suppressor PTEN (Li et al. Science 1997; 275: 1943-7), through the activation of mutations and / or amplifications in PIK3CA (Bachman et al. Cancer Biol Ther 2004; 3: 772-5), or through the activation of mutations in AKT1 (Carpten et al. Nature 2007; 448: 439-44), all of which are frequently observed in HR+ breast cancer.

[0152] Up to 70% of breast cancers may have some form of molecular abnormality in the PI3K / Akt / mTOR pathway (Cancer Genome Atlas Network 2012). Among breast cancer subtypes, HR+ breast cancers are associated with the highest prevalence of mutations that activate the PI3K pathway, accounting for approximately 50% of all HR+ breast cancers (Curtis et al. Nature 2012;486:346-52; Cancer Genome Atlas Network 2012; Wilson et al. NPJ Breast Cancer 2016;2:16022). These abnormalities include PTEN alterations and AKT1 and / or PIK3CA mutations.

[0153] The PI3K / Akt / mTOR pathway can provide an interaction between cyclin D and CDK4 / 6, as well as other mitogenic pathways such as MAPK, NF-kB / IKK and ER (Miller et al. J Clin Invest 2010;120:2406-13). Herrera-Abreu et al. reported that long-term inhibition with CDK4 / 6i therapy was accompanied by increased AKT phosphorylation, which correlated with sustained expression of cyclin E2 or CDK2, preventing inhibition of Rb phosphorylation (Herrera-Abreu et al. Cancer Res 2016;76:2301-13). Furthermore, a study using serial biopsies from patients revealed PTEN loss as a mechanism of acquired resistance to CDK4 / 6i therapy (Costa et al. Cancer Discov 2020;10:72-8). In addition, studies using CDK4 / 6i-resistant breast cancer cell lines showed that these cells remained responsive to PI3K / Akt / mTOR pathway inhibitors such as alpelisib and everolimus in cell proliferation assays, suggesting that PI3K / Akt / mTOR pathway inhibitors may serve as an optimal treatment option for patients whose cancer progresses after treatment with CDK4 / 6i therapy (Iida et al. Breast Cancer 2020;10.1007 / s12282-020-01090-3).

[0154] GDC-9545 is a potent, orally bioavailable ERα antagonist and inducer of ERα degradation that competes with estrogen for binding to the ER with low nanomolar potency and is being developed for the treatment of patients with ER+ advanced or metastatic breast cancer. GDC-9545 has demonstrated robust preclinical activity in ER+ breast cancer models of ESR1 wild-type and ESR1 mutation-carrying disease. Furthermore, the approved SERD molecule, fulvestrant, was less effective than GDC-9545 in the xenograft models evaluated when administered according to clinically relevant dosing schemes.

[0155] GDC-9545 and ipatasertib may exhibit synergistic activity, and each has preliminary efficacy data and a manageable safety profile. Treatment with GDC-9545 + ipatasertib has promising therapeutic potential for patients with ER+ and HER2-negative advanced breast cancer.

[0156] Patients will receive GDC-9545 at a dose of 30 mg PO QD during each 28-day cycle and ipatasertib at a dose of 400 mg PO QD on days 1-21 of each 28-day cycle.

[0157] Patients receiving GDC-9545 should receive the drug PO at approximately the same time each day, beginning 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 and the missed or expelled dose will not be made up. Ipatasertib should be taken at approximately the same time each day and should not be taken more than 4 hours after the scheduled time.

[0158] Patients receiving GDC-9545 and ipatasertib are permitted to use the following concomitant therapies, provided that the patient was dose stable prior to Day 1 of Cycle 1: a) symptomatic antiemetics, antidiarrheal therapy, and other palliative and supportive care for disease-related symptoms; b) analgesics administered in accordance with standard clinical practice; and / or c) bone loss inhibitors (e.g., bisphosphonates, denosumab) for the treatment of osteoporosis / osteopenia or for palliation of bone metastases.

[0159] Patients receiving GDC-9545 and ipatasertib are not permitted to use the following concomitant therapies: a. Investigational therapy (other than the protocol-defined study treatment) within 28 days prior to the first dose of GDC9545 and ipatasertib. b. Any combination therapy aimed at the treatment of cancer, including but not limited to chemotherapy, immunotherapy, biological therapy, radiation therapy or herbal therapy, is prohibited. c. Hormone replacement therapy, topical estrogen (including any vaginal preparation), megestrol acetate and selective ER modulators (e.g., raloxifene). d. Primary preventive 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

[0160] GDC-9545 may be temporarily discontinued in patients experiencing toxicity believed to be related to study treatment. Ipatasertib may be temporarily discontinued in patients experiencing toxicity believed to be related to study treatment. If either GDC-9545 or ipatasertib is discontinued, the other drug may be continued if the patient is likely to derive clinical benefit, as determined by the investigator.

[0161] Throughout this specification and the claims, the words "comprise," "comprises," and "comprising" are used in their non-exclusive sense, unless the context otherwise requires. It is understood that embodiments described herein include "consisting of" and / or "consisting essentially of" embodiments.

[0162] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is to be 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.

[0163] Those skilled in the art having the benefit of the teachings presented in the foregoing description and the associated drawings will envision many modifications and other aspects of the invention described herein. It is to be understood, therefore, that the invention is not to be limited to the specific aspects disclosed, and that modifications and other aspects 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.

[0164] Biological Assays

[0165] The HR+ cell lines ZR-75-1, CAMA-1, EFM-19, T47D, MCF-7, YMB-1-E, MDA-MB-134-VI, YMB-1 and MDA-MB-175-VII were contacted with GDC-9545 (0-10uM) and GDC-0068 (ipatasertib, 0-5uM). The cell lines shown in Figure 1 and Figure 2 were further characterized for expression of PIK3CA mutations (E545K and H1047x) and loss of function of PTEN. Two cell lines (MDA-MB-134-VI and MDA-MB-175-VII) lack these mutations and are considered wild type (WT).

[0166] Combination benefits and synergistic effects were calculated according to the methods described in Hafner et al. (Nature Methods volume 13, pages 521-527 (2016)) and Hafner et al. (Nature Biotechnology volume 35, pages 500-502 (2017)).

Claims

1. 1. A medicament for the treatment of estrogen receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC) in patients with estrogen receptor-positive and HER2-negative laBC or mBC, comprising GDC-9545 or a pharmaceutical acceptable salt thereof in an amount of 30 mg, and ipatasertib or a pharmaceutical acceptable salt thereof in an amount of 400 mg.

2. administering GDC-9545, or a pharma- ceutical acceptable salt thereof, QD on days 1 to 28 of an initial 28-day cycle; administering ipatasertib or a pharma- ceutically acceptable salt thereof on days 1 to 21 of said first 28-day cycle; The pharmaceutical composition of claim 1, further comprising a dosing regimen comprising:

3. 3. The pharmaceutical composition of claim 2, 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.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient is premenopausal.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient is a male.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the patient has a tumor containing one or more mutations of estrogen receptor, prostaglandin receptor, or Ki67.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the patient has a tumor comprising loss of phosphatase and tensin homolog (PTEN).

8. The pharmaceutical composition according to any one of claims 1 to 6, wherein the patient has a tumor containing a mutation in phosphatase and tensin homolog (PTEN).

9. The method of any one of claims 1 to 8, wherein the patient has a tumor containing a mutation in AKT1 corresponding to position E17, L52 or Q79.

10. 10. The medicament of any one of claims 1 to 9, wherein a patient has increased progression free survival after administration of the combination compared to a control, wherein the control is GDC-9545 or a pharma- ceutically acceptable salt thereof administered alone.

11. The method of any one of claims 1 to 10, wherein the patient has previously been treated with one or more cancer therapies prior to administration of the combination.

12. The method of any one of claims 1 to 11, wherein the patient has previously been treated with tamoxifen.

13. The method of any one of claims 1 to 10, wherein the patient has not been previously treated with an aromatase inhibitor or a CDK4 / 6 inhibitor or a combination thereof.

14. A pharmaceutical composition according to any one of claims 1 to 13, wherein if the patient experiences an adverse event, the amount of ipatasertib is reduced by 100 mg up to a total of two times to 300 mg or 200 mg.

15. The pharmaceutical composition of claim 14, wherein the amount of GDC-9545 administered is not changed.

16. A pharmaceutical composition described in any one of claims 1 to 15, wherein the patient has previously been treated with fulvestrant prior to administration of the combination.

17. The pharmaceutical agent of any one of claims 1 to 16, wherein the patient has previously been treated with one or more cancer therapies selected from the group consisting of anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, trastuzumab and pertuzumab, or combinations thereof.

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