HK40084792B - Treatment of breast cancer using combination therapies comprising gdc-9545 and a cdk4/6 inhibitor - Google Patents

Description

Combination therapy for breast cancer including GDC-9545 and CDK4/6 inhibitors

Cross-references to related applications

This application claims the benefit of U.S. Provisional Patent Application No. 63/023,501, filed May 12, 2020, which is incorporated herein by reference in its entirety and used for all purposes.

Technical Field

This article provides a combination therapy for the treatment of breast cancer, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and a CDK4/6 inhibitor (such as palbociclib).

Background Technology

Although endocrine therapy is effective for ER-positive (ER+) breast cancer, many patients eventually relapse or develop resistance. One such resistance mechanism involves mutations in ESR1, which drive ER-dependent transcription and proliferation in the absence of estrogen.

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

This article provides solutions to the above-mentioned problems and other problems in this field.

The embodiments of the present invention can be more fully understood by referring to the specific implementation methods and examples, which are intended to illustrate non-limiting embodiments.

Attached Figure Description

Figure 1 depicts the study timeline of patients described in this article treated with combination therapy of GDC-9545 and palbociclib. uPR = unconfirmed partial response; cPR = confirmed partial response.

Figure 2 depicts the tumor response in patients treated with GDC-9545 and patients treated with GDC-9545 and palbociclib.

Detailed Implementation

Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. See, for example: Singleton et al., *Distractionary of Microbiology and Molecular Biology*, 2nd edition, J. Wiley & Sons (New York, NY 1994); Sambrook et al., *Molecular Cloning, A Laboratory Manual*, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Methods, apparatus, and materials similar to or equivalent to those described, used, or made herein may be used in the practice of this invention.

The following definitions are provided to aid in understanding some of the terms frequently used herein and are not intended to limit the scope of this disclosure. All references cited herein are incorporated herein in their entirety.

As used herein, unless otherwise stated, the terms “about” and “approximately” when referring to a dose, amount, or weight percentage of an ingredient in a composition or dosage form mean a dose, amount, or weight percentage that is recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained by the specified dose, amount, or weight percentage. An equivalent dose, amount, or weight percentage may be in the range of 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percentage.

"GDC-9545" refers to a compound having the following structure:

It has the chemical name 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azacyclobutane-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoroprop-1-ol. GDC-9545 is also known as giredestrant. In one embodiment, GDC-9545 is a tartrate.

"Pabociclib" refers to compounds having the following structure:

Its chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one. Palbociclib is sold under a trademark. Palbociclib is an exemplary "CDK4/6 inhibitor"—a class of agents that target cyclin-dependent protein kinases 4 and 6 (CDK4 and CDK6, respectively).

Other exemplary CDK4/6 inhibitors include, but are not limited to: ribociclib (succinic acid-7-cyclopentyl-N,N-dimethyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidin-6-carboxamide (1/1; for sale); abecitabine (2-pyrimidinylamine, N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5- Fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl], for sale); and Trilaciclib (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).

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

"Time to the presence of pain and worsening of disturbance" refers to the time from the first recorded increase of at least 10 points from the baseline measurement (e.g., by using the linear transformation of the European Organisation for Research in the Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) Pain Scale).

"Time to deterioration of bodily function" refers to the time when a decrease of at least 10 points from baseline measurements is first recorded (e.g., by using the EORTC QLQ-C30 linear transformation body energy scale score).

"Time to deterioration of role function" refers to the time from which a decrease of at least 10 points from baseline measurement is first recorded (e.g., by using the EORTC QLQ-C30 linear transformation role function scale score).

"Time to global health and quality of life deterioration" or "GHS/QoL" refers to the time when a 10-point decrease from baseline measurement is first recorded (e.g., by using the EORTC QLQ-C30 linear transformation of the GHS/QoL scale score).

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

The "objective response rate" or "ORR" refers to the percentage of patients who achieve a confirmed complete or partial response within two consecutive periods of ≥4 weeks, as determined by investigators according to RECIST v1.1.

"Time to Progression" or "TTP" refers to the time from randomization to objective tumor progression.

"Duration of Response" or "DOR" refers to the time from the first recorded objective response to disease progression or death from any cause (whichever comes first), as determined by the investigator according to RECIST v1.1.

"Progression-free survival" or "PFS" refers to the time from enrollment to the date of first recorded disease progression or death from any cause (whichever comes first), as determined by the investigator according to RECIST v1.1.

"Clinical benefit rate" or "CBR" refers to the percentage of patients whose disease has been stable for at least 24 weeks or who have a confirmed complete or partial response, as determined by investigators according to RECIST v1.1.

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

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

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

"Stable disease" or "SD" refers to a condition that has neither shrunk sufficiently to meet the requirements of CR or PR, nor has it grown sufficiently to meet the requirements of PD.

The term "locally advanced breast cancer" refers to cancer that starts in the breast and spreads to nearby tissues or lymph nodes, but has not spread to other parts of the body.

The term "metastatic breast cancer" refers to cancer that has spread from the breast to other parts of the body, such as bone, liver, lungs, or brain. Metastatic breast cancer can also be called stage IV breast cancer.

The term "treatment" refers to a clinical intervention aimed at altering the natural course of the treated patient or cells during the course of clinicopathological development. Ideal treatment outcomes include slowing disease progression, alleviating or reducing disease conditions, and improving or resolving prognosis. For example, a patient is considered successfully "treated" if one or more symptoms associated with breast cancer as described herein are reduced or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), alleviating symptoms caused by the disease, improving the quality of life of patients with the disease, reducing the dosage of other medications required to treat the disease, and/or prolonging the patient's survival.

The term "delayed progression" in this context refers to the postponement, inhibition, slowing, stabilization, and/or delay of the development of breast cancer as described herein. Such delay can vary in length depending on the patient's cancer history and/or the patient's condition. It will be apparent to those skilled in the art that adequate or significant delay can effectively encompass prevention, as the patient will not develop cancer.

An “effective dose” is at least the minimum amount required to achieve a measurable improvement or prevention of breast cancer as described herein. The effective dose described herein can vary depending on factors such as the patient’s disease state, age, sex, and weight, and the ability of the agent to elicit the expected response in the patient. An effective dose is also the amount in which the beneficial effects of treatment outweigh any toxic or harmful effects of treatment. Beneficial or desired clinical outcomes include, for example: elimination or reduction of risk, reduction of severity, delay of disease onset (including biochemical, histological, and/or behavioral symptoms of the disease that occur during disease development, its complications, and intermediate pathological phenotypes), reduction of one or more symptoms caused by the disease, improvement of the quality of life of patients with the disease, reduction of the dosage of other drugs required to treat the disease, enhancement of the effects of another drug (e.g., through targeting), delay of disease progression, and/or prolongation of survival. In some embodiments, an effective dose of the drug may have the following effects: reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing or stopping) the invasion of cancer cells into surrounding organs; inhibiting (i.e., slowing or stopping) tumor metastasis; inhibiting (i.e., slowing or stopping) tumor growth; and/or alleviating one or more of the symptoms associated with the disease. An effective dose may be administered once or multiple times. An effective amount of a drug, compound, pharmaceutical composition, or combination therapy described herein can be an amount sufficient to provide direct or indirect treatment. An effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved when combined with another drug, compound, or pharmaceutical composition or combination therapy, as understood in a clinical context. Therefore, an "effective amount" may be considered when administering one or more therapeutic agents, and an effective amount of a single agent may be considered if the desired outcome can be obtained or achieved when combined with one or more other agents.

As used in this article, the “E2 suppression score” refers to a numerical value that reflects the level of aggregated expression of a predetermined genome, the suppression of which reflects the activity of the estrogen receptor (ER) pathway.

As used in this article, “E2 induction score” refers to a numerical value that reflects the level of aggregated expression of a predetermined genome, the induction of which reflects the activity of the estrogen receptor (ER) pathway.

As used in this article, the “ER pathway activity score” refers to a numerical value that reflects the mathematical difference between the E2 induction score and the E2 inhibition score.

"Application period" or "cycle" refers to a period of time that includes the application of one or more of the agents described herein (i.e., GDC-9545 or its pharmaceutically acceptable salts or palbociclib) and optional periods of time that do not include the application of one or more of the agents described herein. For example, the total length of a cycle may be 28 days, including 21 days of application of one or more agents and a 7-day rest period. "Rest period" refers to a period of time during which at least one of the agents described herein (e.g., GDC-9545 or its pharmaceutically acceptable salts or palbociclib) is not applied. In one embodiment, a rest period refers to a period of time during which no one of the agents described herein (e.g., GDC-9545 or its pharmaceutically acceptable salts or palbociclib) is applied. In some cases, the rest period provided herein may include the application of another agent that is not GDC-9545 or its pharmaceutically acceptable salts or palbociclib. In such cases, the application of another agent during the rest period should not interfere with or impair the application of the agents described herein.

"Dosing regimen" refers to the period of administration of the drug described herein, which includes one or more cycles, wherein each cycle may include administration of the drug described herein at different times and in different amounts.

"Once a day" (QD) means applying the compound once a day.

"PO" refers to the oral administration of the medication described in this article.

Graded adverse events refer to the severity level determined by NCI CTCAE. In one embodiment, adverse events are graded according to the table below.

combination therapy

This document provides 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 may be used to treat certain types of breast cancer described herein. For example, in one embodiment, the combination therapy described herein may 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 may 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 may be used to treat ER+, HER2-laBC. In one such embodiment, the combination therapy described herein may be used to treat ER+, HER2-mBC.

On the other hand, this article provides 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 of palbociclib and any pharmaceutically acceptable salt thereof.

The combination therapies described herein may be provided in the form of a kit comprising one or more of the pharmaceutical agents for administration. In one embodiment, the kit comprises GDC-9545 or a pharmaceutically acceptable salt thereof for administration in combination with palbociclib described herein. In another embodiment, the kit comprises GDC-9545 or a pharmaceutically acceptable salt thereof packaged together with palbociclib, wherein the kit contains individually formulated doses of each pharmaceutical agent. In yet another embodiment, the kit comprises GDC-9545 or a pharmaceutically acceptable salt thereof formulated together with palbociclib.

Treatment

This article provides a method for treating such cancer in patients with ER+, HER2-laBC, or mBC. In one embodiment, the method includes treating such cancer in patients with ER+, HER2-laBC, or mBC by administering the combination therapy described herein to the patient over a 28-day cycle.

This article further provides a method for treating such cancers in patients with ER+, HER2-laBC, or mBC, wherein the method involves administering a combination therapy to the patient comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib, wherein the combination therapy is administered over one or more 28-day cycles.

This article further provides a method for treating such cancers in patients with ER+, HER2-laBC, or mBC, wherein the method comprises administering to the patient a combination therapy comprising a dosing regimen described herein, the dosing regimen comprising: (i) administering GDC-9545 or a pharmaceutically acceptable salt thereof once daily on days 1–28 of the first 28-day cycle; and (ii) administering palbociclib once daily on days 1–21 of the first 28-day cycle.

In one embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in a fixed dose or once daily. In one embodiment, it is administered orally (PO), wherein 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 once daily in amounts 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. In another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of about 1, 5, 10, 15, 20, 25, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of about 10, 30, 50, or 100 mg. In yet another embodiment, GDC-9545 or a pharmaceutically acceptable salt thereof is administered in amounts of about 30 mg.

In one embodiment, palbociclib is administered according to the package insert. In a preferred embodiment, palbociclib is administered in a dose of 125 mg.

This article further provides a method for treating such cancers in patients with ER+, HER2-1aBC, or mBC, wherein the method comprises administering to the patient a combination therapy comprising a dosing regimen described herein, said dosing regimen comprising: (i) administering 30 mg of GDC-9545 or a pharmaceutically acceptable salt thereof once daily on days 1-28 of the first 28-day cycle; and (ii) administering 125 mg of palbociclib once daily on days 1-21 of the first 28-day cycle. In one such embodiment, the dosing regimen comprises two or more cycles as described herein.

The methods for treating breast cancer provided herein may include administering the combination therapy described herein as part of a dosing regimen. In one embodiment, the dosing regimen comprises one or more cycles. In another embodiment, the dosing regimen comprises at least two cycles. In another aspect, this document provides dosing regimens comprising 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, 36, 42, 48, 54, 60, 66, or 72 cycles. In yet another embodiment, the dosing regimen comprises approximately 2-72, 2-66, 2-60, 2-54, 2-48, 2-42, 2-36, 2-30, 2-24, 2-18, or 2-12 cycles. In one embodiment, the dosing regimen includes administering the combination therapy described herein for any number of cycles until the expected response (e.g., PFS, OS, ORR, DOR, CBR) is achieved (e.g., an increase in PFS, OS, ORR, DOR, CBR compared to the control described herein). In another embodiment, the dosing regimen includes administering the combination therapy described herein for any number of cycles until toxicity occurs or the patient experiences one or more adverse events (AEs) that prevent further administration. In yet another embodiment, the dosing regimen includes administering the combination therapy described herein for any number of cycles until disease progression.

In one embodiment, the patient is a postmenopausal woman. In such an embodiment, the patient (i) is ≥60 years old; (ii) is <60 years old and has been amenorrhea for ≥12 months, plus follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range as assessed by a local laboratory in the absence of oral contraceptives, hormone replacement therapy, or gonadotropin-releasing hormone agonists or antagonists; or (iii) has undergone a documented bilateral oophorectomy.

In another embodiment, the patient is a premenopausal or perimenopausal (i.e., postmenopausal) woman. In one such embodiment, the patient is treated with an LHRH agonist in combination with the combination therapy described herein. The LHRH agonist therapy may be initiated 28 days before day 1 of cycle 1. In one embodiment, the LHRH agonist is administered on day 1 of each cycle.

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

In one embodiment, the patient described herein has been tested for the presence of estrogen receptor, prostaglandin receptor, or Ki67. In one embodiment, the patient described herein has a documented ER-positive tumor according to the American Society of Clinical Oncology/American College of Pathologists guidelines. In one such embodiment, the patient described herein has a documented HER2-negative tumor. In one embodiment, the patient described herein has previously been treated 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 not experienced disease recurrence during or within 12 months of completing such treatment with an aromatase inhibitor or CDK4/6 inhibitor.

In one embodiment, the patient described herein has not received prior treatment. In another embodiment, the patient described herein has not received prior chemotherapy prior to administration of the combination therapy. In yet another embodiment, the patient described herein has not previously been 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 previously been treated with letrozole or palbociclib. In yet another embodiment, the patient described herein has not received surgery, chemotherapy, or radiation therapy for at least 14 days prior to administration of the combination therapy described herein. In yet another embodiment, the patient described herein has not previously used SERDs (e.g., fulvestrant) or been treated with tamoxifen. In yet another embodiment, the patient may have previously been treated with tamoxifen, provided that the patient has not experienced a disease relapse within the 24 months prior to treatment with tamoxifen.

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 with breast cancer as described herein is resistant to one or more cancer therapies. In one embodiment of the methods described herein, resistance to cancer therapies includes recurrent or refractory cancer. Recurrence can refer to the reappearance of cancer at the original site or a new site after treatment. In one embodiment of the methods described herein, resistance to cancer therapies includes cancer progression during treatment with anticancer therapies. In some embodiments of the methods described herein, resistance to cancer therapies includes cancer that is unresponsive to treatment. The cancer may be resistant at the start of treatment or during treatment. In some embodiments of the methods described herein, the cancer is in an early or late stage.

Systemic chemotherapy is considered a standard of care (SOC) for patients with mBC, although there is no standard protocol or sequence. In one embodiment of the methods described herein, the patients described herein had previously been treated with one or more of the following therapies selected from groups of: anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxetine, ethinylestradiol 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, ixaprilone, trastuzumab and pertuzumab, or combinations thereof.

In one embodiment of the methods described herein, the patient described herein may have the laBC or mBC described herein that is resistant to one or more monotherapy options selected from the group consisting of: anastrozole, letrozole, exemestane, everolimus, palbociclib and letrozole, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxetine, ethinylestradiol 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, ixaprilone, trastuzumab and pertuzumab, or combinations thereof.

In one embodiment of the methods described herein, the patient, as described herein, may have undergone surgical treatment prior to the administration of the combination therapy described herein, such as breast-conserving surgery (i.e., mass resection focusing on removal of the primary tumor and its margins) or more extensive surgery (i.e., mastectomy aimed at complete removal of all breast tissue). In another embodiment, the patient described herein may undergo surgical treatment following treatment with the combination therapy described herein.

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

In some embodiments, the patients described herein 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 have no active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal surgery, including gastrectomy. In some embodiments, the patients described herein do not have heart disease or cardiac dysfunction.

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

In one embodiment, treatment with combination therapy according to the methods provided herein increases the patient's objective response rate (ORR). In one such embodiment, treatment with combination therapy according to the methods provided herein results in more patients achieving a complete response (CR) or partial response (PR) than the control group. In another embodiment, the patient's total response time (TTP) increases after treatment with combination therapy according to the methods provided herein. In yet another embodiment, the duration of response to combination therapy is increased compared to a control group (e.g., no treatment, standard of care (SOC) treatment, or a 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, the patients described herein have an increased rate of clinical benefit compared to a control group (e.g., no treatment, standard of care (SOC) treatment, or a combination of palbociclib and letrozole). In yet another embodiment, patients have increased progression-free survival compared to a control group (e.g., no treatment, standard of care (SOC) treatment, or a combination of palbociclib and letrozole).

In one embodiment provided herein, a patient is diagnosed with complete remission (CR) after treatment with combination therapy according to the methods provided herein. In one embodiment provided herein, a patient is diagnosed with partial remission (PR) after treatment with combination therapy according to the methods provided herein. In one embodiment provided herein, a patient is diagnosed with severe stunting (SD) after treatment with combination therapy according to the methods provided herein.

This article further provides the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib, for the treatment of the laBC or mBC described herein.

This article further provides the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof, and palbociclib, for the treatment of the mBC described herein. This article also further provides the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof, and palbociclib, for the treatment of the laBC described herein.

This document further provides the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof, and palbociclib, in the preparation of a medicament for treating the laBC or mBC described herein. This document also further provides the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof, and palbociclib, in the preparation of a medicament for treating the mBC described herein. This document further provides the use of the combination therapy described herein, comprising GDC-9545 or a pharmaceutically acceptable salt thereof, and palbociclib, in the preparation of a medicament for treating the laBC described herein.

This article also provides methods for inhibiting tumor growth or achieving tumor regression in the patients described herein, achieved by administering the combination therapies described herein. In one embodiment, this article provides a method for inhibiting tumor growth in a patient with the laBC described herein, by administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib over one or more 28-day cycles described herein. In one embodiment, this article provides a method for inhibiting tumor growth in a patient with mBC described herein, by administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib over one or more 28-day cycles described herein.

In one embodiment, this article provides a method for producing or improving tumor regression in a patient with the mBC described herein, the method comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable saline thereof and palbociclib over one or more 28-day cycles described herein. In one embodiment, this article provides a method for producing or improving tumor regression in a patient with the laBC described herein, the method comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable saline thereof and palbociclib over one or more 28-day cycles described herein.

The development of combination therapies presents challenges, including, for example, the selection of agents for combination therapies that can improve efficacy while maintaining acceptable toxicity. A particular challenge is the need to differentiate 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 pharmaceutically acceptable salt and palbociclib) is administered with a dosing regimen that includes an interleaved dosing schedule. In one such embodiment, the number or frequency of adverse events (AEs) in patients is reduced compared to a control (e.g., SOC therapy or palbociclib and letrozole).

In one embodiment of the method described herein, the dosing regimen reduces the number or frequency of grade 2 or 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.

In another embodiment of the method described herein, the administration reduces the number or frequency of Grade 2 or 3 or higher adverse events compared to administration of any agent alone.

As is generally known, when an adverse event occurs, there are four options: (1) continue the original treatment with optional concomitant therapy; (2) adjust the dosage of one or more drugs in the dosing regimen; (3) suspend the administration of one or more drugs in the dosing regimen; or (4) discontinue the administration of one or more drugs in the dosing regimen.

In one embodiment of the method described herein, the patient experience described herein includes one or more of the following adverse events: fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, weakness, thrombocytopenia, or pruritus. In one such embodiment, the patient described herein experiences one or more of these AEs at the same or reduced level/severity. In another embodiment, the patient described herein experiences one or more of these AEs at a reduced severity. 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.

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

In one embodiment, patients treated with the combination therapy described herein experience a relatively reduced number of one or more adverse events, as described herein.

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%, 60%, 50%, 40%, 33%, 25%, 20%, 12%, or 5% of all treated patients experience one or more of neutropenia, diarrhea, or bradycardia after treatment with the combination therapy described herein. In one embodiment of the methods described herein, less than 85%, 75%, 60%, 50%, 40%, 33%, 25%, 20%, 17%, 10%, or 5% of all treated patients experience diarrhea as described herein after treatment with the combination therapy described herein. In one embodiment of the methods described herein, less than 60%, 50%, 45%, 33%, 25%, 10%, or 5% of all treated patients experience neutropenia after treatment with the combination therapy described herein. In one embodiment of the methods described herein, less than 75%, 60%, 50%, 40%, 33%, 25%, 20%, 15%, 10%, or 8% of all treated patients experienced bradycardia as described herein after treatment with the combination therapy described herein. In some embodiments, when a patient experiences one or more adverse events (AEs) selected from the group consisting of neutropenia, diarrhea, and bradycardia as a result of treatment with the combination therapy described herein, the severity of the AE is grade 2 or lower. In one embodiment, the patients described herein did not experience one or more AEs selected from the group consisting of neutropenia, diarrhea, and bradycardia as a result of treatment with the combination therapy described herein, and the severity of the AE was higher than grade 2.

biomarkers

Breast cancer is a heterogeneous disease with many different subtypes, defined by molecular markers and various mutational signatures. ER+HER2-laBC or mBC in the patients described herein can be tested using diagnostic methods or kits to inform treatment or predict patient response to the combination therapies described herein. In one embodiment, patients can be tested by determining an ER pathway activity score, such as those described in U.S. Patent Application Publication 20200082944. In some embodiments, patient samples are collected and tested to determine the ER pathway activity score. The score can be calculated using 41 gene signatures by subtracting the E2 suppression score (e.g., the average 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 (e.g., the average z-score expression of genes including AGR3, AMZ1, AREG, C5AR2, CELSR2, CT62, FKBP4, FMN1, GREB1, IGFBP4, NOS1AP, NXPH3, OLFM1, PGR, PPM1J, RAPGEFL1, RBM24, RERG, RET, SGK3, SLC9A3R1, TFF1, and ZNF703).

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

In some cases, the combination therapy described herein is administered to the patients described herein, wherein the measured ER pathway activity score is between about -1.0 and about -0.2 (e.g., between about -0.9 and about -0.2, or between about -0.8 and about -0.2, or between about -0.7 and about -0.2, or between about -0.6 and about -0.2, or between about -0.5 and about -0.2, or between about -0.4 and about -0.2, or between about -0.3 and about -0.2). In some cases, the ER activity score from the sample may be less than -1.0.

In some embodiments, samples from the patients described herein may be evaluated for other biomarkers to identify factors that may be related to the safety and efficacy of the investigational treatment.

In one embodiment of the methods described herein, DNA may be obtained from blood samples and tumor tissues of the patients described herein using NGS, whole-genome sequencing (WGS), other methods, or combinations thereof. Such samples may be analyzed to identify germline (e.g., BRCA1/2) and somatic alterations that may predict responses to investigational drugs, be associated with progression to more severe disease states, be associated with acquired resistance to investigational drugs, or may contribute to knowledge and understanding of disease biology.

Example:

Exemplary embodiments of the present invention are provided below.

Example No. 1. A method for treating estrogen receptor-positive and HER2-negative laBC or mBC in a patient with receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC), the method 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.

Example No. 2. A method for treating estrogen receptor-positive and HER2-negative laBC or mBC in a patient with receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC), 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 over one or more 28-day cycles.

Example No. 3. A method for treating estrogen receptor-positive and HER2-negative laBC or mBC in a patient with receptor-positive and HER2-negative locally advanced breast cancer (laBC) or metastatic breast cancer (mBC), the method comprising administering to the patient a combination therapy comprising a dosing regimen, the dosing regimen comprising:

(i) GDC-9545 or its pharmaceutically acceptable salt thereof shall be administered once daily on days 1–28 of the first 28-day cycle; and

(ii) Administer palbociclib once daily from day 1 to day 21 of the first 28-day cycle.

Example No. 4. The method as described in Example 1, wherein the CDK4/6 inhibitor is palbociclib.

Example No. 5. The method as described in any one of Examples 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.

Example No. 6. The method as described in Example 5, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 10, 30, 50 or 100 mg.

Example No. 7. The method as described in Example 5, wherein GDC-9545 or a pharmaceutically acceptable salt thereof is administered in an amount of about 30 mg.

Example No. 8. The method as described in any one of Examples 2 to 7, wherein palbociclib is administered in an amount of about 125 mg.

Example No. 9. The method as described in any one of Examples 3 to 8, 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.

Example No. 10. The method as described in any one of Examples 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.

Example No. 11. The method as described in any one of Examples 1 to 8, wherein the patient is premenopausal.

Example No. 12. The method as described in any one of Examples 1 to 8, wherein the patient is male.

Example No. 13. The method as described in Example 11 or 12, wherein the patient is further administered luteinizing hormone-releasing hormone (LHRH).

Example number 14. The method as described in Example 13, wherein LHRH is administered to the patient on the first day of each cycle.

Example No. 15. The method as described in any one of Examples 1 to 14, wherein the patient is tested for mutations in one or more of the estrogen receptor, prostaglandin receptor, or Ki67.

Example No. 16. The method as described in any one of Examples 1 to 15, wherein the patient adverse events (AEs) are reduced compared to the control.

Example No. 17. The method as described in Example 16, wherein the control is letrozole administered in combination with palbociclib.

Example No. 18. The method as described in any one of Examples 16 to 17, wherein the number or frequency of Level 3 or higher AEs is reduced.

Example No. 19. The method as described in any one of Examples 16 to 18, wherein the severity of one or more adverse events (AEs) in the patient is reduced compared to the control, the one or more AEs being selected from the group consisting of: fatigue, cough, pain, arthralgia, neutropenia, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, weakness, thrombocytopenia, or pruritus.

Example No. 20. The method as described in any one of Examples 1 to 19, wherein, after administration of the combination therapy, the patient has the same or reduced level of neutropenia compared to the control.

Example No. 21. The method as described in any one of Examples 1 to 20, wherein, after administration of the combination therapy, the patient has the same or reduced level of bradycardia compared to the control.

Example No. 22. The method as described in any one of Examples 1 to 21, wherein the patient's overall survival (OS) is increased compared to the control.

Example No. 23. The method as described in Example 22, wherein the patient has an increase of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 24 or more months compared to the control.

Example No. 24. The method of any one of Examples 1 to 23, wherein the objective response rate of the combination therapy in the patients resulted in more patients having a complete response (CR) or a partial response (PR) than the control.

Example No. 25. The method as described in any one of Examples 1 to 24, wherein the duration of response to the combination therapy is increased compared to the control.

Example No. 26. The method as described in Example 25, wherein the response duration is increased by at least 1-3, 2-6, 3-8, 4-10, 5-12, 6-15, 8-20 or 1-24 months.

Example No. 27. The method as described in any one of Examples 1 to 26, wherein patients have an increased rate of clinical benefit compared to the control.

Example No. 28. The method as described in any one of Examples 1 to 27, wherein the patient has increased progression-free survival compared to the control.

Example No. 29. The method as described in Example 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.

Example No. 30. The method as described in any one of Examples 1 to 29, wherein the patient experiences a reduction in the time to deterioration in the following aspects: (i) pain intensity; (ii) pain presence and disturbances; (iii) physical function; (iv) role function; (v) global health status and quality of life; or (vi) a combination thereof.

Example No. 31. The method as described in any one of Examples 22 to 30, wherein the control is palbociclib alone or palbociclib in combination with letrozole.

Example No. 32. The method as described in any one of Examples 1 to 31, wherein the patient is postmenopausal.

Example No. 33. The method as described in Example 32, wherein the patient has undergone bilateral oophorectomy.

Example No. 34. The method as described in any one of Examples 1 to 33, wherein the patient has not received prior chemotherapy prior to the administration of the combination therapy.

Example No. 35. The method as described in any one of Examples 1 to 33, wherein the patient has previously been treated with tamoxifen.

Example No. 36. The method as described in any one of Examples 1 to 33, wherein the patient has previously been treated with an aromatase inhibitor or a CDK4/6 inhibitor or a combination thereof.

Example No. 37. The method as described in any one of Examples 1 to 33, wherein the patient has not previously been treated with aromatase inhibitors or CDK4/6 inhibitors or combinations thereof.

Example No. 38. The method as described in any one of Examples 1 to 33, wherein the patient has not received surgery, chemotherapy or radiation therapy for at least 14 days prior to administration of the combination therapy.

Example No. 39. The method as described in any one of Examples 1 to 33, wherein the patient does not have heart disease or cardiac dysfunction.

Example number 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.

Example number 41. Use in the preparation of a medicament for the treatment of laBC or mBC comprising a combination therapy of GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib.

Example No. 42. A method for inhibiting tumor growth in patients with laBronchiolitis or mBronchiolitis, the method comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib over one or more 28-day cycles.

Example No. 43. A method for producing or improving tumor regression in patients with laBronchiolitis or mBronchiolitis, the method comprising administering a combination therapy comprising GDC-9545 or a pharmaceutically acceptable salt thereof and palbociclib over one or more 28-day cycles.

The following examples are provided for illustrative purposes only and not for limitation.

Example:

Patients: Eligible patients have ER+ (HER2-) metastatic breast cancer, have received ≤2 lines of prior therapy in advanced or metastatic conditions, and have experienced recurrence or progression on endocrine therapy for ≥24 months in incurable, locally advanced, or metastatic conditions and have received clinical benefit from therapy (i.e., tumor response or disease stabilization for at least 6 months). Patients receiving palbociclib have not previously been treated with CDK4/6i.

Table 1: Patient basic information and disease symptoms.

Safety. In cohorts A and B, 78% and 96% of patients, respectively, reported treatment-related adverse events (TEAEs). In cohort A, 58% of patients experienced GDC-9545-related AEs; these were generally grade 1-2, except for three grade 3 events: fatigue, elevated transaminases, and diarrhea. No patients discontinued study treatment due to AEs. In cohort B, 58% of patients experienced GDC-9545-related AEs; these were grade 1 or 2 in severity, except for one 69-year-old woman who reported a grade 3 SAE with QT prolongation and T-wave inversion. This patient had a baseline QTcF of 441 ms and at the visit on day 1 of cycle 6, her QTcF was 506 ms, but she was asymptomatic. This case was confounded by the patient's pre-existing coronary artery disease (30%-50% coronary artery stenosis), right bundle branch block, and possible concomitant use of pregabalin. The patient responded to the QT prolongation by discontinuing palbociclib and GDC-9545 therapy, which resolved approximately 16 days after the onset of the disease.

Three patients (8%) in cohort A and 15 patients (31%) in cohort B reported bradycardia-related adverse events (AEs); all patients were grade 1 and asymptomatic, except for one patient (cohort B) who developed grade 2 bradycardia and also experienced grade 2 dizziness. ECG data showed similar heart rate variability in cohorts A and B, with no further changes in heart rate after palbociclib administration. Heart rate (HR) variability returned to baseline upon completion of treatment. For patients with a baseline HR ≥ 60 bpm, the mean maximum HR variability was 19 and 20 bpm in the two cohorts, respectively; for patients with a baseline HR < 60 bpm, the mean maximum HR variability was 13 bpm in cohorts A and B, respectively.

Table 2: All adverse events occurring in ≥10% of patients

Pharmacokinetics. Exposure to GDC-9545 in combination with palbociclib was generally comparable to that observed with GDC-9545 alone. Palbociclib's pharmacokinetic profile remained unchanged when administered with GDC-9545 and was consistent with reported values.

Pharmacokinetic effects. Decreased ER (10/12, 83%), PR (7/8, 88%) and Ki67 (9/12, 75%) protein levels, as well as ER pathway characterization scores (8/12, 67%), were observed in evaluable paired pre-treatment and in-treatment biopsies (n=12) (Guan et al., Cell, 2019).

The frequency of ctDNA ESR1 mutation alleles decreased from baseline in all patients across both cohorts (n=26).

Clinical activity. In cohort A, 22/40 (55%) patients experienced a clinical benefit, defined as CR, PR, or first presentation of progressive disease observed at or after 24 weeks. Partial response was observed in 4/31 (13%) patients with measurable disease at baseline. In cohort B, 35/48 (81%) patients experienced a clinical benefit, and 14/45 (33%) achieved PR. Clinical benefit was observed in patients who had previously received fulvestrant treatment in both cohorts [2/7 (29%) in cohort A and 2/3 (67%) in cohort B, respectively], and in patients with detectable ESR1 mutations at enrollment [8/13 (62%) and 11/11 (100%), respectively].

Table 3: Efficacy Results

In this specification and claims, unless the context otherwise requires, the words “comprising,” “including,” and “containing” are used in a non-exclusive sense. It should be understood that the embodiments described herein include “consisting of the embodiments” and/or “substantially consisting of the embodiments.”

If a range of values is provided, it should be understood that every intermediate value between the upper and lower limits of that range (to one-tenth of the unit of the lower limit, unless the context explicitly specifies otherwise), as well as any other specified value or intermediate value within the specified range, is included herein. The upper and lower limits of these smaller ranges may be independently included within that smaller range and are also included herein, based on any explicitly excluded limit value within the specified range. Where a specified range includes one or two limits, this document also includes ranges that exclude one or both of those included limits.

Many variations and other embodiments of the invention set forth herein will come to mind for those skilled in the art, taking advantage of the teachings presented in the foregoing description and the accompanying drawings. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed, and that variations and other embodiments are intended to be included within the scope of the appended claims. Although specific terminology is used herein, it is used only in a general and descriptive sense and not for limiting purposes.